Systemic chemotherapy

5-Fluorouracil remains the backbone of chemotherapy regimens for colon cancer, both in the adjuvant and metastatic setting. In the past 10 years, it as established that combination regimens provide improved efficacy and prolonged progression-free survival in patients ith metastatic colon cancer. In addition to 5-fluorouracil, oral fluoropyrimidines such as capecitabine !"eloda# and tegafur are increasingly used as monotherapy or in combination ith o$aliplatin !%lo$atin# and irinotecan !&amptosar#. 'ome of the standard combination regimens employ prolonged continuous infusion of fluorouracil !F()FI*I, F()F("#+,1- or capecitabine !&./(", "%)(", "%)I*I#. .vailability of ne classes of active drugs and biologics for colorectal cancer pushed the e$pected survival for patients ith metastatic disease from 10 months 0 decades ago to about 00 months currently. . meta-analysis of 1 randomi2ed phase II and II trials e$amined the efficacy of capecitabine ith o$aliplatin !&./3("# compared ith fluorouracil ith o$aliplatin !F43("# in metastatic colorectal cancer. &./3(" resulted in a lo er response rate but overall progression-free survival and overall survival ere not affected and ere similar in both treatment regimens. &haracteristic to$icity occurred in the F4 schedules and thrombocytopenia and hand-foot syndrome ere more prominent in the &./ regimens.+,0In a study by 'ehgal et al, capecitabine administered for a eek on3 eek off schedule in a dose of 5000 mg3m0 on days 1-6, combined ith o$aliplatin3bevaci2umab, for treatment of metastatic colorectal cancer did not appear to have any advantages over current standard first-line metastatic colorectal cancer treatment regimens. &ycles ere repeated every 0 eeks.+,5In a phase III multicenter trial, 7im et al compared overall survival of second-line therapy for patients ith advanced colorectal carcinoma refractory to fluorouracil. Fluorouracil, leucovorin, and o$aliplatin !F()F(",# !n80,1# versus irinotecan !n80,5# as compared !crossover to the other treatment as mandated if disease progression occurred#. (verall survival did not significantly differ bet een F()F(", and irinotecan9 ho ever, F()F(" , improved response rate !**# and time to progression !::/# compared ith irinotecan !/80.000; for each ** and ::/#. F()F(", as associated ith more neutropenia and paresthesias.+,,. study by <rou=uet et al found that resection of colorectal liver metastases after a secondline chemotherapy regimen as safe and provided a modest hope for definitive cure, making this approach viable in patients ith advanced colorectal liver metastases.+,57ey clinical =uestions relate to the most advantageous selection of drug combination and the se=uence of different treatment options in individual patients ith colorectal cancer. :his information is to be derived from information on tumor biology, patient performance status, organ function, and pharmacogenomics testing. . study by 'eymour et al found that ith appropriate designs, including reduced starting doses of chemotherapy, frail and elderly patients can participate in randomi2ed controlled trials, hich is important because they are often under-represented in such trials despite being fre=uently treated ith chemotherapy.+,1-

Adjuvant (postoperative) chemotherapy

:he standard therapy for patients ith stage III and some patients ith stage II colon cancer for the last 0 decades consisted of fluorouracil in combination ith adjuncts such as levamisole and leucovorin.+5, ,, 5- :his approach has been tested in several large randomi2ed trials and has been sho n to reduce individual 5-year risk of cancer recurrence and death by about 50>.

In an observational study of 10;1 patients ith stage III colon cancer, adjuvant chemotherapy reduced the risk of distant recurrence after surgery by about half. %lderly patients benefited to a similar degree as younger patients.+,6, ,?(verall, 51> of the study participants received adjuvant chemotherapy, 51> developed distant metastases, and 56> ere 65 years of age or older. In the total population, the use of adjuvant chemotherapy as associated ith a significantly reduced risk of distant recurrence. In separate analyses of patients @65 years of age and those A65 years of age, the effect of adjuvant chemotherapy on recurrence risk as similar in both age groups, ith ha2ard ratios of 0.50 and 0.56, respectively.+,6, ,?: o recent large randomi2ed trials !B('.I& and C.'</-&01# investigated the addition of o$aliplatin to fluorouracil !F()F(", and F)(", respectively# and demonstrated a significant improvement in 5-year disease-free survival for patients ith stage III colon cancer. :he addition of irinotecan to fluorouracil in the same patient population provided no benefit based on the results from t o large randomi2ed trials !&.)D< ?;?05 and /%:.&& 5#. .nother randomi2ed study, ".&:, demonstrated noninferiority of capecitabine !"eloda# compared to 5-F43leucovorin as adjuvant therapy for patients ith stage III colon cancer. . large trial comparing capecitabine plus o$aliplatin !"%)("# versus F()F(" has completed accrual, but survival data have not yet been reported. Eespite its role in the therapy of metastatic colon cancer, bevaci2umab !anti-F%DF monoclonal antibody# did not significantly prolong disease-free survival in patients ith stage II and III colon cancer, hen added to adjuvant chemotherapy !mF()F("1# in a randomi2ed trial !C.'</ &-0?#.+,;:he role of adjuvant chemotherapy for stage II colon cancer is controversial. . large %uropean trial !G4.'.*# demonstrated small but significant benefit !5.1># in terms of absolute 5-year survival rate for those patients ho received 5-fluorouracil3leucovorin versus those in the control group. (ngoing adjuvant trials are investigating additional risk stratification of stage II colon cancer based on clinicopathological and molecular markers !%&(D 5000 trial#. :hough information on results of adjuvant therapy in stage II and III colon cancer is limited, a data set assembled by the .djuvant &olon &ancer %ndpoints group ith fluorouracil-based adjuvant therapy as recently analy2ed. :he authors concluded that adjuvant chemotherapy provides significant disease-free survival benefit because it reduces the recurrence rate particularly ithin the first 0 years of adjuvant therapy but ith some benefit in years 5-,.+50. study by (H&onnor et al found that among Bedicare patients ith stage II colon cancer, ith or ithout poor prognostic features, overall survival as not substantially improved by adjuvant chemotherapy.+51. study by Cg et al found that statin use during and after adjuvant chemotherapy did not result in improved disease-free survival, recurrence-free survival, or overall survival in patients ith stage III colon cancer.+50-

Biologic agents
<evaci2umab !.vastin# as the first anti-angiogenesis drug to be approved in clinical practice and the first indication as for metastatic colorectal cancer. :his is a humani2ed monoclonal antibody to vascular endothelial gro th factor !F%DF# and a pivotal trial demonstrated improved progression-free and overall survival hen bevaci2umab as added to chemotherapy !IF), fluorouracil plus irinotecan#. <evaci2umab, in combination ith 5-fluorouracil-based chemotherapy, is indicated for firstand second-line treatment of metastatic colorectal carcinoma. <evaci2umab is also

approved for second-line treatment in patients ho have progressed on a first-line bevaci2umab-containing regimen. .pproval for continuation treatment as based on a study that sho ed maintenance of F%DF inhibition ith bevaci2umab plus standard second-line chemotherapy beyond disease progression has clinical benefits in patients ith metastatic colorectal cancer. :he risk of death as reduced by 1;> for those ho received bevaci2umab in combination ith standard chemotherapy in both the first- and second-line compared to those ho received chemotherapy alone !I*80.?1, p80.0056#. /rogressionfree survival improved by 50> !I*80.1?, pJ 0.0001#.+6. pooled analysis of cohorts of older patients !aged 15 years or older# from 0 randomi2ed clinical trials e$amined the benefit of bevaci2umab plus fluorouracil-based chemotherapy in first-line treatment of metastatic colorectal cancer. :he study concluded that adding bevaci2umab to fluorouracil-based chemotherapy improved overall survival and progressionfree survival in older patients as it does in younger patients, ithout increased risks of treatment in the older age group.+55: o other biologic agents approved for colorectal cancer are epidermal gro th factor receptor !%DF*#-targeted monoclonal antibodies. &etu$imab !%rbitu$# is a chimeric monoclonal antibody approved for treatment of 7*.' mutation-negative ! ild-type#, epidermal gro th factor receptor !%DF*#-e$pressing, metastatic colorectal cancer as determine by FE.-approved tests !eg, therascreen 7*.' *DG /&* 7it#. &etu$imab may be used as monotherapy or in combination ith irinotecan !&amptosar# in patients ith metastatic colorectal cancer refractory to fluoropyrimidine and o$aliplatin therapy. +5,.dditionally, cetu$imab is approved as combination therapy ith F()FI*I !irinotecan, 5fluorouracil, leucovorin#.+55, 51/anitumumab !Fectibi$# is fully human monoclonal antibody and the current indication as a monotherapy for patients ith colorectal cancer in hom combination chemotherapy failed or as not tolerated. . recent trial by Iecht et al evaluated panitumumab added to bevaci2umab and chemotherapy !o$aliplatin- and irinotecan-based# as first-line treatment of metastatic colorectal cancer and concluded that the addition of panitumumab resulted in increased to$icity and decreased progression-free survival.+56: o clinical trials investigated the role of panitumumab !fully human monoclonal antibody against the %DF*# in the first-line+5?- and in second-line+5;- in combination ith chemotherapy !F()F(" and F()FI*I#. :he results of both studies suggest clinical benefit of adding panitumumab to chemotherapy for patients ith ild-type 7*.' colorectal cancer, in terms of improving progression-free survival !/F'# and response rate. /anitumumab becomes an option, or an alternative to cetu$imab, for those patients ho have tumors ithout 7*.' mutation. Co head-to-head comparisons bet een panitumumab containing combinations versus cetu$imab or even bevaci2umab !anti-F%DF* monoclonal antibody# chemotherapy combinations in patients ith ild-type 7*.' tumors have been reported, leaving it up to the oncologist to prioriti2e the choice or se=uence of monoclonals in this patient population. In a study by :ebbutt et al, bevaci2umab as found to be associated ith a modestly increased risk of arterial thromboembolism !.:%#9 ho ever, safety as not significantly orse in older patients or those ith a history of .:% or other vascular risk factors.+10Intratumoral KRAS gene mutation can predict sensitivity to anti-%DF* antibodies. +11Investigators from a large international trial e$ploring the benefit of adding cetu$imab to first-line chemotherapy ith F()FI*I !&*K':.) :rial# reported that only patients ith ildtype KRAS derived clinical benefit from cetu$imab. /atients ith mutant KRAS had no clinical benefit from adding cetu$imab to chemotherapy and e$perienced only unnecessary to$icity. KRASmutations are present in about ,0> of colon adenocarcinomas. <ased on these results, testing for KRAS mutation has been already added to cetu$imab indication by

%uropean regulatory agency !%B%.# and as approved by the FE. in Luly 0010 in combination ith F()FI*I for first-line treatment. :he addition of anti-%DF* antibody treatment to standard chemotherapy regimens for patients ith advanced colorectal cancer improves progression-free survival for those ith ild-type !but not mutant# KRAS status.+10- :esting for KRAS gene mutation has proven to be a fair prediction for nonresponse to anti-%DF* antibody treatment. <okemeyer et al e$amined the overall response rate hen combining cetu$imab ith o$aliplatin, leucovorin, and fluorouracil !F()F("-,#, as opposed to the regimen ithout cetu$imab, for first-line treatment of metastatic colorectal cancer in a randomi2ed study. :hey also e$amined the influence of the KRAS mutation status. :hey concluded that the overall response rate for cetu$imab plus F()F("-, as higher than ith F()F("-, alone though a statistically significant increase in odds for a response ith the addition of cetu$imab could not be established, e$cept in patients ith KRAS ild-type tumors, for hom the addition of cetu$imab increased chance of response and lo ered risk of disease progression.+15(ther mutations that involve some of the kinases do nstream from KRAS !such as BRAF and PI3K# are being investigated and may result in even more selective methods to identify patients that may benefit from %DF* inhibition. *egorafenib !'tivarga#, a kinase inhibitor, as approved in 'eptember 0010. It is indicated for patients ith metastatic colorectal cancer !m&*&# ho have been previously treated ith fluoropyrimidine-, o$aliplatin-, and irinotecan-based chemotherapy9 an antiMvascular endothelial gro th factor !F%DF# therapy !eg, bevaci2umab, 2iv-aflibercept#9 and, if 7*.' ild type, an antiMepidermal gro th factor receptor !%DF*# therapy !eg, cetu$imab, panitumumab#+1,- . .pproval as based on a multicenter trial !n8610# that randomi2ed patients at a 0N1 ratio to receive regorafenib in addition to best supportive care or placebo plus best supportive care. 'tatistically significant benefit in overall survival and progressionfree survival as observed for regorafenib over placebo in patients ith m&*& in hom all approved standard therapies have failed.+15-

Radiation therapy
Ohile radiation therapy remains a standard modality for patients ith rectal cancer, the role of radiation therapy is limited in colon cancer. It does not have a role in the adjuvant setting, and in metastatic settings, it is limited to palliative therapy for selected metastatic sites such as bone or brain metastases. Ce er, more selective ays of administering radiation therapy such as stereotactic radiotherapy !&yber7nife# and tomotherapy are currently being investigated and may e$tend indications for radiotherapy in the management of colon cancer in the future. . prospective, multicenter, randomi2ed phase III study by Iendlis2 et al compared the addition of yttrium-;0 resin to a treatment regimen of fluorouracil 500 mg3m0 IF infusion !days 1-1, =? k# ith fluorouracil IF alone. Kytrium-;0 as injected intra-arterially into the hepatic artery. Findings sho ed that the addition of radioemboli2ation ith yytrium-;0 significantly improved time to liver progression and median time to tumor progression. +11-

DIET
.bundant epidemiological literature suggests association of risk for developing colorectal cancer ith dietary habits, environmental e$posures, and level of physical activity. )ess is kno n about effect of diet and physical activity on the recurrence of colon cancer. . prospective observational study involving patients from the &.)D< ?;?05 adjuvant trial demonstrated adverse effect ith regards to risk for recurrence and increased mortality for patients follo ing a POesternP diet !high intake of red meat, refined grains, fat, and s eets# compared to patients ith a PprudentP diet !high intake of fruits and vegetables, poultry, and fish#. In another observational study from the same cohort of patients, patients ere prospectively monitored and physical activity as recorded. :he study concluded that physical activity reduces the risk of recurrence and mortality in patients ith resected stage III colon cancer. 7irkegaarde et al reported that adherence to a Phealthy life styleP recommendations based on physical activity, aist circumference, smoking, alcohol intake, and diet may significantly reduce colorectal cancer risk, by about 05>.+?0:hese interesting and important observations pave the ay for future interventional studies involving diet and physical activity in patients ith stage II and III colon cancer.

ACTIVITY Obesity and sedentary lifestyles are associated ith both an increased risk for &*& and
increased mortality for patients ith &*&. Borika a et al determined that obese patients ho modified their <BI and increased physical activity had better &*&-specific survival and overall survival due to activation of &:CC<1.+0?, 0;. study by &ampbell et al also reinforced the value of e$ercise and physical activity. :hey determined that 1 hours or more of sitting per day as associated ith an increase in mortality compared ith only sitting 5 hours or less per day. :he findings suggest that increasing physical activity helps reduce mortality in patients ith &*&.+?1-

.djuvant therapy

5-Fluorouracil Q leucovorin ! eekly schedule, lo dose leucovorin# 5-FluorouracilN 500 mg3m0 IF eekly for 1 eeks )eucovorinN 00 mg3m0 IF eekly for 1 eeks, administered before 5fluorouracil o *epeat cycle every ? eeks for a total of 0, eeks. )F5F40 !de Dramont regimen# o 5-FluorouracilN ,00 mg3m0 IF bolus, follo ed by 100 mg3m0 IF continuous infusion for 00 hours on days 1 and 0 o )eucovorinN 000 mg3m0 IF on days 1 and 0 as a 0-hour infusion before 5fluorouracil o *epeat cycle every 0 eeks for a total of 10 cycles. ($aliplatin Q 5-fluorouracil Q leucovorin !F()F(",# o ($aliplatinN ?5 mg3m0 IF on day 1 o 5-FluorouracilN ,00 mg3m0 IF bolus, follo ed by 100 mg3m0 IF continuous infusion for 00 hours on days 1 and 0 o )eucovorinN 000 mg3m0 IF on days 1 and 0 as a 0-hour infusion before 5fluorouracil o *epeat cycle every 0 eeks for a total of 10 cycles. Betastatic disease
o o o o o o o o o o o o o o o o o o o o o o

Irinotecan Q 5-fluorouracil Q leucovorin !F()FI*I regimen# IrinotecanN 1?0 mg3m0 IF on day 1 5-FluorouracilN ,00 mg3m0 IF bolus on day 1, follo ed by 0,00 mg3m0IF continuous infusion for ,1 hours )eucovorinN ,00 mg3m0 IF on day 1 as a 0-hour infusion, prior to 5-fluorouracil *epeat cycle every 0 eeks. ($aliplatin Q 5-fluorouracil Q leucovorin !F()F("1# ($aliplatinN 100 mg3m0 IF on day 1 5-FluorouracilN ,00 mg3m0 IF bolus on day 1, follo ed by 0,00 mg3m0IF continuous infusion for ,1 hours )eucovorinN ,00 mg3m0 IF on day 1 as a 0-hour infusion, before 5-fluorouracil *epeat cycle every 0 eeks. ($aliplatin Q 5-fluorouracil Q leucovorin !mF()F("6# ($aliplatinN 100 mg3m0 IF on day 1 5-FluorouracilN 5000 mg3m0 IF continuous infusion on day 1 for ,1 hours )eucovorinN ,00 mg3m0 IF on day 1 as a 0-hour infusion, before 5-fluorouracil *epeat cycle every 0 eeks. &apecitabine Q o$aliplatin !"%)("# &apecitabineN ?50-1000 mg3m0 /( bid on days 1-1, ($aliplatinN 100-150 mg3m0 IF on day 1 *epeat cycle every 01 days. F()F(", Q bevaci2umab ($aliplatinN ?5 mg3m0 IF on day 1 5-FluorouracilN ,00 mg3m0 IF bolus, follo ed by 100 mg3m0 IF continuous infusion on days 1 and 0 )eucovorinN 000 mg3m0 IF on days 1 and 0 as a 0-hour infusion before 5fluorouracil <evaci2umabN 10 mg3kg IF every 0 eeks *epeat cycle every 0 eeks.

5-Fluorouracil (5-FU, Adrucil, !ude")

Fluoropyrimidine analog. &ell cycle-specific ith activity in the '-phase as single agent and has for many years been combined ith biochemical modulator leucovorin. Bainstay of medical chemotherapy for colorectal cancer for patients for more than ,0 y. Ias activity as single agent that inhibits EC. replication and transcription. &ytoto$icity is cell-cycle nonspecific. 'ho n to be effective in adjuvant setting. &lassic antimetabolite anticancer drug ith chemical structure similar to endogenous intermediates or building blocks of EC. or *C. synthesis. 5-F4 inhibits tumor cell gro th through at least 5 different mechanisms that ultimately disrupt EC. synthesis or cellular viability. :hese effects depend on intracellular conversion of 5-F4 into 5-Fd4B/, 5-F4:/, and 5-Fd4:/. 5-Fd4B/ inhibits thymidylate synthase !key en2yme in EC. synthesis#, hich leads to accumulation of d4B/, hich then gets misincorporated into the EC. in the form of 5-Fd4:/ resulting in inhibition of EC. synthesis and function ith cytoto$ic EC. strandbreaks. 5-F4:/ is incorporated into *C. and interferes ith *C. processing. &urrent standard adjuvant therapy for colon cancer involves combination 5-F43)F chemotherapy. 'alt2 regimen !5-F43)F3&/:11# no standard first-line therapy for metastatic colon cancer. <ecause of to$icity, ma$imum of ,00 mg3m0 of 5-F4 and 100 mg3m0 of &/:11 can be used as starting dose. )evamisole is no longer an appropriate component of adjuvant therapy.
Fie full drug information

#apecita$ine (%eloda)

Fluoropyrimidine carbamate prodrug from of 5-fluorouracil !5-F4#. &apecitabine itself is inactive. 4ndergoes hydrolysis in liver and tissues to form the active moiety !fluorouracil#, inhibiting thymidylate synthetase, hich in turn blocks methylation of deo$yuridylic acid to th
&eucovorin (Folinic acid, #itrovorum Factor)
*educed form of folic acid that does not re=uire en2ymatic reduction reaction for activation. .llo s for purine and pyrimidine synthesis, both of hich are needed for normal erythropoiesis. &urrent standard therapy for colon cancer involves combination chemotherapy. <inds to and stabili2es ternary comple$ of Fd4:/ !intracellular active metabolite of fluoropyrimidines# and thymidylate synthetase !:'#, augmenting cytoto$ic effects of 5-fluorouracil. 4sed as an adjunct to fluorouracil.

'rinotecan (#amptosar, #()-**)

'emisynthetic derivative of camptothecin, an alkaloid e$tract from theCamptotheca acuminate tree. Inactive in its parent form. &onverted by the carbo$ylesterase en2yme to its active metabolite from, 'C-5?. 'C-5? binds to and stabili2es the topoisomerase I-EC. comple$ and prevents the relegation of EC. after it has been cleaved by topoisomerase I, inhibiting EC. replication. %ffective in treatment of colorectal cancer. &urrent standard therapy for metastatic colon cancer involves combination of 5-F43)F3&/:11 chemotherapy !see 'tandard :herapy#.

<ecause of to$icity problems associated ith 'alt2 regimen !5-F43)F3&/:11#, no standard first-line therapy for metastatic colon cancer, ma$imum of ,00 mg3m0 of 5-F4 and 100 mg3m0 of &/:11 can be used as starting dose.

+"aliplatin ( lo"atin, ,iaminocyclohe"ane platinum, ,A#--platinum)

:hird-generation platinum-based antineoplastic agent used in combination ith an infusion of 5-fluorouracil !5-F4# and leucovorin for treatment of metastatic colorectal cancer in patients ith recurrence or progression follo ing initial treatment ith irinotecan, 5-F4, and leucovorin. .lso indicated for previously untreated advanced colorectal cancer in combination ith 5-F4 and leucovorin. &ovalently binds to EC. ith preferential binding to the C-6 position of guanine and adenine. EC. mismatch repair en2ymes are unable to recogni2e o$aliplatin-EC. adducts in contrast ith other platinum-EC. adducts as a result of their bulkier si2e. Forms interstrand and intrastrand /t-EC. crosslinks that inhibit EC. replication and transcription. &ytoto$icity is cell-cycle nonspecific ith activity in all phases of the cell cycle.

#etu"ima$ ( r$itu")
*ecombinant, human3mouse chimeric monoclonal antibody that specifically binds to the e$tracellular domain of human epidermal gro th factor receptors !%DF*, I%*1, c-%rb<-1#. &etu$imab-bound %DF receptor inhibits activation of receptor-associated kinases, resulting in inhibition of cell gro th, induction of apoptosis, and decreased production of matri$ metalloproteinase and vascular endothelial gro th factor. Indicated for treatment of 7*.' mutation-negative ! ild-type# %DF*-e$pressing, metastatic colorectal cancer for the follo ingN 1# in combination ith F()FI*I for first-line treatment, 0# in combination ith irinotecan in patients ho are refractory to irinotecan-based chemotherapy, and 5# as a single agent in patients ho have failed o$aliplatin- and irinotecan-based chemotherapy or ho are intolerant to irinotecan.

Bevaci.uma$ (Avastin)
Burine derived monoclonal antibody that inhibits angiogenesis by targeting and inhibiting vascular endothelial gro th factor !F%DF#. Inhibiting ne blood vessel formation denies blood, o$ygen, and other nutrients needed for tumor gro th. <evaci2umab is indicated in combination ith a fluoropyrimidine-based chemotherapy as a first-line or second-line treatment for metastatic colorectal cancer. It is also indicated for second-line treatment in patients ho have progressed on a first-line bevaci2umab-containing regimen. For continuation therapy, use bevaci2umab in combination ith a fluoropyrimidine !eg, 5-F4, capecitabine# plus irinotecan or o$aliplatin-based chemotherapy

(anitumuma$ (/ecti$i")
*ecombinant human IgD0 kappa monoclonal antibody that binds to human epidermal gro th factor receptor !%DF*#. Indicated to treat colorectal cancer that has metastasi2ed follo ing standard chemotherapy.

0iv-a!li$ercept (0altrap)
Fascular endothelial gro th factor !F%DF# inhibitor9 prevents F%DF from stimulating cellular responses by binding to tyrosine kinase receptors !ie, the F%DF receptors#. Indicated in combination ith 5-fluorouracil, leucovorin, irinotecan !F()FI*I# for metastatic colorectal cancer that is resistant to or has progressed after an o$aliplatin regimen.

Regora!eni$ (Stivarga)
*egorafenib is a tyrosine kinase inhibitor. It is indicated for metastatic colorectal cancer in patients ho have been previously treated ith fluoropyrimidine-, o$aliplatin-, and irinotecanbased chemotherapy9 an anti-F%DF therapy !eg, bevaci2umab, 2iv-aflibercept#9 and, if 7*.' ild type, an anti-%DF* therapy !eg, cetu$imab, panitumumab#.