Evolving Approaches

to Improve Outcomes
and Minimize Toxicities
in Radiation Therapy
San Francisco, Calif., USA, November 4, 2001

Guest Editor
Gillian M. Thomas, Toronto, Canada

24 figures and 17 tables, 1999

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 Vol. 63, Suppl. 2, 2002

Contents

1 Foreword
Thomas, G.M. (Toronto)

2 Radioprotectants: Current Status and New Directions

Grdina, D.J.; Murley, J.S.; Kataoka, Y. (Chicago, Ill.)

11 Prevalence of Anemia in Cancer Patients Undergoing Radiotherapy:

Prognostic Significance and Treatment
Harrison, L.B.; Shasha, D.; Homel, P. (New York, N.Y.)

19 Raising Hemoglobin: An Opportunity for Increasing Survival?

Thomas, G.M. (Toronto)

29 New Chemotherapeutic Agents: Update of Major Chemoradiation Trials

in Solid Tumors
Curran, W.J. (Philadelphia, Pa.)

© 2002 S. Karger AG, Basel

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 Oncology 2002;63(suppl 2):1
DOI: 10.1159/00067144
Foreword
A variety of techniques are now available to radiation
oncologists to optimize treatment of cancers, including
altered fractionation schedules, enhanced image guidance,
intensity modulation allowing radiation dose escalation
and improved brachytherapy techniques. In recent years,
there has been increasing interest in the concurrent or
sequential use of chemotherapeutic agents with radiosensi-
tizing ability to enhance the effectiveness of radiotherapy.
These agents include cisplatin, 5-fluorouracil, taxanes, to-
potecan, gemcitabine, vinorelbine, and tirapazamine. In
certain malignancies (e.g., non-small-cell lung cancer, head
and neck cancers, esophageal cancer and cervical cancer),
concurrent chemotherapy and radiotherapy protocols have
resulted in better tumor control and/or patient survival
than with radiotherapy alone. The review by Dr. Curran in
this supplement provides an update of recent clinical trials
in this area, and emphasizes that while much has been
achieved in the quest for new combined modality regimens
capable of improving the outcomes for patients with can-
cer, important questions concerning the selection of pa-
tients, and the optimal dosages and timing of sequential
therapies remain to be answered in future studies.
Other evolving approaches to optimizing radiotherapy
include the use of radioprotectants to reduce radio-
therapy-induced toxicity without affecting its antitumor
efficacy, cytotoxic agents such as mitomycin C to specifi-
cally target hypoxic tumor cells, and strategies to counter
anemia such as treatment with epoetin alfa (recombinant
human erythropoietin). It is postulated that anemia in
cancer patients may result in a poor treatment outcome
because of an increased resistance to radiation or chemo-
therapy. Radioprotectants currently under investigation
include amifostine (WR-1065), which has been shown in
experimental studies to prevent both radiation-induced
cell death and radiation-induced mutagenesis. Moreover,
this agent reduced the incidence of early and late radio-
therapy-induced xerostomia in a multicenter clinical
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study of patients with head and neck cancers. Other
potential applications of amifostine are reviewed in the
article by Dr. Grdina and colleagues, along with recent
advances in the development of newer cytoprotectants to
reduce the acute and chronic toxicities associated with
high-dose treatment strategies and aggressive combined
modality protocols.
The occurrence of anemia in cancer patients is an often
overlooked complicating factor that is associated with
poorer outcome possibly by decreasing the response to
radiotherapy, presumably via lowering the oxygen-carry-
ing capacity of the blood and thus exacerbating intratu-
moral hypoxia. In addition, anemia has an adverse effect
on the quality of life of cancer patients, as evidenced by
the increased fatigue that has been associated with low
hemoglobin levels. Studies in various types of cancers
have indicated that a high proportion of patients are
anemic prior to or during radiotherapy, and that low
hemoglobin levels are associated with poor clinical out-
comes with radiotherapy. As emphasized in other articles
in this supplement, these findings underline the impor-
tance of early detection and treatment of anemia in cancer
patients. Administration of epoetin alfa to correct anemia
has been reported to enhance locoregional response rates
to chemoradiation therapy in patients with certain types
of cancers (e.g., oropharyngeal squamous cell carcinomas)
and to improve quality of life. Whether epoetin alfa thera-
py will also increase long-term survival is currently being
investigated. Other ongoing studies are investigating
whether epoetin alfa may also be effective in protecting
against radiotherapy-induced neurotoxicity.
The challenge for the future is to utilize our present
knowledge to optimize the management of cancer pa-
tients undergoing radiotherapy or combined modality
protocols with the objective of improving both the out-
come of treatment and quality of life.
Gillian M. Thomas
Gillian M. Thomas
Radiation Oncology, Obstetrics & Gynecology
University of Toronto
Toronto-Sunnybrook Regional Cancer Centre
Toronto, Onta. (Canada)
 Oncology 2002;63(suppl 2):2–10
DOI: 10.1159/000067146
Radioprotectants: Current Status and
New Directions
David J. Grdina Jeffrey S. Murley Yasushi Kataoka
Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Ill., USA
Key Words
Cytoprotection W Radiotherapy W Radiation-induced
toxicity W Mutagenesis W Amifostine W Thiol compounds
Abstract
The ability to prevent radiotherapy-induced toxicity with-
out affecting antitumor efficacy has the potential to
enhance the therapeutic benefit for cancer patients with-
out increasing their risk of serious adverse effects.
Among the currently available cytoprotective agents ca-
pable of protecting normal tissue against damage
caused by either chemo- or radiotherapy, only amifos-
tine has been shown in clinical trials to reduce radiation-
induced toxicity. Most notably, it reduces the incidence
of xerostomia, which is a clinically significant long-term
toxicity arising in patients undergoing irradiation of head
and neck cancers. In vitro studies with the active metabo-
lite of amifostine (WR-1065) have shown it to prevent
both radiation-induced cell death and radiation-induced
mutagenesis. The potential of this agent to prevent sec-
ondary tumors, as well as other radiation-induced toxici-
ties is now the focus of ongoing research. Among other
novel approaches to radioprotection being explored are
methods to increase levels of the antioxidant mito-
chondrial enzyme manganese superoxide dismutase
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(MnSOD). In addition, the use of epoetin alfa, alone or in
combination with cytoprotectants (e.g., amifostine), to
treat radiation-induced anemia is also being investi-
gated. The objective of developing newer cytoprotective
therapies is to improve the therapeutic ratio by reducing
the acute and chronic toxicities associated with more
intensive and more effective anticancer therapies.
Copyright © 2002 S. Karger AG, Basel
Introduction
Radiotherapy is toxic not only toward cancer cells but
also to healthy cells, particularly those with a high rate of
proliferation, which may result in serious adverse effects
for patients. The risk of cell toxicity is increased with the
application of more intensive radiotherapy techniques
intended to increase tumor cell kill. Radiation-induced
adverse effects commonly include mucositis and/or der-
matitis, and are usually managed symptomatically as they
manifest. However, preventing these complications is
clearly more desirable, and various approaches to reduc-
ing radiation-induced toxicities while maintaining antitu-
mor efficacy have been investigated. These include al-
tered radiation dose fractionation, the use of physical
shielding or intensity modulated radiation therapy to
David J. Grdina
Department of Radiation and Cellular Oncology
University of Chicago Medical Center, MC 1105
5841 S. Maryland Avenue, Chicago, IL 60637 (USA)
Tel. +1 773 702 5250, Fax +1 773 702 5940, E-Mail dgrdina@rover.uchicago.edu
reduce the volume of exposure, and pharmacologic ap-
proaches. The latter can be divided into radiosensitizers
which ideally differentially enhance the sensitivity of
tumors rather than normal tissue, and radioprotectants to
reduce the detrimental effects of radiation on normal tis-
sue while maintaining tumor sensitivity [1, 2]. This article
reviews the current status of radioprotectants in cancer
therapy and provides an insight into some of the new
directions that research in this area is taking.
Typical response curves illustrating the probability of
tumor control and normal tissue damage at varying radia-
tion doses are shown in figure 1. The objective of radio-
protection is to shift the response curve for normal tissue
as far as possible to the right to achieve the highest proba-
bility of tumor control with the least amount of damage to
normal tissue. The ideal radioprotectant is one that pro-
tects normal tissue while preserving antitumor effective-
ness, and is itself without moderate or severe toxicity.
Pharmacologic Strategies for Cytoprotection
of Normal Cells
In recent years, a number of cytoprotective agents
capable of protecting normal tissue against damage
caused by either chemo- or radiotherapy have been devel-
oped. As a result of studies implicating toxic metabolites
of chemotherapeutic agents and/or the generation of high-
ly reactive species or free radicals in the etiology of DNA
damage [3–5], a number of different strategies have been
proposed for cytoprotection of normal cells, including:
E preventing the generation of toxic metabolites of che-
motherapeutic agents;
E enhancing the elimination of toxic metabolites of che-
motherapeutic agents;
E neutralizing DNA adduct-forming metabolites;
E detoxifying free radicals.
A number of compounds have been investigated with
the objective of providing site-specific protection for nor-
mal tissues without compromising the antitumor efficacy
of chemotherapeutic agents and/or radiotherapy, includ-
ing amifostine (WR-2721), dexrazoxane, mesna, gluta-
thione, and N-acetylcysteine. Among these, amifostine,
dexrazoxane and mesna have FDA approval for use in
cytoprotection.
Amifostine
Amifostine (WR-2721) is a nucleophilic sulfur prodrug
that is dephosphorylated in vivo by membrane-bound
alkaline phosphatase to the active, free thiol metabolite
Prevention of Radiation-Induced Toxicity
100
or normal tissue damage (%)
Probability of tumor control
75
Tumor
Normal tissue
50
25
0
A B C
Radiation dose
Fig. 1. Tumor and normal tissue response curves to radiotherapy,
illustrating the probability of tumor control and normal tissue dam-
age at varying radiation doses (reproduced with permission from
Hall [12]).
WR-1065. This metabolite is then oxidized to the disul-
fide form WR-33278 [4–6]. Numerous preclinical studies
have shown that amifostine protects normal cells against
the adverse effects of both radiation and chemotherapeut-
ic agents (e.g., alkylating agents, platinum compounds,
anthracyclines and taxanes) without attenuating their cy-
totoxic effects on large solid tumors. This selective protec-
tion is due, in part, to the more efficient conversion and
uptake of the active metabolite WR-1065 in normal tissue
in comparison with neoplastic tissue, as a result of the
higher alkaline phosphatase activity, greater vasculariza-
tion, and higher pH of normal tissue [4–6].
Following intravenous administration, amifostine is
rapidly and extensively taken up by normal tissue. Ani-
mal studies have indicated that maximal concentrations
of the active metabolite WR-1065 occur 5–15 min after
administration [7]. Uptake of WR-1065 in normal tissue
is not uniform, and appears to be greatest in the kidney,
salivary glands, intestinal mucosa, liver and lung [6].
Once inside the cell, WR-1065 protects against chemo-
therapy- and radiotherapy-induced DNA damage by (1)
binding to and neutralizing the reactive species of organo-
platinum and alkylating agents, thus preventing forma-
tion of adducts with DNA, and (2) scavenging free radi-
cals [5–7].
Oncology 2002;63(suppl 2):2–10 3
Table 1. Net charges of thiol compounds with putative cytoprotec-
tive activity
Compound Net charge
WR-33278 (disulfide metabolite of amifostine) +4
WR-1065 (free thiol metabolite of amifostine) +2
Cystamine +2
Cysteamine +1
Captopril 0
Dithiothreitol (DTT) 0
2-Mercaptoethanol (2-ME) 0 Mesna (sodium 2-mercaptoethane sulfonate) was de-
N-Acetyl-L-cysteine (L-NAC) –1
N-Acetyl-D-cysteine (D-NAC) –1
Mesna –1
Glutathione, reduced (GSH) –1
Glutathione, oxidized (GSSG) –2
The efficacy of amifostine in protecting cancer patients
against radiotherapy-induced toxicity is discussed below.
Currently, amifostine has FDA approval to reduce the
incidence of xerostomia in patients undergoing radiation
treatment for head and neck cancers. It is also approved to
reduce cumulative renal toxicity associated with cisplatin
treatment in patients with ovarian cancer or non-small-
cell lung cancer.
Dexrazoxane
Dexrazoxane (ICRF-187) is a cyclic derivative of the
metal-chelating agent ethylenediamine-tetraacetic acid
(EDTA) that provides protection against the cardiotoxici-
ty of anthracycline-based chemotherapeutic agents, such
as doxorubicin. Although the risk of cardiotoxicity ap-
pears to be reduced with newer formulations, such as
peglyated liposomal doxorubicin [8], cardiotoxicity is a
well-recognized, serious, treatment-limiting adverse ef-
fect of these compounds. It occurs via the generation of
reactive oxygen species, which are highly toxic to cardiac
tissues, by the stable complexes formed between anthra-
cycline drugs and iron [9]. The cardioprotective effect of
dexrazoxane is believed to result from its intracellular
metabolism to a ring-opened hydrolysis product (ICRF-
198), which is a strong chelator of free and bound intracel-
lular iron in the myocardium. As a consequence, the
amount of iron available to form complexes with anthra-
cyclines is reduced and formation of the reactive oxygen
species is blocked. Importantly, the protective effect of
dexrazoxane against the cardiotoxicity of anthracycline
drugs occurs without affecting their antitumor activity.
This may be due, in part, to differences in the intracellular
4 Oncology 2002;63(suppl 2):2–10
metabolism of dexrazoxane and/or differences in its uptake
between normal cardiac cells and tumor cells [5, 9–11].
Currently, dexrazoxane has FDA approval to reduce
the incidence and severity of cardiomyopathy associated
with doxorubicin administration in women with meta-
static breast cancer who have received cumulative doses
1300 mg/m2.
Mesna
veloped as a specific chemoprotectant against the toxicity
of acrolein, a urotoxic metabolite of oxazaphosphorine-
based alkylating agents (e.g., ifosfamide and cyclophos-
phamide), which produces hemorrhagic cystitis following
its excretion into the urinary bladder. Following intrave-
nous administration, mesna is converted into an inactive
disulfide form in the blood and is then metabolized back
to mesna in the urinary tract where its free sulfhydryl
groups bind to and inactivate acrolein, forming a stable,
non-toxic thioether that is rapidly excreted in the urine.
Mesna also inhibits the further formation of acrolein in
the bladder. Because its activity is restricted to the urinary
tract, the systemic activity and non-urologic toxicity of
oxazaphosphorine drugs are not affected [4, 5].
Currently, mesna has FDA approval for the prophylax-
is of ifosfamide-induced hemorrhagic cystitis.
Relationship Between the Net Charge of Thiol
Compounds and Their Ability to Protect
Against Radiation-Induced DNA Damage
The mechanism by which radiation induces DNA
damage is slightly different to that of chemotherapeutic
agents. Radiation-induced damage is introduced into a
genome by either a direct action, where the energy is
deposited directly on the genome, or indirectly via the for-
mation of free radicals which are responsible for the resul-
tant cell killing, mutagenesis, transformation, and carci-
nogenesis. The latter mechanism, which accounts for
about 75% of radiation-induced DNA damage by pho-
tons, can be abrogated with free radical scavengers
present in the local microenvironment at the time the free
radicals are formed. However, in the case of direct dam-
age, there are no known radioprotectants as this process
occurs too rapidly to be prevented by a pharmacologic
agent [12].
Studies performed several years ago by Fahey et al.
have shown that the net charge of thiol compounds with
putative cytoprotective activity (table 1) markedly in-
Grdina/Murley/Kataoka
 1.0
a a
1.0

Surviving fraction of cells

Surviving fraction of cells

0.1
0.1

60
Co γ - radiation
60
Co g-radiation WR - 1065 after 60
Co γ - radiation
WR-1065 before Co γ-radiation
60
0.01
0.01 100 b

HPRT mutants per 106 survivors

100 b
80
mutants per 106 survivors

80

60
60
HPRT

40 40

20 20

0 0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
60
Co g dose (Gy) 60
Co γ dose (Gy)

Fig. 2. Response to varying doses of 60Co Á-radiation of V79 Chinese
hamster lung fibroblast cells in the absence or presence of WR-1065
4 mmol/l added to cell cultures 30 min before irradiation and allowed
to remain until 3 h after irradiation. a Surviving fraction of cells.
b Mutation induction at the HPRT (hypoxanthine-guanine phospho-
ribosyl transferase) locus among surviving cells that were grown in a
non-selective medium for 6 days and then exposed to 6-thioguanine
5 Ìg/ml in ·-MEM-10 medium (containing hypoxanthine, aminop-
terin and thymidine) for 7 days and stained with 0.5% methylene
blue. Bars indicate the standard errors of the mean of two or more
replicate experiments (reproduced with permission from Grdina et
al. [15]).
Fig. 3. Response to varying doses of 60Co Á-radiation of V79 Chinese
hamster lung fibroblast cells exposed immediately after irradiation to
WR-1065 4 mmol/l added to cell cultures and allowed to remain for
3 h. a Surviving fraction of cells. b Mutation induction at the HPRT
(hypoxanthine-guanine phosphoribosyl transferase) locus among sur-
viving cells (assessed as described in fig. 2). The broken lines repre-
sent the radiation-only curves and are presented for comparison.
Bars represent the standard errors of the mean of two or more repli-
cate experiments (reproduced with permission from Grdina et al.
[15]).

fluences the degree of protection that they provide against
the DNA-damaging effects of radiation [13, 14]. Because
WR-1065 has a net charge of +2, it will be attracted to
DNA (which is negatively charged) and is therefore more
likely to exert a protective effect against radiation-
induced damage than a compound with a net charge of 0
or a negative net charge. Evidence in support of this
hypothesis has come from studies with WR-1065, capto-
pril, and N-acetylcysteine in Chinese hamster lung fibro-
blast and ovary cells.
Protective Effect of WR-1065 (Amifostine Metabolite)
Studies in our institution using V79 Chinese hamster
lung fibroblast cells have shown that WR-1065 in a con-
centration of 4 mmol/l protects against radiation-induced
cell death when added to cell cultures 30 min before var-
ious doses of 60Co Á-radiation, but not when it is added
immediately after irradiation (fig. 2a, 3a). This treatment-
schedule dependence in the protective effect of WR-1065
is to be expected if it is acting as a free radical scavenger,
since protection could only be expected to occur when the
compound is present during irradiation [15].

Prevention of Radiation-Induced Toxicity Oncology 2002;63(suppl 2):2–10 5

 10 0
10 0
60
Co γ-radiation 60
Co -radiation
Surviving fraction of cells

Surviving fraction of cells

10 -1

10 -1

Radiation only
10 -2 Radiation +
4 mmol/l N-acetylcysteine
Without captopril Radiation +
0.04 mmol/l N-acetylcysteine
With 1 mmol/l captopril

10 -2 10 - 3
0 200 400 600 800 1,000 0 200 400 600 800 1,000
60
Co γ dose (cGy) 60
Co γ dose (cGy)

Fig. 4. Surviving fractions of Chinese hamster ovary (CHO)-AA8 Fig. 5. Surviving fractions of Chinese hamster ovary (CHO)-AA8
cells exposed to varying doses of 60Co Á-radiation in the absence or cells exposed to varying doses of 60Co Á-radiation in the absence or
presence of captopril 1 mmol/l added to the cell cultures 30 min prior presence of N-acetylcysteine 0.04 mmol/l and 4 mmol/l added to the
to irradiation (Grdina DJ, unpubl. data). cell cultures 30 min prior to irradiation (Grdina DJ, unpubl. data).

As well as increasing the surviving fraction of cells
when administered before irradiation, WR-1065 has also
been shown to reduce the degree of radiation-induced
mutagenesis in V79 Chinese hamster lung fibroblast cells
(expressed as the HPRT mutant frequency per 106 survi-
vors exposed to 6-thioguanine 5 Ìg/ml) (fig. 2b). In con-
trast to the treatment-schedule dependence for the protec-
tive effect against cell killing, the antimutagenic effect of
WR-1065 is also observed when it is administered after
irradiation (fig. 3b), indicating that its post-irradiation
action can effectively alter mutation induction in surviv-
ing cells [16].
of a protective effect against radiation-induced cell killing
with either drug (fig. 4, 5) [Grdina DJ, unpubl. data].
Thus, key factors governing the radioprotective effica-
cy of a drug acting as free radical scavenger are: (1) an
ability to concentrate within the nucleus or microenviron-
ment of DNA (dependent on its net charge), and (2) the
presence of the protectant at the radiation target at the
time it is irradiated (important for prevention of cell
death). No clinical advantage is achieved if the protector
does not differentially protect normal tissues compared to
tumor.

Lack of Protective Effect of Captopril and Dose-Response Considerations with

N-Acetylcysteine
Because the net charges of captopril and N-acetylcys-
teine are 0 and –1, respectively, these thiol compounds
would not be expected to concentrate within the nega-
tively charged nucleus or the microenvironment of DNA
to the same extent as those with positive net charges.
Studies using Chinese hamster ovary (CHO)-AA8 cells
exposed to various doses of 60Co Á-radiation in the
absence or presence of captopril 1 mmol/l and N-acetyl-
cysteine 0.04 mmol/l or 4 mmol/l have shown no evidence
Amifostine: Prevention of Cell Death vs
Prevention of Mutagenesis
The protection factor achievable with a radioprotec-
tant is defined as the ratio of surviving cell fraction for
treated cells as compared with untreated cells following
radiation exposure. The clinical potential of a putative
radioprotectant depends on the tolerability of the drug at
a dosage required to achieve a particular protection fac-
tor. In studies conducted at our institution using CHO-

6 Oncology 2002;63(suppl 2):2–10 Grdina/Murley/Kataoka

AA8 cells, the protection factor for cell survival with the
amifostine metabolite WR-1065 (i.e., the ratio of cell sur-
viving fractions for WR-1065-treated versus untreated
cells) was determined at various concentrations of WR-
1065 added to the incubation medium 30 minutes prior
to exposure to a radiation dose of 750 cGy from a 60Co
Á-ray source. As shown in figure 6, the protection factor
fell sharply from 16 to around 3 as the concentration of
WR-1065 was decreased from 4 to 1 mmol/l, and then
declined further to essentially no protection at lower con-
centrations of 0.01–0.1 mmol/l. In contrast, the protec-
tion against mutagenesis (expressed as the HPRT mutant
frequency per 106 survivors exposed to 6-thioguanine 5
Ìg/ml) remained largely constant over the same WR-1065
concentration range (0.01–4 mmol/l). This suggests that
the mechanism by which WR-1065 provides protection
against mutagenesis differs from that for protection
against cell killing, and that the antimutagenic effect
can be achieved at lower concentrations (as low as
0.01 mmol/l) [16].
Viewed in relation to therapeutic use of amifostine, the
concentrations of WR-1065 achieved with dosages of am-
ifostine used clinically are in the range 1.5–3.85 mmol/l
[17], which suggests that the degree of cytoprotection pro-
vided at antimutagenic dosages are insufficient to in-
crease survival of either normal or neoplastic cells. How-
ever, its effect in reducing the risk of radiation-induced
mutagenesis, carcinogenesis, and secondary tumors is of
considerable interest and this area is now an important
focus for ongoing research into the protective effects of
amifostine, particularly in view of increasing evidence
that the risk of secondary tumors is increased as cancer
therapies become more effective and, coincidentally,
more damaging to normal tissues.
Clinical Studies of Amifostine as a
Radioprotectant
Clinical trials of the radioprotective effect of amifos-
tine have been undertaken in patients receiving radiother-
apy for head and neck, pelvic, and thoracic cancers [6].
Thus far, most studies have involved relatively small
numbers of patients but have generally demonstrated sig-
nificant reductions in the incidence of radiation-induced
local toxicities. In the largest trial conducted to date, the
efficacy of amifostine in ameliorating the adverse effects
of radiotherapy and its influence on the clinical effective-
ness of radiotherapy were evaluated in patients with pre-
viously untreated head and neck squamous cell carcino-
Prevention of Radiation-Induced Toxicity
8
6
Protection factor (cell survival)
4
2
0
0.01 1 4
0.1
WR-1065 concentration (mmol/l)
Fig. 6. Protection factor for survival of Chinese hamster ovary
(CHO)-AA8 cells (i.e., the ratio of cell surviving fractions for WR-
1065-treated to untreated cells) at varying concentrations of WR-
1065 added to the incubation medium 30 min prior to exposure to a
radiation dose of 750 cGy from a 60Co Á-ray source. All plot points
are the average of three separate experiments and the bars represent
the standard errors of the mean (reproduced with permission from
Grdina et al. [16]).
mas [18]. Patients in this multicenter study (n = 303)
received radiotherapy in a dose of 1.8 to 2.0 Gy/day for 30
to 35 fractions (total dose 50–70 Gy), approximately half
of whom (n = 153) were randomized to receive amifostine
(200 mg/m2 intravenously over 3 min) 15 to 30 min be-
fore irradiation and half to receive radiotherapy alone
(n = 150). As shown in table 2, amifostine significantly
reduced the incidence of both early xerostomia within the
first 90 days (as well as the cumulative radiotherapy dose
required to cause this adverse effect) and late xerostomia
at 1 year after initiation of radiotherapy, although it did
not significantly reduce the incidence of acute mucositis.
Patients who received amifostine were also found to pro-
duce more saliva than those treated with radiotherapy
alone (median saliva production 0.26 vs 0.10 g; p = 0.04).
When overall survival data for the two groups of patients
were compared, there was a slight advantage for those
receiving amifostine (fig. 7), but the difference was not
statistically significant. Nor was there any significant dif-
Oncology 2002;63(suppl 2):2–10 7
 100
(124)
90
(104)
80 (119)

70 (98)

Percent survival
60

50 Total No.
Fig. 7. Percentages of survivors over a peri-
Events of patients
od of 27 months among patients with pre- 40 Amifostine + radiotherapy 34 153
viously untreated head and neck squamous
30 Radiotherapy alone 45 180
cell carcinomas who were randomized to
receive either amifostine (200 mg/m2 i.v. 20
Log-rank: p = 0.184
over 3 min) 15–30 min before radiotherapy Hazard ratio: 1.351 (95% Cl 0.865 - 2.109)
doses of 1.8–2 Gy/day for 30 to 35 fractions 10
(total 54–70 Gy) or similar doses of radio- 0
therapy alone. The numbers of patients at
0 3 6 9 12 15 18 21 24 27
risk at 12 and 18 months are indicated in Months
parentheses (reproduced with permission
from Brizel et al. [18]).

Table 2. Incidence of acute and late

xerostomia 6grade 2 (RTOG acute/late Complication Amifostine plus Radiotherapy p value
morbidity scoring criteria) in patients with radiotherapy alone
head and neck squamous cell carcinomas (n = 153) (n = 150)
who received radiotherapy with or without
amifostine (200 mg/m2 i.v. 15–30 min Acute xerostomiaa
prior to irradiation) [18] Incidence (% of patients) 51% 78% ! 0.0001
Cumulative radiotherapy
dose to onset 60 Gy 42 Gy ! 0.0001
Late xerostomiab
Incidence (% of patients) 34% 57% ! 0.002

RTOG = Radiation Therapy Oncology Group.

a Within 90 days of initiation of radiotherapy.
b At 1 year after initiation of radiotherapy.

ference between the two groups in locoregional tumor
control rates. Thus, amifostine significantly reduced acute
and chronic xerostomia in these patients without com-
promising the antitumor effectiveness of radiotherapy
[18].
Potential Future Applications of Amifostine
Other potential roles for amifostine that are being
explored include reducing renal toxicity associated with
cisplatin treatment in ovarian cancer and non-small-cell
lung cancer and reduction of toxicities associated with
doxorubicin- and paclitaxel-containing regimens, high-
dose chemotherapies, and multimodality chemotherapy
and radiotherapy for a variety of solid tumors. Possible
prevention of secondary tumors (see above), is also being
explored. In addition, the observation that amifostine
may stimulate bone marrow progenitor cells has led to
studies of its use as a potential treatment for patients with
myelodysplastic syndrome. As yet, however, clinical data
are limited and its value in this setting remains to be clari-
fied [6].

8 Oncology 2002;63(suppl 2):2–10 Grdina/Murley/Kataoka

 New Advances in Cytoprotection
A number of newer potential radioprotectants are cur-
rently undergoing preclinical research, including: (1) The
amifostine analog S-[2-(3-methylaminopropyl) aminoe-
thyl] phosphorothioate acid, which is orally bioavailable
and less toxic than amifostine; (2) thiolamine compounds
with thioglycoside-protecting groups; (3) covalent conju-
gates of thioamines and antioxidant vitamins, and (4) sel-
enazolidine prodrugs.
In addition, other approaches to radioprotection are
also being explored. These include altering endogenous
levels of antioxidant enzymes (specifically the mitochon-
drial enzyme manganese superoxide dismutase [MnSOD]
which protects against oxidative stress induced by various
agents including irradiation), and enhancement of eryth-
ropoiesis to treat the anemia that commonly occurs dur-
ing irradiation (see review by Harrison in this supple-
ment). Novel approaches that are currently being investi-
gated include:
E The use of MnSOD plasmid/liposome complex gene
therapy to protect against radiation-induced esophagi-
tis. Improved tolerance of the esophageal epithelium to
fractionated radiation has recently been demonstrated
with this approach in a mouse model [19, 20].
E The use of nonprotein thiol-containing compounds to
activate MnSOD gene expression, e.g., the amifostine
metabolites WR-1065 and WR-33278, N-acetylcys-
teine, mesna, captopril, oltipraz, and dithiothreitol
[21–23]. In human microvascular endothelial cells,
exposure to WR-1065 0.04 mmol/l for 30 min has been
shown to cause an increase in MnSOD gene expression
that begins about 12 h after exposure to WR-1065,
peaks at 16 to 18 h, and ends after about 22 h [21].
E The use of epoetin alfa (recombinant human erythro-
poietin; r-HuEPO) alone or in combination with cyto-
protectants (e.g., amifostine) to treat radiation-induced
anemia. The interaction of amifostine with epoetin
alfa may produce a synergy in gene activation/expres-
sion (e.g., of the c-myb gene thereby leading to an
increase in hematopoietic progenitor cells), as well as
an increase in myeloproliferation and a reduction of
genomic instability [24–26].
The objective of developing newer cytoprotective ther-
apies is to be able to reduce the acute and cumulative toxi-
cities associated with more intensive and more effective
therapeutic anticancer regimens now being introduced
into clinical practice, whether delivered as radiotherapy,
chemotherapy, or combined modality regimens. The
merging of these technologies will, it is hoped, enhance
the therapeutic benefit for cancer patients without in-
creasing their risk of serious adverse effects, and thus
improving both their quality and duration of life.

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Grdina/Murley/Kataoka
 Oncology 2002;63(suppl 2):11–18
DOI: 10.1159/000067147

Prevalence of Anemia in Cancer Patients

Undergoing Radiotherapy:
Prognostic Significance and Treatment
Louis B. Harrison a Daniel Shasha a Peter Homel b
a Department of Radiation Oncology, Beth Israel Medical Center/St Luke’s-Roosevelt Hospital Center;
b Department of Grants and Research, Beth Israel Medical Center, New York, N.Y., USA

Key Words hemoglobin in patients with certain malignancies. Radia-

Radiotherapy W Anemia W Hypoxia W Radiation-induced
toxicity W Epoetin alfa W Quality of life
Abstract
As the antitumor activity of radiation is mediated via its
tion oncologists need to be aware of the possibility of
anemia in cancer patients undergoing radiotherapy so
that timely intervention can be instituted whenever ane-
mia is diagnosed.
Copyright © 2002 S. Karger AG, Basel

interaction with oxygen to form labile free radicals, the

intratumoral oxygen level has an important influence on
the ability of radiation therapy to kill malignant cells. By
decreasing the oxygen-carrying capacity of the blood,
anemia may result in tumor hypoxia and may have a
negative influence on the outcome of radiotherapy for
various malignancies, even for small tumors not normal-
ly assumed to be hypoxic. In addition, anemia also has a
negative effect on the quality of life of cancer patients, as
evidenced by worsening fatigue. As a high proportion
(about 50%) of cancer patients undergoing radiotherapy
are anemic prior to or during treatment, strategies to cor-
rect anemia and/or the resultant tumor hypoxia are
increasingly being considered an important component
of treatment. In particular, epoetin alfa (recombinant
human erythropoietin), which has proved an effective
and well-tolerated means of raising hemoglobin levels in
anemic patients receiving radiotherapy, potentially
could reverse the negative prognostic influence of a low
Introduction
The objective of radiotherapy in cancer treatment is to
maximize locoregional tumor control and patient surviv-
al. As the antitumor activity of radiation is known to be
mediated via its interaction with oxygen to form labile
free radicals, the intratumoral oxygen level has an impor-
tant influence on the number of free radicals produced
within a tumor and thus on the ability of radiation thera-
py to induce DNA damage in malignant cells. Conse-
quently, the presence of acute or chronic anemia, which
may decrease the oxygen-carrying capacity of the blood
and results in tumor hypoxia, lowers the propensity of
radiotherapy to produce DNA damage and is an obstacle
to achieving maximal locoregional tumor control [1–3]. It
has been estimated that the dose of radiation required to
kill tumor cells under hypoxic conditions is 2 to 3 times

© 2002 S. Karger AG, Basel Louis B. Harrison, MD

ABC 0030–2414/02/0636–0011$18.50/0 Department of Radiation Oncology, Beth Israel Medical Center
Fax + 41 61 306 12 34 10 Union Square East, New York, NY 10003 (USA)
E-Mail karger@karger.ch Accessible online at: Tel. +1 212 844-8087, Fax +1 212 844-8086
www.karger.com www.karger.com/ocl E-Mail Lharrison@bethisraelny.org

1 Hypoxic
Fraction of survivng cells
0.1
0.01
0.001
0 200 400 600
Fig. 1. Enhancement of radiation resistance by hypoxia. The oxygen
enhancement ratio (OER) is the ratio of the radiation dose required
to kill a given fraction of malignant cells in a hypoxic environment in
relation to that in a normoxic environment.
the dose required in a normoxic environment (fig. 1).
Hypoxia has also been found to produce mutations of the
p53 suppressor gene, which results in an increase in angio-
genesis and an increased tendency for the development of
distant metastases. Thus, overcoming hypoxia may have
positive effects on not only locoregional tumor control but
also on decreasing the risk of developing metastatic dis-
ease [1, 3].
Hypoxia is a common characteristic of solid tumors.
Athough the number and size of their hypoxic regions var-
ies substantially [1], hypoxia may be present in even small
tumors at an early stage of development. In the past, the
prevalence of anemia and tumor hypoxia in cancer pa-
tients receiving radiotherapy has been an underappre-
ciated problem that has frequently led to undertreatment.
This article reviews the prevalence of anemia in patients
undergoing radiotherapy, and emphasizes that effective
reversal of anemia can be achieved. Until recently, little
attention has been paid to hemoglobin levels in cancer
patients.
Prognostic Significance of Anemia in Cancer
Patients
Relationships between low hemoglobin levels and in-
tratumoral hypoxia, and between intratumoral hypoxia
and a less favorable prognosis in various cancers have
been identified in studies in which oxygen partial pres-
sures (pO2) were measured in tumor tissue [4–7]. In
12 Oncology 2002;63(suppl 2):11–18
patients with head and neck cancers, a pretreatment
hemoglobin level !11.0 g/dl was found to be a stronger
Normoxic
predictor of poor tumor oxygenation than other factors
such as tumor stage, tumor volume and smoking status
[4]. Even prostate tumors, which are generally not con-
sidered to be hypoxic, have been reported to be associat-
OER = 1,750 ⴜ 700
ed with significantly lower pO2 levels in comparison
= 2.5 with pathologically normal prostate tissue and muscles,
particularly in patients with more advanced (T2/T3)
prostatic tumors and in older individuals (662 years of
800 1,000 1,200 1,400 1,600 1,800 2,000
age) [5].
Radiation dose (cGy)
Effect on Locoregional Tumor Control and Survival
Recent studies have demonstrated an important rela-
tionship between anemia on locoregional tumor control
and patient survival, principally in head and neck can-
cers. In patients with early stage glottic cancers, which are
amongst the smallest tumors treated by oncologists, a
clear relationship has been demonstrated between the pre-
treatment hemoglobin level and the hazard ratio for local
relapse following radiotherapy (50 Gy in 20 fractions over
4 weeks) during a median follow-up period of 6.8 years
[8]. Similarly, studies in patients with squamous cell car-
cinomas of the glottic larynx and head/neck who were
treated with radiotherapy have noted significantly better
2-year locoregional tumor control rates and 2-year surviv-
al rates in those who presented with normal hemoglobin
levels in comparison with those who presented with
below-normal hemoglobin levels (!13 g/dl) (table 1) [9,
10]. In the patients with head/neck cancers, 5-year locore-
gional control and survival rates were also significantly
better in those with normal hemoglobin levels (p ! 0.001
and p ! 0.01, respectively; table 1) [10].
Other studies have shown a relationship between the
post-radiotherapy hemoglobin level and the outcome of
treatment. Among patients with squamous cell carcino-
mas of either the glottic or supraglottic regions who
received primary radiotherapy in doses ranging from 60
to 70 Gy over 6 to 7 weeks, disease-free survival rates
were significantly better in those who had normal hemo-
globin levels (defined as 12–16 g/dl in women, 13.7–
18 g/dl in men) at day 35 of treatment in comparison with
those who had below-normal hemoglobin levels at this
time (p = 0.0012 for glottic carcinoma; p = 0.05 for supra-
glottic carcinoma) (fig. 2) [11].
Effect on Fatigue
In addition to locoregional tumor control and survival,
other outcomes in patients undergoing radiotherapy may
also be influenced by the presence of anemia. Fatigue is
Harrison/Shasha/Homel
 40 Not anemic 37%
Anemic

Percentage of patients with

30 29% 28%]

a fatigue rating >5

20

14%

10
4%

0
Pre-radiotherapy During radiotherapy Post-radiotherapy
Time relative to radiotherapy

Fig. 2. Disease-free survival among patients with squamous cell car- Fig. 3. Percentages of prostate cancer patients with fatigue ratings
cinoma of the glottic and supraglottic regions treated with primary greater than 5 (on a scale of 0–10) before, during and after radiother-
radiotherapy (60–70 Gy in 30–35 fractions over 6–7 weeks) in rela- apy in relation to whether they were anemic (Hb level ! 12 g/dl) or
tion to their hemoglobin (Hb) levels at day 35 of treatment. p Values not anemic at the time (Harrison LB, unpublished data). * Statistical-
indicate differences between disease-free survival in each group for ly significant versus non-anemic patients (p = 0.015).
patients with normal vs below normal Hb levels. Normal Hb values
were defined as 13.7–18 g/dl (8.5–11.0 mmol/l) for men and 12–
16 g/dl (7.5–10.0 mmol/l) for women (reproduced with permission
from van Acht et al. [11]).

Table 1. Influence of anemia on locoregional tumor control rates and survival rates in two studies in patients with
squamous cell carcinomas of the glottic larynx (n = 109) or head/neck region (n = 504) [9, 10]

Patient group Locoregional control rates, % Survival rates, %

2-year 5-year 2-year 5-year

Glottic squamous cell carcinomas [9]

Normal hemoglobin levels 95* NR 88** NR
Anemiaa 66 NR 46 NR
Head/neck squamous cell carcinomas [10]
Normal hemoglobin levels 52** 48** 51* 36*
Anemiab 34 32 37 22

a Hemoglobin ! 13 g/dl.
b Hemoglobin ! 13 g/dl (women) or ! 14.5 g/dl (men).
* p ! 0.01 vs anemic patients; ** p ! 0.001 vs anemic patients; NR = not reported.

one such outcome that has been strongly associated with
anemia [12–14]. In a group of patients with prostate can-
cer treated with radiotherapy at our institution, the per-
centage with a fatigue rating 15 (on a scale of 0–10) fol-
lowing radiotherapy was found to be significantly higher
in those who were anemic (hemoglobin !12 g/dl) than in
those who were not anemic (fig. 3). This finding is of
interest because fatigue is generally not considered a prob-
lem in prostate cancer patients receiving radiotherapy
alone.

Prevalence and Treatment of Oncology 2002;63(suppl 2):11–18 13

Radiotherapy-Associated Anemia
 100 Baseline
During radiotherapy
77% 79%

Patients with anemia (%)

80 75%

63%
55% 32%
60
Fig. 4. The prevalence of anemia (Hb ! 12 44% 45% 44%
g/dl) before and during radiotherapy in pa- 40 16%
tients with different types of cancer treated 26%
at the Department of Radiation Oncology,
20
Beth Israel Medical Center/St Luke’s-Roo- 9%
sevelt Hospital Center, New York between
December 1996 and June 1999. Baseline 0
Breast Colorectal Lung/ Prostate Uterine/ Head/
was defined as within 4 weeks prior to the cancer cancer bronchus cancer cervical neck
first radiation dose. During therapy was de- (n = 81) (n = 64) cancer (n = 90) cancer cancer
(n = 64) (n = 53) (n = 68)
fined as within 3 to 5 weeks of the first radia-
tion dose.

41% of patients were found to be anemic at baseline

2.0
]
(within 4 weeks prior to radiotherapy) and 54% were
1.8 ]
Mean decrease in hemoglobin

anemic within 3 to 5 weeks after receiving the first dose of

during radiotherapy (g/dl)

1.6 ]
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0 were most notable for those with colorectal and lung/
Breast Colorectal Lung Prostate Cervical
cancer cancer cancer cancer cancer
(n = 71) (n = 48) (n = 101) (n = 78) (n = 48)
Fig. 5. Mean decreases in hemoglobin (Hb) levels during radiothera-
py versus preradiotherapy in patients treated at the Department of
Radiation Oncology, Beth Israel Medical Center/St Luke’s-Roosevelt
Hospital Center, New York between December 1996 and June 1999.
Data shown are for patients whose Hb levels decreased during treat-
ment. * Statistically significant difference versus baseline (p !
0.001).
Prevalence of Anemia in Patients Undergoing
Radiotherapy for Various Cancers
Studies of patients presenting for radiotherapy at our
institution between December 1996 and June 1999 (n =
574) have revealed a high prevalence of anemia (hemoglo-
bin !12 g/dl) both before and during irradiation. Overall,
radiation [15]. The prevalence of anemia was higher in
women than in men (54 vs 28% at baseline; 63 vs 43%
]
during radiotherapy), and was higher in patients with cer-
tain types of cancer than others (fig. 4). In particular, high
prevalences of anemia were noted in patients with colo-
rectal, lung/bronchus and uterine/cervical cancers, and
increases in prevalence from baseline to end of therapy
Head/ bronchus cancers (fig. 4). Among patients who experi-
neck
cancer enced a drop in their hemoglobin level during radiothera-
(n = 86)
py, the mean decreases ranged from 0.75 g/dl for those
with breast cancer to 1.8 g/dl for those with head or neck
cancers, and the decreases were statistically significant
(p ! 0.001) in all groups except those with breast and cer-
vical cancer (fig. 5).
When the prevalence of anemia for each cancer type
was stratified by the hemoglobin level measured at base-
line and the lowest level recorded during radiotherapy,
most patients in each group were found to have mild ane-
mia (hemoglobin levels 610 g/dl), which should be easily
correctable. These data, and the findings of studies re-
viewed previously in this article indicating that the pres-
ence of anemia is associated with poorer treatment out-
comes, provide compelling evidence for employing strate-
gies to correct anemia and/or the resultant tumor hypoxia
in cancer patients undergoing radiotherapy.

14 Oncology 2002;63(suppl 2):11–18 Harrison/Shasha/Homel

 100 HBO4
Air
Local relapse-free rate (%)
80
60
40
20
0
0 1 2 3 4 5
Years
Fig. 6. Local relapse-free survival over 5 years in patients with locally
advanced squamous cell carcinomas of the head or neck who were
randomized to treatment with either radiotherapy under hyperbaric
oxygen at 4 atmospheres (HBO4) delivered in two fractions of
11.5 Gy over 21 days (n = 23), or radiotherapy delivered in air in two
fractions of 12.65 Gy over 21 days (n = 25) (reproduced with permis-
sion from Haffty et al. [17]).
Strategies to Correct Anemia and/or Tumor
Hypoxia
Strategies that have been proposed to correct anemia
and/or the resultant tumor hypoxia include the use of:
E Hypoxic cell sensitizers (e.g., cytotoxic agents)
E Fluosol infusion
E Carbogen breathing
E Hyperbaric oxygen
E Blood transfusions
E Epoetin alfa (recombinant human erythropoietin;
r-HuEPO).
Hypoxic Cell Sensitizers
In a study designed to evaluate the efficacy of the cyto-
toxic agent mitomycin C in sensitizing hypoxic tumor
cells to the effects of radiotherapy, patients with squa-
mous cell carcinomas of the head or neck were treated
with either conventional fractionated radiotherapy
(70 Gy/35 fractions/7 weeks) or continuous hyperfrac-
tionated accelerated radiotherapy (55.3 Gy/17 consecu-
tive days/33 fractions) with or without mitomycin C
(20 mg/m2) given on day 5 of treatment [16]. Local tumor
control and survival rates over a median follow-up period
of 148 months were similar with the two radiotherapy
regimens given alone; however, the addition of mitomy-
cin C to the accelerated regimen significantly reduced
both the local tumor control rate and the overall survival
Prevalence and Treatment of
Radiotherapy-Associated Anemia
Carbogen patients at 18 months (n = 36)
Carbogen patients at 3 years (n = 36)
[estimated probabilities]
Noncarbogen patients at 18 months (n = 36)
100
91% 91%
80 75% 75%
69%
Patients (%)
62% 62%
60 55%
50%
40
20
0
Local control Cause-specific survival Overall survival
Fig. 7. Influence of carbogen breathing on local control, cause-spe-
cific survival and overall survival in patients with advanced head or
neck cancers treated with a hyperfractionated chemoradiotherapy
regimen. Patients received either carboplatin 5 mg/m2 administered
45 min before radiotherapy (115 cGy) with carbogen breathed 4 min
prior to and during irradiation twice per day on 5 days a week for 7
weeks (n = 36), or the same chemoradiotherapy regimen without car-
bogen breathing (comparison group; n = 36). Data at 3 years for the
carbogen breathing group are estimated probabilities [18].
rate in comparison with the accelerated regimen alone (48
vs 34% and 39 vs 28%, respectively), indicating that hyp-
oxia can, in part, be overcome by mitomycin C adminis-
tration. Mitomycin C did not influence the local toxicity
of radiotherapy as neither the intensity nor the duration
of radiotherapy-induced mucositis was altered by its ad-
ministration [16].
Hyperbaric Oxygen and Carbogen Breathing
The use of hyperbaric oxygen to overcome tumor hyp-
oxia has been reported to produce an improved response
to hypofractionated radiotherapy in a randomized trial in
patients with advanced squamous cell carcinoma of the
head or neck. Patients who received radiotherapy under
hyperbaric oxygen at 4 atmospheres showed a higher 5-
year local relapse-free rate than those who received a simi-
lar radiotherapy regimen delivered in air (29 vs 16%;
fig. 6). However, there were no significant differences
between the two groups in 5-year survival, distant metas-
tasis, or second primary tumors [17].
Similarly, carbogen breathing has also been shown to
improve the results of chemoradiotherapy (carboplatin
5 mg/m2 given before radiation doses of 115 cGy twice
Oncology 2002;63(suppl 2):11–18 15
 Table 2. Influence of the pretreatment hemoglobin level and epoetin alfa on the outcome of therapy in patients
undergoing chemoradiation plus surgical treatment for squamous cell carcinomas of the oral cavity or oropharynx
[24]

Patient group Overall complete 2-year locoregional 2-year

response, %a tumor control, % survival, %

Group 1: patients with Hb 614.5 g/dl not treated

with epoetin alfa (n = 43) 65* 88** 81**
Group 2: patients with Hb ! 14.5 g/dl not treated
with epoetin alfa (n = 87) 17 72 60
Group 3: patients with Hb ! 14.5 g/dl treated
with epoetin alfab (n = 57) 61* 95* 88*

* p (0.001 compared with group 2; ** p ! 0.05 compared with group 2; Hb = hemoglobin; SC = subcutaneously.
a Complete responses were determined by histopathologic analysis of the en bloc resection of the primary tumor and
regional cervical lymphatics performed 5 to 6 weeks after the completion of chemoradiotherapy.
b Dosage: 10,000 IU/kg SC 3 to 6 times per week until week of surgery.

daily on 5 days per week for 7 weeks) in patients with
locally advanced head or neck cancer. Anemic patients
also received either blood transfusions or epoetin alfa to
correct the anemia. Patients who breathed carbogen
4 min before and during irradiation exhibited improved
local control, cause-specific survival, and overall survival
at 18 months in comparison with a similar number of
patients who received the same chemoradiotherapy regi-
men without carbogen breathing (fig. 7). The high re-
sponse rates achieved in this study appeared to persist as
the estimated probabilities of local control, cause-specific
survival, and overall survival at 3 years in the carbogen
breathing group were similar to the rates observed at 18
months [18].
Epoetin Alfa (Recombinant Human Erythropoietin;
r-HuEPO)
The ability of epoetin alfa to correct anemia prior to
and during radiotherapy has been evaluated in cancer
patients to determine whether it produces clinically
meaningful benefit. Studies in patients receiving radio-
therapy for various malignancies have shown that the
administration of epoetin alfa, with or without oral iron,
is effective in increasing hemoglobin levels and is well tol-
erated [19–21]. A study in our institution in cancer
patients receiving a variety of different chemotherapy reg-
imens with concomitant or sequential radiotherapy has
shown that weekly epoetin alfa administration improved
the mean hemoglobin level by 1.8–3.4 g/dl [22] (fig. 5).
Improvements of this magnitude are similar to or greater
than the reductions in hemoglobin noted during radio-
therapy in our earlier study of the prevalence of anemia in
patients with various malignancies (fig. 5).
The effects of epoetin alfa on the outcomes of therapy
have been studied in anemic patients (Hb !14.5 g/dl)
with squamous cell carcinomas of the oral cavity or oro-
pharynx [23, 24]. All patients in this study received a regi-
men consisting of mitomycin C (15 mg/m2 on day 1), 5-
fluorouracil (750 mg/m2 on days 1–5) and radiotherapy
(50 Gy in 25 fractions during weeks 1–5), followed by dis-
section of the primary tumor bed and a neck dissection.
Epoetin alfa (10,000 IU/kg subcutaneously 3 to 6 times
per week until the week of surgery) was administered to a
group of patients (n = 57) who had a pretreatment hemo-
globin level !14.5 g/dl. The outcome in this group of
patients was compared with the outcomes in two other
groups who did not receive epoetin alfa. One of these non-
epoetin alfa groups had a pretreatment hemoglobin level
!14.5 g/dl (n = 87) and the other had a pretreatment
hemoglobin level 614.5 g/dl (n = 43). The results are
summarized in table 2. In the two groups of patients who
did not receive epoetin alfa, those with a low pretreatment
hemoglobin level (!14.5 g/dl) (group 2) exhibited signifi-
cantly lower complete response rates, 2-year locoregional
control rates, and 2-year survival rates than those who
had normal hemoglobin levels (614.5 g/dl) (group 1).
However, in the patients with a low pretreatment hemo-
globin level who received epoetin alfa (group 3), the rates
of complete response, 2-year locoregional control and 2-
year survival were equivalent to or higher than those in
patients with normal pretreatment hemoglobin levels
(group 1) [24].

16 Oncology 2002;63(suppl 2):11–18 Harrison/Shasha/Homel

 These findings suggest that epoetin alfa is an effective
and well-tolerated means of achieving normal hemoglo-
bin levels in patients undergoing radiotherapy, and may
reverse the negative prognostic influence of a low pre-
treatment hemoglobin level. Improvements in quality-of-
life parameters (linear analog scale assessment) have also
been noted with epoetin alfa therapy in groups of patients
receiving a variety of different chemotherapy regimens
with concomitant or sequential radiotherapy [22].
Potential Benefit of Epoetin Alfa in Reducing
Radiotherapy-Induced Neurotoxicity
In addition to studies of the efficacy of epoetin alfa in
improving the clinical outcome of radiotherapy in pa-
tients with low hemoglobin levels, its potential to reduce
radiation-induced neurotoxicity is also being investi-
gated. Studies in experimental animals have revealed that
endogenous erythropoietin (EPO) possesses other biologi-
cal activities in addition to erythropoietic effects, and that
many cells besides erythroid progenitors express the
erythropoietin receptor, including brain cells. As in the
periphery, erythropoietin production is known to be in-
duced by hypoxia in the central nervous system (CNS),
and it has been shown in animals to protect CNS neuronal
cells from ischemic injury [25]. A recent study found that
erythropoietin receptors are abundantly expressed in cap-
illaries of the brain-periphery interface, suggesting that
this may provide a route for circulating erythropoietin to
enter the brain [26]. In support of this hypothesis, a study
in mice showed that systemic administration of epoetin
alfa (5,000 IU/kg intraperitoneally) 24 h before or up to
6 h after controlled blunt trauma to the frontal cortex and
then continued once daily for 4 additional days (5 doses
total) attenuated the resultant brain injury. Quantitative
analysis of the cavitary injury volume showed that the
concussive injury in mice treated with epoetin alfa was
significantly less than in those treated with saline. In addi-
tion, epoetin alfa also ameliorated the damage caused by
experimentally-induced focal ischemic stroke in rat
brains, reduced the severity of experimental autoimmune
encephalitis in Lewis rats, and delayed and lessened sei-
zures induced in mice by the glutamate analog kainic
acid. These findings in different models of neurologic
injury suggest that epoetin alfa is able to cross the blood-
brain barrier and may provide protection against CNS
neurologic damage [26].
Further evidence in support of a protective effect of
erythropoietin against neurologic damage is provided by
Prevalence and Treatment of
Radiotherapy-Associated Anemia
the results of studies in our institution in which visual
evoked potentials (VEPs) were measured in animals re-
ceiving radiotherapy in the presence and absence of r-
HuEPO. Pretreatment of animals with epoetin alfa signif-
icantly prolonged VEPs as compared with those not
receiving epoetin alfa, suggesting that it may protect
visual pathways against radiation-induced damage (A.
Evans, unpublished data). If confirmed clinically, this
finding may have substantial implications for the use of
radiotherapy in patients with malignancies of the head,
paranasal sinuses and ocular regions because it suggests
that epoetin alfa may provide biologic protection of the
optic nerve against radiation-induced damage.
Conclusions
Anemia may result in tumor hypoxia by decreasing the
oxygen-carrying capacity of the blood, resulting in radia-
tion and, in some instances, chemotherapy resistance.
Anemia is associated with a poorer prognosis in a variety
of malignancies. It may be an important obstacle to
achieving maximal locoregional tumor control and sur-
vival with radiotherapy, even for small tumors not nor-
mally assumed to be hypoxic. In addition, anemia nega-
tively affects the quality of life of cancer patients, as evi-
denced by worsening fatigue. In view of the high preva-
lence of anemia recorded in cancer patients receiving
radiotherapy (about 50% at our institution), it is evident
that measures to reverse anemia and tumor hypoxia
should be considered an important component of treat-
ment for such patients. Indeed, a number of strategies,
notably the administration of epoetin alfa, have been
found to attenuate the negative prognostic influence of a
low hemoglobin level in patients receiving radiotherapy
with or without chemotherapy.
These findings indicate the need for radiation oncolog-
ists to be aware of the possibility of anemia in cancer
patients undergoing radiotherapy so that timely interven-
tion with strategies to improve the outcome of treatment
can be instituted whenever anemia is diagnosed. In view
of the potential benefits of treating anemia, it is hoped
that this aspect of cancer management will receive more
attention in the future.
Oncology 2002;63(suppl 2):11–18 17
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Harrison/Shasha/Homel
 Oncology 2002;63(suppl 2):19–28
DOI: 10.1159/000067148
Raising Hemoglobin: An Opportunity for
Increasing Survival?
Gillian M. Thomas
Department of Radiation Oncology, Obstetrics & Gynecology, University of Toronto,
Toronto-Sunnybrook Regional Cancer Centre, Toronto, Canada
Key Words
Anemia W Hemoglobin W Hypoxia W Angiogenesis W
Cancer W Radiotherapy W Chemotherapy W Surgery W
Prognostic factor W Epoetin alfa
Abstract
Although the association between low hemoglobin lev-
els and poorer outcomes in radiation oncology has long
been recognized, anemia is often overlooked and un-
treated. However, a growing body of clinical evidence
now indicates that low hemoglobin levels during radia-
tion treatment are associated with decreased response
and survival following radiotherapy. For example, a
large Canadian retrospective study in patients receiving
radical radiotherapy for cervical cancer showed that the
5-year survival rate was 19% higher in those whose
hemoglobin during radiation treatment was =12 g/dl
compared to those with levels ! 12 g/dl. The data suggest
that clinical trials need to be performed to determine
whether increasing hemoglobin levels leads to improved
local control and survival. The mechanism by which low
hemoglobin levels could cause poorer outcomes is not
well understood and needs further elucidation. It is pos-
tulated that lower hemoglobin levels resulting in de-
© 2002 S. Karger AG, Basel
ABC 0030–2414/02/0636–0019$18.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/ocl
creased oxygen carrying capacity may lead to increased
tumor hypoxia, radiation resistance and increased tumor
angiogenesis. The interrelationship of low hemoglobin
levels, hypoxia, tumor angiogenesis and survival is ex-
plored in this article.
Copyright © 2002 S. Karger AG, Basel
Introduction
In radiation oncology, it is widely accepted that tumor
hypoxia causes radiation resistance. Anemia is also asso-
ciated with poorer outcomes to radiation. It has been
inferred that there is a causal relationship between low
hemoglobin levels, the resulting hypoxia and a poor out-
come of radiotherapy in patients with cancer.
Even though hemoglobin levels are monitored at most
radiation oncology centers, anemia is often overlooked by
radiation oncologists and is frequently only treated if
severe. It has been suggested that oncologists do not rou-
tinely treat mild-to-moderate anemia as it is perceived to
be clinically unimportant [1] and that patients are often
not transfused unless hemoglobin levels fell below 10 g/dl
or even 8 g/dl [1, 2]. For example, a US study in 1987
showed approximately two-thirds of academic radiation
Gillian M. Thomas, BSc, MD, FRCPC
GlaxoSmithKline, 7333 Mississauge Road North
Mississauge, Ont. L5N 8L4 (Canada)
Tel. +1 905 814 2256, Fax +1 905 814 2100
E-Mail Gillian.m.thomas@gsk.com
Table 1. Summary of studies which examined the relationship was no consistency in how it was defined (i.e., cut-off
between anemia and outcome (local control B survival) of radiother- hemoglobin levels ranged from 10 to 12.5 g/dl). Neverthe-
apy B chemotherapy in patients with cancer
less, 40 of the 52 (76.9%) studies showed that low hemo-
Tumor site Number of Effect of anemia on outcome, globin levels were adversely related to local control and/or
studies number of studies survival after radical adverse radiotherapy (table 1).
Adverse None
There are two possible explanations, not mutually
exclusive, for the observed relationship between low he-
Bladder 6 6 0 moglobin levels and impaired outcomes with radiothera-
Bronchus 5 4 1 py. First, low hemoglobin levels may be a tumor-related
Cervix 22 19 3 marker for an aggressive cancer. In this scenario, it is
Glioma 1 0 1
unlikely that raising hemoglobin levels will improve the
Head and neck 17 11 6
Prostate 1 0 1 outcome of radiotherapy. The second, and more tradi-
Total 52 (100%) 40 (76.9%) 12 (23.1%) tional, explanation is that there is a causal relationship
between low hemoglobin levels and poor outcome of ther-
apy. With a causal relationship, raising hemoglobin levels
might therefore improve outcome following radiotherapy
[4].
Until recently, clinical evidence to support a causal
oncology departments transfusedpatients only if their he- relationship between low hemoglobin levels and poor out-
moglobin levels were = 10 g/dl [3]. This reluctance to cor- come was relatively limited. A single prospective, ran-
rect anemia was further increased in Canada in the late domized trial, conducted over 30 years ago, was inter-
1980s when the risk of contracting HIV or hepatitis from preted as demonstrating some benefit after correcting
contaminated blood was first recognized. anemia during radiotherapy in patients with cervical can-
Although views are changing, there is still much uncer- cer [5]. Pelvic recurrence occurred in 11 of 67 patients
tainty among radiation oncologists about the clinical im- (16.4%) who received transfusions and maintained hemo-
portance of radiotherapy-associated anemia and the exact globin levels 112 g/dl compared with 21 of 68 patients
benefits of increasing hemoglobin levels. However, a (30.9%) who were given transfusions only if their hemo-
growing body of clinical data is gathering in the medical globin levels dropped to !10 g/dl. No differences in sur-
literature which examines the relationship between hemo- vival were noted between the two treatment groups [5].
globin levels and response to radiotherapy in patients Although this study is widely quoted in the medical litera-
with cancer. The present article reviews these data and ture as proof that correcting hemoglobin levels improves
also seeks to explore some of the downstream mecha- outcomes following radiotherapy, the study was under-
nisms, namely tumor hypoxia and angiogenesis, that may powered and had an inconclusive univariate analysis
link low hemoglobin levels with clinical outcome in pa- which did not assess the possible effect of other prognostic
tients with cancer. It also poses questions for future study factors on patient outcome.
that may help to clarify treatment options for this patient
group.
Studies in Patients with Cervical Cancer

Effect of Hemoglobin Levels on Treatment Radiotherapy Alone

Outcome
Historic Data
More than 50 studies have investigated the effect of
low hemoglobin levels at the start of radiotherapy B che-
motherapy on outcomes in patients with various cancers
[mostly of the cervix (42%) or head and neck (33%)]
mainly using univariate analysis. A summary of these
studies is provided in table 1. It should be noted that,
although the term ‘anemia’ was used in all studies, there
To examine the relationship between anemia and
treatment outcome more rigorously, a large retrospective
study using data from seven Canadian radiation oncology
centers between 1989 and 1992 was performed [4]. The
aim of the study was to examine the prevalence of anemia,
its time course, and the effect of anemia and blood trans-
fusions on the treatment outcome in 605 patients who had
radical radiotherapy for cervical cancer.
At presentation, approximately one-third of patients
had hemoglobin levels of =12 g/dl (i.e., below the lower

20 Oncology 2002;63(suppl 2):19–28 Thomas

Table 2. Significance of prognostic factors on outcome of radiothera-
py in 605 patients with cervical cancer: results of a multivariate anal- 1.0
ysis (with permission from Grogan et al. [4])
—– Hb =12.0 g/dl (n = 337)
0.8 - - - Hb <12.0 g/dl (n = 172)
Prognostic factor p value
0.6

Survival
Significant
Stage 0.0001 0.4
Average weekly nadir hemoglobin level 0.0001
Intracavitary treatment 0.0004 0.2 p <0.003
Squamous histology 0.0446
0.0
Nonsignificant 0 1 2 3 4 5 6
Age Year
Presenting hemoglobin level
Radiation dose
Center
Fig. 1. Survival in patients with carcinoma of the cervix receiving
Transfusion
radiotherapy stratified according to hemoglobin level (Hb) at presen-
Transfusion year
tation (reproduced with permission from Grogan et al. [4]).
Treatment volume
Treatment time
Chemotherapy

1.0

0.8
— L – H (n = 25)
— H – H (n = 228)
limit of the normal range for women). Despite this, only
0.6
Survival

25% of patients received blood transfusions because clini- — L – L (n = 140)

cians were more likely to transfuse patients with nadir
hemoglobin levels of !10 g/dl. This is demonstrated by
the fact that most patients with hemoglobin levels of
!9 g/dl (90%) and !10 g/dl (77%) were transfused, where-
as much fewer patients (3–41%) with hemoglobin levels
between 10 and 12 g/dl received transfusions. In all, four
of the seven centers had policies for blood transfusion
often not followed: two recommended transfusions for
patients with hemoglobin levels of !10 g/dl, and one each
for patients with hemoglobin levels of !11 and !12 g/dl
[4].
The Canadian study showed that hemoglobin levels at
baseline correlated with patient survival (fig. 1). This is
consistent with earlier data indicating a correlation be-
tween anemia and poor prognosis in patients receiving
radiotherapy B chemotherapy (table 1). Using a cut-off
value for hemoglobin levels of 12 g/dl, the Canadian study
reported a 12% greater 5-year survival rate in patients
with baseline hemoglobin levels of 612 g/dl than in those
with baseline levels of 612 g/dl (p ! 0.003; fig. 1). Hemo-
globin levels at baseline also had a significant effect on
disease-free survival (p = 0.005) and control of local pelvic
disease (p = 0.002) according to univariate analysis [4].
Of note, however, are the results of the multivariate
analysis from this study which considered patient-, tu-
mor- and treatment-related factors, as well as hemoglobin
— H – L (n = 82)
0.4
p <0.0002
0.2
0.0
0 1 2 3 4 5 6
Year
Fig. 2. Survival in patients withcarcinoma of the cervix according to
hemoglobin levels at baseline and during radiotherapy, where L indi-
cates hemoglobin levels of ! 12 g/dl and H indicates hemoglobin lev-
els of 612 g/dl. Results are adjusted for disease stage and for the use
of intracavitary irradiation (reproduced with permission from Gro-
gan et al. [4]).
levels (table 2). The multivariate analysis showed that
hemoglobin levels during radiotherapy, rather than at pre-
sentation, were predictive of outcome of radiotherapy in
terms of overall survival (p = 0.0001; table 2) [4] second in
importance only to tumor stage. Average weekly hemoglo-
bin nadir, which was calculated by averaging the weekly
nadir hemoglobin levels for each patient, was taken as an
estimate of hemoglobin levels during radiotherapy. Other
significant prognostic factors for outcome were disease
stage, intracavitary treatment, and squamous histology

Hemoglobin Levels and Outcome in Cancer Oncology 2002;63(suppl 2):19–28 21

Patients
 1.0
0.8
0.6
Survival
0.4
0.2
Fig. 3. Survival in patients with carcinoma
of the cervix according to transfusion status
0.0
and average weekly nadir hemoglobin levels
(Hb) during radiotherapy, where T = trans-
fused and NT = not transfused (reproduced
with permission from Grogan et al. [4]).
(table 2). Initial hemoglobin levels were not significant
suggesting that the effect of low presenting hemoglobin
levels could be overcome by raising the level during treat-
ment.
To further examine the differential impact of low
hemoglobin levels during treatment versus those at pre-
sentation, the survival data were reanalyzed according to
hemoglobin levels both at baseline and during radiothera-
py (fig. 2; n = 475). The analysis showed that patients who
had low hemoglobin levels during radiotherapy, regard-
less of their baseline hemoglobin levels, had a significantly
poorer rate of survival than those whose hemoglobin lev-
els were maintained greater than 12 g/dl during radiother-
apy (fig. 2). The 5-year survival rates for those with low
hemoglobin levels during radiotherapy were 51% or less
compared with rates of at least 70% in patients who had
high hemoglobin levels during radiotherapy (fig. 2). The
relapse rates in patients with low hemoglobin levels dur-
ing radiotherapy (56 and 60%) were almost double those
of patients with high hemoglobin levels during therapy
(32 and 33%). Interestingly, patients with high hemoglo-
bin levels during radiotherapy also showed significant
reductions in both pelvic (p ! 0.0001) and extrapelvic fail-
ure rates (p ! 0.0006) [4].
Finally, the study examined whether raising hemoglo-
bin levels with blood transfusions influenced the outcome
of radiotherapy (fig. 3). A significant stepwise increase in
overall survival was observed with increasing hemoglobin
levels during radiotherapy (fig. 3; p ! 0.0001). Survival
rates were not significantly different between patients
who attained a given hemoglobin level spontaneously and
those who received blood transfusions (fig. 3). These data
22 Oncology 2002;63(suppl 2):19–28
Hb
NT
12.0 g/dl
T
NT
11.0–11.9 g/dl
T
NT
<11.0 g/dl
T
p <0.0001
0 1 2 3 4 5 6
Year
show that it is the hemoglobin level attained, rather than
the use of blood transfusions, that influenced outcome in
these patients. It also confirmed the prognostic signifi-
cance of hemoglobin levels during radiotherapy [4].
It was concluded from the Canadian study that the
hemoglobin level during radiotherapy is an important
prognostic factor, second only to disease stage, in patients
with cervical cancer. The survival data from this study
generate the hypothesis that maintaining hemoglobin lev-
els above 12 g/dl in patients with cervical cancer can
improve the response to radiotherapy. The study further
showed that the mechanism by which hemoglobin levels
are maintained (i.e., transfusion) is not important, but
rather the hemoglobin level that is attained during radio-
therapy.
Concurrent Radiotherapy and Chemotherapy
Since the study by Grogan et al. [4] was completed,
concurrent cisplatin-based chemotherapy and radiothera-
py has emerged as the treatment of choice for patients
with advanced cancer of the cervix [6] as for many other
epithelial cancers.
A recent study by Pearcey et al. [7], however, showed
no benefit for the addition of concurrent cisplatin to
radiation. Contrary to the previous trials in patients with
cervical cancer, which demonstrated a survival benefit for
chemoradiotherapy versus radiotherapy alone [8–12],
Pearcey et al. [7] observed similar 3- and 5-year survival
rates with concurrent cisplatin and radiotherapy versus
radiotherapy alone in patients with advanced cervical car-
cinoma. While there are many possible explanations for
the lack of benefit observed with chemoradiotherapy in
Thomas
Fig. 4. Distribution of patients with ad-
vanced cervical cancer according to decrease
in hemoglobin levels (Hb) during therapy.
Patients were randomized to receive pelvic
radiotherapy alone (n = 126) or radiotherapy
plus cisplatin 40 mg/m2 weekly (n = 127) (re-
produced with permission from Pearcey et
al. [7]).
this trial, one reason may have been a differential drop in
hemoglobin levels during therapy (fig. 4) between treat-
ment groups. As would be expected, decreases in hemo-
globin levels were found to be significantly greater in
patients receiving chemotherapy plus radiotherapy versus
those receiving radiotherapy alone (fig. 4). Thus, is it pos-
sible that the decreases in hemoglobin levels during thera-
py abrogated the beneficial effects of chemotherapy in
this study.
Studies in Patients with Head and Neck Cancer
Several studies have looked at the impact of anemia
on clinical outcome following radiotherapy in patients
with head and neck cancer (for review see Kumar 2001)
[13]. As an example, van Acht et al. [14] observed that
the 10-year rate of disease-free survival was significantly
lower in patients with laryngeal cancer (n = 306) whose
hemoglobin levels were below normal (!8.5 mmol/l in
men and !7.5 mmol/l in women) after radiotherapy
than in those with normal hemoglobin levels. Patients
with glottic carcinoma and hemoglobin levels below nor-
mal at the start and/or the end of radiotherapy had sig-
nificantly reduced 10-year disease-free survival rates
(p = 0.009 and 0.0012, respectively), whereas below-nor-
mal hemoglobin levels at the end of therapy only were
predictive of disease-free survival in those with supra-
glottic cancers (p = 0.05) [14].
These data are of interest because they confirm the
negative association between low hemoglobin levels at the
end of treatment and survival following definitive radio-
Hemoglobin Levels and Outcome in Cancer
Patients
therapy in a cancer type other than cervical cancer. Some
have postulated that the poor results in anemic patients
are a result of the association between anemia and large
tumor volumes and development of distant metastases.
Since laryngeal cancer does not have these characteristics,
these data add weight to the suggestion that the relation-
ship between anemia and outcome is not solely tumor-
related; the hypothesis generated is that some decrement
in response to therapy may occur if the hemoglobin level
is low during treatment.
Effect of Hypoxia on Treatment Outcome
Hypoxia is a characteristic feature of solid tumors
which is thought to occur when tumor growth exceeds the
ability of the local microvasculature to supply oxygen. It is
thought that approximately 60% of locally advanced
squamous cell cervical carcinomas contain hypoxic and/
or anoxic areas of tissue [15]. Resistance to treatment and
accelerated tumor growth and progression occur as a
result of hypoxia. Hypoxia causes resistance to both
radiotherapy and chemotherapy.
It is now well established that intratumoral hypoxia
has a negative effect on locoregional control in patients
receiving definitive radiotherapy for head and neck or
cervical cancer. Table 3 provides a summary of studies
that measured tumor oxygenation levels directly and cor-
related tumor oxygenation status with locoregional con-
trol following radiotherapy [16–21]. Although the defini-
tions assigned to hypoxia differed between studies, four of
six studies showed a significant increase in local failure
Oncology 2002;63(suppl 2):19–28 23
Table 3. Summary of studies investigating
locoregional control following radiotherapy Study Tumor site Local failure rate (patients) p value
according to tumor oxygenation status in nonhypoxic hypoxic
patients with cervical or head and neck tumors tumors
cancer
Fyles et al. [16] Cervix 4/21 6/10 0.03
Höckel et al. [17] Cervix 4/19 10/23 0.13
Kolstad [18] Cervix 4/21 6/10 0.03
Brizel et al. [19] Head and neck 3/10 11/17 0.09
Gatenby et al. [20] Head and neck 1/19 11/12 !0.001
Nordsmark et al. [21] Head and neck 5/18 11/17 0.03

rate in patients who had hypoxic tumors compared with
those whose tumors were oxygenated (table 3).
It has long been recognized that hypoxia adversely
affects the sensitivity of tumor cells to many chemothera-
peutic agents. Although the precise mechanisms are un-
known, oxygen is a radiosensitizer and impairs the ability
to repair DNA damage caused by radiation-induced free
radicals.
More recently, attention has focused on the ability of
tumor hypoxia to enhance malignant progression. This is
based on the findings of Höckel et al. [17] who showed
that, following tumor resection in 47 patients with cervi-
cal cancer, hypoxic tumors had larger extensions, more
frequent parametrial spread and lymph-vascular involve-
ment compared with oxygenated tumors. It is thought
that hypoxia may drive disease progression through clonal
selection and genome changes (for review see Höckel &
Vaupel 2001) [22], which in turn produces a growth
advantage for tumor cells that are resistant to apoptosis.
Hypoxic tumors may overexpress the suppressor gene
p53, a phenotype with a high malignant potential [23].
Hypoxia may also induce changes within the tumor
cells for the expression of oxygen-dependent proteins,
such as vascular endothelial growth factor (VEGF), which
stimulate angiogenesis and increase the potential for tu-
mor growth and metastases [24].
Effect of Angiogenesis on Treatment Outcome
Angiogenesis, the growth of new capillary vessels sup-
porting tumor growth and progression, is stimulated by
hypoxia. A summary of molecular events linking angio-
genesis with intratumoral hypoxia is provided in table 4
[25]. Like hypoxia, angiogenesis has also been shown to
influence outcome to surgery in patients with cancer,
Table 4. Molecular events linking hypoxia and angiogenesis [25]
Hypoxia-regulated genes (e.g., VEGF, EPO, LDHA, Glut-1)
HIF-1· mediates transcriptional response by binding to the hypoxia
responsive elements of genes
HIF-1· induces VEGF and increases expression and half-life of
mRNA
Hypoxia leads to loss of p53, increases VEGF and decreases TSP-1
H-ras and V-src (oncoproteins) amplify response to hypoxia and
lead to increased VEGF and decreased TSP-1
EPO = erythropoietin; HIF-1a = hypoxia-inducible factor 1a;
LDHA = lactate dehydrogenase A; TSP-1 = thrombospondin-1;
VEGF = vascular endothelial growth factor.
although the available data are limited. Obermair et al.
[26] used microvessel density count as a measure of angio-
genesis in patients with stage IB cervical cancer who
underwent surgery. They found that the 5-year overall
survival rate was significantly better in patients with a
microvessel density of 20/field (n = 102) than in those
with higher microvessel densities (n = 64) (80.7 versus
63.0%; p ! 0.0001).
More recently, Birner et al. [27] showed that the
expression of hypoxia-inducible factor 1a (HIF-1a), a
transcriptional factor that promotes angiogenesis and reg-
ulates genes involved in the response to hypoxia, in-
fluenced prognosis in 91 surgically-treated patients with
stage I cancer of the cervix. Once again, patients with
strong expression of HIF-1a had a significantly poorer
overall survival (p = 0.03) and disease-free survival (p !
0.0001) compared with those with moderate or no expres-
sion of HIF-1a.

24 Oncology 2002;63(suppl 2):19–28 Thomas

 Fig. 5. Possible management options to overcome the problems of anemia and hypoxia during radiotherapy. HCRS =
Hypoxic cell radiation sensitizers; HT = hyperthermia; HBO = hyperbaric oxygen.
Anemia, Hypoxia and Angiogenesis: Are They
Linked?
While there is evidence to suggest a direct association
between hypoxia and angiogenesis, less is known about
how anemia is linked to hypoxia and angiogenesis (fig. 5).
Anemia may exacerbate intratumoral hypoxia by lower-
ing the oxygen carrying capacity of the blood, although the
link between the two and its relevance in the clinical set-
ting remain controversial [1]. Nordsmark et al. [28] in
Denmark recently showed that there was no relationship
between hemoglobin levels and pretreatment tumor oxy-
gen partial pressure in 263 patients with head and neck
carcinoma. However, both hemoglobin levels and tumor
oxygenation status (pO2 fraction !2.5 mm Hg) were inde-
pendent prognostic factors for overall survival. Likewise
Brizel et al. [29] noted only a weak association between
low hemoglobin levels and poor tumor oxygenation status
in patients with head and neck cancer receiving primary
radiotherapy; many patients with higher hemoglobin lev-
els (= 13 g/dl) also had hypoxic tumors. These data suggest
that low hemoglobin levels and tumor hypoxia may be
linked in a complex fashion but other factors, tumor
Hemoglobin Levels and Outcome in Cancer
Patients
type and individual patient physiology, may also be in-
volved.
The relationship between anemia and angiogenesis
remains poorly understood and data are sparse. A Ger-
man group [30] showed that there was a trend towards
higher serum VEGF levels in cancer patients with low
hemoglobin levels undergoing radiotherapy, suggesting
that anemia may stimulate angiogenesis via hypoxia. Pa-
tients had previously untreated, non-metastatic gyneco-
logic cancer (n = 22), head and neck cancer (n = 14), gas-
trointestinal cancer (n = 13), lung cancer (n = 4) and pros-
tate cancer (n = 1). In 26 patients with hemoglobin levels
of !13 g/dl, mean serum VEGF levels were 805,656 pg/ml
compared with levels of 438,360 pg/ml in 28 patients with
hemoglobin levels of 113 g/dl (p = 0.016) [30].
Correcting Hemoglobin Levels
There are several potentially reversible causes of ane-
mia (such as nutritional deficiencies, chronic blood loss,
and subclinical disseminated intravascular coagulopa-
thy), which should be sought and, if possible, corrected in
Oncology 2002;63(suppl 2):19–28 25
patients presenting with anemia. A summary of manage-
ment options for the prevention and treatment of hypoxia
and anemia in patients with cancer in the radiation onco-
logy setting, some of which are in the early stages of devel-
opment, are summarized in figure 5.
Transfusion of red blood cells is one readily available
management option for patients with anemia (fig. 5),
although it carries risks of unwanted transfusion reac-
tions, infectious disease transmission, and possibly im-
munomodulation. Concerns about the risks of homolo-
gous blood transfusion, uncertainty about the benefits
and inconvenience, mean that anemia is often under-
treated in patients undergoing radiotherapy unless they
are clearly symptomatic or have very low hemoglobin lev-
els (!10 g/dl) [2].
Recombinant human erythropoietin is an alternative
option that avoids the risks associated with transfusions.
While several trials have already demonstrated that epoe-
tin alfa (Procrit®; Ortho Biotech Products, LP, Bridgewat-
er, NJ; Eprex®/Erypo®; Janssen-Cilag and Ortho Biotech
outside the US) effectively corrects anemia and improves
quality of life in patients with cancer receiving chemo-
therapy [31–35], it is only more recently that its use has
been examined in patients receiving radiotherapy or com-
bined chemoradiotherapy [36–42].
For example, a prospective, multicenter trial per-
formed in Austria [40] showed that 84% of 143 patients
with anemia responded to epoetin alfa, which was ini-
tiated approximately 10 days prior to radiotherapy or che-
moradiotherapy. Hemoglobin levels increased at a me-
dian rate of 0.37 g/dl/week with epoetin alfa. These data
are consistent with previous studies, which demonstrated
the efficacy of epoetin alfa in cancer patients [36–39, 41,
42]. Furthermore, there are now data to support the use of
epoetin alfa administered once weekly [41, 42], rather
than the less convenient 3-times weekly regimen that is
currently approved for use in anemic cancer patients
receiving chemotherapy.
In a multicenter study performed in the US, Shasha et
al. [42] showed that overall patient quality of life, and
energy and activity levels were significantly improved
(p ! 0.05 versus baseline) after subcutaneous epoetin alfa
40,000 units was administered once weekly for 16 weeks.
The size of effect observed with epoetin alfa (0.5–0.7) was
judged to be representative of a medium to large improve-
ment in patient quality of life [42].
26 Oncology 2002;63(suppl 2):19–28
Future Research
Examining the impact of raising hemoglobin levels in
cancer patients and finding ways of overcoming tumor
hypoxia will be important areas of research over the next
decade. The specific questions that need to be addressed
include:
E Does raising hemoglobin levels improve patient sur-
vival?
E If so, by what mechanisms (i.e., does it improve the
effectiveness of radiotherapy or chemotherapy or does
it actually switch off the molecular events that lead to
tumor growth, progression and metastases)?
E What constitutes the ‘optimal’ hemoglobin level in
patients with cancer? This may depend not only on
tumor- and patient-related factors but also on the func-
tional endpoint being studied.
In an attempt to answer some of these questions, the
Gynecologic Oncology Group (GOG) has initiated an
international randomized trial in patients with stage IIB–
IVA cervical cancer and hemoglobin levels of !13 g/dl.
Patients will receive standard combination therapy of
weekly cisplatin and radiotherapy with or without subcu-
taneous epoetin alfa 40,000 units administered once
weekly. Blood transfusions are permitted in the control
group if hemoglobin levels fall to !10 g/dl and in the epoe-
tin alfa group if hemoglobin levels drop precipitously or
are too low to raise to 112 g/dl before chemoradiotherapy
begins. As well as survival, patient quality of life and eco-
nomic outcomes will be evaluated in this trial.
Ancillary studies will also be performed in an attempt
to elucidate the underlying molecular mechanisms. These
include monitoring cell markers of hypoxia (EF5 or 2-(2-
nitro-1-H-imidazol-I-yl)-N-(2,2,3,3,3-pentafluoropropyl)
acetamide) and angiogenesis [VEGF, thrombospondin-1
and platelet/endothelial cell adhesion molecule-1 (PE-
CAM-1 or CD31)]. There will also be an assessment of the
prognostic value of DNA-cisplatin adducts taken from
buckle smears.
Conclusions
A growing body of literature now shows that there is a
relationship between low hemoglobin levels and low rates
of disease control and survival in the radiation oncology
setting. Data suggest that correcting anemia with epoetin
alfa improves quality of life, and we postulate, may
improve response and thus impact survival following
radiotherapy with or without concurrent chemotherapy.
Thomas
Although the long-term implications of correcting anemia
have yet to be definitively established, collectively, these
data suggest that it may be important to maintain adequate
hemoglobin levels in patients receiving radiotherapy.
At present, radiation oncologists are focused on wheth-
er or not it is possible to improve the control of local dis-
ease and survival, but it is important to consider patient
quality of life also. This is particularly relevant given the
aggressive combined modality and high-dose treatment
strategies commonly used in oncology today. Therefore,
the challenge for the future will be to devise a unified
approach to the management of anemia in patients with
cancer, with the aim of improving both disease outcome
and patient quality of life.

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 Oncology 2002;63(suppl 2):29–38
DOI: 10.1159/000067145
New Chemotherapeutic Agents:
Update of Major Chemoradiation Trials
in Solid Tumors
Walter J. Curran
Department of Radiation Oncology, Jefferson Medical College, Philadelphia, Pa., USA
Key Words
Radiotherapy W Chemoradiation W Solid tumors W
Locoregional control W Combined modality therapy
Abstract
The institution of combined modality therapy for unre-
sected solid tumors has resulted in significant improve-
ments in tumor control and survival benefit compared
with radiotherapy (RT) alone. A number of chemothera-
py agents that can enhance the effectiveness of RT, such
as cisplatin and 5-fluorouracil, are now considered stan-
dard treatment for patients with a number of cancer
types. There is growing interest in a number of addition-
al agents that have also been found to have radiosensi-
tizing ability. These include paclitaxel, docetaxel, irinote-
can, gemcitabine, and vinorelbine, as well as biologic
agents. Other agents may be of value because they act to
counter dose-limiting toxicities associated with RT. This
article provides an update of some important, recently
completed and ongoing clinical trials evaluating novel
chemoradiation protocols, with examples taken primari-
ly from studies conducted by the Radiation Therapy
Oncology Group (RTOG). Theoretical approaches to the
development of new agents and combined modality reg-
imens are also discussed.
Copyright © 2002 S. Karger AG, Basel
© 2002 S. Karger AG, Basel
ABC 0030–2414/02/0636–0029$18.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/ocl
Introduction
Combined modality therapy has been instituted for the
treatment of several types of unresectable solid tumors,
with various chemotherapeutic agents used either sequen-
tially or concurrently with radiation. Some of these com-
bination therapies have resulted in significant improve-
ments in tumor control and survival benefit compared
with radiotherapy (RT) alone. For example, Cancer and
Leukemia Group B (CALGB) 8433 was the first major
chemoradiotherapy trial to demonstrate a significant sur-
vival advantage with sequential chemotherapy and radia-
tion in patients with inoperable stage III non-small-cell
lung cancer (NSCLC) [1]. These results were subsequently
confirmed in the same patient population in a phase III
study carried out by the Radiation Therapy Oncology
Group (RTOG) [2].
A number of chemotherapy agents, including radiosen-
sitizing agents such as cisplatin and 5-fluorouracil (5-FU),
that can be used in conjunction with RT have been identi-
fied and found to be effective in enhancing tumor control
and/or improving survival rates in clinical trials. There
has since been growing interest in a number of agents that
have also been found to have radiosensitizing ability,
including paclitaxel, docetaxel, irinotecan, gemcitabine,
and vinorelbine, as well as agents with other antitumor
activities, including the antiangiogenesis drugs [3–5].
Other agents, such as recombinant human erythropoietin
Walter J. Curran, Jr., MD
Department of Radiation Oncology, Jefferson Medical College
111 S. 11th St.
Philadelphia, PA 19107-5097 (USA)
Tel. +1 215 955 6700, Fax +1 215 955 0412, E-Mail walter.curran@mail.tju.edu
(rHuEPO, epoetin alfa), are of potential value because
they may counter dose-limiting toxicities associated with
RT [6–9], and they may potentially increase tumor oxy-
genation, and, therefore, the efficacy of RT.
This article provides an update of some important
recently completed and ongoing trials evaluating novel
chemoradiation protocols. It also highlights methodologic
changes in the way new agents and combined modality
regimens are being developed.
Optimization of Radiotherapy Delivery
The quality and the mode of delivery of RT are of cen-
tral importance to the success of combined modality ther-
apy. An important hypothesis that underlies the develop-
ment of new and more effective RT protocols is that
improvement of radiotherapy delivery will reduce locore-
gional tumor failures. Consequently, this should lead to
decreased mortality, and/or decreased treatment-related
morbidity.
Radiotherapy can be optimized in a number of ways.
These include technical improvements in patient selec-
tion and staging, which involves the use of ever-improv-
ing imaging techniques, radiotherapy sequencing and
fractionation, image guidance during RT procedures, bra-
chytherapy, the provision of high radiation doses directly
to a tumor through the implantation of small radioactive
seeds or sources, radiation intensity modulation, and
radiation dose escalation.
Until 2000, standard treatment for stage III unresected
non-small-cell lung cancer has been sequential chemo-
therapy and radiation. An example of this is the treatment
protocol that was evaluated in the CALGB and RTOG
studies in NSCLC mentioned previously [1, 2]. The com-
bination regimen evaluated in both studies involved ad-
ministration of cisplatin, 100 mg/m2 intravenously on
days 1 and 29, and vinblastine, 5 mg/m2 on days 1, 8, 15,
22, and 29, followed by RT beginning on day 50 (60 Gy).
This was compared with RT alone. Median survival times
for patients treated with this regimen in the CALGB and
RTOG studies were 13.7 and 13.2 months, respectively,
versus 9.6 and 11.4 months for patients treated with RT
alone. It was concluded by the authors of the CALGB
study that the use of sequential chemoradiotherapy in-
creases the projected proportion of 5-year survivors by a
factor of 2.8 compared with standard RT [1]. Even with
this improvement, however, approximately 80–85% of
patients treated with sequential chemoradiotherapy will
be expected to die within 5 years [1]. Therefore, there is a
30 Oncology 2002;63(suppl 2):29–38
need for further improvements in the treatment of locally
or regionally advanced unresectable tumors.
Results from several, recent, prospective phase III
trials provide convincing evidence that further optimiza-
tion of RT delivery in the context of combined modality
therapy, beyond that evaluated in the CALGB and RTOG
trials, can result in better tumor control and/or patient
survival. These studies are described below.
Lung Cancer
RTOG 9410 is a phase III study of 611 patients with
unresected NSCLC, which compared a standard sequen-
tial protocol (chemotherapy followed by 60 Gy RT/7
weeks given once daily, initiated at day 50) with two con-
current chemoradiation protocols (RT initiated on day 1
of chemotherapy) [10]. Concurrent RT was administered
either once daily (60 Gy RT/7 weeks) or as hyperfraction-
ated RT (69.9 Gy/6 weeks, twice daily). Preliminary me-
dian survival times at a median follow-up time of 40
months for sequential, concurrent RT once daily, and con-
current hyperfractionated RT were 14.6, 17.1, and 15.6
months, respectively, from each patient’s registration. The
concurrent RT/cisplatin/vinblastine arm had significantly
better survival than the sequential arm with the same
agents, with a p-value of 0.038. The rates of grade 3–4 non-
hematologic toxicity were higher with concurrent vs. se-
quential chemotherapy, but late toxicity rates were similar
and no differences in grade 5 toxicity rates were noted.
A randomized intergroup study (RTOG 8815) carried
out by Turrisi et al. [11] was aimed at optimizing RT
delivery in patients (n = 417) with small-cell lung cancer
(SCLC). After a follow-up of almost 8 years, patients who
were given 45 Gy RT, concurrently with cisplatin and eto-
poside, twice daily for 3 weeks, had significantly im-
proved median survival rates versus those who received
45 Gy RT given concurrently only once daily over 5 weeks
(23 months vs. 19 months for patients receiving once-dai-
ly vs. twice-daily RT, respectively, p = 0.04). Survival
rates at 5 years were 26 and 16% for patients receiving
concurrent twice-daily or once-daily RT, respectively.
However, patients receiving twice-daily RT experienced
grade 3 esophagitis significantly more frequently than
those receiving once-daily concurrent RT (27 vs. 11%, p !
0.001).
Head and Neck Cancer
The randomized phase III trial RTOG 9111 compared
concurrent chemoradiation (RT initiated on day 1 of che-
motherapy) versus sequential chemoradiation (RT ini-
tiated on day 63 after chemotherapy) vs. RT alone, in 547
Curran
patients with stage 3–4 potentially resectable cancer of the
larynx [12]. The total RT dose was 70 Gy in 7 weeks
(2 Gy/fraction), administered in the same regimen, for all
of the study arms. The results showed that over a 2-year
follow-up period, concurrent chemoradiation was statisti-
cally significantly better for laryngectomy-free survival
time compared with RT alone (66 vs. 52%, respectively,
p = 0.02). Similarly, concurrent chemoradiotherapy was
statistically significantly better than sequential chemora-
diation and RT alone for time to laryngectomy (p =
0.0094 and 0.00035 vs. sequential chemoradiation and
RT alone, respectively) over the same follow-up period.
In another phase III trial (RTOG 9003), Fu et al. [13]
tested the efficacy of hyperfractionation in patients with
locally advanced head and neck cancer, comparing two
types of accelerated fractionation therapy with standard
fractionated RT. A total of 1,113 patients were random-
ized into one of four treatment groups: (1) RT delivered
with standard fractionation at 2 Gy/fraction/day, 5 days/
week, to 70 Gy/35 fractions/7 weeks; (2) hyperfractiona-
tion at 1.2 Gy/fraction, twice daily, 5 days/week, to 81.6
Gy/68 fractions/7 weeks; (3) accelerated fractionation
with split at 1.6 Gy/fraction, twice daily, 5 days/week, to
67.2 Gy/42 fractions/6 weeks including a 2-week rest after
38.4 Gy; or (4) accelerated fractionation with concomi-
tant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5
Gy/fraction/day to a boost field as a second daily treat-
ment for the last 12 treatment days to 72 Gy/42 fractions/
6 weeks. At a median follow-up time of 23 months for all
assessable patients (n = 1,073), those treated with hyper-
fractionation (treatment 2) or accelerated fractionation
with concomitant boost (treatment 4) had significantly
better locoregional tumor control than those treated with
standard fractionation (treatment 1) (54.4 and 54.5% for Fig. 1. RTOG 9003: Phase III trial comparing hyperfractionated RT
treatments 2 and 4, respectively, vs. 46.0% for treatment or accelerated fractionation RT with concomitant boost vs. standard
RT in patients with advanced head and neck cancer. a Twice-daily
1, p = 0.045 and 0.050, respectively) (fig. 1). A trend
(fractionated) RT resulted in significantly better locoregional control
toward improved disease-free survival was also noted for than did standard RT (p = 0.05). b Accelerated fractionation resulted
the same comparisons (37.6 and 39.3% for treatments 2 in significantly better locoregional control than did standard, twice-
and 4, respectively, vs. 31.7% for treatment 1), although daily fractionation (p = 0.05). Follow-up was from the time patients
these differences failed to achieve significance (p = 0.067 were randomized into the study (reproduced with permission from
Fu et al. [13]).
and 0.054, respectively). All three altered fractionation
groups (treatments 2, 3, and 4) had increased grade 3 or
worse acute adverse effects in skin, mucous membranes,
pharynx/esophagus, and larynx compared with the stan- sequential therapy, and in patients with SCLC, RT twice
dard RT group (treatment 1), but there was no difference daily significantly improved survival rates vs. once-daily
in late toxicity (190 days after start of RT). treatment. Clearly, it is important to keep in mind the val-
The results of these studies clearly demonstrate that ue of modifying RT delivery when attempting to optimize
the quality of RT can be modified to improve tumor con- established chemoradiation combinations, and when test-
trol and survival. In patients with NSCLC or laryngeal ing new systemic agents for use in combined modality reg-
cancer, concurrent RT provided a clear benefit over imens.

Update on Chemoradiation Trials in Solid Oncology 2002;63(suppl 2):29–38 31

Tumors
 Integration of New Systemic Therapies with
Optimized Locoregional Therapy
A second important hypothesis that forms the basis for
the development of novel combined modality therapies is
the notion that the integration of new systemic therapies
with optimized locoregional RT will decrease cancer-
related mortality. A number of recent trials were designed
to compare the efficacy of RT with or without systemic
therapy in patients with prostate cancer (RTOG 8531,
8610, 9202), stage III NSCLC (RTOG 8808), laryngeal
cancer (RTOG 9111), esophageal cancer (RTOG 8501),
and cervical cancer (RTOG 9001). Overall, the results
from these trials, described in the following sections, indi-
cate a significant clinical benefit from the addition of one
or more systemic agents to RT regimens.
Prostate Cancer
The benefits of combined modality chemoradiotherapy
were illustrated in the results of three phase III RTOG
studies that evaluated the combination of RT with hor-
monal therapy for treatment of prostate cancer (RTOG
8531, RTOG 8610, RTOG 9202) [14–16]. A total of 977
patients with locally advanced prostate cancer (RTOG
8531) [14] were followed for a median period of 5.6 years.
Results indicated that long-term administration of adju-
vant goserelin (initiated at relapse and continued through-
out the follow-up period) to induce androgen suppression,
in addition to standard external-beam RT (n = 477 analyz-
able patients), significantly improved local tumor control
(p ! 0.0001), freedom from distant metastases, and both
absolute (p = 0.036) and cause-specific (p = 0.019) survival,
as compared with patients who received standard external-
beam RT alone (n = 468 assessable patients).
Another randomized, phase III trial (RTOG 8610) [15]
investigated the effects of androgen ablation with gosere-
lin before and during RT for patients with locally ad-
vanced prostate cancer vs. RT alone (n = 471). The results
at an 8-year follow-up demonstrated that combined mo-
dality therapy was associated with a significant improve-
ment in local tumor control (30 vs. 42% local failure rate;
p = 0.016), reduction in disease progression (34 vs. 45%
distant metastasis; p = 0.04), and improvement in surviv-
al (33 vs. 21% disease-free survival; p = 0.004) compared
with RT alone. A subset analysis of patients with a Glea-
son score of 2 to 6 (indicating relatively less aggressive
tumors) showed a highly significant improvement in all
endpoints, including overall survival (p = 0.015) in pa-
tients treated with combined modality therapy compared
with those treated with RT alone.
32 Oncology 2002;63(suppl 2):29–38
In a prospective, randomized study conducted by
Hanks et al. [16], a total of 1,554 patients with locally
advanced prostate cancer received androgen suppression
therapy (goserelin and flutamide) 2 months before and
during RT. Patients were then randomized to either no
further therapy or 24 months of additional goserelin
alone; the groups were well matched for stratification and
other baseline variables considered. The investigators
found that disease-free survival (54 vs. 34%), local pro-
gression (6 vs. 13%), and reduction in distant metastasis
(11 vs. 17%) were significantly better in patients receiving
the longer-duration hormonal therapy compared with
those receiving no further hormonal therapy after radia-
tion. Patients with a Gleason score of 8–10 (more aggres-
sive tumors) also showed a statistically significant advan-
tage in overall survival compared with the same subset of
patients who did not receive long-term hormone therapy
(p = 0.017). It should be noted that long-term androgen
ablation has hematologic toxicity, which may be detri-
mental to locoregional control with RT [17]. Given this
possibility, these patients may benefit from additional
systemic agents, such as epoetin alfa, to counter treat-
ment-related anemias. The potential benefit of epoetin
alfa for enhancing locoregional tumor control as well as
improving patient quality of life has received support
from recent clinical trials [6–9] and is currently under
investigation in an RTOG phase III trial (9903).
Stage III NSCLC
The final results of an important randomized phase III
trial involving 458 patients with unresectable NSCLC
were published in 2000 (RTOG 88-08) [2]. This study
compared sequential chemoradiation with either hyper-
fractionated or standard RT. Sause et al. evaluated the
efficacy of three regimens: (1) chemoradiation, consisting
of 2 months of cisplatin and vinblastine therapy, followed
by either 60 Gy of radiation at 2.0 Gy per fraction of
radiation delivered once daily (n = 152), (2) hyperfrac-
tionated RT, consisting of 1.2 Gy per fraction of radiation
delivered twice daily to a total dose of 69.6 Gy (n = 152),
and (3) standard RT alone (n = 154). Results indicated
that overall survival was statistically significantly better
in patients receiving chemoradiotherapy compared with
the RT regimens (median survival of 13.2, 12, and 11.4
months for concurrent chemoradiotherapy, hyperfrac-
tionated RT, and standard RT, respectively, p = 0.04 for
chemoradiotherapy vs. the RT regimens); the investiga-
tors did not find a statistically significant difference in
survival between the two RT arms (standard vs. hyper-
fractionated) in this study.
Curran
 Laryngeal Cancer
The objective of RTOG 9111, a randomized, phase III
study described previously, was to compare the ability of
sequential chemoradiation (cisplatin 100 mg/m2 plus 5-
FU 1,000 mg/m2/day ! 120 h for 3 cycles, followed by
RT in responding patients) or concurrent chemoradiation
(cisplatin 100 mg/m2 plus 5-FU on days 1, 22, 43 plus RT)
with that of RT alone, to promote laryngectomy-free sur-
vival in patients with cancer of the larynx (n = 547) [12].
Although the study failed to establish a significant differ-
ence in survival between sequential chemoradiation and
standard RT alone, concurrent chemoradiation resulted
in significantly better survival than RT alone (66 vs. 52%
after 2 years, respectively, p = 0.02). Moreover, concur-
rent chemoradiation was also significantly better than
sequential chemoradiation (p = 0.0094) and RT alone (p =
0.00035) with regard to time to laryngectomy. These
results not only demonstrate the benefit of concurrent
chemoradiation over standard RT for treatment of laryn-
geal cancer, as assessed by either survival or time to laryn-
gectomy, but also highlight the importance of optimizing
RT delivery in the context of the specific combined
modality therapy and the form of cancer involved.
Esophageal Cancer
Long-term follow-up results (of at least 5 years) from a
randomized, controlled trial conducted from 1985 to
1990 (RTOG 8501) demonstrated that concurrent che-
moradiotherapy (50 Gy/5 weeks plus cisplatin and 5-FU
at weeks 1, 5, 8, and 11; n = 134) statistically significantly
increased the survival of patients with squamous cell can-
cer or adenocarcinoma of the esophagus compared with
RT alone (64 Gy/6.4 weeks; n = 62). The overall survival
rate with combined therapy was 26% compared with 0%
for RT alone [18].
Cervical Cancer
RTOG 9001 was a randomized trial that examined the
effects of adding chemotherapy with 5-FU and cisplatin
to treatment with external beam and intracavitary radia-
tion in women with locally advanced cervical cancer [19].
Of 403 patients followed for a mean duration of 43
months, estimated cumulative rates of overall survival
were 73% among patients receiving combined modality
therapy, compared with 58% for patients receiving RT
alone (p = 0.004). Rates of disease-free survival at 5 years
were also significantly higher among patients receiving
chemoradiation (67 vs. 40%; p ! 0.001), and rates of dis-
tant metastases (14 vs. 33%) and locoregional recurrences
(19 vs. 35%) were significantly lower in these patients (p !
Update on Chemoradiation Trials in Solid
Tumors
0.001 for both parameters). These impressive results of
disease-free survival and local control were corroborated
in three important trials involving women with bulky
stage IB cervical cancer [20] or locally advanced cervical
cancer [21, 22], carried out by the Gynecologic Oncology
Group. In both of these studies, chemoradiation regimens
including cisplatin resulted in significantly improved sur-
vival and reduced risk of disease recurrence as compared
with RT alone.
Unique Approaches to Testing Novel Systemic
Therapies With Radiotherapy
A review of trials evaluating combined modality thera-
pies illustrates some of the ways in which the approach to
testing combined modality chemoradiation protocols
may differ from traditional drug development strategies.
It should always be kept in mind that the latest reports of
new systemic agents undergoing testing, or the most
recent modifications in RT delivery, may prove quite
valuable for formulating novel combined modality regi-
mens. It is possible that agents that exhibit only minimal
efficacy when used alone may prove useful when com-
bined with RT. Because of this, many new agents should
be tested concurrently with RT after their safety has been
established, rather than postpone concurrent testing until
their efficacy when used alone has been demonstrated. In
addition, because of the increasing numbers of potentially
useful systemic agents, and the resultant exponential
growth in the numbers of possible therapeutic drug com-
binations, the results of preclinical studies will likely play
an increasing role in decisions on which new agents
should be tested, and in what types of combinations.
It is important to note that the maximum tolerated
dose (MTD) of a systemic agent, or of a RT protocol, may
be defined quite differently when these modalities are
combined because of the potential interactions between
the two forms of therapy. There may be quantitative dif-
ferences, such as the dosages at which toxicity is seen, or
there may be qualitative differences, such as in the types
of adverse effects that occur. For example, the MTD may
relate to organ-specific side effects, such as esophagitis,
pneumonitis, or proctitis, rather than to hematologic pa-
rameters, when combined modality therapy is adminis-
tered. Moreover, interactions between the treatment mo-
dalities render it likely that optimization of RT delivery
will result in changes in optimal drug schedules, and vice
versa.
Oncology 2002;63(suppl 2):29–38 33
 Optimization of Combined Modality Regimens
The results of a phase I trial reported by Fossella et al.
[23], aimed at identifying the MTD of gemcitabine in
patients with NSCLC undergoing thoracic RT, provide an
excellent illustration of how the optimization of RT deliv-
ery can play an important role when devising a combined
modality regimen. These investigators found that dose-
limiting toxicity of gemcitabine occurred at 125 mg/m2
when used with a conventional RT regimen, whereas the
MTD was 190 mg/m2 when gemcitabine was combined
with 3-dimensional conformal RT. Thus, optimization of
the RT protocol with reduction in the radiation volume
allowed for the delivery of a substantially higher dose of
chemotherapy.
RTOG L-0017 is an ongoing phase I trial evaluating
gemcitabine, paclitaxel, and RT vs. gemcitabine, carbo-
platin and RT in patients with NSCLC. The study design
is an example of a technique that is being used within the
RTOG to test more efficiently integrated treatment mo-
dalities. The design includes a first schema that involves
administration of escalating doses of gemcitabine concur-
rently with a constant carboplatin dose, with the combi-
nation at each dose level of gemcitabine given to a group
of 6 patients. A second schema involves an escalation of
gemcitabine while also escalating paclitaxel in an alternat-
ing stepwise fashion, such that the dose of only one of the
drugs is escalated at a time. In both schemata, chemother-
apy is accompanied by adjuvant thoracic RT at a total
dose of 63 Gy in 34 fractions in 7 weeks to affected areas,
commencing on the first day of chemotherapy. Using this
approach, it should be possible to efficiently establish a
MTD for gemcitabine that is specific for its combination
with either carboplatin or paclitaxel.
Novel Systemic Agents Undergoing Testing in
Chemoradiotherapy Regimens
Substantial gains have been made over the past several
years in the induction of remissions with the use of che-
moradiation therapy. Despite these advances, patient sur-
vival rates are still unacceptably low and new treatment
strategies are needed. Several promising, novel systemic
agents are currently undergoing evaluation for use in con-
junction with RT.
Cyclooxygenase-2 Inhibitors
Cyclooxygenase (COX) catalyzes the synthesis of pros-
taglandins from arachidonic acid. One form of the en-
zyme, COX-2, is overexpressed in a variety of different
34 Oncology 2002;63(suppl 2):29–38
tumors, including colon, pancreatic, prostate, lung, and
head and neck cancers, and is also observed in tumor
neovasculature [24]. These and other data suggest that
COX-2-mediated angiogenesis plays a major role in tu-
mor growth. These findings have stimulated initiation of
a number of trials evaluating COX-2 inhibitors used in
conjunction with RT.
A phase I/II RTOG trial (C-0128) is underway to deter-
mine treatment-related toxicity rates in patients with
locally advanced carcinoma of the cervix who are being
treated with a combination of celecoxib, cisplatin, and 5-
FU with concurrent pelvic radiation therapy. In addition,
this study is designed to evaluate whether this regimen
can improve locoregional control rates, distant control,
and/or survival.
Vascular Endothelial Growth Factor (VEGF) Blockade
VEGF is thought to play an important role in tumor
angiogenesis. Blockade of its function is, therefore, con-
sidered a treatment target for a number of tumor types,
and is likely to be tested in conjunction with combined
modality therapy.
Sugen (SU) 5416
SU 5416 is a small molecule that exhibits potent inhi-
bition of the fetal liver kinase (flk) receptor tyrosine
kinase, which is the receptor for VEGF. Expression of flk
is limited to endothelial cells and it appears to play a criti-
cal role in angiogenesis [25]. RTOG S-0120 and S-0121
are two ongoing phase I/II studies aimed at evaluating SU
5416 as part of a chemoradiotherapy protocol for treat-
ment of low-to-intermediate grade (S-0120) or high-risk,
high-grade (S-0121) soft tissue sarcoma.
Angiostatin
In a recent phase I trial at Jefferson Medical College in
Philadelphia involving a small number of patients with
advanced cancer of the head and neck, prostate, breast,
and lung, it was determined that the combination of
angiostatin (an antiangiogenesis drug that has antitumor
activity) plus radiotherapy is well tolerated and partial
local responses were observed. Studies are ongoing to
evaluate longer-term treatment at higher doses [26].
Farnesyl Transferase Inhibitors
Farnesyl transferase inhibitors target the protein en-
coded by the ras oncogene, blocking its membrane anchor-
age, and thereby inhibiting its cell transforming ability [27].
R11577 is a potent and selective farnesyl transferase inhib-
itor that has shown antitumor activity in animal models,
Curran
and was found to have an acceptable tolerability profile in
phase I trials (unpublished data). RTOG 0020 is an ongo-
ing phase II trial in patients with locally advanced pan-
creatic cancer designed to evaluate the one-year survival
rates of patients treated with paclitaxel, gemcitabine, and
RT with or without farnesyl transferase inhibitor
R115777.
The above represents only a small number of the clini-
cal trials and the novel agents currently being evaluated
for use in combined modality therapies. Given the rela-
tively recent understanding of the potential value of com-
bining chemotherapeutic and RT regimens for patients
with unresected solid tumors, this approach can be ex-
pected to further improve outcomes for patients with
unresectable solid tumors.
New Therapeutic Strategies Based on Analyses
of RTOG Clinical and Tissue Databases
The structure of the RTOG and other groups that are
involved in evaluating new combined modality therapies
encourages the development of such treatments from hy-
potheses-based analyses of clinical and tissue databases.
Over the past few years, there has been a large expansion of
knowledge concerning the biology of cancer. These ad-
vances include new information on the control of cancer
cell growth and growth factor expression, regulation of
necrotic and apoptotic cell death, regulation of angiogene-
sis and cell-cell communication, the influence of environ-
mental factors, such as hypoxia, on tumor growth, and
identification of markers that are over- or underexpressed
on cancer cells. By maintaining centralized databases that
make information on basic cancer biology widely available
it will be possible to reassess archived information and uti-
lize proteomic analysis on banked tissue and tumor speci-
mens and apply this knowledge to the formulation of new
combined modality clinical trials.
An example of this process involves evaluation of cell
markers, such as epidermal growth factor receptor
(EGFR), on stored tumor tissue that had been obtained
from patients with advanced head and neck cancer
treated in study RTOG 9003. This was a phase III study
that compared hyperfractionation and standard RT pro-
tocols [13]. Further analysis of the results of this trial
revealed that there was a statistically significant increase
in locoregional failure in cases where the tumor over-
expressed EGFR vs. those without EGFR, resulting in a
difference in survival. Interestingly, there was no differ-
ence in the development of distant metastases. This find-
Update on Chemoradiation Trials in Solid
Tumors
ing, which was derived from archived material and infor-
mation, suggests that the development of a strategy for
EGFR blockade would be useful. Moreover, such a strate-
gy would be most beneficial if used during radiotherapy,
when locoregional failure can be targeted, rather than
after radiotherapy, when attempts to influence distant
metastases would probably be less useful.
New Standards of Care
Although there is still much work to be done, com-
pleted phase III trials carried out by the RTOG, GOG and
other groups have made important contributions to defin-
ing new standards of care in locally advanced cervical
cancer, stage III NSCLC, locally advanced head and neck
and prostate cancer, localized prostate cancer, central ner-
vous system lymphoma, and operable laryngeal cancer.
Some of the RTOG studies are listed in table 1.
A number of RTOG studies, also shown in table 1,
have recently completed accrual, and should be providing
data within the next few years. These trials include much-
needed prospective evaluations of radiosurgery. The re-
sults of two major phase III trials will be presented at the
2002 American Society for Therapeutic Radiology and
Oncology (ASTRO) meeting.
Concurrent Chemoradiotherapy Now the Standard
The adoption of concurrent rather than sequential che-
motherapy exemplifies how a meaningful improvement
in outcome resulted from relatively subtle changes in ther-
apy, including changes in the technique for delivering che-
moradiotherapy. Using progress that has been made in
the treatment of stage III NSCLC as an example, the sur-
vival of good performance status patients with unresected
tumors progressively improved in a number of studies
conducted over approximately 11 years (table 2) [12, 28].
This degree of improvement cannot be explained by stage
migration alone (i.e., changes in staging due to a discrep-
ancy between clinical and pathologic staging or other fac-
tors). As shown in table 3, the administration of concur-
rent rather than sequential chemoradiation, in a random-
ized RTOG study (9410) of patients with NSCLC, re-
sulted in more than a 20% increase in median survival
time, a statistically significant improvement [10]. A simi-
lar result was seen in a Japanese study reported by Furuse
et al. [29]. These results support the positioning of concur-
rent chemoradiotherapy as the current standard of care.
Although the ability to obtain positive results with consis-
tency across studies is encouraging, it is important to note
Oncology 2002;63(suppl 2):29–38 35
 Table 1. Summary of some recently completed and ongoing major chemoradiation trials

Study Treatment evaluated

Completed phase III RTOG studies

9001 Concurrent chemoradiation for locally advanced cervical cancer
9410 Sequential vs concurrent chemoradiotherapy for stage III NSCLC
9003 Hyperfractionated and accelerated fractionated RT vs standard RT for locally
advanced head and neck cancer
9202, 8610 Long- vs short-term adjuvant hormone therapy for locally advanced prostate cancer
8531 Adjuvant hormone therapy plus RT for localized prostate cancer
9111 Sequential or concurrent chemoradiotherapy vs RT alone for operable laryngeal
cancer
Phase III studies with completed accrual
9305, 9508 Radiosurgery for glioma and brain metastases
9501 Chemotherapy for resected head and neck cancer
9408 Androgen ablation for localized prostate cancer
9413 Large-field RT for advanced prostate cancer
9802 Chemotherapy for low-grade glioma
Unreported/active phase III trials for stage III NSCLC (RTOG and other groups)
RTOG 9801 Amifostine as radioprotectant
ECOG 2597 Role of 3 times daily RT
CALGB 39801 Evaluation of induction chemotherapy
R 9309/Intergroup Role of surgery in N2 disease
ECOG Role of thalidomide
SWOG/Intergroup Role of EGFR blockade

CALGB = Cancer and Leukemia Group B; ECOG = Eastern Cooperative Oncology Group; EGFR = Epidermal
growth factor receptor; N2 = mediastinal lymph node metastasis; NSCLC = non-small-cell lung cancer; RT = radio-
therapy; RTOG = Radiation Therapy Oncology Group; SWOG = Southwest Oncology Group.

Table 2. Evidence for improvement over time in the treatment of Table 3. Concurrent vs. sequential chemoradiotherapy for NSCLC –
unresected NSCLC impact on median survival time

Cooperative Group Trial Median survival 3-year Study Median survival time (months)
time (months) survival
concurrent sequential p value
CALGB 8433 RT [1] 9.6 10%
Curran et al. [10] 17.1 14.6 0.03998
CALGB 8433 sequential CRT [1] 13.7 24%
Furuse et al. [29] 16.5 13.3 0.038
RTOG 9104 concurrent CRT 19.6 40%
RTOG 9410 sequential CRT [2] 14.6 31%
NSCLC = Non-small-cell lung cancer.
RTOG 9410 concurrent CRT [2] 17.0 37%
SWOG 9504 concurrent CRT [28] 27 140%

CALGB = Cancer and Leukemia Group B; RT = radiotherapy;

CRT = chemoradiotherapy; NSCLC = non-small-cell lung cancer; Achieving Further Improvement Using
RTOG = Radiation Therapy Oncology Group; SWOG = Southwest-
Combined Modality Regimens
ern Oncology Group.

Based on the results of the most recent phase III trials

that there is much room for further improvement in out-
comes. Moreover, with the concurrent protocols, there is
substantially greater acute toxicity; work on the develop-
ment of systemic agents to counter this is ongoing.
in patients with stage III NSCLC treated with concurrent
chemoradiation, there appears to be a plateau in median
survival time of approximately a year and a half. It is like-
ly that continued optimization of patient selection and the
continued development, selection, and implementation

36 Oncology 2002;63(suppl 2):29–38 Curran

of combined therapies will play important roles in any
further improvements in survival times.
One area of research that is contributing to improve-
ments in both patient staging and treatment planning
involves new uses of computed tomography (CT) and
related techniques to provide more detailed information
on target structures. For example, the use of metabolic
imaging by means of F-18 fluorodeoxyglucose positron
emission tomography (FDG-PET) can improve tumor
definition. This helps the clinician to delineate tumor
extent and determine the areas that will require high-dose
therapy, and to monitor the therapeutic response [30].
Recent work has also indicated that the use of FDG-PET
staging for NSCLC, for example, is a powerful predictor
of survival, and it should prove to be a valuable resource
in treatment planning [31].
Continued improvements in radiotherapy delivery, in-
cluding dose escalation, intensity modulation, develop-
ment of fractionation techniques, enhanced image guid-
ance, and exploitation of brachytherapy technology will
be crucial to achieving further success; likewise, the ongo-
ing search for novel systemic agents without heavy depen-
dence on drugs that have undergone extensive testing
without RT. Because of the possibility of unique interac-
tions between agents with regard to both efficacy and tox-
icity profiles, aggressive concurrent testing, as already
described, should also play a major role.
The use of chemotherapy ‘doublets’ or ‘triplets’, in
which novel interactions between chemotherapy agents
and RT might be exploited, or in which novel biologic
agents may be combined with other chemotherapy agents,
is another promising area of research. For example, work
carried out by Ang and others demonstrated that the com-
bination of EGFR blockade using monoclonal antibody
C225, radiosensitization with docetaxel, and RT resulted
in a significantly greater delay in tumor growth than did
any one or combination of two therapies (unpublished
data). It is likely that in the next several years, what might
be referred to as new trimodality therapy will be devel-
oped for a number of locally advanced malignancies.
Conclusions
Based on the studies described in this review, it is clear
that much has been achieved in the quest for new com-
bined modality regimens that improve outcomes in pa-
tients with cancer. One major problem, however, is the
long duration of patient accrual, which sometimes results
in trials that are inadequately powered. Moreover, there is
very little information available from controlled trials
involving low-performance status patients (based on the
ECOG Performance Status Scale) [32]. Staging of patients
has been variable across studies, which can lead to an
uneven assessment of outcomes. Importantly, there has
been too much reliance on the stage IV drug pipeline,
rather than expending sufficient effort on developing
drugs that might be of specific value when used in con-
junction with RT. This last point relates to differences
between the strategy for developing combined modality
regimens testing concurrent regimens early in drug devel-
opment rather than the approach used in standard drug
development where single agent efficacy is the first pro-
cess.
Many factors will contribute to improving outcomes
for patients with locally advanced lung cancer, as well as
other solid tumors. Testing novel systemic agents with RT
is critical, and should pave the way to substantial im-
provements in outcomes. Conducting large explanatory,
proof of principle trials that address a single question,
such as to determine the role of surgery or the optimum
timing of sequential therapies, may prove more valuable
than complicated studies that mask important principles.
Clearly, improving radiation standards and quality assu-
rance is also critical in this context. All of these ap-
proaches combined will slowly but surely contribute to-
wards improving the survival of many patients with local-
ly advanced solid tumors.

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