1 Institut Gustave Roussy, Villejuif; 2 Hôpital Ambroise Paré, Boulogne; 3 Cvitkovic et Associés Consultants, Kremlin-Bicêtre; 4 Centre Paoli Calmettes, Marseille; 5 Centre Claudius Regaud, Toulouse; 6 Hôpital Avicenne, Bobigny; 7 CHU Robert Debré, Reims; 8 Clinique Armoricaine de Radiologie, St-Brieuc; 9 Centre Hospitalier Intercommunal, Villeneuve-St-Georges; 10 Centre Hospitalier R. Dubos, Pontoise, France
Received 26 June 2003; revised 21 October 2003; accepted 17 December 2003
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ABSTRACT |
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A randomized phase II, open-label multicenter study evaluating oxaliplatin alone (OXA), infusional 5-fluorouracil alone (5-FU) and an oxaliplatin/infusional 5-FU combination (OXFU) in untreated, advanced pancreatic carcinoma (APC).
Patients and methods:
Chemotherapy-naïve patients with advanced or metastatic, histologically/cytologically proven pancreatic carcinoma with measurable disease, received OXA [130 mg/m2, 2-h intravenous (i.v.) infusion] alone, OXA combined with 5-FU (1000 mg/m2/day, continuous i.v., days 14), or 5-FU alone, every 3 weeks.
Results:
Sixty-three patients (42 males/21 females) were treated: 17 patients/52 cycles OXA, 31 patients/ 175 cycles OXFU, 15 patients/41 cycles 5-FU, with a median of three, six and two cycles/patient, respectively. Patient characteristics were similar in all arms. Median age was 57 years (range 2175), and 83% of patients had PS 01. Most patients (62%) had moderate to well-differentiated tumors, 90% had metastatic disease, 81% with liver metastases. All responses (three partial responses; WHO) occurred in the OXFU arm (10% response rate). Five of 32 patients evaluable for clinical benefit were responders (OXA, 14%; OXFU, 21%). Median time to progression and overall survival were higher in the combination arm (4.2 and 9.0 months, respectively) than either single-agent arm (OXA, 2.0 and 3.4 months; 5-FU, 1.5 and 2.4 months, respectively). Moderate hematotoxicity without morbidity was seen in all arms. Two OXFU patients had grade 3 oxaliplatin neurosensory toxicity.
Conclusions:
With a 10% response rate, median overall survival of 9 months and an encouraging safety profile, the OXFU combination is effective, appears superior to infusional 5-FU and warrants further studies in APC patients.
Key words: advanced pancreatic carcinoma, DACH-platinum, 5-fluorouracil, oxaliplatin
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Introduction |
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Prior to approval of gemcitabine, 5-fluorouracil (5-FU) was the most widely used agent in the treatment of APC. With a wide range of reported activities for bolus and continuous infusion (020%) [47], it has failed to show an improvement in disease-related symptoms or survival. Median survival for patients treated with single-agent 5-FU does not exceed 5.5 months [8]. Higher response rates (17.343%) have been reported in phase II trials with 5-FU-based combinations [911]. Nevertheless, these results have not been confirmed in randomized trials and no survival advantage of combination over single-agent 5-FU has been demonstrated [12]. Significant activity has been reported in response and time to progression (TTP) in a controlled trial with cisplatin/infusional 5-FU compared to bolus 5-FU [13]. However, continuous protracted infusion of 5-FU has shown small but consistent activity [8.5% objective response rate (ORR)] in the control arm of a large multicenter trial recently reported by Maisey et al. [14], a rate which is close to the activity seen with single-agent gemcitabine.
Recently, several new drugs have been tested as single agents or in combination regimens assessing response rate and clinical benefit, a novel study end point assessable only in symptomatic patients. A randomized phase III trial comparing gemcitabine with bolus 5-FU using clinical benefit response as the primary end point demonstrated significant, although moderate, superiority of gemcitabine over 5-FU [4]. This led to the approval of gemcitabine in the USA for use as single-agent therapy in APC despite an ORR of only 5.4% in patients with bidimensionally measurable disease. Combinations of gemcitabine and 5-FU or cisplatin and optimized administration of gemcitabine (10 mg/m2/min) have subsequently suggested higher response rates and an increase in reported survival, although this has never been demonstrated in randomized phase III trials. Median survival has consistently been <1 year [1517].
Platinum compounds have been evaluated in pancreatic cancer, notably in 5-FU combination regimens. Single-agent cisplatin demonstrated a tumor response rate of 21%, with median response duration of 5 months [18]. Several phase II trials of cisplatin/continuous infusion 5-FU showed response rates between 15% and 26% [13, 19, 20]. Oxaliplatin, a diaminocyclohexane (DACH) platinum with a large preclinical spectrum of anticancer activity has been recently approved in Europe and elsewhere for use in colorectal cancer (CRC) patients combined with 5-FU. It is active in a variety of tumor types and has a very favorable safety profile, limited only by mild hematotoxicity and cumulative neurosensory toxicity, the latter usually being reversible upon treatment discontinuation [21, 22]. It has shown additive and/or synergistic preclinical anti-tumor activity with many anticancer agents, notably 5-FU [23], which has been clinically validated in advanced CRC [24].
With limited benefit from treatment with available regimens, there is a pressing need for active agents that improve survival in this poor prognosis population. Given the reported activity of cisplatin in APC, we wished to assess the activity of oxaliplatin alone in this indication. Secondly, based on the synergy and favorable toxicity profile of oxaliplatin5-FU combinations, the present study aimed to assess the efficacy and safety of such a combination, benchmarked with infusional 5-FU, the standard reference treatment in France at the time of study conception.
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Patients and methods |
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Patients were excluded from the study if they had any of the following: concomitant second malignancy, with the exception of treated basal cell carcinoma of the skin or cured cervical cancer; symptomatic peritoneal carcinosis or gastrointestinal stenosis; cerebral or leptomeningeal metastasis; bone metastases, pleural effusions or ascites as the only signs of disease; peripheral neuropathy; concurrent treatment with other experimental drugs; another serious illness or medical condition; hypersensitivity to 5-FU; pregnant, breast-feeding or not using adequate contraception (females); or adequate monitoring was not possible.
Study design
The protocol was approved by the CCPPRB (ethics committee) of the Saint-Antoine Hospital. Eligible patients in this open-label study were stratified by center and disease stage (locally advanced versus metastatic) and centralized block randomization was used to assign patients to one of three arms. Patients received either single-agent oxaliplatin 130 mg/m2 as a 2-h intravenous (i.v.) infusion every 3 weeks (OXA); or oxaliplatin (as above) combined with 5-FU 1000 mg/m2/day continuous i.v. infusion, days 14 (OXFU); or single agent 5-FU (as above; FU) repeated every 3 weeks.
The primary end point of this study was evaluation of the tumor response rate. The original randomization scheme foresaw equilibrated inclusion in the three arms; however, an investigator-motivated ad hoc interim analysis carried out after inclusion of the first 55 patients (OXA, 18; OXFU, 21; FU, 16), indicated that activity in the OXA and FU arms was insufficient to warrant further investigation. Accrual in these arms was terminated prematurely, and with a further 10 patients randomized in the OXFU arm, a final ratio of 1:2:1 was established. This study was designed as a parallel assessment of the three arms and not as a comparative study. Patients received anti-emetics and supportive therapies as necessary. Treatment was continued until disease progression, unacceptable toxicity, withdrawal of consent, physician decision or a treatment interruption of >2 weeks.
Pretreatment evaluation included medical history, a physical examination with neurological assessment, complete blood cell (CBC) count, biochemical profile, serum tumor marker assessment (CEA, Ca19.9), ECG, chest X-ray and an abdominal CT scan of measurable lesions. Before each subsequent treatment cycle, patients underwent a physical examination, CBC count, biochemical profile and tumor marker assessment. A CBC count was also performed 14 days after treatment administration. Toxicity was evaluated according to National Cancer Institutecommon toxicity criteria (NCICTC), version 1, guidelines. Neurotoxicity was evaluated using an oxaliplatin-specific scale [25] (grade 1, paresthesia/dysesthesia of short duration, with complete recovery before next cycle; grade 2, paresthesia/dysesthesia persisting between two cycles without functional impairment; grade 3, permanent paresthesia/dysesthesia, resulting in functional impairment).
Patient eligibility was assessed by an independent clinical expert panel composed of an independent non-participating medical oncologist and a sponsor representative. In addition, a panel composed of two radiological experts external to the study, a sponsor representative and monitoring personnel reviewed source documents of all patients with an objective response and 18 of 21 disease stabilizations reported by the investigator. Patients had to receive a minimum of three treatment cycles (i.e. 9 weeks on study) with at least one follow-up tumor assessment to be considered evaluable for response, unless early disease progression occurred. Anti-tumor activity (WHO criteria [26]) was assessed every three cycles. Objective responses were confirmed 4 weeks after initial observation. Patients were observed for 1 month after the last treatment administration. Thereafter, tumor measurement was performed for patients with objective response or stable disease every 3 months up to the date of relapse or progression. Duration of partial response or stable disease dated from treatment start until documentation of progression. TTP was calculated from the first treatment infusion to the first objective evidence of tumor progression, last contact or start of further anti-tumor therapy. Overall survival (OS) was measured from initial treatment until death. Clinical benefit evaluation used the following parameters: pain intensity, analgesic consumption and performance status. In the event of stability of these parameters, weight change was also considered. Clinical benefit was determined using a slightly modified algorithm from Burris et al. [4] (improvement in at least one parameter and stable assessment in the others). Parameters were evaluated on a weekly basis using a patient questionnaire.
Dosing and scheduling modifications were made in the event of toxicities. When the absolute neutrophil count was <1500/mm3 or the platelet count was <100 000/mm3, treatment was delayed for a maximum of 2 weeks and discontinued in the absence of improvement. When NCICTC grade 3 or 4 gastrointestinal toxicity occurred, oxaliplatin was reduced to 100 or 80 mg/m2/day, respectively, and the 5-FU dose to 800 or 650 mg/m2/day, respectively. In the event of grade 2 or 3 handfoot syndrome, 5-FU was reduced to 800 or 650 mg/m2/day, respectively. Treatment was stopped for grade 4 handfoot syndrome. In the event of continuous paresthesia/dysesthesia between cycles, oxaliplatin was reduced to 100 mg/m2. When paresthesia/dysesthesia with pain lasted for >7 days, oxaliplatin was initially reduced to 100 mg/m2/day and subsequently to 80 mg/m2/day if necessary. In the event of paresthesia/dysesthesia with functional impairment lasting for >7 days, oxaliplatin was reduced to 80 mg/m2/day. When paresthesia/dysesthesia with either pain or functional impairment persisted between cycles, oxaliplatin was discontinued.
Statistical methods
The maximal number of evaluable patients to be included per treatment arm was arbitrarily fixed at 28, with analysis using the hypothesis of an expected 25% response rate in the OXFU arm [95% confidence intervals (CI) 10% to 45%]. Safety and efficacy parameters were assessed with descriptive statistics. TTP and OS were analyzed using the KaplanMeïer method. A univariate analysis was performed on time-related efficacy parameters using the log-rank test.
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Results |
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A total of 63 patients were treated, 17, 31 and 15 in the OXA, OXFU and 5-FU arms, respectively. Most patients (51; 81%) discontinued treatment for progressive disease, four (6%) withdrew consent, one went off-study for a biliary endoprosthesis placement, one stopped treatment after achieving a near complete response, and two others died of unrelated causes (pulmonary embolism, suicide). Of these 63 treated patients, three (one in each arm) were considered ineligible: one had non-measurable disease and abnormal bilirubin levels; one had a baseline CT scan 6 weeks prior to study start; one had non-measurable disease and a disease-free interval <3 months between prior locoregional radiochemotherapy and diagnosis of metastatic disease.
Patient characteristics
Patient characteristics at baseline of the 63 treated patients were mostly well balanced between all arms (Table 1). Two-thirds of patients were male and the median age was 57 years (range 2175). Eighty-three per cent of patients had a PS (WHO) of 0 or 1. Most patients had moderately to well differentiated carcinomas, and 83% had stage IVb disease at diagnosis. The most common metastases were liver (81%), locoregional lymph nodes (43%) and peritoneum (21%). Overall, 10% of patients had exclusively locally advanced disease at inclusion. Fifty-three per cent of patients had more than two organs involved (range 15). Nevertheless, some imbalances in clinically relevant parameters were noted, although none were statistically significant. General condition was worse in the 5-FU arm (PS 2; 27%) than the OXA (18%) and OXFU arms (13%). In addition, 6% of OXA patients and 16% of combination patients had exclusively locally advanced disease, whilst all patients in the FU arm were metastatic. The percentage of patients with more than two involved organs was lower in the combination arm (42%) than the OXA (59%) and 5-FU arms (67%).
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Treatment exposure
Sixty-three treated patients received a total of 268 cycles (OXA, 52; OXFU, 175; 5-FU, 41). The median number of cycles given was higher in the OXFU arm (median, 6; range 116) than in the single-agent arms [OXA, 3 (range 16); 5-FU, 2 (range 17)]. In the combination arm, 65% of patients received more than three cycles, compared to only 24% and 20% in the OXA and 5-FU arms, respectively. Median oxaliplatin relative dose intensity (RDI) in the OXA arm was 100% (range 82100) and 96% (range 56100) in the combination arm, and median 5-FU RDI was 100% in the 5-FU arm and 94% in the combination arm. Median cumulative doses were considerably lower in both single-agent arms than the combination arm, reflecting the lower number of cycles administered in these two arms.
Several more patients experienced cycle delays in the OXFU arm (66%) than in either single-agent arm (OXA, 29%; 5-FU, 17%). The majority of patients had a delay in only one cycle, and 50% of delays lasted for 713 days. Fifty-five per cent of cycle delays were treatment related, most of which were due to mild or moderate hematological toxicity recovery. Only one patient in each single-agent treatment arm underwent a dose reduction, while six (21%) patients in the combination arm had dose reductions, which were mostly due to either hematotoxicity or gastrointestinal toxicity.
Efficacy
Of the 63 treated patients, seven (11%) were considered to be non-evaluable for response for the following reasons: four patients withdrew prior to the first disease assessment (cardiac ischemia, withdrawal of consent, death after pulmonary embolism, biliary endoprosthesis obstruction); two had baseline assessments that were too old or missing; one received gemcitabine treatment after only one cycle of study treatment. Thus, 56 of the treated patients were evaluable for response, 15 in the OXA arm, 27 in the OXFU arm and 14 in the 5-FU arm.
Three expert-assessed partial responses occurred, all in the combination therapy arm, yielding an ORR of 10% in the 31 treated OXFU patients (95% CI 2% to 26%). The rate of stable disease in all treated patients was also higher in the combination arm (15/31; 48%) than either the OXA arm (2/17; 12%) or the 5-FU arm (3/15; 20%). All disease stabilizations lasted for 9 weeks. All three responding patients had moderately differentiated stage IVb, metastatic disease with two involved organs, with a TTP of 7.3+, 8.0 and 8.5 months at the data acquisition cut-off date. Of note, one of the responding patients (PR at the data acquisition cut-off date) was still alive after more than 2 years and achieved a near complete response.
As of October 1999, TTP in all treated patients was lower in the single-agent arms (OXA, 2.0 months; 5-FU, 1.5 months) than in the combination arm (4.2 months; Figure 1). Similarly, median OS in the combination arm (9.0 months) was longer than in either of the single therapy arms (OXA, 3.4 months; 5-FU, 2.4 months; Figure 2). In addition, the 6-month survival rate was higher in the combination arm (75%) than in either of the single therapy arms (OXA, 40%; 5-FU, 20%). A 1-year survival of >20% in the combination arm is also of note. Two patients receiving single-agent therapy who did not have disease progression when initiating a second-line treatment were censored at that time.
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Treatment efficacy was also evaluated by clinical benefit. However, only 32 of the treated patients (51%) could be evaluated for clinical benefit due to poor patient compliance. Clinical benefit was observed in five patients, four of 19 evaluable patients (21%) in the combination arm, and one of seven evaluable patients (14%) in the OXA arm.
Safety
All 63 treated patients were assessed for safety. Three patients (5%) in the combination arm discontinued therapy for treatment-related adverse events, two for neurotoxicity (grades 2 and 3; after eight cycles) and one for cardiac ischemic episodes. The most prevalent toxicities were hematological and gastrointestinal (Table 2). Anemia (all grades) was present in 88%, 55% and 73% of patients in the OXA, OXFU and 5-FU arms, respectively, although severe (grade 34) anemia was only reported in the single-agent arms (two patients each). Mild to moderate (grade 12) thrombocytopenia was prevalent (71%, 80% and 40% of patients in the OXA, OXFU and 5-FU arms, respectively), but was rarely severe. Neutropenia was more frequent in the OXA and OXFU arms (29% and 45% of patients, respectively) than the 5-FU arm (13% of patients). Grade 34 neutropenia was rare, occurring in three patients (18%) in the OXA arm and four (13%) in the OXFU arm. No febrile neutropenia was reported.
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Very few differences in toxicity were apparent between arms, with only stomatitis showing a statistically significant difference, occurring more often in the 5-FU containing arms, albeit being rare in all treatment arms. Severe asthenia (grades 34) also occurred less frequently in the combination arm (23%) than in either single-agent arm (OXA, 53%; 5-FU, 43%). This is of note given that asthenia was more prevalent at baseline in patients receiving combination treatment. Similarly, severe pain was recorded in only 10% of combination therapy patients and in 29% of OXA patients and 21% of 5-FU patients. Several baseline symptoms were more prevalent with treatment (digestive, fever, neurosensory), although at a low level. Note that since several non-hematological symptoms (digestive and pain) frequently occur in patients with APC, not all non-hematological toxicities reported were necessarily study drug related.
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Discussion |
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It is of note that the 9.0 months OS with oxaliplatin5-FU combination therapy is within the range of values reported in gemcitabine-based combination regimens [28, 31]. Furthermore, it compares favorably with the APC single-agent gemcitabine phase III study (5.7 months) [4] and a phase III gemcitabinedocetaxel combination study (5.4 months) [32]. Recently, results of an oxaliplatingemcitabine combination multicenter phase II study in APC showed a 30% response rate, 70% median survival at 6 months and a 9 month median survival [33], supporting the reported preclinical synergistic activity of these agents [34]. However, it is important to note that the trial was not randomized and the improved response rate in the combination arm may have been influenced by a potential imbalance between the treatment groups, with five of six non-metastatic patients being found in the combination arm, as well as the highest rate of patients with PS 01. No significant differences in either PS (0/1 versus 2) or histology (well differentiated versus moderately or undifferentiated) were identified when comparing patients included in the combination arm before and after the change in randomization, although the population included subsequent to this change did have a slightly poorer prognosis. It is also of interest that no cases of dissociated response were reported in the current trial as is often the case in pancreatic cancer (i.e. objective response in the liver metastasis, no change in the primary tumor). Median TTP in the combination arm (4.2 months) appears longer than that reported in the pivotal gemcitabine phase III trial (2.1 months) [4]. Analysis of efficacy parameters (response, TTP, OS, 6-month survival) shows the clear advantage of the OXFU combination over either single-agent arm. Furthermore, approximately one-third of combination patients progressed after three cycles of OXFU against the majority of patients receiving either monotherapy.
The safety and tolerance profile in all three treatment arms was excellent with no toxic deaths. In addition, nearly all patients were treated as outpatients, which is of major interest in this frail population. In the combination arm, grade 34 neutropenia and grade 3 thrombocytopenia were observed in only 12% and 3% of patients, respectively, despite the high 5-FU dose. Non-hematological toxicities were also very mild, with grade 34 vomiting in 9% of patients and grade 3 neurosensory toxicity in only 6% of patients. Stomatitis, asthenia and pain were all less prevalent in combination patients than in the single-agent arms. This is of note given that baseline patient characteristics were reasonably well balanced between the three treatment populations, and that pain and asthenia were both more prevalent in the combination arm at baseline than in either single agent.
The safety profile of the combination therapy is particularly encouraging when benchmarked with other chemotherapy combinations recently reported in the same indication. For example, in a gemcitabine5-FU combination, grade 34 thrombocytopenia occurred in 22% of patients, grade 3 diarrhea and grade 23 mucositis in 3% of patients [27]. In a gemcitabineoxaliplatin (GEMOX) combination, grade 34 thrombocytopenia occurred in 9% of patients, and grade 34 diarrhea and nausea/vomiting in 6% and 14% of patients, respectively [33].
Single-agent 5-FU and oxaliplatin therapy failed to display objective anti-tumor activity in these APC patients, confirming that there is little advantage in pursuing further studies with either of these single agents, despite previous reports of a 21% response rate with single-agent cisplatin (which is less active than cisplatin in other gastrointestinal cancers) in this patient population [18]. The 10% ORR in the oxaliplatin5-FU combination arm in this multicentric randomized phase II trial with independent external review supports an anti-tumoral interaction between oxaliplatin and 5-FU. With a median OS of 9 months, and an encouraging safety profile, the oxaliplatin5-FU combination deserves further exploration in APC patients, including prospective controlled trials against gemcitabine and other reported active combinations.
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Acknowledgements |
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FOOTNOTES |
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