Adjuvant therapy in colon cancer: which treatment in 2005?

Annals of Oncology 16 (Supplement 4): iv69 iv73, 2005 doi:10.1093/annonc/mdi911 Adjuvant therapy in colon cancer: which treatment in 2005? F. Di Costanzo* & L. Doni Medical Oncology Unit, Department of Oncology, University Hospital Careggi, Florence, Italy Colorectal cancer is a common malignancy in Europe with approximately 150 000 new cases and 60 000 deaths every year. In Italy, 30 000 new cases are expected annually [1]. Survival for colorectal cancer increased in all European countries from 44% (1986 1989) to 52% (1992 1994), improving equally for men and women, younger and older patients, and rectal and colonic sites. Geographic disparities between European regions persisted according to the results of EUROCARE-3 [2]. It could be that part of the increase in colorectal survival is due to early diagnoses, increase in the resection rate, a decrease in post-operative mortality and finally an increase in the use of adjuvant treatments. This paper discusses the modalities available for adjuvant treatment of high risk colon cancer patients. Surgery is the primary curative treatment of colon cancer, although a high number of patients develop recurrence despite appropriate local therapy. The most important prognostic factor in anticipating the risk of recurrence is the lymph-nodes (LN) involvement at the time of resection. In stage II (LN-) the risk of relapse ranges from roughly 25 30% and 40 60% for stage III (LN+).Survival is influenced not only by the presence of positive LN, but also by the number. Wong et al. reported that patients with LN- had significantly fewer LN examined than did node+ patients (14 versus 20 LN) [3]. Le Voyer et al. reported that 5-yr survival was 73% in stage II, if 10 or fewer LN were recovered, whereas that number improved to 87%, an absolute 14% improvement in survival, if more than 20 LN were recovered. At least 14 LN should be examined to accurately stage a patient with colon cancer [4]. The tumour relapses occur in sites distant from the primary tumor: liver, peritoneum, lung and bone. Seventy-four percent of recurrence occurs within the first 3-years. Adjuvant therapy aims to eliminate this residual disease and to increase the disease free interval and overall survival (OS). Approximately 40% of patients are candidates for adjuvant chemotherapy because LN+, while there is a 15 20% of patients with LNin which there is a large variability in indication for adjuvant treatment. *Correspondence to: Dr Francesco Di Costanzo, Via Pieraccini 17, 50139 Firenze, Italy. E-mail: oncmed02@ao-careggi.toscana.it q 2005 European Society for Medical Oncology Fluorouracil plus LEVA or Leucovorin In 1989 the North Central Cancer Treatment Group (NCTTG) published the results of a randomised trial, demonstrating that 5-FU plus LEVA increases DFS (P = 0.002) with a small, but significant, survival benefit (P = 0.03) [5]. These results were confirmed in a large trial of Intergroup (INT-0035) [6]. In this trial 5-FU + LEVA decreased the relapse by 41% (P <0.0001) and death by 33%. After 6.5 years of median follow-up, the reduction of mortality rate was confirmed. Bleeker et al. randomised 500 patients with Dukes C colon to adjuvant treatment for one year with 5-FU and LEVA with or without leucovorin [7].The addition of low dose leucovorin increased toxicity (mucositis and conjunctivitis) without a significant increase in treatment withdrawal. The addition of low dose leucovorin to the combination of 5-fluorouracil and LEVA does not improve disease-free interval nor OS. Therefore leucovorin 5-FU LEVA is not recommended in a 12 month adjuvant regime of Dukes C colon cancer. The Italian Cooperative Group (INTACC) randomised 1703 patients with radically resected colon cancer (Dukes B 2 3 and C) to receive 5-FU + LEVA versus 5-FU + LEVA + LV [8]. After a median follow-up of 6.4 years no significant difference was seen for either disease-free survival (58% versus 60%, NS) or 5-year OS (68% versus 71%, NS), respectively. Several trials evaluated the biochemical modulation of 5-FU plus leucovorin in advanced disease showing interesting results in terms of objective response, prolonged progression free survival and slightly improved OS [9]. The logical second step, after the interesting results with 5-FU and LEVA, was the evaluation of the biomodulation versus surgery alone and 5-FU + LEVA. 5-FU + LV versus surgery showed a reduction of risk of relapse and mortality by 30 40% in the treatment group. The comparison between 5-FU + LEVA versus 5-FU + LV indicated a small reduction of risk (15%). Two other questions were the duration of treatment and which biomodulation regimen (high versus low dose of LV or weekly versus monthly) is better. INT-0089 and NCCTG-894651 demonstrated that six months of 5-FU + LV is equal to 5-FU + LEVA for 12 months [10, 11]. QUASAR randomised 4 927 patients with colon cancer (2 2 design) to fluorouracil (370 mg/m 2 ) with high-dose (175 mg) or low-dose (25 mg) L-folinic acid and either active or placebo LEVA[12]. The primary endpoint was mortality

iv70 from any cause. Survival was similar with high-dose and lowdose folinic acid (70.1% versus 71.0% at 3 years; P = 0 43), as were 3-year recurrence rates (36.0% versus 35.8%; P = 0.94). Survival was worse with LEVA than with placebo (69.4% versus 71.5% at 3 years; P = 0.06), and there were more recurrences with the active drug (37.0% versus 34.9% at 3 years; P = 0.16). The inclusion of LEVA in chemotherapy regimens for colorectal cancer does not delay recurrence or improve survival. Higher-dose folinic acid produced no extra benefit in these regimens over that from low-dose folinic acid. Andre et al. randomised 905 patients, in a 2 2 factorial study, semi-monthly 5-LV5FU2 (De Gramont s schedule) versus a monthly 5-FU + LV regimen as adjuvant treatment of patients with stage II and III colon cancer [13]. The median follow-up was 41 months. Disease-free survival was similar between De Gramont regimen and control arm (127 versus 124 events; hazard ratio [HR] = 1.04; P = 0.74). Analysis of OS showed a slight excess in the number of deaths in LV5FU2 compared with FU + LV (73 versus 59), but this difference was not statistically significant (HR = 1.26; 95% confidence interval, 0.90 to 1.78; P = 0.18). The most commonly observed grade 3 to 4 toxicities were neutropenia, diarrhea, and mucositis. Toxicities were significantly lower in the LV5FU2 group (all toxicities, P <0.001). This trial also confirms, in adjuvant setting, that protracted 5-FU infusion is less toxic than bolus. No statistically significant difference could be detected in disease-free or OS between the treatment groups or treatment durations. Then, 5-FU + LV for six months has become the standard approach for adjuvant treatment in colon cancer. Fluorouracil plus Oxaliplatin The combination of Oxaliplatin plus 5-FU and LV was associated with significant improvement in response rate (50 53%) and a significant delay in tumour progression in patients with metastatic colorectal cancer, compared to schedule without Oxaliplatin [14]. A multicentre international study randomised 2246 (40% stage II) patients, who had undergone curative resection for stage II or III colon cancer in over 20 countries from October 1998 to January 2001, to receive de Gramont schedule (LV5FU2) alone or plus Oxaliplatin (FOLFOX) for 6 months. The primary end point was disease-free survival [15].The total study population was randomly divided into 2 equal groups of 1123 patients each. At a median follow-up of 37.9 months, it was determined that 237 (21.1%) patients among those receiving FL plus Oxaliplatin had had a cancer-related event, compared with 293 (26.1%) patients among those receiving FL (hazard ratio for recurrence, 0.77; P = 0.002). The rate of disease-free survival at 3 years was 78.2% (95% confidence interval [CI], 75.6 to 80.7) for patients receiving FL plus Oxaliplatin and 72.9% (95% CI, 70.2 to 75.7) for those receiving FL (P = 0.002 by stratified log-rank test). Then the risk reduction for patients treated with FOLFOX-4 was 23%. For patients with stage III disease, a statistically significant improvement in 3-year DFS was achieved. The superiority of the FOLFOX 4 regimen was preserved regardless of baseline prognostic factors, such as nodal stage. The results of this trial based on DFS alone, without any advantage in OS, have generated some perplexity among oncologists. A recent oral presentation by de Gramont confirm the results of DFS without any difference in terms of OS after a median follow-up of 4 years. The incidence of neutropenia was much more common among patients receiving FL plus Oxaliplatin (41.1% versus 4.7%; P <0.001); however, incidence of febrile neutropenia was low (1.8% versus 0.2%; P <0.001). Gastrointestinal toxicity was common in both groups, but incidence of grade 3 to 4 events was relatively low. Incidence of neuropathy (gr.3) among patients receiving FOLFOX was 12.4% versus 0.2% for those receiving FL alone; however, residual neuropathy remained in only 1.1% at 1-year follow-up and further declined to 0.5% at 18 months of follow-up. Two of the patients with residual neuropathy at 1 year had underlying diagnoses of diabetes and hemiplegia. Dose adjustment and active management, such as calciumplus-magnesium infusions or use of calcium channel blockers could ameliorate acute cumulative toxicity. Six patients in each group died during treatment (death rate: 0.5%). Unlike the results achieved in patients with stage III disease, improvement in 3-year DFS for patients with stage II colon cancer did not show statistical significance. This is probably due to sample size. Three-year DFS has been statistically validated as an appropriate intermediate end point in a recent review by the Mayo Clinic group. Sargent et al. showed that results of DFS after 3-years of follow-up can predict OS after 5-years [16]. In this analysis, which included over 17 000 patients, 74% of all recurrences occurred in the first 3 years. The correlation between 3-year DFS and OS in 19 of 22 analysed studies was very strong. The researchers concluded that the use of 3-year DFS was a good end point to evaluate in the adjuvant setting. Although Sargent s theorem is stimulating and interesting, at present in adjuvant treatment the principal end-point remains OS. Mayer commented this trial underlining the value of OS in adjuvant setting and suggested considering FOLFOX-4 for high risk patients: more than 3-LN+(N2) and tumour invasion beyond the serosa (T4). Furthermore, longer follow-up is needed to assess OS data. Additional clinical studies for patients with advanced colon cancer are underway and which hopefully will shed further light on optimal adjuvant therapy regimens based on risk stratification for this diverse group of patients. Fluorouracil and CPT-11 CPT-11, a semi-synthetic derivate of camptothecin that interacts with topoisomerasi-i, is reference treatment in second line and has also shown in first line a response rate of 40 50% with improved in OS and progression free survival.

Saltz et al. in a trial of CALGB (C89803) compared 5-FU and LV versus 5-FU + LV + CPT-11 in stage III colon cancer [17]. After a follow-up of 3 years, there was no difference in terms of OS, DFS or failure free-survival. Although the arm with CPT-11 was associated with significant higher rate of neutropenia (P <0.00 001), neutropenic fever (P <_ 0.0005) and death (P = 0.008), it is unclear whether this study is negative considering that in advanced disease CPT-11 plus 5-FU + LV is comparable with FOLFOX. In Europe, a similar trial (PETACC-3) is ongoing in which CPT-11 plus 5-FU (AIO schedule) is compared with AIO alone. This study could clear the value of CPT-11 in adjuvant therapy of colon cancer. Oral Fluoropirimidine UFT and Capecitabine are two oral fluorinated pyrimidines that have reported interesting results in advanced colorectal cancer. The RR was comparable with Mayo Clinic regimen, but with less neutropenia and stomatitis. The principal toxicity of Capecitabine is hand-foot syndrome (gr.3:17%) while in UFT therapy is diarrhea (12%) [18, 19] The NSABP (C-06) compared 5-FU + LV versus oral UFT both for six months. Seven hundred and seventy patients were randomised to the bolus group and 784 patients to UFT. Forty-six percent of the patients in both groups had stage II disease [20]. The relapse-free survival rate was 76.4% in the Roswell Park regimen vs. 74.5% in the UFT group, while disease-free survival was 68.3% in the 5-FU group vs. 66.9% in the UFT group. The principal toxicities were diarrhea, vomiting, and nausea. There was no difference in quality of life measures between the two groups, but fatigue symptoms and distress appear to favour the oral treatment. Six toxic deaths in the oral therapy group and nine in the standard therapy group were registered. X-ACT study, a phase III trial comparing oral Capecitabine to the Mayo regimen, randomised 1,987 [21]. Patients randomised to Capecitabine were given 1,250 mg/m 2 twice a day on days 1 14 every three weeks. Both regimens were given for 24 weeks. The primary end point of the study was equivalence in disease-free survival. After a median follow-up of 3.8 years, 3-year DFS for patients enrolled on the Capecitabine arm was 65.5% versus 61.9% on the 5-FU/LV arm (P = 0.0528) (HR: 0.89; 95%CI: 0.76 1.04]). The 3-year survival was 81.3% on the Capecitabine arm versus 77.6% on the 5-FU/LV arm (P = 0.0706). The most common adverse effect seen in the Capecitabine group was hand and foot syndrome, but it was easily managed with dose reduction. Dose reduction or dose-delay during the treatment was required in 57% of patients in the Capecitabine arm. In both trials the standard treatment was the Mayo Clinic regimen, which is not considered the best schedule to administer 5-FU + LV, although these results are very interesting and open a new option. The oral treatment required an active management of the dosing to avoid dose reduction or adjustment by patients. In Italy a trial to evaluate the active monitoring of patients during oral therapy with Capecitabine (NEXT TRIAL) is ongoing A meta-analysis by the Japanese Society for Cancer of the Colon and Rectum, evaluated the survival and disease-free survival benefits in adjuvant therapy of colon cancer in patients who received oral fluoropyrimidines for 1 year [22]. The analysis was performed on individual data from three randomised trials, conducted in Japan, involving about 5 233 patients with stages I to III colorectal cancer. The overall hazard ratio in favour of oral therapy was 0.89 for survival (95% CI, 0.80 to 0.99; P = 0.04), and 0.85 for disease-free survival (95% CI, 0.77 to 0.93; P <0.001). Authors concluded that oral fluoropyrimidines reduced the risk of death by 11% and the risk of recurrence or death by 15%. There was no significant heterogeneity between trials, nor did the benefit of oral therapy depend on tumour stage (I, II, or III), tumor site (rectum or colon), patient age, and patient sex. Stage II colon cancer: treat or not? iv71 The role for adjuvant chemotherapy in stage II colon cancer remains controversial. The absolute benefit from adjuvant treatment in stage II is estimated in the 5-year survival rate of 2 4%. The treatment-related deaths are approximately 1%. The American Society of Clinical Oncology recommendations do not support the routine use of adjuvant chemotherapy for patients with stage II colon cancer [23]. However, patients with stage II with inadequately sampled LN, T4 lesions, perforation, or poorly differentiated histology could be eligible for adjuvant chemotherapy. Although these factors are unquestionably associated with a poorer prognosis, whether adjuvant therapy improves that outcome is not clear. Molecular genetic prognostic and/or predictive factors have been identified which may be correlated with a higher recurrence risk and/or resistance to chemotherapy. These include deletion of the long arm of chromosome 18, the presence or absence of microsatellite instability, lack of p27 expression, mutations of p53, high levels of thymidilate synthase [24]. The ASCO recommendations discuss the current status of molecular predictive/prognostic markers and concluded that: there are no prospective studies completed to demonstrate clinical usefulness of these techniques; and we have no data demonstrating whether a patient without negative prognostic markers will or will not benefit from the current adjuvant therapies available. It is important to remember that factors that predict disease do not necessarily predict response to treatment. The Panel emphasises that the treatment decisionmaking process in stage II colon cancer must incorporate patient choice, and that the responsibility of both surgical and medical oncologists is to ensure that the patient has adequate information to make a well-informed decision that incorporates personal preferences. Many studies have determined patients preference for adjuvant therapy and have shown that patients are willing to accept adjuvant therapy for small or even no clinical benefit. Jansen et al. reported in a review of determinants of patients preferences for adjuvant therapy in cancer that patients are more positive toward adjuvant treatment in the case of (1) larger benefits (2) less toxicity,

iv72 Percent of 3-yrs DFS 80 70 60 50 40 30 20 52 3-yrs Disease free survival in adjuvant therapy of colon cancer 65 67 65 62 64 61 44 73 10 0 (3) personal experience in the particular treatment and (4) having dependents (especially children) living at home [25]. Then, in our opinion, the decision to treat a patient should be taken by medical oncologist with a large experience in this field, it is not correct to leave this decision to patient, whose preferences and views vary can depend on personal situation. In the clinical practice about 40 60% of patients with stage II receive adjuvant chemotherapy in Italy. Patients with stage II disease should be encouraged to participate in randomised trials. Conclusion Control Control IMP ACT FUFA Figure 1. 3-yrs DFS with adjuvant therapy in colon cancer. Punt FUFA Substantial advances have been made in the adjuvant treatment of colon cancer over the past 15 years. 5-FU/leucovorin remains a gold standard (Figure 1). FOLFOX-4 demonstrated a significant improvement over 5-FU + LV in terms of 3-years DFS, but not for long enough to determine impact on overall 5-year survival. Dramatic results seen with bevacizumab and cetuximab in advanced colon cancer in combination with chemotherapy open the door to the utilisation in adjuvant setting. (NSABP, ECOG) [26 33]. Will they, with their various toxicity and benefit profiles, improve still on the use of adjuvant therapy in colorectal cancer? Or will there be no benefit, and they will best be left for the patients who present advanced disease or go on to advanced disease? Numerous clinical trials in advanced disease have reported that longer survival has been seen in patients that receive multiple effective agents as 1 st line. NCCTG will randomise patients with colon cancer to receive FOLFOX-6 versus FOLFIRI versus FOLFOX-6! FOLFIRI. Another important consideration is the duration of adjuvant chemotherapy. At present, six months is considered the best duration. Fields FUFA Andre LV6FU2 The Italian cooperative group is starting a large trial in which the patients receive FOLFOX-4 or CAPOX for 6 or 3 months. Finally, it is very important identified prognostic and predictive markers to facilitate the selection of patients and reduce costs. References Mosaic LV5FU2 Capecitabine MOSAIC FOLFOX 1. Jemal A, Murray T, Ward E et al. Cancer statistics, 2005. CA Cancer J Clin 2005; 55: 10 30. 2. Sant M, Aareleid T, Berrino F et al. EUROCARE-3: survival of cancer patients diagnosed 1990 94 results and commentary. Ann Oncol 2003; 14: 61 118. 3. Wong JH, Bowles BJ, Bueno R et al. Impact of the number of negative nodes on disease-free survival in colorectal cancer patients. Dis Clon Rectum 2002; 45: 1341 1348. 4. Le Voyer TE, Sigurdson ER, Hanlon AL et al. Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol 2003; 21: 2912 2919. 5. Laurie JA, Moertel CG, Fleming TR et al. Surgical adjuvant therapy of large-bowel carcinoma: An evaluation of levamisole and the combination of levamisole and fluorouracil: The North Central Cancer Treatment Group and the Mayo Clinic. J Clin Oncol 1989; 7: 1447 1456. 6. Moertel CG, Fleming TR, Macdonald JS et al. Levamisole and fluorouracil as adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322: 352 358. 7. Bleeker WA, Mulder NH, Hermans J et al. The addition of low-dose leucovorin to the combination of 5-fluorouracil-levamisole does not improve survival in the adjuvant treatment of Dukes C colon cancer. IKN Colon Trial Group. Ann Oncol 2000; 11: 547 552. 8. Di Costanzo F, Sobrero A, Gasperoni S et al. Adjuvant chemotherapy in the treatment of colon cancer: randomised multicenter trial of the Italian National Intergroup of Adjuvant Chemotherapy in Colon Cancer (INTACC). Ann Oncol 2003; 14: 1365 1372.

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