FOLFOX in Patients Aged Between 76 and 80 Years With Metastatic Colorectal Cancer

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1 2666 FOLFOX in Patients Aged Between 76 and 80 Years With Metastatic Colorectal Cancer An Exploratory Cohort of the OPTIMOX1 Study Arie Figer, MD 1 Nathalie Perez-Staub, MD 2 Elisabeth Carola, MD 3 Christophe Tournigand, MD 2 Gerard Lledo, MD 4 Michel Flesch, MD 5 Ramon Barcelo, MD 6 Andre Cervantes, MD 7 Thierry Andre, MD 8 Philippe Colin, MD 9 Christophe Louvet, MD 2 Aimery de Gramont, MD 2 1 Beth Sourasky Medical Center Tel Aviv, Israel. 2 Hopital Saint-Antoine, Paris, France. 3 Centre Hospitalier de Senlis, Senlis, France. 4 Clinique Saint-Jean, Lyon, France. 5 Hospital Devron, Dijon, France. 6 Hosptial de Gruces Osakidetza Barakaldo, Vizcaya, Spain. 7 Hospital Clinico-Universitario, Valencia, Spain. 8 Hosptial Tenon, Paris, France. 9 Clinique Courlancy, Reims, France. A. Figer and C. Tournigand have received honoraria from Sanofi-Aventis. U. Gerard has received honoraria from Sanofi-Aventis and Merck. A. Cervantes is a consultant to Sanofi-Aventis and Amgen. C. Louvet has received honoraria from Sanofi-Aventis, Pfizer, and Roche. A. de Gramont is a consultant and advisor to Sanofi-Aventis, Roche, and Genentech and has received honoraria from Sanofi-Aventis, Roche, and Yakult. Sponsored by the GERCOR, Paris, France. BACKGROUND. Patients older than 75 years of age are usually excluded from metastatic colorectal cancer randomized studies. The OPTIMOX1 study evaluated FOLFOX7, a simplified (s) leucovorin (LV) and 5-fluorouracil (5FU) regimen (slv5fu2) with high-dose oxaliplatin, in a new oxaliplatin stop-and-go strategy. An exploratory cohort of patients aged 76 to 80 years was included in the study. METHODS. In all, 620 previously untreated patients were randomized between FOLFOX4 until progression (arm A), or FOLFOX7 for 6 cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). RESULTS. A total of 37 patients aged 76 to 80 years were included, 20 in arm A and 17 in arm B. The overall response rate (ORR) was 59.4%, comparable to younger patients (59%). Median progression-free survival (PFS) was 9.0 months and median overall survival (OS) was 20.7 months. These results did not differ from that in younger patients 75 years in the OPTIMOX1 study with PFS 9.0 months (P 5.63) and OS 20.2 months (P 5.57). They experienced slightly more grade 3 of 4 toxicity than younger patients: 65% versus 48% (P 5.06), mainly with more neutropenia (41% vs 24%, P 5.03) and neurotoxicity (22% vs 11%, P 5.06). Tolerability, however, was manageable and no toxic death occurred in this elderly population. CONCLUSIONS. The efficacy of FOLFOX-based treatment was maintained in patients >75 years with both FOLFOX regimens. The oxaliplatin stop-and-go management strategy performed well in this population. Cancer 2007;110: Ó 2007 American Cancer Society. KEYWORDS: elderly patients, FOLFOX, 5-fluorouracil, metastatic colorectal cancer, oxaliplatin. Colorectal cancer (CRC) is 1 of the most common malignancies and the second cause of cancer deaths in the US and most European countries. Its incidence has been increasing in the last decade, primarily as a consequence of the aging of the population. 1 In Europe >40% of new CRCs are diagnosed in patients older than 75 years. 2,3 In the US the incidence of CRC is 250 per at 75 years and 310 per at 80 years. 3 In the elderly population the frequent incidence of other age-related comorbidities such as impaired renal, cardiac, and liver function, general decline in health, loss of autonomy, and cognitive impairment can all impact the ther- Address for reprints: A. de Gramont, Hopital St.-Antoine, 184, rue du Faubourg St.-Antoine, Paris Cedex 12, France; Fax: (011) ; aimery.de-gramont@sat. ap-hop-paris.fr Received April 17, 2007; revision received July 6, 2007; accepted July 11, ª 2007 American Cancer Society DOI /cncr Published online 26 October 2007 in Wiley InterScience (

2 FOLFOX in Elderly CRC/Figer et al apeutic decision, especially when the patient s family and physician are involved. 4,5 Moreover, in a palliative context some elderly patients would prefer immediate relief and a comfortable quality of life to potentially toxic chemotherapy or a clinical trial. 6 One study reported that fewer than 50% of elderly patients aged older than 65 years with advanced CRC received systemic chemotherapy. 7 Given the great importance of the elderly population in CRC, it is important to assess systematically the management of elderly CRC patients with modern chemotherapeutic regimens. Unfortunately, elderly patients are usually excluded from randomized studies. 8 Up to now, no randomized phase 3 study has accurately compared the effect of therapy between young and elderly patients, and there has not even been a standard definition of the elderly patient, with the age limit fixed variably between 65 and 75 years. Only phase 2 or retrospective studies have addressed the issue of elderly patients with advanced CRC. Two studies have shown that palliative 5-fluorouracil (5FU)-based chemotherapy could be performed in elderly patients (>74 years) without increasing toxicity or morbidity, while obtaining response rates and survival (14 17 months) comparable to those of younger patients. 9,10 Another study has shown that combination therapy with 5FU and oxaliplatin or irinotecan was active, with manageable toxicity in patients older than 74 years. 11 A new high-dose stop-and-go strategy FOLFOX7 regimen 14,15 has been investigated in the OPTIMOX1 study in comparison to the FOLFOX4 regimen 12,13 and the results are now published. 16 To investigate response rates, median progression-free survival (PFS), and overall survival (OS) of older patients to both FOLFOX regimens, an exploratory cohort of patients aged 76 to 80 years was included in the OPTIMOX1 study. The results in this patient cohort are reported here. MATERIALS AND METHODS OPTIMOX1 was an international multicentric randomized study. A detailed description of patient selection, chemotherapy with dose adaptation, evaluation criteria, and statistical considerations have been previously reported in the main OPTIMOX1 study. 16 The principal characteristics of patients included were: adenocarcinoma of the colon or rectum; unresectable metastases; at least 1 bidimensionally measurable lesion of 1 cm or a nonmeasurable evaluable lesion; adequate bone marrow, liver, and renal function; World Health Organization (WHO) performance status (PS) of 0 to 2; age 18 to 80 years; no peripheral sensory neuropathy at inclusion; and no previous chemotherapy for metastatic disease. Patients older than 75 years of age (reported here) or patients with alkaline phosphatase over 3 upper limit of normal (UNL) constituted an exploratory cohort. Patients were randomized between FOLFOX4 (leucovorin 200 mg/m 2 followed by 5FU bolus 400 mg/m 2 and 22-hour infusion 600 mg/m 2 on 2 consecutive days with oxaliplatin 85 mg/m 2 on Day 1) every 2 weeks (arm A), or FOLFOX7 (leucovorin 400 mg/m 2 followed by a 5FU 46-hour infusion 2400 mg/m 2 and oxaliplatin 130 mg/m 2 on Day 1, every 2 weeks) for 6 cycles, maintenance with 12 cycles of simplified LV5FU2, and reintroduction of FOLFOX7 for 6 cycles (arm B). In both arms the treatment was continued until progression on FOLFOX therapy, unacceptable toxicity, or the patient chose to discontinue. In the case of progression during slv5fu2 alone and sensory neuropathy <grade 2, reintroduction of oxaliplatin was scheduled in arm B and allowed in arm A. Evaluation with physical examination, blood count, liver and renal function tests, and computedtomography (CT) scans was performed at baseline, after 4 cycles, 6 cycles, and then every 6 cycles. The primary assessment criterion for the overall OPTIMOX1 study was time to treatment failure or duration of disease control (DDC). 16 Secondary assessments were PFS, OS, response rates, and tolerance, all of which were assessed in the elderly cohort. In the OPTIMOX1 study 16 randomization was performed using a minimization technique, 17 stratifying patients by center, performance status, number of metastatic sites involved, age, and baseline alkaline phosphatase. The randomization was stratified so as to ensure a reasonable treatment balance for prognostic factor values that usually make patients ineligible (age >75 years and baseline alkaline phosphatase >3 3 ULN). The Kaplan-Meier method was used to estimate survival and PFS curves and the log-rank test was used to compare the curves. 18 The cutoff date for the final analysis was October 1, RESULTS Patient Characteristics In total, 37 patients were older than 75 years in the OPTIMOX1 study. Their median age was 77 years (range, 76 80). Twenty patients were randomly assigned to arm A and 17 to arm B. Patients characteristics are reported in Table 1. Six (16%) patients had a performance status of 2. Five patients (14%) had an alkaline phosphatase level more than 3 times the ULN. Twenty-seven (73%) patients had only 1 metastatic site, usually in the liver (65%). The most common comorbidities were hypertension (17 patients, 46%), other severe cardiovascular disease (4

3 2668 CANCER December 15, 2007 / Volume 110 / Number 12 TABLE 1 OPTIMOX1 Patient Characteristics, >75 Years Arm A (N 5 20) Arm B (N 5 17) All (N 5 37) (%) Median age [range] 77 [76 80] 78 [76 80] 77 [76 80] Male/female 12/8 10/7 22/15 (59/41) WHO PS 0/1/2 9/8/3 9/5/3 18/13/6 (49/35/16) Alkaline phosphatase <3/3 UNL 17/3 13/2 30/5 (81/13.5) Colon/rectum 12/7 13/4 25/11 (68/30) Prior adjuvant chemotherapy (19) Synchronous metastasis (41) No. metastatic sites 1/>1 16/4 11/6 27/10 (73/27) Liver/lung/other sites 13/7/1 11/2/3 24/9/4 (65/24/11) Comorbidity (68) WHO PS indicates World Health Organization performance status; UNL, upper limit of normal. FIGURE 1. Progression-free survival. Patients >75 years versus patients 75 years. patients, 11%), and other cardiovascular or related metabolic diseases such as vasculitis, phlebitis, and diabetes (11 patients, 30%). Treatment Cycles and Dose Intensity In total, the patients in the elderly cohort received 469 cycles of treatment, including 307 cycles with oxaliplatin. The median number of cycles was 12 (range, 2 51) for all patients, 10 (2 19) in arm A and 16 (2 51) in arm B. The median number of cycles with oxaliplatin was 9 (range, 2 18) in arm A and 6 (2 7) in arm B. In arm A 16 (80%) patients received at least 6 cycles of FOLFOX4 in first-line therapy. In arm B 13 (76%) patients received the 6 planned cycles of FOL- FOX7. In patients who received 6 cycles the median oxaliplatin dose-intensity was 38 mg/m 2 /week (89% of the planned dose) in arm A and 50 mg/m 2 /week in arm B (77% of the planned dose). These results are very similar in patients 75 years (89% and 77% of the oxaliplatin planned dose in arm A and B, respectively). In arm A the median dose intensity of 5FU bolus was 362 mg/m 2 /week (90% of the planned dose) and of 5FU infusion 500 mg/m 2 /week (83% of the planned dose). In arm B the median dose-intensity of 5FU infusion was 1000 mg/m 2 /week (83% of the planned dose). Responses Thirty-five patients were assessable for response. The overall response rate (ORR: complete response [CR] 1 partial response [PR]) was 59.5% for all patients (range, 43.4% 75.6%), 65% in arm A and 53% in arm B. In addition, 29.7% of all patients had stable disease (SD) and only 5.4% progressive disease (PD). FIGURE 2. Overall survival. Patients >75 years versus patients 75 years. Response rates of patients from 76 to 80 years are comparable to results found for younger patients in the OPTIMOX1 study (ORR: 59%, range, 55.1% 62.9%, SD: 28%, PD: 10%). Following response to chemotherapy, a metastasis surgery was performed in 6 patients >75 years and the resection was complete for 4 of them (R0 resection). Five patients in arm B (29%) had a per-protocol oxaliplatin reintroduction. Of these, 1 had a partial response, another stable disease, and 3 progressed after oxaliplatin reintroduction. Progression-Free and Overall Survival Median PFS was 9.0 months for all patients, 7.6 months in arm A and 9.4 months in arm B. Median OS was 20.7 months for all patients, 14.0 months in arm A and 25.1 months in arm B. Survival curves are shown in Figures 1 and 2.

4 FOLFOX in Elderly CRC/Figer et al TABLE 2 Comparison of Elderly Patients (>75 years) With Younger Patients ( 75 years) in the OPTIMOX1 Study >75 y n y n Response rate 59.5% 59% NS Median PFS 9.0 months 9.0 months NS Median OS 20.7 months 20.2 months NS Grade 3 4 neutropenia 41% 24% 0.03 Grade 3 neurotoxicity 22% 11% 0.06 All grade 3 4 toxicity 65% 48% 0.06 PFS indicates progression-free survival; OS, overall survival. P TABLE 3 OPTIMOX1 Grade 3 4 Toxicity per Patient (%) FOLFOX4 FOLFOX7-LV5FU2s 75 y >75 y 75 y >75 y n n 5 20 n n 5 17 Neutropenia Platelets Nausea-vomiting Diarrhea Mucositis HF syndrome Neurotoxicity (grade 3) Alopecia (grade 2) As with tumor response rates, PFS and OS in the elderly cohort did not differ from that in younger patients in the OPTIMOX1 study (respectively, 9.0 months, P 5.63, and 20.2 months, P 5.57) (Figs. 1, 2). Twenty-one patients died of CRC, 1 of pulmonary embolism and pneumonia, 1 of a cerebrovascular event, 1 of myocardial infarction, 1 of postsurgical complication, and 1 from an unknown cause. The remaining 11 patients >75 years were alive at the cutoff date. Additional Therapeutic Lines Twenty-six patients (70%) received a second-line treatment, of which 13 received an irinotecan-based regimen. One partial response and 3 stabilizations were observed. Ten patients received a third-line and 2 a fourth-line treatment. Comparatively, about 75% of patients younger than 75 years received a secondline treatment in the OPTIMOX1 study. Safety Grade 3 4 toxicity occurred in 65% of patients (Table 2). The main toxicities were neutropenia, which occurred in 41% of patients, 11 patients in arm A (55%) and 4 patients in arm B (24%), and sensory neurotoxicity attributed to oxaliplatin, which was observed in 8 patients (22%), 4 in each arm. Only 1 patient in arm A was hospitalized for febrile neutropenia. A total of 17 patients (46%) had a dose reduction due to toxicity-related or unrelated to oxaliplatin, including 11 in arm A (55%) and 6 in arm B (35%). In comparison to younger patients, as shown in Table 3, elderly patients experienced more neutropenia (41% vs 24%, P 5.03), neurotoxicity (22 vs 11%, P 5.06), and overall grade 3 4 toxicity (65% vs 48%, P 5.06). However, tolerability was manageable and no toxic death occurred in any group of older patients >75 years. DISCUSSION In this small and selected but randomized and genuinely elderly population, chemotherapy with both FOLFOX4 and stop-and-go FOLFOX7 demonstrated high activity in the treatment of advanced CRC, with response rates, PFS, and OS comparable to those observed in younger patients (Table 2). These results are impressive, but caution should be exercised in extrapolating them to elderly patients in general. Not only was the cohort small in number, but in addition the general health of the participants selected to be included in the clinical trial was comparatively good: although two-thirds had at least 1 comorbidity, only 16% had a performance status of 2. To fully evaluate therapy in elderly patients, more specific evaluations will be necessary, 19 although this was not feasible within the setting of this large randomized study. The results of this cohort study are consistent with previous findings that chemotherapy is active in elderly patients with advanced CRC. Leucovorin and 5FU have achieved response rates between 20% and 44%, median PFS between 5.5 and 8.8 months, and median survival between 10.8 and 16.4 months. 9,10,20 22 Raltitrexed was reported to achieve a response rate of 22%, with a median PFS of 3.5 months and OS of 9.5 months. 23 In most studies, even if the definition of elderly patients included younger patients, age was not usually found to be an independent prognostic factor. 20,24 Polychemotherapy has not been extensively studied. 11 In this study the results achieved, including a response rate of 59%, a median PFS of 9 months, and a median OS of more than 20 months, suggest that FOLFOX has an improved efficacy in patients older than 76 years as in younger patients. The toxicity of fluoropyrimidine-based chemotherapy in elderly patients appears manageable,

5 2670 CANCER December 15, 2007 / Volume 110 / Number 12 especially with 5FU-infusion regimens. 10,21,22 Specific concerns about safety have emerged with 5FU bolus regimens or raltitrexed in patients with impaired renal function. 23,25,26 Elderly patients treated with irinotecan as single agent second-line therapy did not experience more toxicity than younger patients, 27 but in cases of combination chemotherapy in which oxaliplatin or irinotecan were given with 5FU or raltitrexed, 42% of patients aged >75 years experienced grade 3 or 4 toxicity. 11 In our study, therapeutic compliance of patients aged >75 years was good. With comparable duration of treatment and dose intensity achieved, elderly patients experienced only slightly more toxicity than younger patients, including the 2 most common side effects of FOLFOX, neutropenia and sensory neuropathy (Table 3). However, there were no deaths due to FOLFOX. Our results are confirmed by a recent retrospective pooled analysis in a large number of older patients >70 years, where FOLFOX4 had efficacy and safety, except with a few more adverse events without outcome modifications, comparable to younger patients. 28 In that study the comparison was done between patients aged under or older than 70 years but only a few of them were older than 76 years (13.5%). Our study more specifically concerned patients older than 76 years, with similar results of FOLFOX efficacy and tolerability. The comparison of the 2 arms in such a small subset of the treated population is not relevant, although their efficacy was similar. The general conclusions of the OPTIMOX1 study can, however, be extrapolated to elderly patients, namely, that the 2 arms had a similar activity but that convenience and tolerability favored the OPTIMOX1 strategy (6 cycles of FOLFOX7 followed by slv5fu2). In this analysis the OPTIMOX1 strategy, which allows a greater median number of cycles (10 in arm A vs 16 in arm B), is as safe and efficient for patients older than 76 years as for younger patients. Toxicity could be further decreased using a reduced oxaliplatin dose intensity. The convenience of safety and the stop-and-go strategy are important issues in this population. In conclusion, performance status and geriatric assessment are surely better criteria than age to predict the efficacy and toxicity of chemotherapy. The results of this study support our belief that the increasing population of elderly patients >75 years, with appropriate motivation and performance status, benefit from FOLFOX regimens to a similar degree as younger individuals, and consequently that this treatment can be offered to these patients. REFERENCES 1. Hill C, Doyon F. 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