Annals of Oncology Advance Access originally published online on October 9, 2006
Annals of Oncology 2007 18(1):77-81; doi:10.1093/annonc/mdl336
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© 2006 European Society for Medical Oncology
gastrointestinal tumors |
Phase II study of an optimized 5-fluorouracil-oxaliplatin strategy (OPTIMOX2) with celecoxib in metastatic colorectal cancer: a GERCOR study
1 Hôpital Tenon, Department of Medical Oncology, Paris
2 Hôpital Saint Antoine, Department of Medical Oncology, Paris
3 Clinique Sainte Catherine, Department of Medical Oncology, Avignon
4 Hôpital Devron, Dijon
5 Hôpital Foch, Department of Medical Oncology, Suresnes
6 Hôpital Huriez, Department of Internal Medicine, Lille
7 GERCOR (French Oncology Research Group), Paris, France
* Correspondence to: Dr T. André, Service d'Oncologie Médicale, Hôpital Tenon, 4, rue de la Chine, F-75970 Paris Cedex 20, France. Tel: +33 156 0160 21; Fax: +33 156 0173 04; E-mail: thierry.andre{at}tnn.aphp.fr
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Abstract |
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Background: Oxaliplatin stop and go in combination with leucovorin and 5-fluorouracil has been successfully used in a previous study (OPTIMOX1) in metastatic colorectal cancer (MCR). Celecoxib is an anti-cyclooxygenase-2 drug with anti-neoplastic properties. In the present study, celecoxib was evaluated in combination with FOLFOX7 regimen and as a single agent in maintenance therapy.
Patients and methods: This phase II study examined for previously untreated MCR patients the stop-and-go procedure [six cycles of folinic acid, 5FU and oxaliplatin (FOLFOX7) followed by chemotherapy-free intervals (CFIs) and reintroduction at progression] with continuous administration of celecoxib (800 mg/day).
Results: Forty-four patients were included, 42 eligible: performance status (%) 0/1/2 = 45/40/15, median age 60 (31–76) years. Response rate (RR) was 43% (95% CI 28%–58%). Median progression-free survival (PFS) was 6 months; median overall survival was 15.8 months. Grade 3/4 toxicity criteria were neurotoxicity 9.5%, thrombocytopenia 21.4%, neutropenia 7.1%, diarrhea 7.1%, nausea 4.8% and vomiting 2.4%. Median CFI 1 (n = 27) duration was 3.9 months (range 2–39 months).
Conclusion: With an acceptable safety profile, celecoxib combined with FOLFOX7 achieved RR and PFS in the lower range of that obtained with FOLFOX7 alone. These results indicate the lack of synergy between FOLFOX7 and celecoxib. PFS of 6 months appears lower than PFS obtained in OPTIMOX1 study with simplified LV5FU2 in maintenance therapy.
Key words: celecoxib, colorectal metastatic cancer, 5-fluorouracil, oxaliplatin
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introduction |
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Colorectal cancer is the second leading cause of cancer deaths in western countries [1]. However, with the availability of new drugs and new regimens and a better management of the disease, median overall survival (OS) has improved from <1 year to
2 years [2–4], leading to also consider new parameters like quality of life (QoL) and benefit–cost ratio. The FOLFOX4 regimen has been established as a standard first-line therapy for advanced disease after the European C95 and the USA N9741 studies [4, 5]. The limiting toxicity of FOLFOX4 in these studies is the specific reversible sensory neuropathy of oxaliplatin. The occurrence of sensory neuropathy often causes oxaliplatin discontinuation, while patients are still responding to treatment. One potential approach to limit oxaliplatin neurotoxicity is to administer the dose-dense FOLFOX7 regimen for a defined and short period of time, stopping therapy before severe neurotoxicity occurs and further reintroduce the regimen in case of disease progression. FOLFOX reintroduction was recently found to be active for patients who stopped oxaliplatin for neurotoxicity [6, 7].
In the OPTIMOX1 study, previously untreated patients were randomized between FOLFOX4 until progression and FOLFOX7 for six cycles followed by a maintenance LV5/LV without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 [3]. Median progression-free survival (PFS) and OS were 9.0 and 19.3 months in patients allocated to FOLFOX4 versus 8.7 and 21.2 months in patients allocated to FOLFOX7, demonstrating that oxaliplatin can be safely stopped after six cycles of FOLFOX7 regimen [3].
Others have shown that >3 months of 5-fluorouracil (5-FU)-based chemotherapy do not improve survival [8]. A recent study reported the outcome of 62 patients who underwent a therapeutic break after a first-line chemotherapy in advanced colorectal cancer. The median duration of the first chemotherapy-free interval (CFI) was 6 months. After the pause, 57 patients had another treatment, 18 responses were observed and 27 patients had stable disease (SD). Overall, the median duration of treatment was 8.5 months and the median duration of CFI was 11 months [9]. These data support the new concept of short-duration chemotherapy (3 months) with CFI and reintroduction of the same regimen in patients responding to chemotherapy. Furthermore, the potential improvement in QoL may allow a better tolerance of chemotherapy and the possible decrease in tumor resistance induced by constant exposure to the drugs may lead to an improved efficacy of a stop-and-go strategy.
Cyclooxygenase-2 (COX-2) is an isoenzyme of COX undetectable in normal colonic mucosa and overexpressed in 80% colonic tumor [10]. Celecoxib is an anti-COX2 compound with anti-neoplastic properties such as angiogenic inhibition and apoptosis induction. COX-2 has been shown to be up-regulated in colorectal adenocarcinomas [11]. Several in vitro and in vivo studies have showed that COX-2 plays a key role in the multistep process of colorectal tumorigenesis [12]. The new selective COX-2 inhibitors reduced the size and number of intestinal carcinomas in many animal models [13–16]. Inhibition of COX-2 attenuates the growth and metastatic potential of colorectal carcinoma in mice [17]. Prevention of colorectal carcinogenesis by nonsteroidal anti-inflammatory drugs (NSAIDs) is a well-known phenomenon [18–19]. In patients with familial adenomatous polyposis (FAP), 6 months of twice-daily treatment with 400 mg of celecoxib, a COX-2 inhibitor, leads to a significant reduction in the number of colorectal polyps [20]. Celecoxib has been approved by the Food and Drug Administration as an adjunct to endoscopic survey and surgery in patients with FAP.
We evaluated in this study a new strategy exploring FOLFOX7 stop-and-go procedure with the addition of celecoxib during FOLFOX7 and CFI. The primary objective of this phase II study was the response rate (RR) in first-line treatment in patients with metastatic colorectal cancer (MCR).
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patients and methods |
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inclusion criteria
The eligibility criteria in this study were histologically proven adenocarcinoma of the colon or rectum; unresectable metastasis; no previous chemotherapy for metastatic disease; measurable lesion as assessed by computed tomography (CT) scan or magnetic resonance imaging with at least one dimension (longest diameter to be recorded)
20 mm with conventional CT scan or 10 mm with spiral CT scan; no central nervous system metastasis; no second malignancy other than adequately treated in situ carcinoma of the cervix or nonmelanoma skin cancer; age >18 years and <76 years; World Health Organization performance status 0–2; previous adjuvant chemotherapy was required to have been completed at least 6 months before inclusion; no peripheral sensory neuropathy; no active gastric or duodenal ulceration or gastrointestinal bleeding in the last year; no history of hypersensitivity to celecoxib; no other therapy with COX-2 inhibitors, NSAIDs, salicylates or sulfonamides; initial evaluation <3 weeks before inclusion; no bowel obstruction and no symptomatic angina pectoris. Patients were also required to have adequate hematological (neutrophil count >1.5 g/l, platelet count >100 g/l), renal [(serum creatinine <1.5x the upper limit of normal value (ULNV)] and hepatic (alkaline phosphatase <3 ULNV) functions. Written informed consent was obtained from each patient. Ethical Committee approval was obtained before the protocol started accrual.
treatment
Celecoxib, 400 mg twice per day, was taken by oral route, continuously. It was stopped in case of toxicity, patient refusal, progression on FOLFOX7 or progression without possibility of FOLFOX7 reintroduction related to toxicity. The FOLFOX7 regimen consisted of oxaliplatin 130 mg/m2 d1 and LV 400 mg/m2 d1 and continuous infusion (46 h) of 5-FU 2400 mg/m2, every 2 weeks for six cycles. In responders or stable patients after six cycles, chemotherapy was stopped until progression. FOLFOX7 was then resumed, for six additional cycles (Figure 1). In cases of grade 3–4 neutropenia, diarrhea or thrombocytopenia, 5-FU dose was decreased to 2000 mg/m2 and oxaliplatin to 100 mg/m2; 5-FU was decreased to 2000 mg/m2 in case of the National Cancer Institute (NCI) grade 3 or 4 stomatitis or skin toxicity; oxaliplatin dose was decreased to 100 mg/m2/cycle in case of non-persistent paresthesia between course or paresthesia associated with pain or stopped until symptom improvement in case of persistent paresthesia associated with pain or functional impairment persisting among cycles (14 days). Oxaliplatin infusion time was increased from 2 to 6 h in case of NCI 
grade 2 suspected allergy or in case of ‘laryngeal spasm’ syndrome. In case of heart toxicity grade 2, 5-FU and LV were permanently interrupted and patients were withdrawn from the study for toxicity. Therapy was discontinued when disease progressed or toxicity was intolerable. Concomitant treatment allowed were premeditation for nausea and vomiting, treatment of diarrhea and adjustment of antihypertensive therapy. Prophylactic fluconazole therapy was prohibited; among NSAIDs, only cardioprotective doses of aspirin were allowed.
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Surgical excision of metastasis was allowed after six cycles of treatment. In case of complete resection of metastasis (R0), patient received 12 cycles with LV and 5-FU with celecoxib. In case of relapse after surgery, patients remained in the study.
study parameters
Physical examination and complete blood counts were carried out at each cycle. Carcinoembryonic antigen, alkaline phosphatases, total bilirubin, aspartate aminotransferase, alanine aminotransferase, serum creatinine, lactate dehydrogenase (LDH), CT scans were repeated at cycles 4 and 6, and after every 2 months or earlier in case of clinical deterioration. The modified response evaluation criteria in solid tumors criteria were used for objective tumor response assessment. Complete response (CR) was the disappearance of all target lesions; partial response (PR) was at least a 30% decrease in the sum of the longest diameter of target lesions; progressive disease (PD) was at least a 20% increase in the sum of the longest diameter of target lesions or the appearance of one or more new lesions; SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Toxicity was evaluated according to the USA National Cancer Institute's common toxicity criteria (NCI-CTC March 98).
objectives, statistical and data management
The primary objective was RR. Secondary objectives were toxicity, PFS, duration of disease control (DDC) [3], salvage surgery rate, tolerance and duration of CFI.
The expected number of patients was calculated following a Simon design, with a type I error of 0.05 to conclude the efficacy of an uninteresting regimen (RR < 40%) and a type II error of 0.20 implying the rejection of an active regimen (RR > 70%); it was necessary to recruit 39 patients. External review of CT scans was not carried out. The median PFS, DDC and OS (and their 95% confidence interval) were estimated using the Kaplan–Meier method from the start of chemotherapy. The DDC was defined as PFS, or, if FOLFOX was reintroduced, addition of the initial PFS and the PFS after reintroduction in case of no progression after FOLFOX reintroduction [3].
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results |
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patient characteristics
Two patients were not analyzed, being not eligible (one neuro-endocrine tumor and one withdrawal of consent before the first cycle) and not treated. Forty-two patients were included from December 2002 to June 2003 by nine centers. Their characteristics are described in Table 1.
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toxicity
The frequencies of the main toxic effects/patient during the first six cycles are reported in Table 2.
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Maximal toxic effects/patient for all cycles are reported in Table 3. Maximal toxic effects per patient grade 3 or 4 for all cycle (342 cycles) were thrombocytopenia (21.4%), neutropenia (7.1%), nausea (4.8%) and grade 3 neuropathy (9.5%). Two patients presented grade 1–2 epigastralgia without ulcers and one digestive hemorrhage with gastritis. Other toxic effects were acute episode of dyspnea (7.1%) or laryngospasm (2.4%).
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objective tumor responses and characteristics of first CFI
Two CRs, 16 PRs, 14 SDs and 9 PDs were observed. One patient was not assessable for tumor response. The RR was 43% (95% CI: 28%–58%). Secondary surgery to remove metastases was carried out in four patients after cycle 6 (9.5%); all had complete resection (R0). One of them relapsed, and three remained in complete remission. A CFI was obtained for 27 patients. Fifteen patients did not have a CFI, one refused, nine had PD, one was nonassessable and four achieved CR after metastasis surgery (these patients received after surgery 12 cycles of LV5FU2 + celecoxib). Median CFI 1 (n = 27) was 3.9 months (range 2–39).
DDC, PFS and OS
Median DDC was 31 weeks (95% CI 25.5–39.5 weeks). Median PFS was 26 weeks (95% CI 23–29 weeks). Median OS was 15.8 months (69 weeks) (95% CI 11.5–21.7 months). Thirty-five patients stopped the study for progression (n = 27), toxicity (n = 2), personal choice (n = 5) or investigators decision (n = 1).
reintroduction of FOLFOX therapy and second-line and subsequent therapy
For the 27 patients with CFI, 13 had FOLFOX7 reintroduction according to the protocol and four outside of the protocol (Table 4). Reasons for not reintroducing oxaliplatin in the 18 eligible patients for reintroduction included patient's decision or physician's decision (n = 5), neurotoxicity grade 2 or 3 (n = 8), performance status 3 (n = 1) and no PD at the time of analysis (n = 1).
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Seven patients had a second FOLFOX7 (six cycles) with a median CFI of 62 days, two of these patients had a third FOLFOX7 (six cycles) reintroduction and one a fourth FOLFOX7 (six cycles) reintroduction.
Out of 42 patients, 26 received a second-line chemotherapy (irinotecan-based chemotherapy), five did not receive further chemotherapy, and data were missing for 11 patients. Out of the 26 patients, 13 received a third-line chemotherapy.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionAcknowledgementsReferences |
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Improving the OS while maintaining a decent QoL is the main challenge in MCR. In this study, RR was 43% (95% CI 28%–58%). RR is rather disappointing despite the addition of celecoxib, since RR obtained in the OPTIMOX1 study [3] with the same regimen without celecoxib was 58%.
In this study with FOLFOX7 combined with celecoxib, safety was acceptable, with low (9.5%) grade 3 sensory neuropathy and low grade 3–4 neutropenia (7%) rates. However, we observed an unusual asymptomatic high rate of thrombocytopenia grade 3–4 (21%).
In the present study, we explore CFI which is a new concept in the MCR. Our study reflects the clinical practice and brings information about CFI in FOLFOX-based chemotherapy. The question of duration of treatment among responders or SD had been introduced with 5-FU regimen. The literature concerning CFI in MCR is scarce. Maughan et al. [8] evaluated CFI after 5-FU chemotherapy and showed that a complete break in therapy was feasible after LV and 5-FU alone for stable or responding patients. With oxaliplatin-based chemotherapy, CFI should be more considered since toxicity is cumulative, especially the neurotoxicity. Tournigand et al. [3] (OPTIMOX1) showed that oxaliplatin can be safely stopped after six cycles of FOLFOX regimen with a 5FU and leucovorin (FULV) maintenance reducing the cumulative neurotoxicity due to oxaliplatin.
At the American Society of Clinical Oncology meeting in June 2006, four presentations demonstrated the feasibility of break in therapy in MCR [21–24]. Two studies evaluated a CPT11-based chemotherapy (LV5FU2 + CPT11) with or without break. Median PFS and median OS were not statistically different between both arms in both studies [21, 22]. Plantade et al. have shown in a retrospective study for patients with metastatic colorectal cancer (MCRC) that CFI is feasible and should be considered, especially for patients with good prognostic factors in first-line therapy [24]. In the randomized OPTIMOX2 trial, conducted by the group GERCOR after the present study, patients received six cycles of modified FOLFOX7 (leucovorin 400 mg/m2 and oxaliplatin 100 mg/m2 days 1 followed by 3000 mg/m2 5-FU as a 46-h continuous infusion repeated every 2 weeks) followed by CFI or a 5-FU maintenance for stable and responder patients [24]. Maintenance therapy improved PFS (8.7 versus 6.9 months; P = 0.009) but not DDC (12.9 versus 11.7 months; P = 0.42). Median duration of CFI was 20 weeks (4.6 months) [24].
In the present study, median PFS was 6.0 months and median CFI 3.9 months, which indicate that celecoxib is not useful as a single-agent maintenance therapy.
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Acknowledgements |
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This study was supported by a grant from Pfizer and was sponsored by the GERCOR, Paris, France. Presented in part at the Thirty-eighth Annual Meeting of the American Society of Clinical Oncology, June, 2004, New Orleans, Louisiana.
Received for publication May 9, 2006. Revision received August 2, 2006. Accepted for publication August 14, 2006.
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References |
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