Rjoh 1 (1) 2013

Jurnal dedicat rezidenilor, specialistilor i Nume
cercettorilor
din domeniul
autori
oncologiei, hematologiei, medicinei paliative i terapiei durerii
Revist publicat sub egida
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R o m a n i a n
J o u r n a l
o f
O n c o l o g y & H e m at o l o g y
Nr. 1/ Vol. I/ 2013
www.mediasyscom.ro
Dr. Valentin RDOI

Editor-sef
Un nou jurnal pentru un domeniu

care este ntotdeauna nou
ei mortalitatea determinat de cancer s-a aflat ntr-o continu scdere n ultimii 5-15
ani (1), incidena i prevalena determinate de aceast afeciune sunt n continuare
la niveluri alarmante, iar incidena se ateapt chiar s creasc de la 12.7 milioane
n 2008 la 21 de milioane n 2030, la nivel global(2). Mortalitatea n urma cancerelor se ridic
n continuare la niveluri ridicate: de exemplu, n SUA, au fost descoperite 1.660.290 de noi
cazuri de cancer n 2013, n acelai an nregistrndu-se 580.350 de decese ca urmare a
acestei afeciuni (3).
De asemenea, de la nceputul acestui secol, s-au fcut progrese enorme n nelegerea
acestor boli la nivel molecular i n gsirea unor tratamente intite i personalizate. Un astfel
de exemplu de succes este Imatinib, inhibitorul protein-kinazei BCR-ABL, folosit n tratamentul leucemiei mieloide cronice (4). Totui, o complicaie neateptat a aprut o dat cu
dezvoltarea ponatinib (inhibitor al protein-kinazei BCR-ABL de generaia a doua), medicament care a prezentat o frecven crescut a cheagurilor de snge amenintoare pentru
viaa pacientului i o ngustare sever a vaselor de snge (5). Astfel, dei noile tratamente
scad mortalitatea i comorbiditile, reprezentnd un pas nainte n lupta mpotriva acestor afeciuni, efectele secundare ale noilor medicamente care deseori sunt pe pia doar
de civa ani atrn greu n balana decizional a oricrui medic, transformnd decizia
terapeutic ntr-una i mai grea.
n aceste condiii, apariia unui nou jurnal dedicat oncologiei, hematologiei i medicinei
paliative aplicate n aceste domenii reprezint o consecin logic a necesitilor medicilor
romni i nu numai de a fi informai i de a avea capacitatea de a-i publica rezultatele
studiilor i prezentrile cazurilor ntr-un jurnal modern care s le asigure vizibilitate la nivel
naional i internaional. nc de la primul numr, Romanian Journal of Oncology and Hematology acoper o serie dintre problemele prezentate anterior, precum rolul pe care l va
juca evoluia geneticii, genomicii i a epigeneticii n diagnosticarea i tratamentul cancerelor (6,7), dar i o prezentare integral a durerii viscerale, des ntlnit n tumori, celebrnd,
n acest fel, ncheierea anului IASP (International Association for the Study of Pain) dedicat
acestui tip de durere (8).
Valentin Rdoi
Universitatea de Medicin i Farmacie Carol Davila, Bucureti
valentin.radoi@mediasyscom.ro
Bibliografie
1. American Cancer Society. Cancer Facts & Figures 2013 [Internet]. 2013 [cited 2013 November
17]. Available from: http://www.cancer.org/acs/groups/content/@epidemiologysurveilance/
documents/document/acspc-036845.pdf.
2. World Cancer Research Fund International. Cancer Statistics [Internet]. 2013 [cited 2013
November 17]. Available from: http://www.wcrf.org/cancer_statistics/world_cancer_statistics.
php.
3. Siegel R., Naishadham D., Jemal A. Cancer Statistics, 2013. CA Cancer J Clin. 2013; 63:11-30.
4. Groarke J.D., Cheng S., Moslehi J. Cancer-Drug Discovery and Cardiovascular Surveillance. N
Engl J Med. 2013; 369:1779-1781.
5. Food and Drug Administration. FDA drug safety communication: FDA investigating
leukemia drug Iclusig (ponatinib) after increased reports of serious blood clots in arteries
and veins. [Internet]. 2013 [updated 2013 November 11; cited 2013 November 17].
Available from: http://www.fda.gov/Drugs/DrugSafety/ucm370945.htm.
6. Markman M. Pharmacogenetic analyses and genome-wide association studies of
cancer risk: increasingly easy to obtain, but difficult to interpret. Rom J Oncol Hematol.
2013; 1(1): 6-7.
7. Paul D. Taming cancer. Rom J Oncol Hematol. 2013; 1(1): 8-10.
8. Boeru A.M. Visceral Cancer Pain. Rom J Oncol Hematol. 2013; 1(1): 39-47.
R o m a n i a n
J o u r n a l
o f
O n c o l o g y & H e m at o l o g y
Nr. 1/ Vol. I/ 2013
Revist publicat sub egida
Societatea naional de oncologie medical din romnia; societatea romn de hematologie;
asociaia romn pentru studiul durerii; Societatea Romn de Cancer Vasile Pcurar
Chief Editor
Dr. Valentin Rdoi
Senior Editors
Prof. Dr. Florin Bdulescu (Universitatea de Medicin i Farmacie Craiova, Craiova, Romnia)
Prof. Dr. Anca Roxana Lupu (Universitatea de Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
ef LucrriDr. Lucia Stnculeanu(Universitatea de Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
ef LucrriDr. Simona Mihuiu (Universitatea de Medicin i Farmacie Oradea, Oradea, Romnia)
Cerc. St. Gr. I. Dr. Grigorescu Alexandru (Institutul oncologic Prof. Dr. Alexandru Trestiorean, Bucureti, Romnia)
Romanian Editorial Board

Prof. Dr. Oltean Galafteon (Universitatea of Medicin i Farmacie Trgu Mure, Trgu Mure, Romnia)
Prof. Dr. Ljubomir Petrov (Universitatea of Medicin i Farmacie Iuliu Haieganu, Cluj-Napoca, Romnia)
Prof. Dr. Ioni Hortensia (Universitatea of Medicin i Farmacie "Victor Babe" , Timioara, Romnia)
Prof. Dr. Ctlina Poian(Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Conf. Dr. Monica Dragomir(Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Conf. Dr. Coriu Daniel (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Conf. Dr. Anca Coli (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Conf. Dr. Horia Bumbea (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Conf. Dr. Elena Copaciu (Universitatea of Medicin i Farmacie Carol Davila, Bucureti, Romnia)
ef Lucrri Dr. Coli Andrei (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
ef LucrriDr. Cristian Silviu Voinea(Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Asist. Univ. Dr. Carsote Mara-Laura (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Asist. Univ. Dr. Trandafir Maria Silvia (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Dr. Adrian Udrea (Medisprof, Cluj-Napoca, Romnia)
Dr. Radu Niculescu (Universitatea of Medicin i Farmacie "Carol Davila", Bucureti, Romnia)
Dr. Ana Maria Boeru (Asociaia Free of Pain, Bucureti, Romnia)
Dr. Anca Coli (Institutul Clinic Fundeni, Bucureti, Romnia)
Dr. Virgil Dinc (Asociaia Romn pentru Studiul Durerii, Bucureti, Romnia)
International Editorial Board:

Prof. Dr. Shibo Li (University of Oklahoma Health Sciences Center,Oklahoma City,USA)
Prof. Dr.Mariusz Z. Ratajczak (University of Louisville,Louisville,USA)
Prof. Dr. Arnold Ganser (Hannover Medical School, Hanover, Germany)
Prof.Dr. Saverio Bettuzzi (University of Parma Via Volturno,Parma, Italy)
Prof. Dr.Lodovico Balducci (Moffitt Cancer Center,Tampa,USA)
Prof. Dr. Leonard Wartofsky (Georgetown University School of Medicine,Washington, USA)
Prof. Dr. Robert Amato (Memorial Hermann Cancer Center,Texas, USA)
Prof Dr.Kevin R. Loughlin (Harvard University,Cambridge,USA)
Prof. Dr. Maureen Markman (Drexel University College of Medicine, Philadelphia, USA)
Prof. Dr.Stephen P. Hunger (University of Colorado School of Medicine, Colorado,USA)
Prof. Dr. M.W.M. van den Brekel (Academic Medical Center Amsterdam, Amsterdam, Netherlands)
Prof. Dr.M Sitki Copur (University of Nebraska Medical Center, Nebraska, USA)
Prof. Dr. Derek Raghavan (UNC School of Medicine, Levine Cancer Institute, Charlotte, NC, USA)
Prof. Dr. Richard J. Ablin (University of Arizona, Arizona, USA)
Prof. Dr. Florian Strasser (CantonalHospital St. Galen, Sweden)
Prof. Dr. Michel Rigaud (Scientific advisor - IRST, Meldola, Italy)
Associate Prof.Dr.Mishu Popa McKiver (Massachusetts General Hospital,Massachusetts, USA)
Assistant Prof. Dr. Alina Mihai (Univ Pittsburgh School Medicine, Pittsburgh, USA)
Assistant Prof. Dr. Doru Paul (Hofstra North Shore-LIJ School of Medicine,New York,USA)
Assistant Prof.Dr. Bruno Vincenzi (University Campus Bio-Medico,Rome, Italy
Assistant Prof.Dr. Elizabeta C. Popa (Weill Cornell Medical College,NY, USA)
Assistant Prof.Dr.Gabriela Oprea (Emory University, Atlanta,USA)
Dr. Wainer Zoli (Director of the Bioscience Laboratory, IRST, Meldola, Italy)
Dr. Ciprian Enachescu (Centre Hospitalier Lyon Sud, Lyon, France)
Dr. Javier Martn Broto (Son Espases Hospital,Palma de MallorcaSpain)
Dr. David Gmez Almaguer (Universidad Autnoma de Nuevo Len, Monterrey, Mxico)
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Editorial
A new journal for the always new domains of Oncology and Hematology [ro]
Rdoi V.
Pharmacogenetic analyses and genome-wide association studies

of cancer risk: increasingly easy to obtain, but difficult to interpret [en]
M. Markman
Taming cancer [en]

Paul D.
11
Provisional type of nonhodgkin lymphomas, a challenge in clinical practice [ro]
12
News
16
Events
20
Case presentation
24
Bumbea H.
Genomics and Cancer [ro]

Implantable cameras for chemotherapy and an easier treatment [ro]
The first national conference of Private Romanian Oncologists [ro]
Calendar
Scientific Events [en]
B-cell lymphoma, unclassifiable, with features intermediate
between diffuse large B-cell lymphoma and classical Hodgkin lymphoma [ro]
Reviews
Visceral Cancer Pain [ro]

Boeru A.M.
35
Stereotactic body radiotherapy for early stages non-small cell lung cancer [en]
39
Testicular Cancer: diagnosis and treatment [ro]
3
6
Enachescu C.
Grigorescu A.
Editorial
Un nou jurnal pentru un domeniu care este ntotdeauna nou [ro]

Rdoi V.
Analize farmacogenomice i studii de asociere la nivelul genomului

n oncologie: din ce n ce mai uor de obinut, dar dificil de interpretat [en]
Markman M.
Cancerul poate fi mblnzit [ro]

Paul D.
11
Limfomul nonhodgkin provisional, o provocare n practica clinic [ro]
12
tiri
16
Evenimente
20
Prezentare de caz
24
Bumbea H.
Era genomicii n cancer [ro]

Camere implantabile pentru administrarea chimioterapiei
i uurarea tratamentului [ro]
Prima conferin naional a Oncologilor privai din Romnia [ro]
Calendar
Manifestri tiinifice [en]
Limfomul cu celul B neclasificabil, cu trsturi intermediare
ntre limfomul difuz cu celul mare B i limfomul Hodgkin clasic [ro]
Referate Generale
Radioterapia stereotactic pentru cancerul pulmonar non-microcelular precoce [en]

Enachescu C.
35
Durerea Visceral din Cancer [ro]
39
Cancerul testicular: diagnostic i tratament [ro]
Boeru A.M.
Grigorescu A.
Editorial
PHARMACOGENETIC ANALYSES AND GENOME - WIDE ASSOCIATION STUDIES OF CANCER RISK: INCREASINGLY EASY TO OBTAIN, BUT DIFFICULT TO INTERPRET
PHARMACOGENETIC ANALYSES AND

GENOME - WIDE ASSOCIATION STUDIES
OF CANCER RISK: INCREASINGLY EASY TO
OBTAIN, BUT DIFFICULT TO INTERPRET
Analize farmacogenomice i studii
de asociere la nivelul genomului
n oncologie: din ce n ce mai uor
de obinut, dar dificil de interpretat
Maurie Markman*
*Prof. dr. at Cancer Treatment Centers of America, Philadelphia, PA;
and Drexel College of Medicine, Philadelphia, PA
Coresponding author: Maurie Markman
Email: maurie.markman@ctca-hope.com
Cite this article:

Markman M,
Pharmacogenetic analyses
and genome - wide
association studies of
cancer risk: increasingly
easy to obtain, but difficult
to interpret. Rom J Oncol
Hematol. 2013; 1(1):6-7
It has been well-documented that over the

past several years there have been rather dramatic reductions in the costs associated with obtaining molecular profiles of the tumors present
within individual cancer patients(1). Assuming
these costs continue their rather steep decline,
this exciting state-of-affairs has the potential to
substantially alter the management paradigm in
many clinical settings.
Today, while it is routine to examine breast cancers for the presence of Her2 over-expression and
lung cancers for the presence of EGFR mutations
and (increasingly) ALK rearrangements, one can
envision in the not-so-distant future that such analyses will become standard-of-care in many additional malignancies. This strategy has the potential
to not only improve the opportunity for patients
to receive anti-neoplastic regimens with the greatest opportunity to achieve an objective response
against their specific cancer, but also decrease the
overall costs and morbidity of therapy by avoiding
expensive treatments that are realistically unlikely
to result in clinical benefit.
Less often discussed in this exciting and rapidly evolving world of molecular cancer medicine are two somewhat related dimensions associated with genetic profiling in the cancer arena.
The two areas to be briefly highlighted in this
commentary are: (a) genome-wide association

studies of cancer risk, and (b) pharmacogenetic
association studies of cancer outcomes.
In genome-wide association studies investigators explore potential relationships between
individual normal human genetic polymorphisms and the development of a particular serious
medical illness, such as cancer. The general concept is to define risk such that early intervention or modifications in environmental influences
under the individuals control may reduce the
suggested risk. For example, in the case of a documented increased risk of cancer based on a
particular genetic profile individuals may be suggested to undergo more frequent or intensive
screenings or modify their lifestyle/diet with the
goal of favorably impacting that statistically-determined risk.
While in theory this is a potentially important
use of germline genetic testing it is critical to
appreciate that most such associations, while
possibly revealed to be highly statistically significant, are of dubious clinical utility (2). Consider,
for example, the known association between
particular polymorphisms and the development
of Parkinson disease. While the presence of specific variants may more than double the lifetime
risk of this serious illness, this actually translates
Romanian Journal of Oncology & Hematology (2013) 1 (1): 6-7
Markman M
to an absolute lifetime risk for Parkinson disease of only 0.35% (compared to a baseline risk of
0.14%) (2).
So, the question to be asked is whether this
increased risk is worthy of any additional intervention or more focused surveillance compared
to the patient without this degree of risk. Of
course, the same question should be asked regarding the clinical relevance of any current or
future suggested associations between normal
polymorphisms and cancer risk.
Studies examining the relationship between
specific polymorphisms and cancer outcomes
have the potential to identify factors that may
substantially impact efficacy or toxicity (3). Particularly promising are suggestions that the genetically-determined metabolism of individual
anti-cancer agents may be a major determinant
of outcome, and knowledge of the presence of
particular genetic variants can allow for the modification of the planned therapeutic regimen to
enhance the opportunity for a favorable clinical
result.
Unfortunately, despite the unquestionable potential utility of this therapeutic concept it has
been difficult to objectively confirm the validity
of suggested claims such that the data are able
to be accepted as a component of routine oncologic cancer. For example, several studies
have suggested particular polymorphisms that

influence the metabolism of tamoxifen may directly impact this drugs anti-neoplastic effects
in breast cancer (4). However, these results have
not been confirmed in other large databases
and the breast cancer research community has
not embraced the idea that such testing should
be considered standard-of-care.
How much data should be required to permit
the conclusion that a proposed pharmacogenetic association with a meaningful cancer outcome can be considered for use in routine clinical
practice? Are data from retrospective analyses,
no matter how compelling, ever acceptable or
will the results of a large prospective trial be required which will certainly take years (if not more
than a decade) to complete?
It is essential that the cancer research community critically addresses these issues as it is virtually certain there will be an increasing number
of cancer-related pharmacogenomic studies reported in the oncology literature in the relatively
near future. Finally, it will be important for practicing oncologists to both understand the limitations of such associations and their potential
clinical relevance.
Conflicts of Interest/Conflict de Interese:
none/nici unul.
Bibliography
1. MacConaill LE. Existing and emerging technologists for tumor genomic profiling. J Clin Oncol
2013; 31(15):1815-1824.
2. Klein C, Lohmann K, Ziegler A. The promise and limitations of genome-wide association studies.
JAMA 2012; 308:1867-1868.
3. Dawood S, Leyland-Jones B. Pharmacology and pharmacogenetics of chemotherapeutic

agents. Cancer Invest 2009; 27:482-488.
4. Peppercorn J, Hamilton E, Marcom PK, et al. Pharmacogenetic testing in the face of unclear
clinical efficacy. Cancer 2013; 119:3703-3709.
Editorial
Taming cancer
Taming cancer
Cancerul poate fi mblnzit
Doru Paul*
*Assistant Professor at Hofstra North Shore-LIJ School of Medicine, Hematology-Oncology Attending
Monter Cancer Center, 450 Lakeville Rd # A, Lake Success, NY 11042
Tel. 516.734.8900, Fax. 516.734. 8924
Coresponding author: Doru Paul
Email: dpaul4@nshs.edu
Cite this article:

Paul D, Taming cancer.
Rom J Oncol Hematol.
2013; 1(1):8-10
Despite the recent discoveries in genetics and

molecular biology that led to several new classes of
anti-neoplastic agents the fundamental mechanisms
responsible for the emergence and development of
cancer are only partially understood. This explains, in
our opinion, the lack of efficacy of current cancer treatments. The failure of cancer treatments reflects the
lack of understanding of the nature of this disease.
First of all, cancers are of very different types. When
we say cancer we designate a large and heterogeneous class of diseases with extremely different molecular characteristics, prognostics and treatments.
For example, the majority of patients diagnosed
with thyroid cancer can be cured, and their chances
of surviving at least 15 years are approximately 90%.
On the other hand, the prognostic of patients with
metastatic solid tumors such as pancreas, stomach,
small cell carcinoma of the lung, is extremely sober
and these patients` chance of surviving 5 years is less
than 7%.
The current dogma of Oncology sees cancer as
a genetic disease caused by mutations of genes responsible for key functions of the cells (cell growth, local invasion, differentiation, cell death etc.).
In support of this view, it has been demonstrated
that all cancer cells contain a variable number of mutations. For example, the genome of smoker patients
with non-small cell lung cancers contains ~200 mutations, as opposed to the genome of non-smoker patients with the same type of cancers, which contains
ten times less mutations.
Are all mutations present in the genome of the cancer cells involved in pathophysiology of the disease?
A recent seminal review article recently published in
Science (1) by Bert Vogelstein and his collaborators
from Johns Hopkins Kimmel Cancer Center, made
clear that many of the mutations present in cancer
are passenger mutations with no effect on the neoplastic process, and only those mutations that confer a
selective growth advantage to the tumor cells, called
driver mutations, are responsible for the cancer phenotype. As mentioned in this review, the number of
driver mutations found so far is 138 (67 oncogenes
and 74 tumor suppressor genes), with an average of
five to eight driver genes per tumor. It appears that
there are only a limited number of altered cellular signaling pathways in cancers, and the authors further
classified these 138 driver genes into 12 pathways
that confer a selective growth advantage.
The model of cancer as a genetic disease that affects
key pathways of the cells, led, over the past fifteen
years, to the development of rationally designed new
classes of drugs that target specific key molecules involved in the malignant process. The term biological
targeted therapy refers to this new generation of cancer drugs designed to interfere with a specific molecular target (typically a protein) that has been proven to
have a critical role in tumor growth or progression (2).
The introduction of biological targeted agents has
revolutionized the management of certain cancer
types, and has contributed to recent improvements in
survival rates of cancer patients, in certain subgroups
of novel nosological entities (3).
For certain cancer types, treatment with biological
targeted agents represents a progress. For example, in
a recent long-term follow-up data on the Imatinib treatment of patients with chronic myelogenous leukemia
(CML), the overall survival rate of patients was very impressive, with 80-90% of the patients taking this drug
being alive at 10 years (4). Also, since its approval in US
in 1998, Trastuzumab has revolutionized the management of Her2-positive breast cancer, specifically, in the
subset of patients whose tumors express the human
epidermal growth factor receptor (HER)-2 protein. The
use of Trastuzumab has reversed the worse prognosis
associated with HER2-positive status in women with
breast cancer. In a multivariate analysis published in
2010, Trastuzumab recipients with Her2-positive disease had a 44% reduction in the risk of death, versus
women with Her2-negative disease. (HR 0.56; 95% CI,
0.45 to 0.69; P < 0.0001) (5).
It is important to note that although the molecular
target of these agents is known and, generally, these
agents act more selectively on tumor cells than chemotherapy, they may still have significant side effects.
It became quickly clear that the benefit of these smart
agents that target epidermal or vascular growth factors and tyrosine kinases is restricted to only a subgroup of patients, and the quality of life of some
patients may be worsened by taking them. For ex-
Paul D
ample, it has been estimated that in US approximately

100,000 patients with metastatic colorectal cancer,
with tumors harboring mutant KRAS, have received
unhelpful and potentially detrimental therapy, before
clinical studies had shown that these patients do not
benefit from Cetuximab (6). Also, in patients with breast
cancer treated with Trastuzumab, for each life saved,
between 10 and 25 patients will develop heart disease; also, despite effective treatments, some of these
patients will decease due to cardiac complications.
For example, in the N9831 (arm C) and NSABP B31
studies joint analysis, approximately two patients died
of excess heart disease or other complications for every three lives saved by reducing breast cancer (7).
The more worrisome aspect of the use of targeted
agents is the phenomenon of resistance that appears,
sooner or later, in the vast majority of patients treated
with these agents. The fact that the prognosis of patients with CML has improved significantly after the
introduction of Imatinib on the market should not
make us extrapolate positive results of this level of
magnitude (4) to other tumor types. Imatinib`s success
seems to be the exception rather than the rule. The
reason for Imatinib`s efficacy in CML is related to the
special pathophysiology of this disease: in CML the
tumors become addicted to a unique, constitutively
active ABL kinase that has a direct, causal relationship
with the development of CML (8). Transgenic mice with
BCR/ABL DNA construct develop leukemia shortly
after birth. In contrast to this idiosyncratic pathologic
mechanism, solid tumors are much more complex
than CML, and numerous mutations have been described in each solid tumor type (1). On average, breast
tumors may have at least 105 mutated genes and colorectal cancer may have at least 81 mutated genes
from which an average of 20 and 14, respectively, are
driver cancer genes directly involved in the malignant
process (9). This complexity and heterogeneity makes
solid tumors much more difficult to treat than CML.
After a period of an initial response (10-16 months),
targeting single clones, in a heterogeneous tumor
background, may foster tumor adaptation through
Darwinian selection (10). Cancer cells are not the same
at the genetic level. Heterogeneity is present not only
between cancers of different patients but also, inside
a tumor itself. A single tumor may contain clones with
differently mutated genes and also, the tumor and
the metastasis, may be genetically very different. Additionally, individual metastasis may harbor different
mutations (11). If resistant clones are present before
administration of therapy, treatments designed to kill
maximum numbers of cancer cells remove this inhibitory effect and, actually, promote more rapid growth
of the resistant populations (12). Acquired resistance to
targeted agents is inevitable and, future therapies will
have to address more effectively spatial and temporal
tumor heterogeneity.
It is clear that the model of cancer as a genetic disease is incomplete and, for the prognostic of patients
diagnosed with this disease to improve, the cancer

treatment field urgently needs a paradigm shift. The
clinical benefit of targeted agents that resulted from
this model is modest, at best, in the majority of solid
tumors. Also, the market cost of targeted agents is
far from being negligible. Currently, more than 90%
of the biological target agents approved by the FDA
in US in the last decade cost at least $20,000 for a
4-month course of treatment. Recently, two world experts in metastatic renal cell cancer made a sobering
statement about the therapeutic progress in this disease: despite advances in treatment, most patients
with advanced disease still face a dramatically shorted
life expectancy. An objective look at the therapeutic
landscape shows development of only 2 classes of
agents after an expenditure of billions of dollars and
involvement of thousands of patients in clinical trials,
with little or no effort to understand the determinants
of response and resistance (13).
Ideally, in order to optimize cost-effectiveness, biological targeted agents should rise to the promise of
their name and be used only in patients with tumors
expressing the relevant molecular target. Standardized
and reliable means of measuring the target should
be made available before blindly using new drugs. A
retrospective analysis published in June 2011 in the
Journal of Clinical Oncology supported the idea that
molecular targeted agents produced the highest relative benefit when the target population was selected
by a biomarker (14). However, in practice, the priorities
and rationales of drug marketing are different from
those of scientific research. The development of biomarkers is a laborious and costly process. Marketing
departments in the pharmaceutical industry tend to
favor organ-based drug registrations, while scientific
data increasingly suggest that only those that express
the relevant biomarker target will benefit from the
treatment (3).
In a recent editorial, researchers from the Weizmann
Institute of Science in Israel illustrated the pitfalls of
targeted therapy and personalized therapy concepts
(15)
. They pointed up the fact that although the targeted approach was heralded as a new paradigm in
the treatment of cancer Paul Ehrlich had more than a
century ago, the idea of the magic bullet, a treatment
that would specifically target pathogens without affecting healthy tissues. They clearly stated the field of
oncology would benefit from a new framework that
would integrate theories within and outside the normal modes of research. For the new paradigms to be
developed a multidisciplinary approach was suggested. An inter-disciplinary collaboration should bring
together biologists, physicians, bioinformaticians, as
well as bioengineers that would open the oncology
field towards innovative ideas, particularly, those proven successful in the treatment of other medical conditions.
There is an interesting alternative model of cancer
that needs, I think, to be further explored. Last year,
Editorial
Sir John Bertrand Gurdon and Shinya Yamanaka were
awarded the Nobel prize for their discovery that mature cells can be converted to stem cells. In 1958,
Gurdon, successfully cloned a frog using intact nuclei
from the somatic cells of a Xenopus tadpole. Few
years later, in a series of experiments, Pierce and collaborators transplanted teratocarcinoma cells into
mice and noticed that the tumor cells can differentiate into benign tissue (16, 17). Subsequently, it has been
shown, in several nuclear transfer experiments, that
it is it possible to revert the malignant phenotype of
a cancer cell to a non-malignant phenotype, without
correcting the genetic abnormalities of the cancer cell
genome. Nuclei from malignant cells are reprogrammable, if placed in a different environment. This finding supports the idea that epigenetic conformation of
a tumor cell may determine whether a cell manifests a
malignant phenotype or not (18). As a recent example,
researchers from UK, demonstrated that breast cancer cells can be directly reprogrammed by amphibian
oocyte extracts. The tumor reversion occurred, in the
absence of DNA replication, and included epigenetic
mechanisms. (DNA demethylation and removal of
repressive histone marks at the promoters of tumour
suppressor genes) (19).
Despite the fact that these experiments took place
more than half a century ago and they have been replicated in different cancer cell models many times (20),
the field of genetic reprogramming is still in its infancy
and the mechanisms by which cells, in a multicellular
organism, are constrained to adopt a certain state are
still not well understood.
These experiments suggest a different view of cancer. If cancer cells can be reprogrammed, then the genome of cancer cells appears to be a modified deve
lopmental program, that can be rewritten or switched
to a different program, that may lead to non-neplastic
states. Such reprogramming could bypass the genetic
Taming cancer
abnormalities present in cancer, through rerouting the

cancer cell phenotype to a benign phenotype.
In an article published in Nature Reviews of Cancer
in March 2009, Adam Telerman and Robert Amson,
two researchers from cole Normale Suprieure in
Paris, France, who have been modeling tumor reversion for more than 20 years, stated that the reversion
process involves a reprogramming mechanism using
epigenetic and probably genetic tools that will supersede the changes in cancer by assembling and triggering alternative ways leading to the suppression of
tumorigenicity (20). As many as 300 genes seem to be
involved in the process of cancer reprogramming. Importantly, these genes which are different from tumor
suppressor genes are not mutated in a wide variety of
cancers (20).
In the same line of thinking, researchers from John
Hopkins School of Medicine in Baltimore, US, proposed a unifying model of cancer combining epigenetic dysregulations and genetic mutations (21).
The characterization of the signals that initiate transitions between different cellular states is only partially understood and deserves further exploration.
The model of cancer as a reversible cellular program
complements and refines the genetic model. A better
understanding of the epigenetic factors that define
cell commitment to a specific phenotype will help
establish better cancer prevention and therapeutic
strategies. Instead of focusing our efforts on killing
the cancer cells with prohibitively expensive targeted
agents that are doomed to resistance, we should try to
improve the quality and the duration of life of cancer
patients, through research approaches that will tame
the malignant cell to a less aggressive behavior, and
transform cancer into a chronic disease.
Conflicts of Interest/Conflict de Interese: none/nici
unul.
Bibliography
1. Vogelstein, Papadopoulos N, Velculescu VE, and al. Cancer Genome Landscapes. Science,
2013, 339; 1546: 1546-1558.
2. Sawyers C. Targeted cancer therapy. Nature, 2004, 432: 294-298.
3. Soria JC., J. Y. Blay JY, Spano JP, et al. Added value of molecular targeted agents in
oncology. Annals of Oncology, 2011, 22; 8:1703-1716.
4. Kantarjian H, OBrien S, Garcia-Manero G, et al. Very long-term follow-up results of
imatinib mesylate therapy in chronic phase chronic myeloid leukemia after failure of
interferon alpha therapy. Cancer, 2012, 118; 12: 31163122.
5. Dawood S, Broglio K, Buzdar AU, et al. Prognosis of women with metastatic breast Cancer
by HER2 status and Trastuzumab treatment: An institutional-based review. J Clin Oncol,
2010, 28; 1, 92-98.
6. Fojo T and Parkinson DR. Biologically targeted cancer therapy and marginal benefits: Are
we making too much of too little or are we achieving too little by giving too much? Clin
Cancer Res, 2010; 16:5972-5980.
7. Littlejohns, P Trastuzumab for early breast cancer: evolution or revolution? Lancet
Oncology, 2006; 7;1: 223.
8. Weisenberg E, Manley PW, Cowan-Jacob SW, et al. Second generation inhibitors of
BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nature Reviews
Cancer, 2007, 7; 345-356.
9. Sjoblom T, Jones S, Wood LD, et al. The Consensus Coding Sequences of Human Breast
and Colorectal Cancers Science, 2006, 314; 5797: 268-274.
10. Gillies RJ, Flowers CI, Drukteinis JS, Gatenby RA. A unifying theory of carcinogenesis, and why
targeted therapy doesnt work. European Journal of Radiology, 2012, 81S1: S48S50.
10
11. Kimmel M. Evolution and cancer: a mathematical biology approach. Biology Direct,
2010, 5:29.
12. Gatenby RA, Silva AS, Gillies RJ, Frieden BR. Adaptive therapy. Cancer Res. 2009, 69;
11:4894-903.
13. Jonasch E and Motzer RJ. Ten years of progress in Renal Cell Carcinoma. JNCCN, 2012,
10; 6: 690-693.
14. Amir E, Seruga B, Martinez-Lopez J, et al. Oncogenic targets, magnitude of benefit, and
market pricing of antineoplastic drugs. J Clin Oncol, 2011, 29; 18:2543-2549.
15. Goldstein I, Madar S, Rotter V. Cancer research, a field on the verge of a paradigm shift?
Trends Mol Med., 2012, 18; 6 :299-303.
16. Pierce, GB and Dixon, FJ. Testicular teratomas. I. Demonstration of teratogenesis by
metamorphosis of multipotential cells. Cancer, 1959, 12, 573583.
17. Kleinsmith LJ and Pierce GB. Multipotentiality of single embryonal carcinoma cells.
Cancer Research, 1964. 24, 15441551 (1964).
18. Hochedlinger K, Blelloch R, Brennan C, et al. Reprogramming of a melanoma genome
by nuclear transplantation. Genes & Dev. 2004. 18: 1875-1885.
19. Allegrucci C, Rushton MD, Dixon JE, et al. Epigenetic reprogramming of breast cancer
cells with oocyte extracts. Molecular Cancer, 2011, 10; 7:1-14.
20. Telerman A and Amson R. The molecular programme of tumour reversion: the steps
beyond malignant transformation. Nat Rev Cancer, 2009, 9; 3:206-216.
21. Timp W and Feinberg AP. Cancer as a dysregulated epigenome allowing
cellular growth advantage at the expense of the host. Nat Rev Cancer, 2013, 13;
7:497-510.
Limfomul nonhodgkin provisional, o provocare n practica clinic
Bumbea H
Limfomul nonhodgkin provisional,

o provocare n practica clinic
Provisional type of nonhodgkin
lymphomas, a challenge in clinical
practice
Horia Bumbea*
*Conf. dr. Spitalul Universitar de Urgen Bucureti, Universitatea de Medicin i Farmacie Carol Davila, Bucureti
Coresponding author: Horia Bumbea
horiabum@gmail.com
Limfoamele nonhodgkiniene sunt un grup heterogen de limfoproliferri cronice care pot fi corect clasificate prin analiza integrat a caracteristicilor morfologice,
imunofenotipice i de genetic molecular. Clasificarea
acceptat i larg utilizat n acest moment este clasificarea Organizaiei Mondiale a Sntii (OMS) din 2008 (1).
Limfoamele cunoscute iniial ca grey zone lymphomas
sau de grani (borderline) n clasificarea limfoamelor
nonhodgkiniene au fost incluse n ultima clasificare OMS.
Astfel, dei majoritatea limfoproliferrilor cronice sunt
clar definite pe baza criteriilor amintite, exist un grup
de entiti provizionale care au fost introduse n clasificarea OMS 2008 n vederea obinerii de date suplimentare care s definitiveze ncadrarea ulterioar a acestora
(2)
. Dintre entitile provizionale, se disting dou entiti
provizionale majore: limfomul difuz, cu celul mare B, n
special forma primitiv mediastinal (PMBCL), i limfomul
Hodgkin clasic, cu scleroz nodular (cHL-NS), care au
caracteristici clinice, anatomopatologice i moleculare
similare. Astfel, att limfomul difuz cu celula mare B, ct i
limfomul Hodgkin au frecvent determinare mediastinal
i supraclavicular, cu afectare predominant la femei.
De asemenea, n limfomul difuz cu celule B se pot des
crie celule Reed Sterneberg, specifice limfomului Hod
gkin, iar absena CD15 i prezena CD30 i a markerilor
asociai liniei limfoide B, cum sunt CD19, CD20, CD79a,
sau PAX5, pot s orienteze diagnosticul. Mai mult, expresia factorilor de transcripie asociai imunoglobulinelor,
BOB1, OCT2, i PUI, sau lipsa EBV i expresia MAL pot
ajuta la distincia PMBCL (3). Analiza profilului genic este
o alt metod prin care se poate face distincia ntre cele
dou entiti. Diagnosticul este cu att mai dificil n mo-
mentul n care cele dou entiti se prezint ca limfom

composite, situaie n care toi aceti factori distinctivi
trebuie analizai (4,5). C. Drgan et al., prin articolul din
acest numr al jurnalului (6), aduc n discuie un astfel de
caz rar, de limfom difuz cu celul B, cu tablou sugestiv
pentru forma clinic primitiv mediastinal, cu prezentare
clinic i histopatologic nalt sugestiv pentru limfomul
Hodgkin clasic, la care lipsa de rspuns terapeutic a dus
la reevaluarea diagnosticului iniial i orientarea ctre
diagnosticul de PMBCL. Sunt prezentate etapele de
diagnostic clinic i de evaluare terapeutic n dinamic,
cu testarea detaliat a rspunsului la tratament, un indicator prognostic foarte important n limfoproliferrile
cronice. Cazul prezentat susine necesitatea de a aborda
complex diagnosticul limfoamelor nonhodgkiniene i
urmrirea atent a prezentrii clinice i a rspunsului la
linia terapeutic, ceea ce poate fi extrem de important n
identificarea corect a limfoamelor provizionale. Utilizarea reevalurii histopatologice sau a second-opinion
este, de asemenea, strlucit utilizat n acest caz, n care
schimbarea liniei terapeutice a condus la rspunsul terapeutic optim i la posibilitatea consolidrii tratamentului prin transplant cu celule stem. Acest articol ofer un
exemplu de atitudine clinic performant, n care puterea diagnosticului modern al formelor complexe i
rare de limfoproliferri maligne prin folosirea metodelor
de nalt performan imunofenotipice de diagnostic la
nivel celular permite depirea barierelor n cazurile de
limfoproliferri neclasificabile.
unul.
Bibliografie
1. Swerdlow S.H., Campo E., Harris N.L., Jaffe E.S., Pileri S.A., Stein H., Thiele J, Vardiman J.W. WHO
Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008.
2. Ott M.M,Horn H., Rosenwald A., Ott G. Grey zone lymphomas: limitations of the classification
of aggressive B-cell lymphomas, Pathologe. 2013; 34(3):225-32.
3. Hoeller S., Copie-Bergman C. Grey zone lymphomas: lymphomas with intermediate features.
Adv Hematol. 2012; 2012:460801.
4. Hoeller S., Zihler D., Zlobec I., et al. BOB.1, CD79a and cycline are the most appropriate markers
to discriminate classical Hodgkins lymphoma from primary mediastinal large B-cell lymphoma.
Histopathology. 2010; 2(56):217228.
5. Eberle F.C., Salaverria I., Steidl C., et al. Gray zone lymphoma: chromosomal aberrations with
immunophenotypic and clinical correlations. Modern Pathology. 2011; 12(24):15861597.
6. Drgan C., aguna C., Manolache R., Ciortan S., Lupu A.R., Limfomul cu celul B neclasificabil,
cu trsturi intermediare ntre limfomul difuz cu celul mare B i limfomul Hodgkin clasic. Rom J
Oncol Hematol. 2013; 1(1): 20-23.
Romanian Journal of Oncology & Hematology (2013) 1 (1): 11
Cite this article:

Bumbea H, Limfomul
nonhodgkin provisional,
o provocare n practica
clinic. Rom J Oncol
Hematol. 2013; 1(1):11
11
News
Foto Shutterstock
Camere implantabile pentru administrarea chimioterapiei i uurarea tratamentului
Camere implantabile
pentru administrarea chimioterapiei
i uurarea tratamentului
sociaia Medisprof a demarat o ampl

campanie social de strngere de fonduri pentru bolnavii de cancer, cu prilejul
participrii la Trgul de Servicii Medicale i ngrijire
Corporal care a avut loc n perioada 18-20 octombrie la Cluj-Napoca. Scopul campaniei este de a
asigura pacienilor oncologici 100 de camere implantabile pentru administrarea chimioterapiei i
uurarea tratamentului.
Administrarea citostaticelor, dincolo de efectele
secundare bine cunoscute pe care le produce,
afecteaz att sistemul venos periferic, ct i pielea sau esutul muscular al pacienilor, mai ales n
cazul puncionrilor repetate. Toate aceste efecte
pot fi prevenite cu ajutorul camerelor implantabile,
sisteme de tipPort-a-Cath (PAC), ce se monteaz
printr-o intervenie simpl sub piele i permit un
acces venos sigur i facil n administrarea citostaticelor. Bolnavii de cancer sunt supui unor nume
roase investigaii i tratamente ce necesit injectri
frecvente, riscul de infecie este crescut, iar orga
nismul lor slbit suport cu greu aceste proceduri.
Tocmai de aceea ne-am propus s dm o mn de
ajutor i s oferim pacienilor oncologici aceste
camere implantabile care le vor uura tratamentul,
avnd multiple beneficii: reduc efectul toxic al chi-
12
mioterapicelor, diminueaz riscul de infecie sau

tromboz venoas i permit distribuia imediat a
medicamentelor n sistemul venos central , afirma
dr. Adrian Udrea, medic primar oncolog.
Sub sloganul Doneaz pentru o cauz, campania se va desfura pe o perioad de 3 luni, timp n
care Asociaia Medisprof i propune s desfoare
diverse aciuni prin care s strng fondurile ne
cesare pentru a oferi bolnavilor de cancer 100 de
camere implantabile. Oferirea celor 100 de camere
implantabile reprezint doar nceputul unui proiect
mult mai cuprinztor marca Asociaia Medisprof. n
viitor se dorete s se ofere constant sprijin financiar
i medical pacienilor diagnosticai cu cancer: acces
la tratamente i terapii de ultim or, asigurarea sau
decontarea transportului pentru pacienii venii din
afara oraului Cluj-Napoca, precum i alte faciliti.
Asociaia Medisprof a fost nfiinat n anul 2011
n Cluj-Napoca, principalele sale obiective pe parcursul dezvoltrii fiind: sprijinirea i mbuntirea
reelei medicale oncologice din Romnia, promovarea i susinerea unor politici de depistare precoce a cancerului i de reducere a factorilor de risc
la care este expus populaia, dar i susinerea unor
activiti educative profesionale la nivelul cadrelor
medicale specializate. (Asociaia Medisprof)
Era genomicii n cancer
Foto Shutterstock
Era genomicii n cancer
ncologia, prin ritmul achiziiilor n

diagnostic i tratament, se afl n prezent
n avangarda specialitilor medicale.
Cancerul este o boal condiionat genetic, iar
visul de a descifra mecanismele apariiei sale
devine ncet-ncet realitate. n acest context devine
posibil i tratamentul personalizat, adaptat tipului
de tumoare i stadiului bolii, pentru pacienii
diagnosticai cu cancer.
Cancerul este o boal complex i dificil de
tratat, n special din cauza faptului c fiecare
tumoare este diferit prin nsi natura sa, cauzele
ce determin apariia ei, precum i modul n care
progreseaz pe parcurs. De aceea este important
ca pacientul oncologic s poat beneficia de un
tratament personalizat, iar terapiile genetice intite
promit s devin terapiile viitorului n cancer.
n majoritatea rilor occidentale exist deja
posibilitatea de tratament intit pentru categorii de
pacieni unde diagnosticul molecular a fost stabilit
prin testri de laborator. Este cazul anumitor
tumori de sn, colon, gastrointestinale i mai nou
pulmonare sau chiar melanoame maligne. Dac
metoda clasic de diagnostic presupune biopsia
i studierea aspectului unei celule la microscop, n
cazul diagnosticului molecular se determin modul
n care genele i proteinele interacioneaz ntr-o
celul, mbuntind capacitatea clinicienilor de a
depista n timp util cancerul sau de a administra un
tratament personalizat.
Cu toate c eficiena unui astfel de diagnostic
este net superioar, n cazul Romniei accesul
pacienilor la acesta este anevoios. n prezent,

n ara noastr, diagnosticul molecular nu este
rambursat de CNAS. Este susinut, pentru anumite
tipuri tumorale, de firmele farmaceutice care
produc medicamentele cu indicaie n situaia
dat, ns n cele mai multe cazuri pacientul trebuie
s susin financiar testarea genetic. Este posibil
ca aceast situaie s fie o urmare a lipsei de
informare la nivelul CNAS-ului i mai ales a lipsei
unor studii de cost/eficien, afirm dr. Adrian
Udrea, medic primar oncolog la clinica Medisprof
din Cluj-Napoca.
Tratamentele personalizate ce se administreaz
ulterior diagnosticului sunt n parte rambursate
de CNAS, cu excepia celor aprute pe pia
dup 2008. Prin natura meseriei medicul este
sau ar trebui s fie interesat n primul rnd de cea
mai bun, cea mai actual conduit terapeutic
i cu cele mai bune rezultate publicate pentru
fiecare pacient. Or, este evident c n 2013 orice
furnizor romn de servicii medicale n oncologie
este ntr-o dificultate date fiind cele menionate
mai sus, concluzioneaz dr. Adrian Udrea.
Clinica Medisprof a fost nfiinat n anul 2003
n Cluj-Napoca, unul dintre principalele sale
obiective pe parcursul dezvoltrii fiind sprijinirea
i mbuntirea reelei medicale oncologice din
Romnia. Pe lng secia de oncologie, clinica
Medisprof pune la dispoziia pacienilor i servicii
de medicin de familie, medicina muncii, analize
de laborator, psihologie clinic i nutriie-dietetic.
(Asociaia Medisprof)
13
Events
Prima conferin naional a oncologilor privai din Romnia
Foto Shutterstock
Prima conferin naional

a oncologilor privai din Romnia
sociaia Naional a Oncologilor Privai

din Romnia pregtete pentru primvara
anului urmtor prima conferin naional
cu tema Abordarea multidisciplinar n cancer.
Noi modaliti de tratament n 2014. Pornind de la
ideea c este nevoie de o colaborare strns ntre
diverse specialiti medicale pentru a salva vieile
atinse de cancer, ANOPR mpreun cu Asociaia
Medisprof i Centrul Medical Diasan propun pentru conferina din 9-10 mai 2014, ce va avea loc la
Sibiu, cteva sesiuni ample care vor aduce laolalt
medici oncologi, chirurgi, ginecologi, pneumfti
ziologi, gastroenterologi, dar i ali specialiti.
Pentru prima dat n cadrul unui astfel de eveniment ce vizeaz tratamentul cancerului, alturi de
oncologii din Romnia vor fi invitai i reprezentani
ai pacienilor, echipelor paramedicale, firmelor
farmaceutice i oficiali ai Ministerului Sntii i
CNAS. Zeci de mii de romni mor n fiecare an
de cancer i un numr i mai mare se lupt zilnic
cu aceast boal. Pacienii notri merit ngrijiri de
calitate, de aceea dorim ca la aceast conferin
anual s reunim reprezentanii tuturor prilor
implicate n sistemul oncologic i s le artm c
i Romnia se poate alinia la standardele occidentale , afirm dr. Adrian Udrea, medic primar oncolog, preedinte n exerciiu al ANOPR.
Manifestarea va avea ca subiecte principale de
dezbatere tumorile gastrointestinale, mamare i
pulmonare, fiind structurat astfel nct sesiunile
educaionale s se adreseze att cadrelor medicale, ct i celor paramedicale (asisteni medicali, farmaciti, psihologi, nutriioniti). Tematica
14
lucrrilor de tip poster va aduce n prim plan

prevenia, diagnosticul sau tratamentul tumorilor
solide, iar o alt parte important a conferinei se
va adresa problemelor pacienilor oncologici.
Conferina Abordarea multidisciplinar n
cancer. Noi modaliti de tratament n 2014 va
fi un eveniment creditat de Colegiul Medicilor
cu puncte EMC, iar nscrierile vor ncepe din
ianuarie 2014. Timp de doi ani consecutivi,
ncepnd cu 2011, acest eveniment medical
pe teme oncologice s-a desfurat sub forma
unui simpozion local la Cluj-Napoca, iar o dat
cu nfiinarea ANOPR s-a simit nevoia unei extinderi la nivel naional. La lucrrile tiinifice
sunt invitai s participe cadrele medicale specializate, medicii rezideni, asistenii medicali i
farmacitii, iar la discuiile i dezbaterile privind
sistemul medical sunt ateptai i reprezentanii
Federaiei Asociaiilor Bolnavilor de Cancer din
Romnia, precum i autoritile avizate din domeniul sntii , adaug dr. Adrian Udrea.
Asociaia Naional a Clinicilor Private de Oncologie din Romnia a fost nfiinat n anul 2012,
membrii fondatori fiind 6 dintre cei mai importani
furnizori de servicii medicale de profil din ntreaga
ar: Euroclinic (Iai), Medisprof (Cluj-Napoca),
Oncomed (Cluj-Napoca i Timioara), Oncolab
(Craiova) i Kron Elpis (Braov). Scopul Asociaiei
este de a contribui la dezvoltarea reelei medicale
oncologice i de a oferi pacienilor oncologici servicii medicale la standarde europene de calitate
prin furnizarea de servicii profesioniste. (Asociaia
Medisprof)
Foto Shutterstock
Cursuri pe teme oncologice pentru medicii de familile i asistenii medicali
Cursuri pe teme oncologice

pentru medicii de familie
i asistenii medicali
Cluj-Napoca, 18 noiembrie 2013
edicii de familie i asistenii medicali sunt

ateptai la cursurile pe teme oncologice
ce vor avea loc n perioada 12-13 decembrie la centrul de conferine al hotelului Topaz din
Cluj-Napoca. Organizate sub egida Asociaiei Medisprof, atelierele de lucru trateaz problematica
procedurilor de screening n diverse tipuri de cancer, precum i importana camerelor implantabile
n administrarea intravenoas a medicamentelor.
Aflat la cea de a treia ediie, cursul de screening
n oncologie pentru medicii de familie va aduce
n discuie totalitatea tehnicilor prin care se poate
depista cancerul naintea manifestrii simptomelor. Acest proiect educaional i propune s
pregteasc medicii de familie cu privire la procedurile de screening n cazul cancerului de sn,
de colon, de prostat, de col uterin, dar i n alte
localizri oncologice. Screeningul este o modalitate ce ajut la descoperirea timpurie a bolii i
contribuie la creterea anselor unui prognostic
favorabil. Cursul a mai fost organizat n luna septembrie la Trgu-Mure i Bistria, unde a fost pri
mit cu mare interes de medicii participani datorit
diversitii subiectelor abordate i noutilor
prezentate precizeaz dr. Andrei Ungureanu,
medic oncolog.
Atelierul de lucru pe tema camerelor implantabile se adreseaz n special asistenilor
medicali, ns modulul poate fi parcurs i de
medicii de familie. Cursul se va axa pe admi
nistrarea intravenoas periferic a citostaticelor,
complicaiile i dificultile ntlnite n aceast
procedur, precum i rolul i montarea came
relor implantabile, sesiunile plenare teoretice

fiind susinute de medici oncologi i chirurgi.
Aspectele practice ale utilizrii camerelor implantabile vor fi prezentate detaliat de ctre
asisteni medicali specializai n utilizarea unor
astfel de dispozitive. Dei n Occident camerele implantabile se folosesc pe scar larg de mai
bine de douzeci de ani, n Romnia nc nu sunt
foarte bine cunoscute. Pentru domeniul oncologic,
aceste dispozitive reduc semnificativ efectul toxic
al citostaticelor, iar substanele ajung mai repede n
sistemul venos central al pacientului, dar ele pot fi folosite i pentru administrarea antibioticelor, transfuzii
i recoltri de snge sau administrarea substanei de
contrast pentru RMN i CT, adaug dr. Adrian Udrea,
medic primar oncolog.
Cursurile sunt creditate cu puncte EMC i fac
parte dintr-un proiect mai amplu al Asociaiei Medisprof prin care aceasta i-a propus s formeze
personalul medical din ntreaga ar cu privire
la metodele de screening n oncologie i utilizarea camerelor implantabile. n anul ce va urma se
vor organiza aceste seminarii i n alte orae din
Romnia.
Asociaia Medisprof a fost nfiinat n anul 2011
n Cluj-Napoca, principalele sale obiective pe parcursul dezvoltrii fiind: sprijinirea i mbuntirea
reelei medicale oncologice din Romnia, promovarea i susinerea unor politici de depistare precoce a cancerului i de reducere a factorilor de risc
la care este expus populaia, dar i susinerea unor
activiti educative profesionale la nivelul cadrelor
medicale specializate. (Asociaia Medisprof)
15
Events
Scientific Events
Scientific Events
ONCOLOGY
2014 Gastrointestinal Cancers Symposium
16-18 January 2014
San Francisco, California, USA
opportunity to reflect upon the past and discuss

new approaches for the future.
The abstract submitter, registration, and housing
will open in mid-August so check back often for
Meeting updates.
APOS 11TH ANNUAL CONFERENCE

13-15 February 2014
Tampa, Florida, USA
Join us for the 2014 Gastrointestinal Cancers

Symposium (January 16-18, 2014 in San Francisco,
California) and participate in three days of
translational research, novel clinical therapies, and
state-of-the-art science in GI oncology.
Key Dates
Abstract Submission Opens: Late July
Registration and Housing Open: Late July
Abstract Submission Deadline: September 17,
2013 at 11:59 PM (EDT)
Meeting Dates: January 16-18, 2014
2014 Genitourinary (GU) Cancers Symposium

30 January - 1 February 2014
San Francisco, California, USA
Mark your calendar for the 2014 Genitourinary (GU)

Cancers Symposium, which will be held January
30-February 1, 2014 in San Francisco, California.
Through didactic presentations, engaging debates
and case-based discussions, the meeting will
provide a comprehensive analysis of emerging
scientific data and clinical strategies.
This years Meeting marks the 10th anniversary of
the GU Cancers Symposium offering attendees the
16
Preconference Workshops
APOS plans a day of preconference workshops that
are a mix of two and four hours in length. Topics
will be determined by the process of proposal
submission and acceptance.
We are excited to announce our keynote speakers
for the 11th Annual Conference!
Keynote Speakers
Philip A. Pizzo, M.D.
Former Dean and Professor of Pediatrics and of
Microbiology and Immunology, Stanford University
School of Medicine
Philip A. Pizzo, MD, became dean of the Stanford
School of Medicine in April 2001. Before joining
Stanford, he was the physician-in-chief of Childrens
Hospital in Boston and chair of the Department
of Pediatrics at Harvard Medical School. Pizzo
is recognized for his contributions as a clinical
investigator, especially in the treatment of children
with cancer and HIV.
Philip A. Pizzo, MD, became dean of the Stanford
School of Medicine in April 2001. Before joining
Stanford, he was the physician-in-chief of Childrens
Hospital in Boston and chair of the Department
of Pediatrics at Harvard Medical School. Pizzo
is recognized for his contributions as a clinical
investigator, especially in the treatment of children
with cancer and HIV.
Pizzo devoted much of his distinguished medical
career to the diagnosis, management, prevention
and treatment of childhood cancers and the
infectious complications that occur in children

whose immune systems are compromised by
cancer and AIDS.
Pizzo has received several awards from the U.S.
Public Health Service, including the Outstanding
Service Medal in 1995. He has been cited in
Best Doctors of America since 1995, and in
1990 was declared Washingtonian of the
Year by Washingtonian Magazine for helping
to found the Childrens Inn, a temporary home
for children undergoing treatment at the
National Institutes of Health and their families.
He is a member of a number of prestigious
organizations and in 1997 was elected to
membership in the Institute of Medicine of the
National Academy of Sciences.
Carolyn D. Runowicz, M.D.
Executive Associate Dean for Academic Affairs
Professor of Obstetrics and Gynecology, Florida
International University, Herbert Wetheim College
of Medicine
Dr. Runowicz is a nationally and internationally
recognized leader in womens health and
gynecologic cancer. Her research has focused
on the development, initiation and conduct of
clinical trials in gynecologic cancer and in cancer
prevention. She has authored more than 200
scientific articles.
Dr. Runowicz is a nationally and internationally
recognized leader in womens health and
gynecologic cancer. Her research has focused
on the development, initiation and conduct of
clinical trials in gynecologic cancer and in cancer
prevention. She has authored more than 200
scientific articles.
She has received numerous honors and awards
and has served in leadership roles in the major
cancer organizations. She served as the first
woman president of the Society of Gynecologic
Oncologists (2000), was President of the American
Cancer Society (2005) and served on the National
Cancer Advisory Board (NCAB), appointed by
President George W. Bush. She served as Chair of
the NCAB for 4 years (2006-2010). She is currently
serving on the Board of Directors of the American
Society of Clinical Oncology (2011-2015) and as
Vice President of the American Gynecological and
Obstetrical Foundation Board.
She is a reviewer for medical journals and serves
on several editorial boards in recognition of her
expertise in womens health and gynecologic
cancers. She is on several scientific advisory
boards, including the National Cancer Institute
and the Ovarian Cancer Research Foundation.
Meet the Expert Lunches
Grab lunch with the leaders in your field! We offer
five topics that allow you to meet and mingle
with the experts. Past lunch topics have included
Cancer Survivorship, Pediatric Distress Screening,
and Caring for Yourself as a Psychosocial Oncology
Clinician with experts like Paul Jacobsen PhD, Matt
Loscalzo, MSW and Jimmie Holland, M.D. Stay

tuned for details on this years lunches.
Networking Opportunities
Join in the fun with the APOS speed networking
event. This will be an exciting opportunity for you
to meet leading researchers and clinicians in the
field. During the event, you will receive a box lunch
and have a chance to discuss your career goals
and common professional interests with multiple
potential mentors.
Beautiful Tampa, Florida
From family-friendly events and culinary adventures
to great hotel deals and special museum exhibits,
its all in Tampa Bay. And you wont find a better
home-base for exploring Tampa than the beautful
Tampa Marriott Waterside.
Sarcoma & GIST Conference 2014

18-19 February 2014
Milan, Italy
Sarcoma and GIST 2014 will offer participants a

complete update of current medical therapy of
these diseases from a multidisciplinary and clinical
approach while also covering molecular and
pathological issues.
ELCC 2014 European Lung Cancer Conference

26-29 March 2014
Geneva, Switzerland
Main Themes:
Molecular testing in advanced NSCLC: clinical
practice, clinical trials, emerging biomarkers
Immunotherapy in NSCLC: new findings and how
to select patients for this approach
Oncogenic-driven diseases: potential role of local
therapies, strategies for overcoming resistance
Clinical trials in advanced NSCLC: worldwide
landscape
Targeted therapies: new developments
Advanced NSCLC without driver mutations:
treatment approaches
Mesothelioma: standards and controversies
Oligometastatic NSCLC: definition, biology, chan
ging the role of local treatments
17
Events
Scientific Events
HEMATOLOGY
2013 ASH Annual Meeting and Exposition
7-10 December, 2013
New Orleans, LA
It is an absolute honor to invite you to join me for

the preeminent celebration of research, education,
and patient care in hematology at the 55th
American Society of Hematology Annual Meeting
and Exposition in New Orleans.
For those of you who have been to the meeting
previously, you will notice that 2013 marks the
debut of several new, expanded, or special
sessions that have not been offered previously.
Those of you attending for the first time are in for
a treat as you will have access to the most diverse
range of clinical and research sessions we have
ever offered, along with enhanced networking
opportunities. We will showcase the full spectrum
of translation in hematology from new basic
research to new insights into disease pathogenesis
to new therapies for patients to outcome analyses.
With that in mind, I wanted to highlight several
offerings of this years meeting that I am particularly
excited to share with you:
The Special Symposium on Innovation and the
Future of Hematology (Monday, December 9, 1:00
p.m. 2:30 p.m.), to be held on Sunday just prior to
the Plenary Scientific Session, will celebrate what
would have been the 100th birthday of Wallace
H. Coulter, a prolific inventor whose discoveries
became the basis for CBC determinations and
flow cytometry. I hope youll join me at this session
that honors this occasion with lectures from two
outstanding and creative physician-scientists, Drs.
Stuart Orkin and Bruce Beutler, who will discuss
how novel concepts and technologies should
revolutionize hematology research and practice in
the future.
The Presidential Symposium (Tuesday, December
10, 9:50 a.m. 11:20 a.m.), will delve into an important
and timely topic using genomics for clinical decision
making that you wont want to miss. During this
years Symposium Drs. James Downing, Matthew
Walter, and David Ginsburg will discuss advances in
genomic sequencing and when and how we might
integrate this information into patient care decisions
for individuals with acute leukemia, MDS, and clotting
and bleeding disorders.
Two Special Symposia offered as part of the
Scientific Program, one on approaches for inhibiting
18
undruggable targets in cancer (Saturday,

December 7, 4:00 p.m. 5:30 p.m.) and another
on the role of reduction/oxidation chemistry in
hematology (Sunday, December 8, 9:30 a.m.
11:00 a.m.), will explore topics that cut across our
vast discipline, bringing together scientists with
diverse interests.
For the first time, the Scientific Program will
feature four ticketed Scientific Spotlight Sessions.
Similar to the Education Spotlights, these sessions
are intended to focus on areas of special interest
and, in some cases, address controversies in
hematology.
More than any other meeting in the past, this years
meeting will focus on honing and maintaining a
sense of community among our various smaller,
sometimes distinct, and sometimes overlapping,
constituencies. We will employ several strategies
at this years meeting to accomplish this objective,
including grouping like sessions geographically
and synchronizing the timing of the talks and Q&A
periods, allowing attendees to slip seamlessly
between presentations in nearby rooms. Tables
and chairs will also be grouped outside sessions on
similar topics to encourage informal conversations
and networking among attendees with common
clinical or research interests.
While there are many new features of this years
meeting that I encourage you to explore, I would
also like to call your attention to the superb
programming in store for you via two of the
hallmark offerings of each ASH annual meeting:
the Education and Scientific Programs. This years
Education Program, chaired by Drs. Wendy Stock
and John Tisdale, will present the practicing
hematologist with updates on the latest clinical
advances via nearly 30 sessions on topics ranging
from optimizing therapies for non-Hodgkin
lymphoma to sports medicine and hematology.
This years Scientific Program, chaired by Drs.
Jos Lpez and Kevin Shannon, will present the
latest scientific breakthroughs from non-coding
RNAs in normal and malignant hematopoiesis to
transfusion medicine for the pregnant mother, fetus,
and neonate in 18 key areas of hematology.
Of course, the Societys annual celebration of
groundbreaking advances in hematology would
not be complete without honoring some of the
distinguished leaders in the field through awards
and special lectures. I am extremely proud of the
exceptional, diverse program that my colleagues
have assembled. I hope you will join me in
December to experience these talks first-hand,
reconnect with old friends, and enjoy the sights
and sounds of historic New Orleans.
Sincerely yours,
Janis L. Abkowitz, MD
2013 President
Clinical And Multidisciplinary Hematology And

Oncology 11th Annual Review 2014
24-26 January 2014
Scottsdale, Arizona, USA
This course will be a comprehensive update of

issues in hematologic and oncologic malignancies
presenting new disease classification, treatment,
and challenging cases. Course topics will include
up-to-date American Society of Hematology (ASH)
highlights and medical oncology. Topics focus on
key hematologic diseases (dysproteinemias, acute
and chronic leukemias, lymphomas), key solid
tumors (breast, thoracic, GI, GU), and overlap topics
of supportive, ancillary and diagnostic care. The
course offers challenging and interactive sessions on
pertinent issues involved with the care of patients and
includes breakout sessions for one-on-one interaction
between faculty and learners. Hematologists,
oncologists, physician assistants, nurse practitioners,
nurses, pharmacists, and anyone interested in
the diagnosis and treatment of hematologic and
oncologic disorders should attend.
The 10th European Congress on Hematologic

Malignancies: From Clinical Science to Clinical
Practice
28 February - 2 March 2014
Vienna, Austria
Dear Colleague,
We invite you to join us in the beautiful city of
Vienna, Austria, for the 10th European Congress on
Hematologic Malignancies: From Clinical Science
to Clinical Practice which will be held February 28
March 2, 2014.
Given the rapid pace of research in this field, it is
essential for our community to stay informed of the
latest findings and their potential impact on our
clinical practice. Advances in our understanding
of the mechanisms of hematologic malignancies
have resulted not only resulted in novel therapies
and improvements in disease management
such as maintenance strategies and new and
improved regimens involving targeted therapies,
proteasome inhibitors, monoclonal antibodies,
and immunomodulatory agents but have also

given rise to new challenges and debates.
For the last ten years, the European Congress on
Hematologic Malignancies has provided cuttingedge updates and expert perspectives on the
diagnosis and management of hematologic
malignancies, including multiple myeloma, chronic
lymphocytic leukemia, and Hodgkins and nonHodgkins lymphomas. By combining stimulating
didactic sessions, interactive panel discussions,
and lively debates by internationally renowned
specialists, this Congress continues to provide
healthcare professionals with the information they
need to optimize care and outcomes for their
patients with hematologic malignancies.
To complement the exceptional scientific experience
of this Congress, Vienna, the City of Music, offers
the perfect educational backdrop, with its Baroque
castles and gardens, as well as Ringstrasse, which is
lined with grand buildings, monuments and parks.
We hope you will join us in this beautiful and historic
city for what is sure to be an exciting, interactive
and educational experience.
10th European congress on Hematologic

Malignancies: From Clinical Science
to Clinical Practice
7-9 March 2014
Vienna, Austria
Are you up-to-date on current clinical best

practices?
New findings, new techniques, and recent efforts
in research and discovery have changed the way
physicians treat their patients taking a more
individualized approach. The 10th European
Congress on Hematologic Malignancies from
Clinical Science to Clinical Practice will provide
important clinical updates in the management of
your patients.
You will find 10th European Congress on Hema
tologic. Malignancies from Clinical Science to Clinical
Practice to be of immediate value, and we look
forward to welcoming you to Vienna in March!
Dont forget to bring your laptop or tablet!
In a continuing effort to be environmentally con
scious, all slide presentations, pending speaker
approval, will be available to view on the electronic
device of your choicelaptop, tablet, smart phone,
etc., via ARRAY technology. A printed summary
book will not be available and we encourage you
to bring your electronic device to the conference
for optimal participation.
This technology is the most convenient way to provide
attendees with the most up-to-date information. After
the conference, a link to download the presentations
will be emailed to attendees.
19
Case presentation

between diffuse large B-cell lymphoma and classical Hodgkin lymphoma
B-cell lymphoma, unclassifiable,

with features intermediate between
diffuse large B-cell lymphoma and
classical Hodgkin lymphoma
Limfomul cu celul B neclasificabil,
cu trsturi intermediare ntre
limfomul difuz cu celul mare B
i limfomul Hodgkin clasic
Cornel Drgan*, Carmen aguna*, Raluca Manolache*, Silvia Ciortan*, Anca Roxana Lupu*
* Clinica de Hematologie Clinic, Spitalul Clinic Colea Bucureti
Coresponding author: Cornel Drgan
Email: dragan_cornel@yahoo.com
Abstract:
Keywords:
grey zone lymphoma,
diffuse large
B-cell lymphoma,
Hodgkins lymphoma,
immunohistochemistry,
immunochemotherapy,
complete remission
Cite this article:

Dragan C., Saguna C.,
Manolache R., Ciortan
S., Lupu A.R., Limfomul
cu celul B neclasificabil,
cu trsturi intermediare
ntre limfomul difuz cu
celul mare B i limfomul
Hodgkin clasic. Rom J
Oncol Hematol. 2013;
1(1):20-23
20
B-cell lymphoma, unclassifiable, with features intermediate between

diffuse large B-cell lymphoma and classical Hodgkin lymphoma,
known as being part of grey zone lymphoma category, displays
clinical and biological characteristics which overlap between diffuse
large B-cell lymphoma and classical Hodgkin lymphoma. The rarity
of these cases represents an extraordinary challenge for both
pathologists and hematologists, because the differential diagnosis
has direct inferences for the therapeutic strategies.
In this paper we present the case of a 29 year old young man
diagnosed in April 2010 with classical Hodgkin lymphoma,
histologic subtype lymphocyte depletion, that followed 6 cycles
chemotherapy (ABVD Doxorubicin, Bleomycin, Vinblastine,
Dacarbazine) without getting an adequate response after salvage
chemotherapy (DHAP - Dexamethasone, high-dose Cytarabine,
Cisplatin, IGEV - Ifosfamide, Gemcitabine, Vinorelbine) and
radiotherapy after which the progressive disease was diagnosed.
Reassessment of the lymph node biopsy has led to the diagnosis of
unclassifiable B-cell lymphoma with features intermediate between
diffuse large B-cell lymphoma and classical Hodgkin lymphoma,
and after immunochemotherapeutic treatment (R-EPOCH Rituximab, Etoposide, Vincristine, Doxorubicin, Cyclophosphamide,
Prednisolone), partial remission was achieved, which has been
consolidated by an autologous stem cell transplant which resulted
in a complete remission.
Drgan C, aguna C, Manolache R, Ciortan S, Lupu AR
Rezumat:
Cuvinte-cheie:
grey zone lymphoma,
limfom difuz cu
celul mare B,
limfom Hodgkin,
imunohistochimie,
imunochimioterapie,
remisiune complet
Limfomul cu celul B neclasificabil, cu trsturi intermediare

ntre limfomul difuz cu celul mare B i limfomul Hodkin clasic,
cunoscut ca aparinnd categoriei grey zone lymphoma,
prezint caracteristici clinice i biologice suprapuse ntre
limfomul difuz cu celul mare B i limfomul Hodkin clasic.
Raritatea acestor cazuri reprezint o provocare extraordinar att
pentru anatomo-patologi, ct i pentru hematologi, deoarece
diagnosticul diferenial are implicaii directe asupra strategiei
terapeutice.
n aceast lucrare vom prezenta cazul unui tnr n vrst
de 29 de ani diagnosticat n aprilie 2010 cu limfom Hodkin
clasic subtip histologic depleie limfocitar, care a urmat 6
cicluri polichimioterapice (ABVD Doxorubicin, Bleomicin,
Vinblastin, Dacarbazin) fr a obine un rspuns adecvat, ulterior
chimioterapie de salvare (DHAP Dexametazon, Citarabin n
doz mare, Cisplatin, IGEV Ifosfamid, Gemcitabin, Vinorelbin)
i radioterapie n urma crora s-a stabilit diagnosticul de boal
progresiv. Reevaluarea blocului ganglionar obinut iniial a pus
diagnosticul de limfom cu celul B neclasificabil, cu trsturi
intermediare ntre limfomul difuz cu celul mare B i limfomul
Hodkin clasic, iar n urma tratamentului imunochimioterapic
utilizat (R-EPOCH Rituximab, Etopozid, Vincristin, Doxorubicin,
Ciclofosfamid, Prednisolon) s-a obinut remisiune parial
consolidat prin autogref de celule stem hematopoietice cu
obinerea remisiunii complete.
Introducere
Limfomul cu celul B neclasificabil, cu trsturi
intermediare ntre limfomul difuz cu celul mare B
i limfomul Hodkin clasic, cunoscut ca aparinnd
categoriei grey zone lymphoma, prezint
caracteristici clinice i biologice suprapuse ntre
limfomul difuz cu celul mare B i limfomul Hodkin
clasic (1). Acest diagnostic a fost inclus n clasificarea
limfoamelor a Organizaiei Mondiale a Sntii din
anul 2008 (2). Aceast categorie a fost conceput ca
o msur de a ncadra cazurile de grani care nu
pot fi cu certitudine ncadrate ntr-o singur entitate
dup efectuarea tuturor investigaiilor morfologice,
imunofenotipice i moleculare. n mod tipic aceste
cazuri cuprind caracteristici intermediare ntre cele
dou afeciuni sau caracteristici ale amndurora.
nsi raritatea acestor cazuri reprezint o provocare
extraordinar att pentru anatomo-patologi, ct
i pentru hematologi, deoarece diagnosticul
diferenial are implicaii directe asupra strategiei
terapeutice (3). n aceast lucrare vom prezenta
cazul unui tnr n vrst de 29 de ani diagnosticat
n aprilie 2010 cu limfom Hodkin clasic subtip
histologic depleie limfocitar n urma efecturii
examenelor histopatologic i imunohistochimic ale
unei adenopatii supraclaviculare, care a urmat 6
cicluri polichimioterapice fr a obine un rspuns
adecvat, ulterior chimioterapie de salvare i
radioterapie n urma crora s-a stabilit diagnosticul
de boal progresiv. Reevaluarea blocului
ganglionar obinut iniial a pus diagnosticul de

limfom cu celul B neclasificabil, cu trsturi
intermediare ntre limfomul difuz cu celul mare B
i limfomul Hodkin clasic, iar n urma tratamentului
imunochimioterapic utilizat s-a obinut remisiune
parial consolidat prin autogref de celule stem
hematopoietice cu obinerea remisiunii complete.
Prezentarea cazului
V prezentm cazul unui pacient n vrst de
29 de ani, fr antecedente heredo-colaterale
sau personale patologice semnificative, fr
expunere la substane toxice, care descrie debutul
aparent al afeciunii n urm cu aproximativ 6 luni
prin apariia unor formaiuni pseudotumorale
supraclaviculare bilaterale, nsoite de transpiraii
nocturne, tuse seac, sindrom febril prelungit,
scdere ponderal (5 kg n 6 luni). Examenul clinic
la internare deceleaz pacient cu stare general
bun, blocuri adenopatice supraclaviculare
bilateral de aproximativ 3-4 cm, echilibrat cardiopulmonar, murmur vezicular prezent simetric,
bilateral, fr raluri, ficat cu marginea inferioar la
rebordul costal, splina cu pol inferior nepalpabil.
Radiografia mediastino-pleuro-pulmonar efec
tuat a evideniat lrgirea mediastinului mijlociu
i superior bilateral, mai important de partea
dreapt, de aceea s-au continuat investigaiile prin
efectuarea unui examen computer-tomograf care a
pus n eviden multiple adenopatii cu dimensiuni
21
Case presentation

between diffuse large B-cell lymphoma and classical Hodgkin lymphoma
maxime de 37/27 mm, conglomerate, dispuse

paratraheal drept, prevascular, n loja Baretty i
fereastra aorto-pulmonar, cu uoar deplasare a
traheei spre stnga. Ficat, splin cu aspect normal.
Fr adenopatii lombo-aortice pn la nivelul
emergenei arterei mezenterice superioare.
S-a practicat biopsie ganglionar excizional
de la nivelul adenopatiilor supraclaviculare cu
efectuarea examenului histopatologic care a
decelat prezena a numeroase celule tumorale de
tip Hodgkin/Reed-Sternberg dispuse n plaje pe
un fond relativ srac n limfocite mici, cu frecvente
eozinofile, histiocite, plasmocite, i a examenului
imunohistochimic care a evideniat CD30 pozitiv
n celule tumorale; L26/CD20 pozitiv n frecvente
celule tumorale, pozitivare inegal (30%); CD15
negativ n celule tumorale, pozitiv n granulocite;
CD3 negativ n celule tumorale, pozitiv n limfocite
mici, PAX5 pozitiv n celule tumorale izolate; OCT2
pozitiv n celule tumorale izolate; CD79a negativ n
celule tumorale, pozitiv n limfocite mici, reactive,
CD45 pozitiv. Acestea stabilesc diagnosticul de
limfom Hodgkin clasic depleie limfocitar de tip
reticular (sarcom Hodgkin).
Investigaiile paraclinice efectuate au pus n
eviden prezena anemiei uoare (Hg=12,5g/
dL) normocrome, normocitare, hiporegenerative
(reticulocite=0,6%), a leucocitozei (10100 celule/
mmc) cu neutrofilie (77%), a monocitozei relative
(13,2%, 1300 monocite/mmc), a trombocitozei
uoare (528000/mmc), a sindromului biologic
inflamator, valoarea sideremiei n limite normale
i a feritinei uor crescute (504 ng/mL), valorile
lactatdehidrogenazei i a acidului uric n limite
normale, funcia hepatic i renal n limite normale,
testele serologice pentru infecia cu virusul hepatitic
B, C i HIV negative.
Biopsia osteo-medular efectuat nu a evideniat
prezena infiltratelor maligne.
Astfel s-a stabilit diagnosticul de limfom Hodgkin
clasic subtip histologic depleie limfocitar (sarcom
Hodgkin), iar conform clasificrii ANN ARBOR
a fost stadializat n stadiul IIBb (determinare
supradiafragmatic). Conform scorului prognostic
EORTC/GELA, pacientul este ncadrat n grupa de
risc intermediar.
Pacientul a urmat 4 cicluri polichimioterapice tip
ABVD cu obinerea remisiunii pariale (scderea
numeric a adenopatiilor mediastinale) obiectivat
imagistic (CT). S-a continuat tratamentul cu
efectuarea a nc dou cicluri ABVD, iar reevaluarea
imagistic (PET-CT) a evideniat boal progresiv
(meninerea adenopatiilor supradiafragmatice cu
activitate metabolic crescut la nivel ganglionar
supradiafragmatic). Se decide continuarea
tratamentului prin chimioterapie de salvare,
efectundu-se dou cicluri DHAP, ns cu persistena
adenopatiilor supradiafragmatice. n acel moment
s-a considerat boal chimiorefractar i s-a decis
efectuarea
radioterapiei
supradiafragmatice
conformaionale (doz total de 36 Gy) pe volumul
cervico-mediastinal. De asemenea s-au efectuat
probe de compatibilitate n sistem HLA cu fratele
22
pacientului, care au identificat semiidentitate HLA

clasa I nivel generic ntre pacient i fratele su.
Reevaluarea imagistic (PET-CT) post-radioterapie
a stabilit diagnosticul de boal progresiv postchimioterapie i radioterapie (prin evidenierea
adenopatiilor
suprasi
subdiafragmatice,
determinrilor osoase, splenic, pulmonare).
Pacientul a fost restadializat n stadiul IV B ANN
ARBOR.
Post-radioterapie reapar simptomele generale
de boal (sindromul febril, transpiraii nocturne),
pacientul fiind investigat ntr-un serviciu de
boli infecioase, excluzndu-se febra de cauz
infecioas: hemoculturi i urocultura negative,
iar proba terapeutic cu Naproxen a fost pozitiv.
Avnd n vedere lipsa rspunsului att la prima
linie de tratament, ct i la chimioterapia de
salvare, s-a decis reevaluarea blocului ganglionar
iniial concomitent cu nceperea demersurilor
n vederea efecturii autogrefei de celule stem
hematopoietice. Astfel s-au efectuat dou cicluri de
chimioterapie de salvare tip IGEV, urmate de aplazii
severe post-chimioterapie, dar i de reducerea
sindromului tumoral, ulterior efectundu-se cura
de mobilizare a celulelor stem hematopoietice.
Reevaluarea blocului ganglionar iniial la
Laboratorul de Histopatologie Szeged: examenul
imunohistochimic a pus n eviden CD30+,
CD40+, NFATc+, CD20+ (30%), CD15-, EBVLMP1, concluzionnd c aspectul histopatolgic i
imunohistochimic pledeaz pentru diagnosticul
de limfom cu celul B neclasificabil, cu trsturi
intermediare ntre limfom cu celul mare B difuz i
limfom Hodgkin clasic.
Astfel, s-a reconsiderat conduita terapeutic i s-a
continuat tratamentul prin imunochimioterapie tip
R-CHOP (un ciclu), ns cu persistena sindromului
tumoral i a strii generale alterate (datorate n
mare msur epanamentului pleural bilateral
n cantitate medie-mare ce a necesitat puncii
evacuatorii repetate cu refacerea rapid a lichidului).
Ca urmare a lipsei de rspuns la tratament s-a
modificat schema chimioterapic, continundu-se
cu cicluri R-EPOCH. Reevaluarea dup 4 astfel de
cicluri a evideniat remisiune parial (prin scderea
numeric i n dimensiuni a adenopatiilor supra- i
subdiafragmatice), iar ulterior s-a efectuat autogrefa
de celule stem hematopoietice cu obinerea
remisiunii complete obiectivate imagistic (examen
PET-CT: fr zone cu activitate metabolic crescut
sugestive pentru modificri cu substrat oncologic).
Reevaluarea prin PET-CT efectuat la un an de la
transplantul de celule stem hematopoietice a
evideniat meninerea remisiunii complete. n
prezent, pacientul se afl n remisiune complet.
Discuii i particulariti ale cazului

n aceast lucrare este prezentat cazul unui
pacient cu limfom cu celul B neclasificabil, cu
trsturi intermediare ntre limfomul difuz cu celul
mare B i limfomul Hodkin clasic la care stabilirea
diagnosticului a reprezentat o provocare. Debutul
afeciunii a fost reprezentat de prezena simptomelor
Drgan C, aguna C, Manolache R, Ciortan S, Lupu AR
B, a adenopatiilor superficiale i profunde

supradiafragmatice; examenul histopatologic a
pus n eviden prezena celulelor Reed-Sternberg
dispuse n plaje pe un fond relativ srac n limfocite
mici, iar examenul imunohistochimic a evideniat
CD30 pozitiv, CD79a negativ, caracteristic pentru
limfomul Hodgkin, ns CD15 negativ discordant
cu diagnosticul de limfom Hodgkin, PAX5 pozitiv
i Oct2 pozitiv; de remarcat expresia CD20 n
frecvente celule tumorale cu pozitivare inegal.
Astfel, diagnosticul diferenial a fost efectuat
cu: limfomul Hodgkin nodular cu predominan
limfocitar susinut prin faptul c acesta apare mai
frecvent la brbai tineri (vrsta medie de 35 ani),
CD15 negativ, CD20 pozitiv i infirmat prin faptul
c n mod tipic este localizat la debut, nu prezint
simptome generale de boal, i CD30 pozitiv,
CD79a negativ(4); cu limfomul nonHodgkin difuz cu
celula mare B mediastinal care apare mai frecvent
la femei tinere (sub 30 ani) printr-o mas tumoral
mediastinal i prezena CD20(5); cu limfomul
nonHodgkin anaplazic cu celula mare T care
intereseaz n mod tipic adenopatii dintr-o singur
regiune i care prezint markeri de suprafa
pan-T, CD30 pozitiv, CD20 negativ, CD15 negativ,
ALK pozitiv(6); cu limfomul T periferic nespecific
de tip limfoepitelioid (Lennert) care a fost descris
iniial ca o variant a limfomului Hodgkin, la care
examenul histologic pune n eviden prezena
celulelor epitelioide, celulelor T i inconstant a
celulelor Reed-Sternberg i care ulterior a fost
demonstrat a avea originea n celulele T (CD4
pozitive)(7); cu celelalte subtipuri ale limfomului
Hodgkin clasic. Diagnosticul pozitiv a fost stabilit:
limfom Hodgkin clasic subtip histologic depleie
limfocitar (sarcom Hodgkin) i a fost stadializat
n stadiul IIBb. De menionat faptul c tratamentul
cu anticorp monoclonal anti-CD20 nu a putut fi
adugat schemei iniiale de tratament.
De remarcat este absena rspunsului la tratament
att la prima linie (cicluri ABVD), ct i la radioterapie
i la chimioterapia de salvare (DHAP, IGEV), fapt
care a condus la decizia reevalurii blocului
ganglionar care a stabilit diagnosticul de limfom

cu celul B neclasificabil, cu trsturi intermediare
ntre limfomul cu celul mare B difuz i limfomul
Hodgkin clasic, cu pozitivitate CD20 n aproximativ
30% din celule, examenul imunohistochimic oferind
cele mai relevante argumente n favoarea acestuia:
CD20 pozitiv (30%), CD30 pozitiv, CD15 negativ,
CD40 pozitiv, NFATc pozitiv (factorul nuclear al
celulelor T activate citoplasmatic), ABV-LMP1. Astfel,
este subliniat importana imunohistochimiei n
stabilirea diagnosticului corect, aceasta influennd
major conduita terapeutic ulterioar.
O alt particularitate a cazului este reprezentat
de rspunsul foarte bun la chimioterapia specific
limfomului nonHodgkin (EPOCH) n asociere cu
anticorpul monoclonal anti-CD20, cu obinerea
remisiunii complete (consolidate prin autogrefa
de celule stem hematopoietice), n special datorit
faptului c pacientul era considerat avnd boal
progresiv sub chimio- i radioterapie, cu stare
general profund alterat. Avnd n vedere c nu s-a
putut obine remisiunea complet prin chimioterapia
de salvare (DHAP, IGEV), care are indicaie de utilizare
att n cazul limfomului Hodkin, ct i a limfomului
nonHodgkin, ne duce la supoziia c nsi asocierea
anticorpului monoclonal anti-CD20 a avut un rol vital
n obinerea remisiunii complete.
Rmne de discutat dac asocierea anticorpului
monoclonal anti-CD20 (care nu a putut fi accesat la
acel moment) la chimioterapia iniial, tip ABVD, ar
fi condus la o evoluie diferit a pacientului.
Limfomul cu celul B neclasificabil, cu trsturi
intermediare ntre limfomul cu celul mare B difuz i
limfomul Hodgkin clasic, se asociaz n mod tipic cu
prezena unei formaiuni mediastinale, iar afectarea
extranodal este rar (1). De remarcat este faptul
c n cursul tratamentului iniial sunt descoperite
determinri extranodale importante (pulmonare,
osoase, splenice), necaracteristice pentru acest tip
de limfom.
unul.
Bibliografie
1. Iwaki N., Sato Y., Kurokawa T., Maeda Y., et al, B-cell lymphoma, unclassifiable, with features
intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma without
mediastinal disease: mimicking nodular sclerosis classical Hodgkin lymphoma.,Med Mol
Morphol. 2013 Mar 20.
2. Sabattini E., Bacci F., Sagramoso C., et al., WHO classification of tumours of haematopoietic and
lymphoid tissues in 2008: an overview., Pathologica. 2010;102:8387.
3. Carbone A., Gloghini A., Aiello A., et al., B-cell lymphomas with features intermediate
between distinct pathologic entities. From pathogenesis to pathology., Hum Pathol
2010;41:621631.
4. Fanale M.A., Younes A., Nodular lymphocyte predominant Hodgkin's lymphoma,Cancer Treat
Res. 2008;142:367-81.
5. Hutchinson C.B., Wang E., Primary mediastinal (thymic) large B-cell lymphoma: a short
review with brief discussion of mediastinal gray zone lymphoma., Arch Pathol Lab Med. 2011
Mar;135(3):394-8. doi: 10.1043/2009-0463-RSR.1.
6. Medeiros L.J., Elenitoba-Johnson K.S., Anaplastic Large Cell Lymphoma, Am J Clin Pathol. 2007
May;127(5):707-22.
7. Yamashita Y., Nakamura S., Kagami Y., et al., Lennert's lymphoma: a variant of cytotoxic T-cell
lymphoma?, Am J Surg Pathol. 2000 Dec;24(12):1627-33.
23
Reviews
Stereotactic body radiotherapy for early stages non-small cell lung cancer
Stereotactic body radiotherapy

for early stages non-small cell
lung cancer
Radioterapia stereotactic
pentru cancerul pulmonar
non-microcelular precoce
Ciprian Enachescu*
*Centre Hospitalier Lyon Sud, Pierre Benite, France
165, Chemin du Grand Revoyet
69495 Pierre-Benite cedex
Coresponding author: Ciprian Enachescu
Email: ciprian.enachescu@chu-lyon.fr
Abstract:
Keywords:
lung cancer,
non-small-cell, earlylocalised, stereotactic
radiotherapy
Cite this article:

Enachescu C, Stereotactic
body radiotherapy for early
stages non-small cell lung
cancer. Rom J Oncol
Hematol. 2013; 1(1):24-34
24
For patients with stage III Non Small Cells Lung Cancer (NSCLC)
lobectomy remains the standard treatment with 5-year survival rates
of about 6080% for stage I and 4050% for stage II. For medically
inoperable patients (or who decline surgery), with good general
medical condition that justifies aggressive local treatment and early
localised T1-T2 NoMo NSCLC, the Stereotactic Body Radiation Therapy
(SBRT) represents a validated therapeutic option. The SBRT deliver
a very high dose per fraction (5 Gy to 34 Gy per fraction) in 1 to 5
total fractions. The minimum Biologically Effective Dose, calculated
according to the Linear Quadratic (LQ) model with an / value of 10,
needed to achieve a local control rate of more than 90%, is 100 Gy. To
provide highly accurate, precise, and focused radiation delivery, SBRT
requires correct patient immobilization, accurate tumour identification
and control of the tumour motion. The radiotherapy regimen choice
depends on the tumor localization, central versus peripheral, up to 1
cm or more than 1 cm from the chest wall for peripheral tumours and
respectively tumor size. The main critical organs at risk that must be
delineated are the spinal cord, oesophagus, heart, chest wall and, for
apical tumors, the brachial plexus. Regardless of the technique used,
when the biological effective dose (BED) is >100 Gy, the local control
rate is 88-96%. The estimated 3-year primary tumour control rate is
more than 90% and the survival probability is 70% at 2 years and more
than 55% at 3-years and the most important Grade 3 toxicities are
pulmonary (dyspnoea and pneumonitis) and chest pain for peripheral
tumours. In conclusion, SBRT is superior to conventionally fractionated
radiotherapy and today is the standard of care for medically inoperable
and early-localised lung cancer patients.
Enchescu C
Rezumat:
Cuvinte-cheie:
cancer pulmonar,
non-microcelular,
localizat i precoce,
radioterapie
stereotactic
Pentru pacienii cu stadiul I i II de cancer pulmonar nonmicrocelular (NSCLC), lobectomia rmne tratamentul de
referin, rata de supravieuire la 5 ani fiind de 60-80% pentru
stadiul I i de 40-50% pentru stadiul II. Pentru pacienii
inoperabili (sau care refuz chirurgia), cu stare generala bun
care s justifice un tratament local agresiv i cu cancer localizat,
clasificat T1-2NoMo, radioterapia stereotactic (SBRT) reprezint
o opiune terapeutic validat. Radioterapia stereotactic
elibereaz o doz foarte mare pe edin (de ordinul 5 Gy pn
la 34 Gy pe edin) pentru un total de 1-5 edine de iradiere.
Doza eficace biologic este calculat cu modelul matematic Linear
Ptratic (LQ). Pentru a realiza o iradiere precis, focalizat i de
mare acuratee, este necesar o corect imobilizare a pacientului
pe masa de tratament, o identificare precis a tumorii i un
control al micrilor tumorale. Regimul de iradiere depinde de
localizarea tumoral, central versus periferic i, respectiv, la mai
mult sau mai puin de 1 cm de peretele toracic n cazul tumorilor
periferice, ct i de dimensiunea tumorii. Organele la risc care
trebuie conturate sunt mduva spinrii, esofagul, cordul, peretele
toracic, iar pentru tumorile apicale i plexul brahial. Independent
de tehnica de iradiere, atunci cnd doza biologic efectiv este
cel puin 100 Gy se obine un control local de 88-96%. Rata de
control tumoral la 3 ani este de peste 90%, iar probabilitatea de
supravieuire este de 70% la 2 ani i aproximativ 55% la 3 ani.
Cele mai importante toxiciti de grad 3 sunt cea pulmonar
(dispnee i pneumonit) i durerea toracic, n cazul tumorilor
periferice. n concluzie, radioterapia stereotactic este superioar
iradierii convenionale i reprezint un standard terapeutic pentru
pacienii inoperabili cu cancer pulmonar localizat i precoce.
Regarding the outcome and the adapted

therapeutic approach, Non Small Cells Lung
Cancer (NSCLC) patients can be classified in
early-localised, locally-advanced and metastatic
stages. Early-localised stages, approximately
25% of patients, are represented by Stage I
and II including T1-T2 and No-N1 tumors. The
tumors less than 3 cm (T1a 2 cm and T1b 2 -3
cm) and without invasion of the visceral pleura
or more proximal than the lobar bronchus (not in
the main bronchus) are classified as T1 tumors.
The T2 tumors are tumors > 3 cm but 7 cm (T2a
3-5 cm and T2b 5-7 cm) or tumors with any of
the following features: involve the main bronchus
(but at 2 cm distal to the carina); invades the
visceral pleura; is associated with atelectasis or
obstructive pneumonitis that extends to the hilar
region but does not involve the entire lung. The No
stage means no regional lymph nodes metastasis
and the N1 stage means metastasis in ipsilateral
peribronchial and/or ipsilateral hilar lymph nodes
and intrapulmonary nodes, including involvement
by direct extension. The stage I-A is defined as T1a
and T1b No tumors , the stage I-B as T2a No , the
stage II-A includes T2bNo , T1-T2a N1 tumors, and
the stage II-B includes T2bN1 and T3No tumors (1).
Early-localised stages NSCLC

Surgery for Early stage I and II
Non-Small Cell Lung Cancer
For patients with stage III NSCLC surgery
represents the treatment of choice with 5-year
survival rates of about 60-80% for stage I and 40
50% for stage II (2). Regarding surgery 2 problems
exist:
1. The extent of pulmonary resection: pneu
monectomy versus lobectomy versus limited
resection (segment or wedge);
2. Mediastinal dissection versus mediastinal
sampling.
The extent of pulmonary resection

Pneumonectomy versus Lobectomy
Shi et al. realized a meta-analysis (2012) on
3878 patients enrolled in 19 studies, out of
which 1316 patients (33.9%) underwent sleeve
lobectomy and 2562 patients (66.1%) underwent
pneumonectomy. The final results shows that
Sleeve lobectomy is significantly better than
pneumonectomy in terms of postoperative
mortality (2.91% versus 5.86%) and survival
25
Reviews
(54% versus 33% at 5 years) and equivalent in

terms of locoregional recurrences (14.44% for
lobectomy versus 28.06% for pneumonectomy,
nonsignificant). The study conclusion is that
sleeve lobectomy could offer better long-term
survival than pneumonectomy with less loss of
pulmonary function and better quality of life (3).
Lobectomy versus Limited resection

The only clinical randomised trial that compared
lobectomy with limited resection demonstrated no
significant differences for perioperative morbidity,
mortality, or late pulmonary function but an
observed 75% increase in recurrence rates, a 30%
increase in overall death rate and a 50% increase
in cancer-specific mortality rate in comparison to
patients undergoing lobectomy (4). A Japanese
phase III study (conducted by the Japan Clinical
Oncology Group and the West Japan Oncology
Group)
comparing
segmentectomy
with
lobectomy in patients with small-sized (diameter
2 cm) peripheral non-small cell lung cancer was
started in August 2009 and is planned to include
a total of 1100 patients from 71 institutions within
3 years. The primary endpoint is overall survival
and the principal secondary endpoints are postoperative respiratory function and post-operative
morbidity, relapse-free survival and proportion of
local recurrence (5).
Mediastinal sampling versus

Mediastinal dissection
Complete mediastinal lymph node dissection for
non-small cell lung cancer remains a controversial
procedure, providing optimal staging for
resectable NSCLC, but without a clear therapeutic
role. The randomised study ACOSOGZ 0030 of
The American College of Surgeons Oncology
Group (ACOSOG) randomised 1111 patient with
early T1-2 NSCLC to evaluate whether mediastinal
lymph node dissection (MLND) improves overall
survival for pNo patients. In the mediastinal
dissection group 20 patients (3.8%) were found
to have occult N2 disease. The median survival
was 8.1 years (mediastinal sampling) versus 8.5
years (mediastinal dissection) (p=0.531) and
the median time to recurrence was 5.7 years in
the mediastinal sampling group (24 local; 42
regional; and 110 distant) versus 6.1 years in
the mediastinal dissection group (30 local; 31
regional; and 114 distant) (p=0.655).
In conclusion, mediastinal dissection does
not improve survival and does not decrease
the incidence of local or distant recurrences in
patients with early stage NSCLC when a thorough
preresection sampling of the mediastinal lymph
nodes is negative (6).
Recommendations
For early NSCLC, lobectomy remains the
standard treatment, more limited resections
(segmentectomy and wedge resection) being
associated with increased local recurrence. In
26
terms of Lymph Nodes management, randomised

trials have not solved the controversial issue of
sampling versus systematic nodal dissection.
These two options do not differ in terms of
complication rates, but data are conflicting with
respect to survival outcome. The International
Association for the Study of Lung Cancer (IASLC)
recommends a minimum six nodes/stations
dissection , three of which should be mediastinal
including the sub-carinal station, with negativity
of the highest resected node (7).
The role of Radiotherapy in the treatment

of Early stages I and II Non-Small Cell Lung
Cancer
External Beam Radiation Therapy (EBRT) versus
Observation
In absence of any curative treatment, long-term
survival of Stage I NSCLC is uncommon and the
vast majority of patients die of lung cancer. For
non-treated Stage I NSCLC patients, the median
survival is 9-14 months, the 5-year overall survival
is 6-11% and the lung cancer-specific survival
rates is 16-22% (8). Using population-based cancer
data From The Surveillance, Epidemiology, and
End Results (SEER) Registry 2004, Wisnivesky
compare the survival of 4,357 patients diagnosed
between 1988-2004 with stage I (88%) and II (12%)
lung cancer and treated with radiotherapy alone
or observed (no treatment). The radiotherapy
increased the median survival time by 5 to 7
months, from 14 to 21 months for stage I patients
and from 9 to 14 months for stage II patients. The
mortality of other causes was similar among the
radiotherapy group and the observation group,
27% vs. 23%, for stage I patients and 19% vs. 19%
for stage II patients (9).
External Beam Radiation Therapy

versus Surgery
Rowell identified 26 non-randomised and
retrospective studies (no randomised trials)
comparing surgery versus radiotherapy for the
patients diagnosed with early-localised (T1-2/
N0-1 and T3No tumors) NSCLC considered not
sufficiently fit for or declining surgery. For the
irradiated patients, the overall survival varied
between 33-72% at 2 years and 0-42% at 5 years
and the cancer-specific survival between 54-93%
at two year and 13-39% at five years. Complete
response rates were 33-61%, local failure rates
between 6-70% and the distant metastases rate
is about 25%.
Better outcome (local control and survival)
is seen in those with tumours less than 3 cm in
diameter, those achieving a complete response,
and in those treated by hyperfractionated and
accelerated radiotherapy. Worse outcomes are
seen in those with performance status WHO/
ECOG 2 or Karnofsky 80% and those with weight
loss 5% body weight. There is no evidence that
age or histological subtype significantly affects
Enchescu C
Figure 1
outcome. There is no evidence to support the

use of mediastinal irradiation for stage I tumours,
but there is some evidence to support the use of
mediastinal irradiation in stage II tumours (10).
External Beam Radiation Therapy.

Regimes comparation
The randomised CHART Trial compare the
conventionally fractionated EBRT (60 Gy in
30 fractions over six weeks) with continuous
hyperfractionated and accelerated radiotherapy
(54 Gy in 30 fractions over 12 days, 1.5 Gy/fraction,
3 time per day). The CHART regims produce an
increase in 2-year survival from 24% to 37% and
in 4-years survival from 12% to 18%. The majority
of these patients ( 77%) had T2N0 tumours, 20%
were T1N0 and only 4% were stage IIA (11).
Stereotactic Body Radiation Therapy (SBRT)

in NSCLC treatment
SBRT definition
Stereotactic Body Radiation Therapy (SBRT) is a
type of external-beam radiation therapy in which
few and very high-doses fraction of radiation are

delivered to small, well-defined tumors. The dose
per fraction is more than 5 Gy (5 Gy to 34 Gy per
fraction) and the total treatment is represented
by 1 to 5 fractions. The dose is heterogeneously
delivered, with an inhomogeneous dose inside
the target volume and a rapid dose decline (dose
fall off) outside the tumor volume (12).
Therefore, two issues need to be discussed:
A. Very high-doses fraction.
B. Small and well-defined volume. Target
volume definition and high practical precision of
radiation delivery.
A. High dose fraction. Radiobiological

aspects of SBRT
1. Cancer cells direct effects. The effectiveness
of conventionally fractionated radiotherapy is
directly influenced by the 4 radiobiological effects
(4R): Reoxygenation of hypoxic tumor cells, Repair
of sub-lethal radiation damage, Redistribution of
cells in cell cycle phases and Repopulation of
cells.
27
Reviews
a) Reoxygenation. Oxygen concentration at the

time of irradiation is an important radio-sensitivity
factor; the presence of oxygen (aerated cells)
increases radiation effectiveness and, on the
contrary, lack of oxygen (hypoxic cells) results in
more radioresistant cells. To obtain the same final
effect (cell killing) in the case of hypoxic cells the
radiation dose should be increased by 2-3 times
(Oxygen Enhancement Radio). When tumors are
treated with conventional fractionated radiation,
the proportion of hypoxic cells are reoxygenated
during the interval of fractions resulting restoration
of their radiosensitivity. For a single fraction or
extremely high-dose but few fractions, SBRT does
not allow adequate reoxygenation because of
vascular damage. The intratumor environment
will become hypoxic leading to secondary cell
death (12).
b) Repair of sub-lethal radiation damage.
Ionizing radiation is considered to produce two
different types of lesion: non-repairable (i.e. lethal)
lesions and repairable (i.e. potentially lethal)
lesions , the final tissue survival rate depending
on the repair of some of these last lesions.
The time needed for reparation is defined by T
(the half time of repair) , the time when half the
repair has taken place . The T is usually about
-1 hours for cells in culture but can be longer
for tissues and the full repair may take 6-8 hours
or longer in tissues (e.g. in CNS it may be more
than 24 hrs).
The sublethal lesion repair depends on the
radiation dose, the interval between doses and
the cellular repair capacity. When tumors are
treated with SBRT, considerable repair of sublethal radiation damage may take place during
the prolonged radiation exposure. The estimated
loss of radiation effect due to repair of radiation
damage is greater than 10% when the irradiation
of tumors lasts longer than 30 min (13 , 14).
c) Reassortment or Redistribution
Do to the selective killing and to the dosedependent arrest of cells in the cell cycle phases
(activation of cell cycle checkpoints to prevent the
progression into next cell cycle phase before the
damage is repaired) ionising radiation delays cell
cycle progression. Irradiation with moderate doses
causes transient cell cycle arrest predominantly
in G2 phase and may induce mitotic cell death
(if cells enter mitosis with incompletely repaired
DNA) but the cell cycle arrest eventually
disappears and the distribution of cells though
the cell cycle phases is restored to preirradiation
state. After an exposure to high-doses of radiation
cells tend to be arrested indefinitely and die in
the cell cycle phases in which they are irradiated
(in the G1 phase, S-phase or G2 phase wherever
they were at the time of irradiation) (14).
d) Repopulation
The rapid repopulation is due to the proliferation
of surviving clonogenic tumour cells during
fractionated radiotherapy, and is an important
factor in radiotherapy resistance. Since SBRT
28
treatment lasts for a short period, at most 2 weeks

(repopulation is evoked usually 3-4 weeks after
initiation of radiotherapy), repopulation of tumor
cells will not be substantial during the treatment
course(13,14).
2. Vascular effects
There is an observation that radiation may
destroy the tumor vessels and therefore the tumor
response to radiation may be regulated by the
degree of apoptosis in tumor endothelial cells,
so the tumor vasculature may be an important
therapeutic target for radiation(15). Since the blood
vessels are serial tissues, injury even at a single
focal point of vessels may cause obstruction,
thereby causing tumor cell death along the
damaged vessels. When human tumors are treated
with conventional fractionated radiotherapy
(usually 2.0 Gy per fraction), the morphological
and functional status of the vasculature is
preserved, if not improved, during the early part
of a treatment course (the blood perfusion tends
to increase) and then decreases toward the end
of treatment (the blood perfusion returns to or
declines lower than the pre-irradiation level).
Irradiation with 5-10 Gy in a single dose causes
relatively mild vascular damages, but increasing
the radiation dose to higher than 10 Gy/fraction
induces severe vascular damage resulting in
reduced blood perfusion.
The results for experimental tumors strongly
indicate that SBRT with doses higher than about
10 Gy/fraction is likely to induce considerable
vascular damages and thereby damages the
intratumor microenvironment, leading to indirect
tumor cell death(16).
Radiobiological models
The Linear Quadratic (LQ) model is most
frequently model used for conventionally
fractionated radiotherapy to evaluate the
biological effect of irradiation and to calculate
equivalent dose for different fractionation
regimes. The LQ model assumes there are 2
components to killing a cell by radiation:
a) the linear component (a parameter): a single
hit produce cell death and therefore the proportion
of cells killed is proportional to the dose;
b) the quadratic component (b parameter): two
or more hits are necessary to produce cell death
and therefore cell kill is proportional to the square
of the dose (17).
The mathematical formula to the equivalence
of 2 different regiment of radiotherapy is:

D and D =total dose
d and d= dose per fraction
a/b ratio=tissue parameter (about 10 for tumors
and acute toxicity and 1-3 for late normal tissue
toxicity)
Enchescu C
Figure 2
The Biologically effective dose (BED) is a

measure of the true biological dose delivered by
a particular combination of dose per fraction and
total dose to a particular tissue characterized by a
specific / ratio.
It must be understood that a physical radiation

dose has different biological effects in terms of
tumor control and normal tissue complications
depending on fractionation schedule, and
therefore the Stereotactic Radiotherapy, delivering
a high dose in a short period of time, is more
effective in tumor control and can be more toxic
than conventionally fractionated radiotherapy (18).
B. Treatment Accuracy
The Stereotactic Body Radiation Therapy (SBRT)
must deliver a high dose of radiation to a welldefined targeted tumor and at the same time
to minimize the amount of radiation received
by surrounding normal tissues, so the accuracy
and precision of SBRT treatment planning and
delivery are critical. The adjective stereotactic

describes a procedure during which a target
lesion is localized relative to a known threedimensional reference system that allows for a
high degree of anatomic accuracy and precision.
To provide highly accurate, precise, and focused
radiation delivery SBRT requires correct patient
immobilization, accurate tumor identification
and control of the tumor motion. The treatment
position should be comfortable enough for the
patient to hold still for the entire duration of the
SBRT procedure. Immobilization may involve use
of a body aquaplast mold, a thermoplastic mask,
a vacuum mold, a vacuum pillow, immobilization
cushions, etc. The Computer Tomography (CT)
simulation must have been performed with the
patient in the treatment position in order to define
and delineate the tumoral target volume and the
Organs at Risk. Along with CT simulation images,
the treatment-planning system may also import
and fuse diagnostic magnetic resonance imaging
(MRI), positron emission tomography (PET),
combined PET/CT with the CT simulation images
to add functional data to optimize the treatment
plan. The irradiation planning should provide
an adequate dose coverage for the Planning
29
Reviews
Target Volume (PTV) and to minimize the volume

of surrounding normal tissues exposed to high
dose levels. Quantification of the dose/volume
statistics for the organs at risk is needed so that
volume-based tolerances are not exceeded. It
should be understood that reduction of high dose
levels within normal tissue volume may require
additional exposure of normal tissues to low dose
levels (i.e., increased integral dose). Treatment of
extracranial sites should take account of internal
organ motion, which is possible by using the
breath-hold CT or four dimensional-respirationcorrelated techniques (4D CT) (19, 20).
SBRT NSCLC treatment

Indication and Patient selection
The patient must be considered medically
inoperable or decline surgery after consulting
with a thoracic surgeon. Standard justification for
deeming a patient medically inoperable based
on pulmonary function for surgical resection of
NSCLC may include any of the following:
- Baseline FEV1 <40% and/or Postoperative
FEV1 <30% predicted;
- Severely reduced diffusion capacity with
baseline hypoxemia and/or hypercapnia;
- Severe pulmonary hypertension;
- Diabetes mellitus with severe end organ damage;
- Severe cerebral, cardiac, or peripheral vascular
disease (21)
From the point of view of the radiation treatment
(American Society for Radiation Oncology-ASTRO
recommendations), SBRT is indicated for primary
or metastatic tumors only if the patients general
medical condition (notably, the performance status)
justifies aggressive (local) treatment and if the tumor
burden can be completely targeted with acceptable
risk to critical normal structures (22). For NSCLC, only
the patients with MoNo stages and with tumors up
to 5 cm must be eligible for SBRT. Nodal stage is
considered No if the hilar or mediastinal lymph
nodes are 1 cm and without any abnormal uptake
on Positron Emission Tomography (PET). For the
hilar or mediastinal lymph nodes >1 cm on CT or
with abnormal PET uptake, the No stage should
be confirmed by a directed tissue biopsy (23, 24). The
European Organisation for Research and Treatment
of Cancer (EORTC) consider SBRT suitable for
patients with peripheral stage I NSCLC that
measures 6 cm or less, but accepts central tumors
as well, which must be irradiated with lower dose
per fraction (e.g. 60 Gy in 8 fractions). SBRT can be
proposed even for patients age 75 years or older
who have a median Charlson comorbidity score
of 4 or for patients with severe chronic obstructive
pulmonary disease, without significant toxicity
risk. (25)
Treatment planning
Patient Positioning and Immobilization
The patients should be positioned in a stable
and reproducible position, with both arms above
the head, permitting a greater choice of beam
30
access (360 degree gantry rotation), which in turn

improves target coverage and sparing of normal
tissues.
Reproducible patient setup can be achieved by
using a stable arm support in combination with
knee supports to improve patient comfort.
CT Scanning
The planning CT scan is extended from the
level of the cricoid cartilage to the second
lumbar vertebra in order to include the entire
lung volume, and the slice thickness should be 2
to 3 mm to permit a better tumour and Organs at
Risk (OAR) delineation and the generation of high
resolution digitally reconstructed radiographs
(DRR) needed for setup verification. To better
evaluate and control the tumor motion during
radiotherapy a 4D-CT (also known as respirationcorrelated CT) or a breath holding CT have to be
performed (26).
Volumes definition/delineation
A. Tumoral target volumes
1. The Gross Target Volume (GTV) is
represented by the lung tumor and is delineated
on a pulmonary window (width=1,600 and
level=600) (27)
2. The Clinical Target Volume (CTV) is an
anatomical concept and represents the tissue
volume that contains a GTV and subclinical
microscopic malignant disease. For SBRT, the CTV
is assumed to be identical to the GTV (i.e. with no
margin for microscopic disease added)
3. The Internal Target Volume (ITV) represents
the volume encompassing all the variations in
size, shape and position of the CTV during the
treatment. The ITV definition depends on the
type of scan and treatment technique:
a) 3D-CT scan (free breathing and without tumor
motion recording). The internal motion should be
considered at least 1 cm in the inferior-superior
direction and 0.5 cm in the axial plane;
b) 4D-CT-Gating scan (free breathing but with
tumor motion recording). The ITV result from the
sum of all GTV that must be delineated on all
breathing phases (figure 1);
c) Breath holding technique. In this case, the
ITV=CTV=GTV since there is no respiratory
movement.
4. The Planning Target Volume (PTV) is a
geometrical concept that must consider the net
effect of all the possible geometrical variations
and inaccuracies in order to ensure that the
prescribed dose is actually absorbed in the CTV.
Usually the PTV is obtained by an additional
margin of 5-10 mm in all directions around the
CTV (28).
A clear dose-response relationship for local
tumor control exist and therefore the minimum
Biologically effective dose needed to achieve a
local control rate of more than 90% is considered
100 Gy. The BED is calculated according to
the Linear Quadratic (LQ) model with an /
value of 10, and corresponds in conventional
Enchescu C
Figure 3
radiotherapy to a dose of 83.3 Gy in 42 fractions

(8 weeks). In comparison, 60 Gy in 30 fractions
(6 weeks) and 70 Gy in 35 fractions (7 weeks
of treatment) represent a BED of 72 Gy and
respectively 84 Gy (29).
The radiotherapy regimen choice depend on
the tumor localization and size.
a) Central versus peripheral tumors. According
to the Radiation Therapy Oncology Group (RTOG)
the peripheral lesions are located outside a 2 cm
radius of the main airways and proximal bronchial
tree, including the most inferior 2 cm of the distal
trachea and the proximal airways on both sides up
to the segmental bifurcation (figure 2). Peripheral
lung tumors are surrounded only by parallel
tissue (normal lung), and no maximum pointdose limit has been identified for their treatment.
Centrally located tumors are in proximity to both
parallel tissues (normal lung) and serial tissues
(trachea, bronchial tree, or oesophagus), as well
as imperfectly categorized tissues (heart and
great vessels) and therefore, limited dose/fraction
regimen should be used (30).
b) for peripheral tumors: position towards the
chest wall (CW) (>1 cm or <1 cm from the chest
wall)
c) tumor size: up to 2 cm, 2 to 5 cm.
B. Critical Organs At Risk (OAR)
On the premise that SBRT treats only the
small targets, in contrast to the conventional
radiotherapy, most of the SBRT limits are
defined for the maximum point dose or a small
percentage of the OAR volume. I present the
RTOG recommendations
for critical organs
delineation:
Spinal Cord. The spinal cord will be contoured
based on the bony limits of the spinal canal.
The spinal cord should be contoured starting

at least 10 cm above the superior extent of
the PTV and continuing on every CT slice to at
least 10 cm below the inferior extent of the PTV.
To calculate the BED and the 2-Gy equivalent
dose an / value 2 for spinal cord late effect
(radiation mylopathy) must be used. The recent
recommendations limit the thecal sac maximum
dose to 12.4 Gy in 1 fraction, 17.0 Gy in 2
fractions, 20.3 Gy in 3 fractions, 23.0 Gy in 4
fractions, and 25.3 Gy in 5 fractions to reduce
the risk of RM to less than 5% (32).
Oesophagus. The oesophagus will be
contoured using mediastinal windowing on CT
to correspond to the mucosal, submucosal and
all muscular layers out to the fatty adventitia.
The oesophagus should be contoured starting
at least 10 cm above the superior extent of the
PTV and continuing on every CT slice to at least
10 cm below the inferior extent of the PTV. The
main toxicities are esophagitis (grade 2) and
oesophageal perforation (grade 4). The single
fraction dose constraint could be estimated at
15-17 Gy to Dmax and 12-14 Gy to 1 cc of the
oesophagus (31). If 4 fractions are used, up to 5 cc
of oesophage must receive 30 Gy (7.5 Gy/fraction
to the oesophageal wall) and circumferential
irradiation should be avoided (33).
Trachea and the Proximal Bronchial Tree. The
trachea and the proximal bronchial tree will
be contoured as two separate structures using
mediastinal windows (width=400 and level=40)
on the CT to correspond to the mucosal,
submucosal and cartilage rings and airway
channels associated with these structures.
The proximal trachea will be contoured as
one structure, at least 10 cm superior to the
extent of the PTV or 5 cm superior to the
carina (whichever is superior) and continued
distally to the superior aspect of the proximal
bronchial tree, and the distal 2 cm of trachea
will be included in the structure identified as
the proximal bronchial tree.
Heart. The heart will be contoured along with
the pericardial sac. The superior aspect (or
base) for purposes of contouring will begin at
the level of the inferior aspect of the aortic arch
(aortopulmonary window) and extend inferiorly to
the apex of the heart. An indicator of myocardial
injury after radiotherapy is the focal increased
uptake of 18F-fluorodeoxyglucose (FDG) on
positron emission tomography (PET) , which is
correlated best with the V20, specifically for those
receiving 20Gy to 5cm3 of the heart (34).
Commonly used SBRT regimens

Peripheral tumors, more than 1 cm from CW and up to 2 cm:
1 fraction
25-34 Gy/fr 25-34 Gy total dose
Peripheral tumors, more than 1 cm from CW and 2 to 5 cm:
3 fractions 15-20 Gy/fr 45-60 Gy total dose
Peripheral tumors, more than 1 cm from CW:
4 fractions 12-12.5 Gy/fr 48-50 Gy total dose
Central tumors
8 fractions 7-7.5 Gy/fr
60-70 Gy total dose (31)
31
Reviews
Table 1
OAR/ N0 fraction
1 fraction
3 fractions
4 fractions
5 fractions
8 fractions
Spinal Cord
Dmax=14 Gy
10 Gy <0.35 cc
Dmax=18 Gy
Dmax =26 Gy
28.8 Gy <0.35 cc
Dmax =30 Gy
22.5 Gy <0.25 cc
Dmax =28 Gy
Oesophagus
Dmax =15.4 Gy
11.9 Gy <5 cc
Dmax =25.2 Gy
17.7 G <5 cc
Dmax=30 Gy
18.8 Gy <5 cc
Dmax =105%
27.5 Gy <5 cc
Dmax= 40 Gy
Tracheea
Dmax =20.2 Gy
Dmax =30 Gy
Dmax =34.8 Gy
15.6 Gy <4 cc
Dmax =105%
18 Gy <5 cc
Dmax= 44 Gy
Heart
Dmax= 22 Gy
16 Gy <15 cc
Dmax =30 Gy
Dmax =34 Gy
28 Gy <15 cc
Dmax =105%
32 Gy <15 cc
Brachial plexus
Dmax= 17.5 Gy
14 Gy <3 cc
Dmax =24 Gy
20.4 Gy <3 cc
Dmax =27,2 Gy
23.6 Gy <3 cc
Dmax= 32 Gy
30 Gy <3 cc
Dmax =36 Gy
Chest wall
Dmax= 30 Gy
22 Gy <1 cc
30 Gy <30 cc
60 Gy <3 cc
Dmax= 27,2 Gy
32 Gy <1 cc
30 Gy <30 cc
60 Gy <3 cc
Organs at risk tolerance dose for different SBRT regimens (39, 40)
Brachial Plexus. The defined ipsilateral bra
chial plexus originates from the spinal nerves
exiting the neuroforamina on the involved
side from around C5 to T2. Only the major
trunks of the brachial plexus will be contoured
using the subclavian and axillary vessels as
a surrogate for identifying the location of the
brachial plexus. This neurovascular complex
will be contoured starting proximally at the
bifurcation of the brachiocephalic trunk into the
jugular/subclavian veins (or carotid/subclavian
arteries) and following along the route of the
subclavian vein to the axillary vein ending after
the neurovascular structures cross the second
rib. Stereotactic body radiotherapy for apical
lesions carries a risk of brachial plexopathy, the
2-year risk of brachial plexopathy being 46%
after a biologically effective dose (BED) >100
Gy versus 8% for BED <100 Gy (p = 0.04) (35).
Chest wall. For SBRT planning, the chest wall is
defined as an ipsilateral hemibody that excludes
the lungs and the mediastinum. In conventional
radiotherapy, the threshold dose of radiationinduced fracture is considered to be 50 to 60 Gy.
In Stereotactic radiotherapy, the better parameter
to predict the risk of chest wall toxicity are V30
Gy and V40 Gy (the volume receiving 30 and
40 Gy) for 3 to 5 fractions irradiation regimens.
No rib fractures occurred with <35 ml of chest
wall receiving >30 Gy and at >35 ml, half of the
patients developed rib fracture(36).
32
Whole Lung. Both the right and the left lungs

should be contoured as one structure using
pulmonary windows, excluding the tumor
(GTV) and trachea/ipsilateral bronchus. For
conventional thoracic radiotherapy the radiationinduced pneumonitis (RP) is besides esophagitis
the major toxicity and The Quantitative Analysis
of Normal Tissue Effects in the Clinic (QUANTEC)
recommended a lung V20 30% to 35% and mean
lung dose (MLD) 20 to 23 Gy to limit the risk of
RP to 20% (37). For SBRT in order to evaluate the
effects of different fractionation schedules, the
dose should be converted to 2Gy equivalent total
dose using the linear quadratic (LQ) model with
an a/b ratio of 3Gy. Development of symptomatic
RP correlated significantly with MLD (cut-off 4 Gy)
and V20 Gy (cut-off 10%) but not with V5 Gy, V10
Gy, or tumor location (38).
In conclusion, the most common SBRT toxicities
are rib fractures and chest wall pain (rarely fracture)
for peripheral tumors and for more central locations,
the necrosis/fistula of the oesophagus, bronchi and
large vessels, as well that of cardiac arrhythmias
(very rare but life-threatening) (table 1).
SBRT planning and dosimetry

Stereotactic radiotherapy is characterized by
an inhomogeneous dose inside PTV and a sharp
dose fall off outside PTV, reason for which the
dose is prescribed to the periphery of the PTV
(60% to 80% isodose), so that 99% of the target
Enchescu C
Figure 4
volume (PTV) receives a minimum of 90% of the

prescription dose (figure 3). Any areas receiving
greater than 105% of the prescription dose,
commonly referred to as high-dose spillage,
must be confined to the PTV (41). In order to
respect the high irradiation accuracy, a daily kV
verification is performed (figure 4).
Studies, results, recommendations

In the RTOG 0236 phase II trial, 59 patients
with peripheral T1 and T2 (<5 cm) tumors are
irradiated by 3 fractions of 18 Gy (total dose 54
Gy), with entire treatment lasting between 1 and
2 weeks.
The complete response is obtained 6.5
months (median) from completion of treatment
for 28 patients (51%) and partial response was
recorded in 21 patients (35.9%). The median
follow-up was 34.4 months. The estimated
3-year primary tumor control rate was 97.6%
with only 1 tumor recurrence. Regional failures
were reported in 2 patients, one occurring at
33.0 months and the other at 36.1 months post
protocol therapy and disseminated recurrence
was reported in 11 patients, meaning that 14
patients had recurrence of cancer. Median
disease-free survival was 34.4 months and the
disease-free survival at 3 years was 48.3%.
Median overall survival for all patients was 48.1
months and the overall survival at 3 years was
55.8% respectively, but only 10 patients (18%)
died of lung cancer, the other 16 died of other
causes (9 of unknown causes, 5 of comorbid
problems and 2 of non-protocol-related medical
interventions)(42).
In the phase II trial of Japan Clinical Oncology
Group (JCOG-0403), from 2004 to 2008, 104 patients
with inoperable and operable stage IA lung cancers
were treated by stereotactic radiotherapy, 48 Gy
at the isocenter in 4 fractions over 4-8 days. The
median follow-up was 46.8 months. The results at
3 years show a 59.9% Overall Survival (OS), a 49.8%
Progression-free Survival (PFS) and a 52.8% LocalProgression-free Survival. Grade 3 adverse events
were dyspnoea (9%), hypoxia (8%), pneumonitis

(7%), chest pain (2%), and cough (1%). Grade 4 AE
were in dyspnoea (1%) and hypoxia (1%). No grade
5 AE were observed (43).
Systematic Reviews
The systematic review published by van
Baardwijk includes 1076 patients with cT1
(66%) and T2 (34%) N0M0 NSCLC, treated by
stereotactic radiotherapy or accelerated highdose conventional radiotherapy with prescribed
total doses from 30 Gy to 72.5Gy in 311 fractions.
For a median biologically equivalent dose in
2Gy (EQD2,) for tumours of 76.917.4Gy (50
126Gy), the local tumour control rates are over
90%, the remaining local failure might be due to
biological (e.g. hypoxia) or technical factors such
as a geographical miss (44).
The systematic review published by Sold F. on
the 2456 SBRT articles published between 2006
and June 2012 selected 45 reports with a total of
3641 patients with stage I NSCLC patients treated
with SBRT with a median follow up of minimum
of 1 year. At 2 years, the local control rate is
91% and the survival probability is 70% which
is comparable to survival of a cohort of clinical
stage I patients treated with surgery (45).
Conclusions
Stereotactic body radiotherapy (SBRT) is a method
for a highly precise application of percutaneous
high dose radiotherapy of extracranial targets in a
limited number of treatment fractions.
For the early-localised but inoperable lung
cancer, SBRT showed high local control rates with
acceptable toxicities. Regardless of the technique
used, when the biological effective dose (BED) is
>100 Gy, the local control rate is 88-96%. SBRT
is today considered superior to conventionally
fractionated radiotherapy and is the standard of
care for medically inoperable patients.
unul.
33
Reviews
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Grigorescu A
Cancerul testicular:
diagnostic i tratament
Testicular Cancer:
diagnosis and treatment
Alexandru Grigorescu*
*Medic primar oncologie medical, cercettor tiinific gradul I - Institutul Oncologic Bucureti
Coresponding author: Alexandru Grigorescu
Email: alexgrigorescu2004@yahoo.com
Abstract:
Keywords:
testicular cancer,
prognostic,
chemotherapy
Testicular cancer is relatively rare, but is the most common cancer in males between
the ages of 15 and 34. Testicular cancer is highly treatable, even when the cancer
has spread beyond the testicle. If it is identified early, the chance for successful
treatment of testicular cancer is highest. We will discuss in this article the main
diagnostic means and treatment indications taking into account the stage and the
prognostic factors of disease. Sonoelastography is a new procedure which could
help for diagnostic of disease. The first treatment is surgery (testicular ablation)
followed by retroperitoneal lymph node dissection. If lymph nodes are involved,
radiotherapy and chemotherapy are indicated. The most indicated combination
of chemotherapy is BEP (Bleomicin, Etoposid and Cisplatin). The number of cycles
of chemotherapy varies due to the histological type of tumor (seminoma or nonseminoma), the risk factors represented by tumor TNM stage and tumor markers
levels. For the resistant disease, after first line chemotherapy, a combination of
Vinblastine, Iphosphamide and Cisplatin is recommended. For metastatic disease
which is resistant to first/second line of chemotherapy or relapsed disease we could
use GENOX chemotherapy (Gemcitabine plus oxaliplatin). The actual management
of testicular cancer may lead to a better overall survival then in other localizations of
cancer.
Rezumat:
Cuvinte-cheie:
cancerul testicular,
prognostic,
chimioterapie
Cancerul testicular este relativ rar, dar este cel mai frecvent cancer la vrste cuprinse
ntre 15 i 34 de ani la populaia masculin. Cancerul testicular este tratabil chiar cnd
este descoperit ntr-o form mai avansat, care depete testiculul. Totui, dac este
depistat timpuriu, ansele de vindecare sunt mai mari. Vom discuta n acest articol
despre diagnosticul cancerului testicular i tratamentul n funcie de stadiu i factorii
de prognostic. Mijloacele diagnostice s-au mbogit recent cu sonoelastografia, o
procedur care ajut cnd ecografia nu este concludent. Primul act terapeutic este
cel chirurgical. Ulterior, tratamentul se face n funcie de existena sau nu a invaziei
ganglionare. Dac aceasta este prezent, se face radioterapie sau chimioterapie.
Tratamentul citostatic cel mai des indicat este EP sau BEP (etoposid plus cisplatin, la
care se poate asocia i bleomicina). Numrul ciclurilor de chimioterapie este dictat n
funcie de factorii de prognostic reprezentai de stadiul TNM i valoarea markerilor
tumorali. Tratamentul bolii rezistente la linia I de chimioterapie se face cu schema VIP
(vinblastin, ifisfamid i cisplatin). Pentru stadiile metastatice rezistente la chimioterapia
de linia I sau II, ct i pentru recidive se poate folosi i schema GEOX (gemcitabin plus
oxaliplatin). Cancerul testicular prin managementul actual poate fi curabil i n general
are o durat de supravieuire mai ndelungat fa de alte localizri ale cancerului.
Cite this article:

Grigorescu A, Cancerul
testicular: diagnostic i
tratament. Rom J Oncol
Hematol. 2013; 1(1):35-38
35
Reviews
Cancerul testicular: diagnostic i tratament
n Romnia, n 2012, incidena cancerului testicular a fost de 3000 (13)

Cancerul testicular este cel mai frecvent cancer
la adolesceni i tineri (15-40 ani) n Statele Unite
ale Americii. 95% dintre tumorile testiculare sunt
tumori germinale. Exist ns i tumori testiculare,
care nu sunt gonadale, i, de asemenea, exist
tumori germinale localizate i n alte regiuni ale
corpului, nu numai la nivel testicular. O frecven
crescut a acestui cancer se ntlnete i n zona
nordic a Europei (Scandinavia), Elveia, Germania i Noua Zeeland. O frecven mai sczut se
ntlnete n Africa i Asia (1).
n Norvegia i Danemarca, rata cancerului testi
cular este de 10 ori mai mare dect n celelalte ri
ale Europei, lucru greu explicabil.
LDH = lactat dehidrogenaza, HCG = gonadotropina uman corionic, AFP = alfa fetoproteina;
* Toi markerii trebuie s fie la valoarea indicat,
pentru a se considera S1.
+ Numai un marker trebuie s fie la valoarea indicat, pentru a se considera S2 sau S3.
Adaptat dup (7)
Etiologie
Ca la orice cancer, nu vorbim de factori etiologici, ci
de factori de risc. Civa factori de risc au fost identificai
i n cazul cancerelor testiculare, acetia fiind corelai
mai frecvent cu apariia bolii, absena lor neducnd
implicit la sigurana c boala nu va aprea, iar prezena
lor nu semnific imposibilitatea de apariie a bolii. Cel
mai des citai factori de risc sunt: criptorhidia, antecedentele heredocolaterale, infecia cu HIV, carcinomul in situ descoperit cu ocazia testrilor pentru
fertilitate sau a diagnosticrii criptorhidiei, un alt
36
cancer testicular n antecedente, vrsta (20-34 ani),

rasa i etnicitatea (frecven mai mare la rasa alb
n SUA, frecven redus n general la populaia
asiatic i african). Unele studii au fcut o corelaie
cu nlimea persoanei, cancerul testicular fiind mai
frecvent la persoanele nalte. Aceast observaie nu
s-a confirmat ns n alte studii (3).
Ali cercettori incrimineaz prin rezultatele unor
studii i ali factori de risc, cum ar fi hipospadiasul, unele hernii inghinale, nivelul unor hormoni
ai mamei (dihidroepiandrosteronul sulfat crescut
duce la un risc sczut, iar nivelul crescut al androstendionului i estradiolului crete riscul) n perioada de nceput a sarcinii. Unele rezultate n ceea ce
privete influena hormonal din timpul sarcinii sunt
contradictorii, astfel, dup unele studii, scderea
nivelului estradiolului n timpul sarcinii ar favoriza
lipsa coborrii testiculului n scrot i apariia cancerului. Un alt factor de risc decelat este vasectomia,
dar rezultatele observaiilor sunt contradictorii i n
acest caz (4). Sindromul Klinefelter (prezena unui
cromozom X suplimentar) a fost i el incriminat n
predispoziia de apariie a cancerului testicular.
Diagnostic
Simptomele principale sunt reprezentate de o
senzaie neplcut la nivelul scrotului, greutate
sau durere resimit la nivelul testiculului, dureri la
nivel abdominal inferior sau la nivelul spatelui (5).
Examenul fizic poate decela o formaiune
tumoral la nivelul unuia dintre testicule. Exami
narea prin iluminare trans-scrotal deceleaz tumora care nu este transparent.
Grigorescu A
Tabelul 1. Grupele de risc n cancerul testicular

LDH (U/L)
HCG (mIU/ml)
AFP (ng/ml)
Markeri nedisponibili
SX
S0
Normal
Normal
Normal
S1*
<1.5 x Normal
<5,000
<1,000
S2+
1.5 - 10 x Normal
5,000 - 50,000
1,000 - 10,000
S3+
>10 x Normal
>50,000
>10,000
Estimarea numrului de cancere testiculare n 2008. Adaptat dup (2)
Examinrile paraclinice i de laborator
Tratamentul seminomului testicular
Tomografia computerizat pelvin, dar i cea la nivelul abdomenului i al pelvisului sunt necesare pentru diagnostic i pentru stadializare. Ecografia trans-scrotal
este i ea inclus n standardul de examinri.
Markerii tumorali care trebuie investigai: alfafetoproteina, gonadotropina uman corionic (beta
HCG ale crei valori de peste 10,000 ng/ml se ntlnesc numai n tumori germinale sau carcinomul hepatocelular) i lactat dehidrogenaza (LDH).
Sonoelastografia reprezint o achiziie recent
n mijloacele de diagnostic ale cancerului testicular, ea avnd avantaje fa de ultrasonografia
clasic (6).
Stadializarea tumorilor testiculare este complex
i constituie o preocupare permanent a instituiilor
specializate n acest sens. n mare avem boal
localizat, boal extins loco-regional sau boal
extins la distan. O particularitate a cancerelor
testiculare o reprezint clasificarea pe baza factorilor de prognostic. Astfel, exist trei categorii de
tumori: cu risc sczut, intermediar i mare, aceast
clasificare jucnd un rol important n alegerea
tratamentului.
Grupul Internaional de Consens pentru Cance

rele cu Celule Germinale (IGCCCG) a elaborat o
clasificare bazat pe factorii de prognostic (extensia
bolii, nivelul markerilor tumorali).
La seminoamele cu risc sczut (good risk seminoma), nu se mai deceleaz situsul primar, nu exist
metastaze pulmonare. Riscul intermediar cuprinde,
de asemenea, cazurile unde nu se deceleaz situsul
primar i nu sunt metastaze pulmonare. Pacienii cu
seminom pur nu au categoria de risc avansat (poor
risk).
Pentru stadiul IA i IB se recomand rezecia
chirurgical (orhiectomie radical inghinal).
Intervenia chirurgical poate fi urmat de radio
terapia 20-25 Gy la nivelul ganglionilor para-aortici i la nivelul ganglionilor inghinali ipsilaterali.
Orhiectomia poate fi urmat i de chimioterapie
cu carboplatin AUC7, o singur doz. Unele echipe
de clinicieni apeleaz doar la supraveghere postorhiectomie.
Stadiul IS necesit radioterapie post-operator n
dozele i ariile ganglionare amintite anterior.
Tratament
Tratamentul este n funcie de tipul histologic al
tumorii i stadiul bolii. O particularitate a cancerelor testiculare care impun decizia terapeutic este
clasificarea acestora n funcie de gradul de risc,
n tumori cu risc sczut, mediu i ridicat.
Principalele entiti histologice ntlnite sunt: tumorile seminomatoase (seminomul pur), tumorile
nonseminomatoase i tumorile mixte.
Examenele imagistice ajut la realizarea
stadializrii bolii. n stadiul I, tumora este localizat
exclusiv la nivel testicular, n stadiul II se deceleaz
invazia ganglionar la nivel abdominal, stadiul III
cuprinde extensia i la alte structuri dect cele ganglionare.
Tratamentul este diferit pentru seminoame i tumorile nonseminomatoase.
Tratamentul stadiului II
Radioterapia la nivelul ariei subdiafragmatice
la nivelul ganglionilor para-aortici, iliaci. Pentru stadiul II B se recomand i chimioterapie
tip EP (etoposid plus cisplatin), 4 serii, sau BEP
(bleomicin, etoposid, cisplatin), 3 serii, ca
alternativ la radioterapie.
Tratamentul stadiului IIC i III

Aceti pacieni sunt clasificai ca avnd un risc
bun, cu excepia stadiului III cu metastaze viscerale,
altele dect cele pulmonare. Pentru cei cu risc bun
se fac 4 serii de EP sau 3 BEP, iar pentru cei cu risc
intermediar se vor administra 4 serii BEP.
n linia a II-a se poate administra schema VeIP
(vinblastin, ifosfamid, cisplatin), TIP (paclitaxel,
ifosfamid, cisplatin) sau TIP (paclitaxel, ifosfamid,
cisplatin).
37
Reviews
Cancerul testicular: diagnostic i tratament
Boala persistent sau recurent poate beneficia de chimioterapie cu gemcitabin i oxaliplatin

(GEMOX) (8,10,11).
Tratamentul tumorilor non-seminomatoase

Niveluri de risc
Pacienii clasificai cu un nivel de risc bun:
prezena tumorii testiculare sau retroperitoneale
fr metastaze viscerale non-pulmonare i markeri
S1, pentru care supravieuirea fr progresie (PFS)
este, la 5 ani, de 89%, iar supravieuirea global, la 5
ani, de 92-94%. Riscul intermediar este reprezentat
de prezena tumorii testiculare sau retroperitoneale
fr metastaze viscerale, altele dect cele pulmonare, cu markeri S2, PFS, la 5 ani, 75%, supravieuirea
la 5 ani 80-83%. Riscul crescut: prezena tumorii la
nivel mediastinal, metastaze viscerale non-pulmonare, markeri S3, PFS, la 5 ani, 41%, supravieuire la
5 ani 71%.
Tratamentul recomandat
Stadiul IA (SIA): orhiectomie, supraveghere n cazul pacienilor complianei sau disecia ganglionilor
retroperitoneali (RPLND). Dac examenul histologic al ganglionilor relev N0, nu exist indicaie
de chimioterapie. Chimioterapia este indicat n
cazul invaziei ganglionare pN2-pN3. Chimioterapia
recomandat este reprezentat de asocierea de
etoposid 100 mg/m2/zi, 5 zile, plus cisplatin 20 mg/
m2/zi, 5 zile, cu repetare la 21 de zile (2 cicluri EP),
sau se poate aduga bleomicin n doz de 30 mg/
m2 n zilele 1, 8 i 15, cu repetare la 21 de zile (2
cicluri BEP).
Stadiul IB (SIA): orhiectomie + RPLND sau chimioterapie reprezentat de dou cicluri BEP. Pacienii
compliani cu T2 pot fi supui numai supravegherii.
Stadiul IS cu persistena markerilor crescui se va
trata adjuvant cu 4 cicluri EP sau 3 cicluri BEP.
Stadiul IIA: dac dup orhiectomie markerii sunt
normali, se va face RPLND sau 4 cicluri EP sau 3 BEP.
Pacienii care dup RPNLD vor avea pN1 sau pN2
vor beneficia de 2 cicluri EP sau BEP. Cei cu pN3
vor fi tratai cu 4 cicluri EP sau 3 BEP. Stadiul IIB va fi
tratat adjuvant, ca i stadiul IIA, dup confirmarea invaziei ganglionare i n prezena markerilor negativi.
Pentru pacienii cu extensie multifocal i invazie

ganglionar cu drenaj limfatic nu se recomand
RPLND.
Stadiile IIC i IIIA vor fi tratate ca i stadiul IIB.
Stadiile IIIB i IIIC vor fi tratate post-orhiectomie, cu
citostatice (4 cicluri BEP), ulterior discutndu-se posibilitatea RPLND. Dac markerii sunt pozitivi dup
prima linie de chimioterapie, sau n prezena maselor
tumorale reziduale, se va lua n discuie chimioterapia de linia a II-a cu etoposid 75 mg/m2/zi, 5 zile, +
ifosfamid 1,2 g/m2/zi, 5 zile (mesna 20% din fiecare
doz de ifosfamid, 15 minute nainte de ifosfamid,
la 4 i respectiv 8 ore dup ifosfamid) + cisplatin 20
mg/m2/zi/5 zile. Tratamentul chirurgical i radioterapia
local sunt indicate atunci cnd sunt fezabile, pentru
localizrile metastatice. naintea fiecrui ciclu de chimioterapie se vor determina markerii tumorali.
Tratamentul de linia a II-a al bolii metastatice: VelP
(vinblastin 0.11 mg/kg IV/zi/ziua 1-2, ifosfamid
1.200 mg/m2, 5 zile, mesna 400 mg/m2 nainte, la
4 i respectiv 8 ore dup ifosfamid, cisplatin 20
mg/m2/zi, 5 zile) la 21 de zile, 4 cicluri. Alt schem
recomandat este cu paclitaxel 250 mg/m, ziua 1,
ifosfamid 1.500 mg/m2/zi, zilele 2-5, mesna 400
mg/m2 la 4 i respectiv 8 ore dup fiecare doz de
ifosfamid i cisplatin 25 mg/m2/zi, zilele 2-5, 4 cure
la 21 de zile.
Trialurile clinice sunt recomandate la pacienii
cu prognostic nefavorabil sau la cei care nu mai
rspund la terapia standard.
Boala recurent sau persistent poate beneficia
de combinaia citostatic GEMOX: gemcitabin
1.000-1.250 mg/m2 ziua 1 i 8 + oxaliplatin 130 mg/
m2 ziua 1, cu repetare la 21 de zile. O alt opiune
este reprezentat de chimioterapia n doze mari, cu
transplant de celule stem (9, 10, 11).
Noi tendine
n practica actual, disecia laparoscopic a ganglionilor retroperitoneali a dat rezultate bune, cu un
risc operator mai redus i complicaii post-operatorii
mai puin importante fa de intervenia clasic(12).
Conflicts of Interest/Conflict de Interese: none/
nici unul.
Bibliografie
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4. http://www.cancerresearchuk.org/cancer-help/type/testicular-cancer/about/
testicular-cancer-risks-and-causes#factor.
5. http://health.nytimes.com/health/guides/disease/testicular-cancer/overview.html.
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[Internet] 2012. Available from: http://www.medscape.com/viewarticle/769100.
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8. Sachdeva K., Harris J.E. SEM. [Internet] 2013. Available from: http://emedicine.
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medscape.com/article/2006821-overview.
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emedicine.medscape.com/article/2006613-overview.
10. Einhorn L.H. Testicular cancer. In Goldman L., Schafer A.I., eds. Cecil Medicine.
24th ed. Philadelphia, PA: Saunders Elsevier; 2011: chapter 206.
11. National Comprehensive Cancer Network. National Comprehensive Cancer Network
Clinical Practice Guidelines in Oncology: Testicular cancer. 2012. Version 1.2012.
12. Busch J., Magheli A., Erber B. Laparoscopic and Open Postchemotherapy
Retroperitoneal Lymph Node Dissection in Patients With Advanced Testicular Cancer, A
Single Center Analysis. BMC Urol.2012; 12:15.
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H., Forman D., Bray F. Cancer incidence and mortality patterns in Europe: estimates for
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Boeru AM
Durerea visceral din cancer

Visceral Cancer Pain
Ana Maria Boeru*
*Asociaia Free of Pain, Bucureti
Coresponding author: Ana Maria Boeru
Email: anamariaboeru@yahoo.com
Abstract:
Keywords:
visceral pain,
nociception, cancer
pain, visceral cancer
pain
Pain in cancer may be caused by tumour infiltration of pain sensitive

structures or by the treatment which injures visceral, musculoskeletal, and
nervous tissues. Surgery, chemotherapy, and radiation therapy, which are
necessary to treat cancer are all associated with potentially painful sequelae.
Visceral cancer pain results from infiltration, compression, distension, or
stretching of thoracic, abdominal and pelvis viscera. This type of pain is
poorly localized and is often referred to cutaneous sites which may be
remote from the site of the lesion. I will talk about this specific physiological
type of cancer pain, neurobiological mechanism of nociception, modulation,
acute and chronic visceral pain, the locations of the primary tumour and
where is the referred pain.
Rezumat:
Cuvinte-cheie:
durere visceral,
nocicepie, durerea
n cancer, durerea
visceral n cancer
Durerea oncologic rezult fie dup invazia tumoral, fie dup

tratamentele oncologice de specialitate care afecteaz esuturile viscerale,
musculoscheletale, nervos periferice i centrale. Chirurgia oncologic, chimio
i radioterapia asociaz potenial durere post-terapeutic. Durerea visceral
apare ca rezultat al invaziei, compresiei, distensiei, ntinderii organelor din
interiorul toracelui, abdomenului i pelvisului. Acest tip de durere este foarte
puin localizat i adesea este referit n zone cutanate destul de departe de
leziunea primitiv. Am s scriu despre specificul acestui tip de durere, despre
neurotransmitere, modulare, durerea visceral acut i cea cronic, despre
localizrile tumorilor primitive viscerale i unde este resimit aceast durere.
Tipul specific de durere visceral are anumite

caractere care o difereniaz definitoriu de cea
somatic (cutanat, musculoscheletal), neuropat
sau de durerea meninut (ntreinut) prin sistemul
simpatic sau durerea din sindromul complex regional.
Sindroame dureroase tip visceral specifice

cancerului
Acestea au fost descrise de mai bine de 20 de
ani i se clasific n sindroame dureroase acute i
cronice (1).
Cite this article:

Boeru A M, Durerea
visceral din cancer.
Rom J Oncol Hematol.
2013; 1(1):39-47
39
Reviews
Figura 1. Calea de transmitere a durerii. Adaptat dup (1)
Sindroamele dureroase acute

De obicei, durerea este cronic, dar exist dureri
acute asociate cu intervenii diagnostice (cefalee postpuncie lombar, biopsie medular, biopsie percutan,
toracocentez etc.), dureri acute post-operatorii, cauterizarea suprapubian, cateterul intercostal, inseria
nefrostomiei, embolizarea tumorii etc. Mai exist dureri acute asociate cu tratamentele curative: cu chimioterapia (infuzie prin artera hepatic, chimioterapia
intraperitoneal, dureri de angin pectoral dup
5-fluorouracil, ginecomastie post-hormonoterapie, durere acut indus de interferon, enterit i proctocolit
radic acut, plexopatie brahial). Le-am enumerat pe
cteva dintre acestea pentru sublinierea necesitii diagnosticului diferenial cu durerea cronic la bolnavul
cu cancer, fiecare tip de durere beneficiind de tratament diferit.
Sindroame dureroase cronice

n legtur cu invazia tumoral (70-80%): sindroame dureroase viscerale (sindromul de distensie hepatic, sindromul retroperitoneal, obstrucia
intestinal cronic, carcinomatoza peritoneal, durerea perineului malign, mialgia planeului pelvin
malign, obstrucia ureteral).
n legtur cu tratamentele specifice antineoplazice: sindroame dureroase post-chimioterapie
(durerea asociat cu infuzia intraarterial, ginecomastia asociat cu hormonoterapia cancerului de
prostat), sindroame dureroase post-chirurgicale
(post-mastectomie, post-toracotomie, post-tumorectomie i evidare ganglionar n regiunea cervical
anterioar pentru tumorile din sfera ORL), sindroame
40
de membru fantom (sn fantom, anus fantom,

vezic urinar fantom), mialgia planeului pelvin
post-chirurgical, sindroame cronice dureroase
post-radioterapie (mielopatii cronice radice, enterite
i proctite radice, sindromul perineului ars).
Enumerarea acestor sindroame a fost fcut cu
scopul de a sublinia faptul c, cu ct diagnosticarea
acestora este posibil mai devreme, cu att tratamentul durerii cauzate de acestea este posibil mai
intit i devine optim.
Durerea visceral
Este rezultatul infiltrrii, compresiei, distensiei
sau ntinderii organelor toracice sau viscerale (de
exemplu, metastaza hepatic, cancerul pancreatic).
Este slab localizat, descris ca torsiune, presiune,
profund, poate fi asociat cu grea, vom. Este ade
sea referit la teritorii cutanate la distan de locul
leziunii (de exemplu, durerea de umr din iritaia
diafragmatic). Zona cutanat referit poate fi i la
palpare superficial sau profund, sensibil sau chiar
dureroas (2). Exist dou mecanisme fiziopatologice
predominante ale durerii oncologice: nociceptiv i
neuropat. Durerea nociceptiv este rezultatul afectrii
structurilor somatice i viscerale, apare n urma activrii receptorilor nociceptivi. Acetia se gsesc n piele,
viscere, muchi i esuturile conjunctive. Durerea nociceptiv poate fi durere somatic i durere visceral.
Diferenele clinice dintre durerea somatic i cea
visceral:
1. Viscerele au mai puini nociceptori dect suprafaa corpului, care e dotat cu foarte muli nociceptori.
Boeru AM
Tabelul 1. Exemple de durere visceral referit. Adaptat dup (2)

Organ
Inervaie
Localizarea durerii
Esofag
T2-T8
Retrosternal, interscapular, regiunea cervical anterioar,

membrul superior stng sau ambele.
Diafragm
C3-C4
Regiunea cervical anterioar i umeri.
Stomac, duoden
T6-T9
Epigastru, hipocondrul drept sau stng, iradiere regiunea

toracic posterioar.
Ficat, ci biliare
T6-T9
Hipocondrul drept, scapula sau umrul drept.
Pancreas
T6-T10
Etaj abdominal superior i regiunea toracic posteroinferioar.
Intestin subire
T8-T12
Periombilical, uneori suprapubian.
Colon
T10-L2
Periombilical, flancul drept sau stng.
Rinichi
T10-L1
Regiunea lombar i flancul corespunztor.
Jonciune ureterovezical
T10-L2
Regiunea lombar, flancul,+/- testiculul sau ovarul ipsilateral.
Uretr
T12-L2
Regiunea suprapubian, esutul cutanat scrotal sau labial.
Vezic urinar
T12-L2
Brbat: hipogastru, uretra i penisul;

Femeie: hipogastru, uretra i esutul cutanat perineal.
2. Durerea visceral este mai difuz localizat dect

cea somatic i poate fi i referit.
3. Durerea visceral este mai puternic influenat
de emoii dect cea somatic. Deci, o nevoie crescut de tratament complex inclusiv al anxietii i depresiei.
Durerea nociceptiv visceral ar putea fi descris
cu urmtoarele caractere: mai difuz, ca un junghi,
colicativ. Este urmare a compresiei, infiltrrii sau distensiei organelor intratoracice i a viscerelor abdominopelvine (3).
Sindromul dureros complex regional este o entitate distinct, cu tratament diferit. nlocuiete termenii mai vechi folosii: distrofia reflex simpatic i
durerea meninut prin aciune simpatic. Se refer la
posibilul rol pe care l joac sistemul nervos simpatic
n unele dureri: acut visceral i durerea neuropat.
Se refer la creterea intensitii durerii la bolnavii
cu cauzalgie prin stimulare simpatic sau controlul
parial al unor forme de durere prin blocarea nervilor
simpatici sau prin folosirea medicamentelor blocante

adrenergice (propranololul). Se caracterizeaz prin
senzaie de arsur superficial, cu modificri vasculare i pe un traseu arterial (de exemplu, durerea din
Sindromul Pancoast). Este important s se disting
senzaia de arsur superficial asociat lezrii nervoase periferice (de obicei cea mai frecvent) de
aceeai senzaie dureroas de cauz meninut simpatic (foarte puin frecvent) (1).
Anatomia i fiziologia durerii

Stimulul algogen sau nociceptiv acioneaz asupra receptorilor nociceptivi, somatici sau viscerali
reprezentai de terminaiile libere ale fibrelor nervoase A Delta slab mielinizate i C, nemielinizate ale
neuronilor senzitivi situai n ganglionii rdcinilor
medulare posterioare. Fibrele A Delta mielinizate,
mai groase, au o vitez de transmitere mai mare
17-25 m/sec i conduc impulsurile provenind de la
receptori nociceptivi specifici, de exemplu, mecano-
41
Reviews
ceptorii, mediind durerea acut, n timp ce fibrele

C subiri, nemielinice, conduc impulsuri provenind
de la nociceptorii polimodali, cu o vitez redus i
laten mare, aproximativ 100 m/sec i remanen
mare 100-150 m/sec., mediind durerea lent, difuz,
cu caracter de cauzalgie (1).
Receptorii viscerali sunt mai puin studiai dect
cei somatici. S-au pus n eviden receptori pentru
durere n plmni, testicul, vezica biliar. Alte organe
nu posed astfel de receptori, putnd fi incizate fr
a se percepe durerea. Durerea visceral se produce
pentru viscerele cavitare prin contracia izometric
prelungit sau prin distensie, iar pentru viscerele
parenchimatoase, prin distensia capsulei. Hipoxia i
anoxia sunt resimite ca durere de miocard infarct.
Durerea visceral este perceput ca durere referit
la un teritoriu somatic durerea referit supraiacent
sau la distan de viscerul n suferin. Explicaia durerii viscerale resimit ca durere referit este prin
sinapsele pe care fibrele algomediatoare viscerale
le fac n cornul medular posterior cu aceiai neuroni
ca i fibrele somatice, cortexul localiznd durerea n
teritoriul somatic, de la care primete n mod normal mai muli stimuli nociceptivi (3). Axonul fibrelor
algoconductoare face sinaps n cornul dorsal
medular, n zone bine determinate, cu celule nervoase intercalate sau direct cu neuronii de origine ai
tractului medular, tracturilor medulare ascendente
(figurile 2 i 3).
Cile medulare ascendente algoconductoare
sunt reprezentate n principal de fasciculele spinotalamice laterale i anterioare. Mediatorul chimic
specific nociceptorilor periferici nu este bine
definit, pare s fie bradichinina, substan care se
elibereaz din celule n momentul unei traume,
concomitent cu amorsarea cascadei eicosanoizilor, a coagulrii i fibrinolizei, toate constituind
mecanisme umorale, locale, imediate de autoconservare.
Pe lng mediatorul specific, exist o serie de
alte substane chimice care, acionnd asupra
terminaiilor libere, le sensibilizeaz la aciunea
acesteia: ionii de K, H, Cl, ATP, grupul aminelor biogene (histamina, serotonina, acetilcolina), peptide
(substana P, peptide colecistokinin-like, bombezina,
tahikininele, substana K), prostaglandinele i leukotrienele, hormoni, ca de exemplu noradrenalina, angiotensina (figura 2).
Aminele biogene i hormonii adrenergici joac un
rol paradoxal n transmiterea stimulului nociceptiv:
la nivel periferic, sensibilizeaz receptorii la stimulii nociceptivi, n timp ce la nivelul cilor de transmitere medular au un rol modulator al impulsului
nociceptiv, constituind mediatorii chimici ai unor ci
descendente, inhibitoare ale durerii, care fac parte
din sistemul modulator descendent (1,2).
Sensibilizatorii receptorilor periferici, mediatori ai
inflamaiei (figura 4), accentueaz descrcrile n neuronii sistemului nociceptiv, astfel nct un stimul banal
poate fi perceput ca durere. n plus, acionnd asu-
42
Figura 2. Calea de transmitere a durerii.

Adaptat dup (3)
pra tonusului musculaturii, crescnd permeabilitatea

vascular, chemotactismul leucocitar, influennd coagularea i fibrinoliza, declaneaz cercuri vicioase
care accentueaz durerea.
Mediatorul chimic la nivelul sinapsei medulare,
ntre fibra periferic i fibra traiectului spino-talamic,
pare s fie substana P, care se elibereaz n cantiti
importante n LCR, la stimularea intens a fibrelor nociceptive subiri A Delta i C, dar nu i la stimularea
slab, selectiv a fibrelor sensibilitii proprioceptive
i tactile (A Beta). Transmisia medular a nocicepiei
se face prin intermediul tracturilor spino-talamiceneo, paleo i arhi-spino-talamice, primele dou cu
rol dovedit la om (figura 5). Cunoaterea anatomiei
acestor tracturi are importan pentru procedeele
neurochirurgicale antialgice lezionale, explicnd att
logica, ct i cauzele insuccesului acestora (3).
Pe parcursul transmisiei medulare, cel mai important loc l ocup jonciunea medular, locul unde se
face sinaps ntre fibra periferic i cea a fasciculului spino-talamic. La acest nivel acioneaz sistemele
modulatoare descendente ale durerii; la acest nivel
Boeru AM
Figura 3. Mediatori chimici specifici nocicepiei. Adaptat dup (1)
este unul dintre locurile de aciune ale analgezicelor

opioide prin intermediul receptorilor opioizi (4).
Proiecia mezencefalic a fibrelor spino-talamice
(figura 6) este diferit n funcie de tractul din care fac
parte: tractul neo-spino-talamic proiectndu-se preponderent n nucleii talamici ventro-postero-laterali.
n general, se admite c aceast proiecie mpreun
cu cea talamo-cortical particip la aspectul discriminativ al durerii (mediate de fibrele A Delta). Fibrele
tractului paleo-spino-talamic se proiecteaz tot n
talamus, dar o mare parte a lor sau colaterale ale
lor fac sinaps n substana reticulat mezencefalic,
n special n zonele profunde ale coliculului superior, preponderent fibrele mecanoceptoare, care
formeaz reprezentarea somatotopic, coinciznd
cu reprezentarea vizual din zonele superficiale ale
coliculului superior n nucleii pretectali i parabrahiali unde predomin fibrele sensibilitii tactile n
substana periapeductal, care are un rol primordial
n modularea durerii. Fibrele tractului reticulo-spinotalamic (paleospinotalamic) sunt suportul anatomic
al transmisiei durerii lente, difuze, nediscriminative,
iar prin proieciile lor bulbare i n nucleii cenuii
mezencefalici particip la rspunsul motor i vegetativ al organismului la durere. Prin proiecia lor
ascendent n nucleii ventrali ai talamusului i n hipotalamus i de acolo n sistemul limbic intervin n integrarea psihoafectiv a durerii i n crearea unor arcuri
reflexe care adeseori accentueaz nocicepia(1).
Proiecia talamo-cortical se face n ariile senzitive S1 (girusul post-central i lobul paracentral),
S2 (partea posterioar a anului lui Sylvius), S3
(neconfirmat unanim, pe faa medial a emisferelor
cerebrale). n general, proieciile corticale ale fibrelor

algomediatoare cuprind structuri care fac parte att
din neo, ct i din paleo i arhicortex.
Neocortexul particip la componenta discriminativ
a durerii (localizare temporospaial), n timp ce structurile vechi filogenetic (sistemul rinencefalic) intervin
n evaluarea durerii, constituie substratul reaciilor
afective, emoionale, att de importante n durerea
cronic. Prin strnsa legtur ntre sistemul nociceptiv i talamus, hipotalamus, substana reticulat i
nucleii din trunchiul cerebral, el particip la reacia
vegetativ a organismului. Sistemele paleo i arhicorticale constituie punctul-cheie n modularea durerii.
Modularea durerii
Una dintre achiziiile foarte importante ale ultimilor
20 ani n studiul durerii este faptul c transmisia sti
mulului nociceptiv de la periferie spre cortex nu se
face simplu, direct proporional cantitativ cu stimulul
periferic, uneori neavnd nevoie de existena unui
stimul periferic pentru a aprea durerea, ci sufer
de-a lungul drumului su ascendent o serie de
transformri, modulri, care pot ajunge uneori pn
la producerea analgeziei. Acest mecanism face parte
din contextul reaciei de supravieuire. Se pune pro
blema rolului fiziologic al sistemelor modulatoare ale
durerii. n diferenierea stimulilor nociceptivi de ali
stimuli senzoriali, mai probabil n reacia de aprare a
organismului, stimulul s-a dovedit a fi activat n mod
cert, ns rolul lui nu este de a produce analgezie n
toate condiiile.
Calea algomediatoare este o cale polisinaptic, n
acest fel oferind multiple posibiliti de modulare,
43
Reviews
Figura 4. Mediatori chimici ai inflamaiei. Adaptat dup (3)
cea mai important fiind la nivelul sinapsei din cornul

medular posterior, unde nocicepia este nc bine
individualizat de celelalte senzaii somatice (1-3).
Activarea cilor algomodulatoare descendente se
poate face prin stimularea periferic sau prin stimulare central. Tehnica de stimulare periferic pentru
producerea analgeziei se cunoate de mult timp:
acupunctura, cauterizarea unor puncte dureroase,,
trigger, aplicarea de ventuze, recent se face prin
stimularea electric a unor fibre nervoase cu un curent
electric cu anumii parametri (sub 100 Hz, 5080 m/
sec pentru fibrele mielinice i sub 20 Hz i mai mult
de 200 m/sec pentru fibrele A Delta i C). Stimulul se
aplic pe nervii periferici transcutanat, stimularea activnd cile modulatoare descendente i, n acest fel,
producnd analgezia. Stimulul poate fi aplicat direct
n SNC n zonele de origine a tracturilor modulatoare
descendente: substana periapeductal n principal.
Aceste tehnici se utilizeaz n mod frecvent n tratamentul durerii cronice.
Cile algomodulatoare descendente sunt multiple, cu neuromediatori specifici, cele mediate de
opioidele endogene i de noradrenalin fiind cele
mai bine studiate. Receptorii opioizi din aceste ci
modulatoare descendente, cel de-al 2lea loc de
aciune al analgezicelor opiacee n producerea analgeziei, al 3-lea, dar nu cel mai puin important, fiind la
originea acestor ci. Alte ci sunt mediate de GABA,
neuromediator cu funcie depresoare n SNC, de
serotonin i de alte substane peptidice (4).
Efectul stimulrii cilor modulatoare descendente
este n final inhibarea descrcrilor neuronilor din
cornul medular posterior, n felul acesta blocnd
transmisia stimulului nociceptiv spre ariile corticale i
subcorticale.
Prima meniune a neuromediatorilor de tip peptide opioide s-a fcut de Hughes n anul 1975, grupul
acestor substane fiind numit,,endorfine.
Endorfinele descoperite pn n prezent fac parte
din 3 grupuri mari, clasificate aa dup parcursul molecular din care provin:
44
Grupul opiomelanocortin care include beta endorfina. Molecula precursoare d natere i ACTHului i MSH-ului de tip alfa i beta. Aceasta ar fi
explicaia analgeziei n cursul unei situaii de stres.
Grupul dynorfin care include dynorfina i leuenkefalina.
Grupul proenkefalin care include met-enkefalina.
Ulterior s-au pus n eviden receptorii specifici
acestor substane denumii receptori opiacei. Pn
n prezent s-au identificat 5 asemenea tipuri de receptori: miu, delta, kappa, sigma i epsilon, primele 4
avnd cu certitudine rol n modularea durerii.
Substanele analgezice majore de tipul morfinei
se leag de aceti receptori. Fiecare tip de receptor
produce la activarea lui un anumit efect. De aici se
deduce c specificitatea de legare a opioidelor la
receptori este responsabil de producerea efectelor
caracteristice.
Substan
ele care se leag de receptor i l activeaz se numesc agoniste, cele care se leag, dar nu l
activeaz se numesc antagoniste, efectul lor fiind evident numai dac s-au administrat dup o substan
agonist al crui efect l combate, l antagonizeaz.
Afinitatea receptorilor pentru agoniti este mai slab
dect pentru antagoniti, n acest fel explicndu-se
antagonizarea efectului unui agonist care va fi deplasat de pe receptor i disponibilizat pentru metabolizare i excreie. Efectul activrii diferiilor receptori i
locul de legare al liganzilor naturali i ai opiaceelor
sunt prezentate n tabelul nr. 2 (4).
Investigaii paraclinice
Evaluarea paraclinic este rezervat doar cazurilor
unde exist dubiu n legtur cu cauza durerii sau
cazurilor la care decizia asupra tratamentelor antineoplazice specifice ulterioare depinde de precizarea
localizrii bolii. n durerea visceral cu proveniena
tumorii primare digestive, colonoscopia, ecografia
abdominal, tomografia computerizat abdominal
pot informa despre localizarea, volumul i extensia
tumorii digestive pentru stabilirea oportunitii me-
Boeru AM
Figura 5. Ci spinotalamice. Adaptat dup (4)
todelor terapeutice de reducere a volumului tumoral

prin radiochimioterapie paliativ, dac acestea sunt
posibile (innd cont de indicaiile i contraindicaiile
lor n cazul dat), prin chirurgie paliativ n scop fie
reducional (debulking), iar dac aceasta nu este
posibil, n scop de by-pass acolo unde este nevoie
i posibil (1,2).
n durerea visceral metastatic, de exemplu
metastazele hepatice, ecografia abdominal, CTul abdominal pot stabili existena lor, numrul lor,
localizarea n plin parenchim hepatic, localizarea
n vecintatea unor structuri importante vasculare
sau ci biliare, a cror compresie sau invazie prin
semnele i simptomele pe care le determin s
dicteze conduita terapeutic: metastaze mici, pn
la 3, n plin parenchim hepatic, fr vecintate
periculoas cu sistemul vascular port sau hepatic
(cav) sau cu sistemul canalicular biliar, ofer posibilitatea metastazectomiei. De asemenea, aceleai
ecografii, CT hepatice pot stabili invazia capsulei
hepatice care n mod sigur va determina ca bolnavul s fie candidat la morfin n scurt timp, dac
nu este deja. n legtur cu neoplazia pancreatic,
ecografia i tomografia computerizat stabilesc
localizarea tumorii, invazia de vecintate i oportunitatea by-pass-ului digestiv pentru evitarea
insuficienei hepatobiliare datorit compresiei totale a cii biliare principale (coledocului) sau oportunitatea blocrii anestezice (alcoolizare) a plexului
celiac. n durerea visceral de proveniena tumorii
primare a aparatului urinar, urografia UIV, ecografia, CT-ul, cistoscopia pot stabili oportunitatea
tratamentelor specifice urologice (dezobstrucii,
by-pass-uri, intervenii endoluminale sau ure-
terostomii). n durerea toracic de provenien

bronhopulmonar, bronhoscopia i CT-ul toracic
stabilesc oportunitatea interveniilor chirurgicale,
n particular cele legate de invazia pleural, sau
stabilesc oportunitatea interveniilor endoluminale
dezobstructive.
Deci durerea visceral devine exprimat dup:
a. distensia capsulei hepatice;
b. sindromul de mas retroperitoneal;
c. ocluzia intestinal cronic;
d. carcinomatoza peritoneal.
Durerea se produce prin exces de nocicepie legat
de hiperstimularea fibrelor nervoase periferice care
transmit influxul nociceptiv. Aceast hiperstimulare
poate s rezulte din compresia tumoral, inflamaia
local i ischemia cu eliberare de substane algogene (3,4).
Tumora malign produce o distrugere difuz a
proceselor fiziologice. Creterea necontrolat duce
la compresia i invazia structurilor vecine. Datorit
locului de origine pentru multe dintre cancerele
organelor interne, durerea nu apare de la nceput,
invazia tumoral fiind progresiv, mult vreme este
asimptomatic pn la un moment critic caracterizat prin producerea ischemiei, compresiei sau
obstruciei organelor din vecintate. Cnd acestea
se ntmpl, durerea visceral devine manifest,
ncepe s existe. Poate fi urmare a unui tratament
oncologic de specialitate sau poate marca recidiva
cancerului. Diagnosticul diferenial dintre cele dou
de mai sus e dificil. De aceea pacientul care continu
s simt durerea dup tratament dezvolt o imens
anxietate, depresie: M-am tratat, de ce m mai
doare, sau sunt nevindecabil?. Intervine n plus i
45
Reviews
Tabelul 2. Tipuri de receptori. Adaptat dup(4)

Opioide
Endorfine
Miu (m)
Delta (d)
Kappa (k)
Enkephaline
Antagonist
Agonist
Beta-endorfina
Agonist
Agonist
Dynorfin
Agonist slab
Codeine
Agonist slab
Agonist slab
Etorphine
Agonist
Agonist
Fentanyl (Sublimaze)
Agonist
Meperidine (Demerol)
Agonist
Methadone (Dolophine)
Agonist
Morphine
Agonist
Buprenorphine
Parial agonist
Dezocine (Dalgan)
Parial agonist
Nalbuphine (Nubain)
Antagonist
Agonist
Pentazocine (Fortral)
Antagonist sau parial

agonist
Agonist
Naloxone (Narcan)
Antagonist
Agonist
Agonist
Agoniti
Agonitiantagoniti
Antagonist
componenta psihologic la fel ca n colonul iritabil,

care va ntreine durerea (2,3).
Exist patru categorii de stimuli care pot produce
durerea visceral oncologic:
1. distensia mecanic acut a structurilor viscerale;
2. tulburrile ischemice;
3. stimuli biochimici ai invaziei tumorale;
4. durere neuropat compresiv prin invadarea
inervaiei viscerului.
Fiziopatologia, ca mecanism de producere al durerii viscerale, este diferit n funcie de categoria din
care face parte organul:
- organele cavitare: obstrucie, n primul moment asociat cu sindrom de lupt, apoi ocluzie;
asemntor n cazul canalelor excretoare biliare i
urinare;
- organele parenchimatoase: durerile sunt legate
de invazia capsulei cu vasele i nervii din interiorul
46
Agonist slab
Agonist
Antagonist
Antagonist
ei, de exemplu capsula hepatic; caz particular pancreasul, unde durerea este produs de distrugerea
esutului pancreatic de ctre propriile enzime;
- durerea seroaselor: pleura, mezoteliomul, pericardul, peritoneul, carcinomatoza peritoneal prin
distensie, inflamaie, aderene (5).
Durerea abdominopelvin: cu originea tumorii in
ficat, pancreas, stomac, intestine sau n pelvis (6).
Ficat: durere constant, n adncime, caracter compresiv, situat n hipocondrul drept, aici fiind nsoit
de o senzaie de plenitudine n etajul abdominal
superior. Poate s se exprime i n regiunea toracic
posterioar median sau n dreptul umrului drept
dac e i diafragmul iritat.
Pancreas: durere insuportabil, sfredelitoare,
caracter de junghi, n bar etaj abdominal superior mai ales zona median, iradiaz n spate, se
amelioreaz prin rsucire n poziia fetal sau n
Boeru AM
se blocheaz sistemul venos i cel limfatic, zonele

corespunztoare devin contractate, umflate, edematoase i cu eritem sau cianoz. Exemplu: tromboza
venoas profund a gambei unde apariia durerii
marcheaz urgena medical.
Alte dureri viscerale oncologice (3,7):
Figura 6. Proiecia mezencefalic a fibrelor

spino-talamice. Adaptat dup (1)
Reticular formation (RF), vestibular nuclei (V),
cerebellar roof nuclei (R), periaquiductal gray (PG).
Posterior hypothalamic nuclei (P), paraventricular
hypothalamic nucleus (PV), substantia nigra (SN),
Thalamic nuclei (T), preoptic hypothalamic nuclei
(PO), locus ceruleus (LC), median raphe nuclei (MR).
poziie eznd pe un scaun moale, comod i se

agraveaz n clinostatism cu picioarele ntinse.
Stomac: durere asemntoare celei din tumorile
pancreatice sau cu caracter de arsur ca n ulcer.
Intestin: prin blocarea coninutului intestinal
apar dureri colicative, balonare, grea i vom.
Tumorile intrapelvine care pot produce durere
sunt cele ale colonului, ovarelor, corp i col uterin sau
sarcoame de pri moi din abdomen cu invazie n
pelvis. Durere vag, difuz, cu caracter de neptur,
umfltur, presiune, adnc sau disconfort n ambele
flancuri. Uneori aceast durere poate fi intermitent
cu caracter de neptur de cuit, pumnal, sau
resimit ca o arsur intens n rect. Cnd este vorba
de vezica urinar, durerea este cu caracter de spasm,
colic sau arsur i poate exista i senzaie de vezic
urinar foarte plin.
Cnd circulaia sistemic sau cea limfatic este
blocat, apar alte dureri specifice. Blocajul arterial
produce amoreal, slbiciune n zona respectiv,
cnd apare i ischemia, ea se nsoete de durere
profund cu caracter de junghi i deficit motor. Cnd
Xerostomia: scderea secreiei glandelor salivare

produs direct prin invazia tumoral n tumorile din
sfera ORL, post-chirurgie sau radioterapie e nsoit
i ea de durere.
Stomatitele: cauze directe ale invaziei tumorale, efecte adverse ale chimio i radioterapiei sau
malnutriiei n stadii avansate provoac durere mixt
nociceptiv.
Disfagia: nsoit de odinofagie.
Esofagita: prin invazie tumoral nsoit de disfagie, odinofagie, reflux esofagian cauzator al durerii
retrosternale fr etiologie cardiac.
Radioterapia toracic: pleurita, pericardita postradice.
Sarcomul de pri moi retroperitoneal: durere
asemntoare celei din cancer de pancreas.
Incontinena de materii fecale i scurgerile anale:
provoac dureri anale i perineale.
Cistita interstiial postradic: durere ca aceea
descris la vezica urinar.
Incontinena urinar: durere suprapubian.
Prostatita, orhiepididimita i vaginita: durere
post iradiere pelvis.
Concluzii
Durerea visceral de cauze oncologice este o durere recurent, devine i intermitent acut, pe fondul
unei dureri cronice progresive, produs prin exces
de nocicepie datorit compresiei volumului tumoral, inflamaiei locale, ischemiei, toate aceste informaii fiind transmise specific cortexului, sunt modulate
prin metode speciale susinute de sistemul simpatic
i parasimpatic, de aceea ea este difuz i referit.
Emoiile puternice, ca de exemplu anxietatea, sunt
evocate prin stimulii viscerali i n acelai timp pot
exacerba simptomele viscerale, preponderent durerea. De aceea terapia durerii viscerale oncologice
trebuie s se adreseze att factorilor emoionali, ct i
celor fizici pentru a i se respecta dreptul pacientului
diagnosticat cu aceast boal s nu sufere i s i se
amelioreze durerea.
unul.
Bibliografie
1. Doyle D., Hanks G.W.C., Mac Donald N. Oxford Textbook of Palliative Medicine. Oxford
University Press. 2001.
2. Woodrruff R. Palliative Medicine. Evidence-based symptomatic and supportive care for patients
with advanced cancer. Oxford University Press. 2005.
3. De Leon-Casasola O.A. Cancer Pain. Pharmacological, Interventional and Palliative Care
Approaches. Saunders Elsevier. 2006.
4. Davis M., Glare P., Hardy J. Opioids in Cancer Pain. Oxford University Press. 2005.
5. Vibes J. Guide de la Douleur. Le syndrome douloureux chronique. Editions Estem. 2001.
6. Patt R.B, Lang S.S. The Complete Guide to Relieving Cancer Pain and Suffering. Oxford
University Press . 2004.
7. Simpson K.H., Budd K. Cancer Pain Management. A comprehensive approach. Oxford
University Press. 2000.
47
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- perspectives;
- consensus declaration coming from an asso
ciation or from a group of specialists;
- letters to the editor.
3. Permissions and Ethics

For citations, tables, figures etc. which are not
original, these must be accompanied by the
written permission for their use and the full
reference. Photographs of identifiable persons
must be sent alongside the written permission of
the person(s) and all regions that may allow the
identification of the subject must be covered.
The author must have obtained, for all studies
including human subjects, the permission of the
subjects to be part of the study whilst keeping
their anonymity. By sending the article, the
author declares that he obtained this permission
from all his subjects. All studies must respect the
Helsinki Declaration (1975).
For human and animal studies, the authors
must have obtained the approval of the ethics
committee from the University/Institute/etc.
where the study was done.
4. Writing the article

Abstracts and Keywords. Each article must
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and bilingual keywords (3-5).
For case presentations we recommend that the
authors first describe the initial condition of the
patient, followed by the clinical and laboratory
exams, the discussion of the differential diagnosis
and treatment. The case report should end with
the presentation of the evolution of the patient
from admission until the last contact.
For reviews, consensus declarations and
perspective articles the abstract will contain
a general description of the article contents.
48
Letters to the editor must not be accompanied

by an abstract.
The Article Text
For original articles:
Introduction
Methods
Results
Discussion
For all other types of articles we recommend the use of
a clear structure based on sections and sub-sections.
5. Bibliography
The references will be written using the
Vancouver style.
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By sending the article for publication the
author(s):
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the text and for the accuracy of the send data;
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further plagiarism accusation are addressed
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manuscript);
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editorial office reserves the right to publish the
materials in any journals/magazines.
The official recommendations for medical
journals and articles can be consulted at:
www.icmje.org.
Not
taking
into
consideration
the
recommendations mentioned before can lead
to delay in publishing the materials or may
lead to not publishing the article.
For more detailed instructions visit the journals
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Instruciuni pentru autori

1. Trimiterea materialelor
Materialele vor fi trimise la:
valentin.radoi@mediasyscom.ro.
Fiecare articol este evaluat de comitetul de peerreview, format din doi refereni independeni, respectndu-se anonimatul autorului, conform protocolului de peer-review.
2. Manuscrise publicate/transmise spre publicare

Revista Romanian Journal of Oncology and Hematology public:
- articole originale;
- rezumate ale literaturii (review);
- prezentri de caz;
- articole de perspectiv;
- declaraii de consens din partea unei asociaii sau
grup de profesioniti;
- scrisori ctre editor.
3. Permisiuni i etic
Pentru citri, tabele, figuri etc. care nu sunt originale,
acestea trebuie nsoite de permisiunea scris pentru reproducere a autorului mpreun cu referinele
n ntregime. Fotografiile persoanelor identificabile
trebuie s fie nsoite de acordul acestora semnat
pentru publicare sau, n caz contrar, vor trebuie
acoperite toate regiunile care permit identificarea
persoanei. Autorul trebuie s fi obinut anterior,
pentru toate studiile care includ subieci umani, permisiunea acestora pentru a face parte din studiu,
fiindu-le respectat anonimitatea. Prin trimiterea articolului autorul declar c a obinut aceast permisiune de la toi pacienii. n cazul studiilor cu subieci
umani, protocolul trebuie s respecte Declaraia de
la Helsinki (1975). n cazul studiilor cu oameni sau
animale, autorii trebuie s fi obinut acordul comisiei
de etic de la Universitatea/Institutul/etc. n cadrul
cruia studiul a fost realizat.
4. Redactarea articolelor
Rezumate i cuvinte-cheie. Fiecare articol trebuie
nsoit de un rezumat redactat obligatoriu n limbile romn i englez i de cuvinte-cheie n limbile
romn i englez (3-5).
Pentru prezentrile de caz se recomand descrierea
strii iniiale a bolnavului, examenul clinic i paracli
nic efectuat, discutarea diagnosticului diferenial i a
tratamentului, urmat de prezentarea evoluiei bolnavului pn la ultimul contact cu acesta.
Pentru rezumate ale literaturii (review-uri), declaraii
de consens i articole de perspectiv, rezumatele vor
cuprinde descrierea general a tematicii prezentate.
Scrisorile ctre editor nu trebuie nsoite de abstract.
Text. n cazul articolelor originale n text se va respecta urmtoarea succesiune:

Introducere
Metode
Rezultate
Discuie
n cazul celorlalte tipuri de articole publicate de ctre
revista Romanian Journal of Oncology and Hematology, se recomand folosirea unei structuri clare
bazate pe capitole i subcapitole.
5. Bibliografie
Pentru referine se va folosi stilul de citare Vancouver.
6. Drepturi de autor
Prin transmiterea ctre redacie a manuscriselor spre
publicare, autorii:
- i asum rspunderea integral pentru coninutul
tiinific al manuscrisului transmis i acurateea datelor prezentate;
- i asum calitatea de (co)autor al manuscrisului (orice eventual acuzaie ulterioar de plagiat
adresndu-se exclusiv autorului/autorilor care au
semnat manuscrisul respectiv);
- declar c sunt proprietarii de drept ai imaginilor
i/sau informaiilor propuse spre publicare sau c au
permisiunea de reproducere n vederea publicrii
n revista Romanian Journal of Oncology and Hematology pentru materialele ale cror drepturi de
proprietate intelectual nu le aparin;
- declar pe propria rspundere c mesajul/coninutul
manuscrisului nu este influenat i/sau dictat de interese
comerciale, de angajamente prealabile sau de orice
alte relaii cu tere persoane care ar putea fi considerate
conflicte de interese;
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System Communications.
7. Alte precizri
Limitrile expuse anterior pot fi ignorate n situaii
deosebite, cu acceptul prealabil al redactorului-ef
i/sau Publisher-ului.
Materialele publicate nu se restituie. Redacia i
asum dreptul de a republica materialele n aceeai
revist i/sau de a aviza favorabil republicarea manuscriselor n alte reviste.
Versiunea oficial i integral a recomandrilor pentru revistele biomedicale se poate consulta la adresa:
www.icmje.org. Nerespectarea recomandrilor de
mai sus poate duce la ntrzieri n publicarea materialelor sau la decizia de nepublicare a acestora.
Pentru instruciuni mai detaliate v rugm s vizitai
site-ul web al jurnalului.
49
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