Second-Line Therapy in Colorectal Cancer

December 1, 2000

Second-line therapy is a relatively newconcept for gastrointestinal oncologists. Although retreatment with fluorouracil

ABSTRACT: Second-line therapy is a relatively newconcept for gastrointestinal oncologists. Although retreatment with fluorouracil(5-FU) is common, offering colorectal cancer patients a differentchemotherapeutic agent as second-line therapy is a fairly recent strategy. Thefocus of this article is on the use and efficacy of oxaliplatin (Eloxatin) assecond-line therapy for colorectal cancer. As such, this article will presentvery limited data on the toxicity of oxaliplatin regimens. [ONCOLOGY14(Suppl 11):21-26, 2000]


With the exception of surgicallyresectable liver or lung metastases, the majority of patients with metastaticcolorectal cancer are treated primarily with systemic chemotherapy. It is nowcommon for many of these patients to not only receive one, but two or morechemotherapy regimens during the course of their illness.

In a recently reported randomized trial, 45% of patientsreceiving first-line fluorouracil (5-FU) and leucovorin received second-lineirinotecan (CPT- 11, Camptosar).[1] Most of the current available data forsecond-line therapy of colorectal cancer comes from phase II trials. Thesetrials have all the limitations of other phase II trials. In addition, there issignificant heterogeneity in the colorectal cancer population considered for"second-line" therapy. This group may include patients who firstpresented with metastatic disease, patients who have progressed rapidly afteradjuvant therapy, patients who have had more than one resection for disease, andpatients who may have had liver-directed therapy. In addition, as more knowledgedevelops on the molecular basis of disease, properties of the cancers themselveshave been identified that may predict chemotherapy effects.

The data regarding the use of oxaliplatin as second-line (orlater-line) chemotherapy will be highlighted herein. The article willdemonstrate that phase II data in this setting are mature and that the time hascome for randomized trials to establish the true role of oxaliplatin insecond-line chemotherapy.

Combinations asFirst-Line Therapy

An important variable in future results of second-line therapymay be the shifting paradigm for first-line therapy. (Use of oxaliplatin(Eloxatin) as first-line therapy is discussed elsewhere.) Recently, two clinicaltrials compared fluorouracil (5-FU) and leucovorin with 5-FU, leucovorin, andirinotecan combination therapy. Both trials showed that the addition ofirinotecan increased the response rate, time to progression, and overallsurvival compared to 5-FU and leucovorin alone, at the expense of potentialadded toxicity.[1-3] Thus, at least in the United States, many patients are nowreceiving a combination regimen as first-line therapy.

However, investigators initially assessed irinotecan assecond-line therapy for metastatic colorectal cancer. In that respect, data fromthose trials remain the best framework in which to evaluate second-lineoxaliplatin. Single-agent irinotecan as second-line therapy has yielded responserates of 10% to 22% and median survivals of 8 to 10 months.[4] In two randomizedtrials, irinotecan also established a survival benefit over both best supportivecare and second-line infusional 5-FU.[5,6] The trials had different eligibilitycriteria and, therefore, patient populations.[7-12]

Single-Agent Oxaliplatin

The activity of single-agent oxaliplatin as second-line therapywas established in three trials reported in two articles.[7,13] In the trials byMachover et al, patients received intravenous infusions of oxaliplatin over 2hours. Doses were repeated every 3 weeks.[7] The study by Levi et al used achronomodulated infusion, with the peak dose administered at 4 PM,over 5 days, also repeated every 3 weeks.[7]

Response rates were 10% to 11%, with stable disease seen in 24%to 42% of patients. Median time to progression was 4.5 to 6 months and mediansurvival was 8 to 9 months. These results are comparable to the results achievedwith irinotecan as second-line therapy.[4-6]

Combination Regimens

The Folfox Regimens

De Gramont and colleagues have pioneered several regimenscombining 5-FU and leucovorin with oxaliplatin.[7-11] The majority of theseregimens are administered every 2 weeks, and contain infusions of leucovorin and5-FU. Most also contain one or two bolus doses of 5-FU. For example, folfox4(oxaliplatin, leucovorin, and fluorouracil) administers oxaliplatin at 85 mg/m2over 2 hours on day 1. Patients then receive leucovorin at 200 mg/m2over 2 hours on days 1 and 2 followed each day by bolus 5-FU at 400 mg/m2on days 1 and 2 and 22 hours of infusional 5-FU 600 mg/m2on days 1 and 2. These cycles are repeated once every 2 weeks, for up to 12doses of oxaliplatin (Table 1).[7-12]

When combined, the response rate plus stable disease rate isgenerally greater than 50% for the folfox regimens. Of particular note, most ofthe patients in these trials had progressed while on the same 5-FU andleucovorin regimen that they later received on trial with the addition ofoxaliplatin, suggesting that the addition of oxaliplatin resulted in theantitumor effect. Although these data are from phase II trials, response ratesfor the folfox regimens were higher than for single-agent oxaliplatin,suggesting a possible additive effect when combining 5-FU and oxaliplatin.

Differences in the incidence of toxicity were seen among thefolfox regimens with grade 3/4 neutropenia occurring in 20% to 39% of patientsreceving folfox2, 3, 4, or 6, and grade 2/3 neuropathy in 16% to 29% of thosereceiving folfox2, 3, 4, or 6.[11]


Chronomodulated 5-FU has also been combined with oxaliplatin inseveral phase II trials listed in Table 2.[14-18]Although two trials involved both previously untreated and previously treatedpatients, the data are separated when possible for patients with refractorydisease. As with the folfox trials, response rates were high, ranging from 15%to 58%. In addition, a progression-free survival ranging from 5 to 10 months andan overall survival as high as 17 months was observed.

Recently, Giacchetti et al reported results that combinedpatients from some of the trials listed in Table3 with other patients being considered for resection of hepaticmetastases.[19] In total, 196 patients had been treated with chronomodulated5-FU and oxaliplatin. Of these, 60% had received only one previous chemotherapyregimen and 40% had received greater than or equal to two regimens. Medianprogression-free survival was 9 months and overall survival was 17 months.However, hepatic metastases were resected in 18% of patients.

With chronomodulation, grade 3/4 neutropenia occurred in lessthan 5% of patients, while grade 2 or higher neuropathy occurred in up to 32% ofpretreated patients and grade 3/4 mucositis in up to 28% of patients.[14,15]

Other 5-FU Regimens

Several schedules and doses for 5-FU, leucovorin, andoxaliplatin have been investigated; many of these are listed in Table3.[20-24] Although some of the bolus schedules for 5-FU appeared to yieldlower response rates, overall survival was similar to that achieved with thefolfox and chronomodulated schedules shown in Table1 and Table 2. Table3 is not a comprehensive list of all the trials performed, and moretreatment schedules are likely to be tried. In fact, the Extended Access FrenchProgram (EAFP) allowed the use of over 25 different regimens of oxaliplatin incombination with 5-FU.[25] This data set incorporated 490 patients from 147centers, only 18 of whom received single-agent oxaliplatin.

Antitumor effects were reviewed for 370 patients, and 14.6%responded to therapy with a 9.7-month overall median survival. Response rateswere higher for the biweekly oxaliplatin regimens (36.1%) than for the triweeklyregimens (13.3%) but survivals were similar at 11.1 and 10.0 months,respectively. The current "compassionate-use trial" in the UnitedStates will accumulate progression and survival data that may help guide adecision on whether it is worthwhile to explore different regimens in arandomized fashion.

A single randomized phase II/III trial has been reported thatcompared oxaliplatin plus 5-FU vs one of two other second-line regimens, 5-FU oririnotecan.[26] The trial was divided into two treatment arms with 49 patientsassigned to the oxaliplatin plus 5-FU arm vs 36 patients in the control arm. Theresponse rate was 37% for the oxalipatin plus 5-FU arm vs 11% for the controlarm, and progression-free survival was 5.1 months vs 2.2 months for theoxaliplatin plus 5-FU and control arm, respectively.

The final data from this trial may help to clarify the role ofoxaliplatin plus 5-FU in second-line therapy of colorectal cancer. However,interpretation may be limited by the inclusion of two different single-armregimens in the "control" arm.

Overall, it appears that 5-FU plus oxaliplatin is active in thesecond-line therapy of colorectal cancer. A number of regimens have been testedas listed in Tables 1 to 3. While response rates for combination therapy oftenseem higher than response rates for single-agent oxaliplatin, survival does notappear to differ significantly.

Oxaliplatin AfterIrinotecan

Although many of the oxaliplatin clinical trials allowed priortherapy with irinotecan as well as 5-FU, only a few specified prioririnotecan-based regimens. In one trial, a folfox2 regimen was investigatedafter patients received previous treatment with both 5-FU/leucovorin andirinotecan-based regimens.[27] At the time of the report, 29 of 45 enrolledpatients were evaluable. Approximately 75% had received one prior regimen thatcontained all three drugs while the other 25% had received two prior regimens.Among the 29 evaluable patients, there was one complete response and threepartial responses, for an overall response rate of 13.7%. Stable disease wasachieved by 10 patients and the estimated 1-year survival was 52%.

A more recent trial is testing the strategy of administering asequential regimen of oxaliplatin and irinotecan.[28] A total of 226 patientshave been randomized to 5-FU/leucovorin plus irinotecan, with a switch to5-FU/leucovorin plus oxaliplatin upon progression vs first-line 5-FU/leucovorinplus oxaliplatin, with a switch to 5-FU/leucovorin plus irinotecan uponprogression. The primary end point is time to progression, which has not yetbeen reached. First-line response rates are approximately 60% for both arms.Results from this trial may help define sequencing of chemotherapy.

Oxaliplatin asThird-Line Therapy

In the United States, oxaliplatin is currently available only ina clinical trial or through compassionate use. In the latter capacity,oxaliplatin is often used as third-line therapy. One recently reported studyevaluated 79 patients, 50 of whom had received only one prior chemotherapyregimen (second-line) and 29 of whom had received two prior regimens(third-line).[29] All received oxaliplatin in combination with high-dose 24-hourinfusional 5-FU and leucovorin. The response rate for patients receiving thesecond-line regimen was 24%, while for patients receiving the third-lineregimen, it was 14%.

Another analysis retrospectively reviewed patients treated infour phase II trials of oxaliplatin with chronomodulated 5-FU.[30] Patients inthese trials may have been treated with a variety of previous regimens. In fact,some patients were enrolled on oxaliplatin as seventh-line chemotherapy. For the118 second-line patients, the response rate was 44%, with a median survival of19 months. For 78 third-line to seventh-line patients, the response rate was36%, with a median survival of 16 months.

Oxaliplatin PlusIrinotecan

With the development of new agents for use in colorectal cancer,it is worthwhile exploring chemotherapy couplets that do not include 5-FU.Oxaliplatin combinations with irinotecan are showing some evidence of promise. Table4 lists the results of early trials.[31-33] A phase I trial is currentlyongoing at Vanderbilt University in which irinotecan and oxaliplatin areadministered on a biweekly schedule (M. Rothenberg, personal communication,2000). Although a variety of tumor types have been treated in this protocol,responses were seen in 6 (40%) of the first 15 patients enrolled with colorectalcancer.

Responses were noted at all dose levels tested and in patientswith previous progression while on irinotecan. An additional response was seenin a patient with carcinoma of the appendix.

Several trials combining oxaliplatin with 5-FU and irinotecanare currently accruing patients. One study enrolled 33 patients, 21 of whom hadpreviously received chemotherapy.[34] This trial employed a variety of dosesdepending on the site of disease. Yet, despite this variety, the overallresponse rate was 57.6%, with a median time to treatment failure of 8 months.Median survival had not yet been reached, with 54% of patients alive at a medianfollow-up of 18 months.


Oxaliplatin has been thoroughly studied in the phase II settingfor the treatment of colorectal cancer. From the available data, it appears thatoxaliplatin is active as a single agent, but may be more effective incombination with either 5-FU or possibly irinotecan. The trials presented heresuggest high response rates and long median survivals for patients treated withoxaliplatin (and who are eligible for the clinical trials).

Oxaliplatin has demonstrated laboratory synergy when combinedwith 5-FU. Phase II data suggest that the combination of oxaliplatin with 5-FUmay have a higher response rate than single-agent oxaliplatin, but there are nodata to show a survival benefit for combined therapy. In fact, due to the knownactivity of second-line 5-FU, it is unclear what contribution each of the drugsplay in responses seen in phase II studies. These questions have led to thelarge randomized study in the United States now open. In this trial, patientswill be randomized to one of three arms: oxaliplatin alone, oxaliplatin incombination with 5-FU and leucovorin on a folfox 4 regimen (outlined earlier),and 5-FU and leucovorin without oxaliplatin. Eligible patients will haveprogressed after receiving 5-FU, leucovorin, and irinotecan as givien in theSaltz trial mentioned earlier.[1] This trial can answer the question as to therole of each component of a 5-FU, leucovorin, and oxaliplatin regimen. Thistrial will not answer which combination regimen may be best. However, after 4decades of research comparing different methods of administering 5-FU incolorectal cancer, there has been no regimen established as a best method fordrug administration. It is unlikely that this will change when oxaliplatin isplaced in the mix.

Finally, for those patients who receive 5-FU and leucovorin onlyas first-line therapy for colorectal cancer, irinotecan is the establishedsecond-line agent in the United States. Building on the promising early datafrom combining oxaliplatin and irinotecan, a second trial (4585) has beendesigned to evaluate a role for oxaliplatin in this setting. In this study,patients will be randomly assigned to single-agent irinotecan or to combinedoxaliplatin plus irinotecan therapy. It is unfortunate that a single-agentoxalipaltin arm was not included in this trial. Concerns about cross-over tothird-line irinotecan would exist, but with a good enough agent, cross-overwould not significantly change results.

Thus, oxaliplatin has demonstrated significant response rateswith promising survival times in the phase II setting, but only minimaladditional data can be obtained from more phase II trials. Answers need to comefrom randomized trials that are now starting in the United States.


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1a. Saltz LB, Douillard J, Pirotta N, et al: Combined analysisof two phase III randomized trials comparing irinotecan (C), fluorouracil (F),leucovorin (L) vs F alone as first-line therapy of previously untreatedmetastatic colorectal cancer (abstract 938). Proc Am Soc Clin Oncol 19:242a,2000.

2. Saltz LB, Locker PK, Pirotta N, et al: Weekly irinotecan(CPT-11), leucovorin (LV), and fluorouracil (FU) is superior to daily ´5 LV/FU in patients with previously untreated metastatic colorectal cancer(abstract 898). Proc Am Soc Clin Oncol 18:233a, 1999.

3. Douillard JY, Cunningham D, Roth AD, et al: Irinotecancombined with fluorouracil compared with fluorouracil alone as first-linetreatment for metastatic colorectal cancer: A multicentre randomised trial.Lancet 355:1041-1047, 2000.

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5. Rougier P, Van Cutsem E, Bajetta E, et al: Randomised trialof irinotecan vs fluorouracil by continuous infusion after fluorouracil failurein patients with metastatic colorectal cancer. Lancet 352:1407-1412, 1998.

6. Machover D, Diaz-Rubio E, de Gramont A, et al: Twoconsecutive phase II studies of oxaliplatin (L-OHP) for treatment of patientswith advanced colorectal carcinoma who were resistant to previous treatment withfluoropyrimidines. Ann Oncol 7:95-98, 1996.

7. De Gramont A, Vignoud J, Tournigand C, et al: Oxaliplatinwith high-dose leucovorin and 5-fluorouracil 48-hour continuous infusion inpretreated metastatic colorectal cancer. Eur J Cancer 33:214-219, 1997.

8. Andre T, Louvet C, Raymond E, et al: Bimonthly high-doseleucovorin, 5-fluorouracil infusion, and oxaliplatin (FOLFOX3) for metastaticcolorectal cancer resistant to the same leucovorin and 5-fluorouracil regimen.Ann Oncol 9:1251-1253, 1998.

9. Andre T, Bensmaine MA, Louvet C, et al: Multicenter phase IIstudy of bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatinfor metastatic colorectal cancer resistant to the same leucovorin andfluorouracil regimen. J Clin Oncol 17:3560-3568, 1999.

10. Maindrault-Goebel F, Louvet C,Andre T, et al: Oxaliplatinadded to the simplified bimonthly leucovorin and 5-fluorouracil regimen assecond-line therapy for metastatic colorectal cancer (FOLFOX6). GERCOR. Eur JCancer 35:1338-1342, 1999.

11. Maindrault-Goebel F, de Gramont A, Louvet C, et al:High-dose oxaliplatin with the simplified 48h bimonthly leucovorin (LV) and5-fluorouracil (5-FU) regimen in pretreated metastatic colorectal cancer(FOLFOX) (abstract 1017). Proc Am Soc Clin Oncol 18:265a, 1999.

12. Beretta GD, Cascinu S, Zaniboni A, et al: Oxaliplatin(L-OHP) in combination with leucovorin and bolus-continuous infusion5-fluorouracil (LV5FU2) in advanced colorectal cancer (ACC) pretreated with5-FU. Eur J Cancer 35(suppl 4):256, 1999.

13. Levi F, Perpoint B, Garufi C, et al: Oxaliplatin activityagainst metastatic colorectal cancer: A phase II study of 5-day continuousvenous infusion at circadian rhythm modulated rate. Eur J Cancer 29A:1280-1284,1993.

14. Berheault-Cvitkovic F, Jami A, Ithzaki M, et al: Biweeklyintensified ambulatory chronomodulated chemotherapy with oxaliplatin,fluorouracil, and leucovorin in patients with metastatic colorectal cancer. JClin Oncol 14:2950-2958, 1996.

15. Levi F, Misset J-L, Brienza S, et al: A chronopharmacologicphase II clinical trial with 5-fluorouracil, folinic acid, and oxaliplatin usingan ambulatory multichannel programmable pump. Cancer 69:893-900, 1992.

16. Guerin-Meyer V, Delva R, Lortholary A, et al: Combination ofoxaliplatin (OXA)/5-FU/FA in 5-FU refractory advanced colorectal cancer (RACRC)patients treated with 5-FU/FA weekly PK guided regimen (abstract 1001). Proc AmSoc Clin Oncol 18:260a, 1999.

17. Berheault-Cvitkovic F, Mefti F, Francois E, et al: A phase Istudy of bimonthly 48 hours (hrs) chronomodulate 5-FU/folinic (FA) incombination with oxaliplatin (OXA) in pretreated patients with advancedcolorectal cancer (ACRC) (abstract 997). Proc Am Soc Clin Oncol 18:259a, 1999.

18. Bertheault-Cvitkovic F, Mefti F, Seitz JF, et al:Chronomodulated (CRM) bimonthly 48 hour (hr) 5-fluorouracil (5-FU), folinic acid(FA), oxaliplatin (OXA) ‘FOLFOX CRM’ in FU-refractory (FUR) advancedcolorectal cancer (ACRC) patients: Phase II study (abstract 1242). Proc Am SocClin Oncol 19:314a, 2000.

19. Giacchetti S, Zidani R, Chollet P, et al: Chemotherapy ofmetastatic colorectal cancer (MCC) with 5-fluorouracil (5-FU)-leucovorin(LV)-oxaliplatin (L-OHP) as second- to seventh- line treatment (abstract 1255).Proc Am Soc Clin Oncol 19:318a, 2000.

20. Roca E, Montiel M, Barugel M, et al: 5-FU and leucovorin(MAYO regimen) plus bimonthly oxaliplatin (OXA) in patients with advancedcolorectal cancer (ACC) (abstract 1144). Proc Am Soc Clin Oncol 18:298a, 1999.

21. Van Cutsem E, Szanto J, Roth A, et al: Evaluation of theaddition of oxaliplatin (OXA) to the same Mayo or German 5-FU regimen inadvanced refractory colorectal cancer (abstract 900). Proc Am Soc Clin Oncol18:234, 1999.

22. Tassinari D, Panzin I, Pasquini E, et al: Oxaliplatin, 5-FUand folinic acid (OFFA) as II-line chemotherapy in advanced colorectal cancer.Eur J Cancer 35 (suppl 4):1999.

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24. Gerard B, Bleiberg H, Van Daele D, et al: Oxaliplatincombined to 5-fluorouracil and folinic acid: An effective therapy in patientswith advanced colorectal cancer. Anticancer Drugs 9:301-305,1998

25. Bensmaine MA, Marty M, de Gramont A, et al: Extended AccessFrench Program (EAFP) of oxaliplatin ± 5-FU in 5-FUrefractory colorectal cancer (RACRC) patients (abstract 973). Proc Am Soc ClinOncol 18:253a, 1999.

26. Adenis A, Douillard J, Lacroix H, et al: Randomized phaseII-III trial of oxaliplatin (OXA) with 5-fluorouracil (5-FU) continuous infusion(CI) vs a control arm with either 5-FU or irinotecan (CPT11) in previouslytreated metastatic colorectal cancer patients (abstract 1088). Proc Am Soc ClinOncol 19:279a, 2000.

27. Kouroussis CH, Mavroudis D, Giannakakis N, et al: Biweeklyoxaliplatin (L-OHP) with high-dose leucovorin (LV) and 5-fluorouracil (5-FU)48-hour continuous infusion in pretreated patients with advanced colorectalcancer (abstract 1111). Proc Am Soc Clin Oncol 18:290a, 1999.

28. Tournigand C, Louvet C, André T, et al: FOLFIRI followed byFOLFOX or FOLFOX followed by FOLFIRI in metastatic colorectal cancer: Which isthe best sequence? Safety and preliminary efficacy results of a randomized phaseIII study (abstract 949). Proc Am Soc Clin Oncol 19:245a, 2000.

29. Bleiberg H, Brienza S, Gerard B, et al: Oxaliplatin combinedwith a high dose, 24-hour continuous 5-FU infusion and folinic acid basedregimen in patients with advanced colorectal cancer (abstract 1999). Proc Am SocClin Oncol 18:241a, 1999.

30. Giacchetti S, Zidani R, Dogliotti L, et al: Chronotherapy ofmetastatic colorectal cancer with 5-fluorouracil (5-FU)-leucovorin(LV)-oxaliplatin (L-OHP) as second to seventh-line treatment (abstract 1255).Proc Am Soc Clin Oncol 19:318a, 2000.

31. Scheihauer W, Kornek GV, Roderer M, et al: Combinedirinotecan and oxaliplatin plus granulocyte colony-stimulating factor inpatients with advanced fluoropyrimidine/leucovorin-pretreated colorectal cancer.J Clin Oncol 17:902-906, 1999

32. Becouam Y, Mousseau M, Gamelin E, et al: CPT-11 and L-OHPcombination vs alternated combination of LV5FU2 +CPT-11/LV5FU + L-OHP in 5-FU resistant advanced colorectalcancer: Preliminary results (abstract 219). Eur J Cancer 35(suppl 4):1999.

33. Wasserman E, Kalla S, Misset JL, et al: Oxaliplatin (L-OHP)and irinotecan (CPT11) phase I/II studies: Results in 5-FU refractory (FR)colorectal cancer (CRC) patients (abstract 913). Proc Am Soc Clin Oncol 18:238a,1999.

34. Calvo E, Gonzalez-Cao M, Cortes J, et al: Combinedirinotecan, oxaliplatin, 5-FU in patients with metastatic colorectal cancer(abstract 1008). Proc Am Soc Clin Oncol 19:259a, 2000.