1 Oncosurgery, Services of 2Visceral Surgery and 3 Radiooncology, Geneva University Hospital, Geneva; 4 University Hospital (CHUV), Multidisciplinary Oncology Center, Lausanne; 5 Kantonspital St. Gallen, Division of Oncology, Department of Medicine C, St. Gallen; 6 Zetup Clinic, St. Gallen, Switzerland
* Correspondence to: Dr A. D. Roth, Geneva University Hospital, Oncosurgery, Geneva, Switzerland. Email: arnaud.roth{at}sim.hcuge.ch
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Abstract |
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Patients and methods:: CRC patients not pretreated with palliative chemotherapy, with performance status 1 and adequate haematological, kidney and liver function, were eligible. Treatment consisted in weekly 24-h infusion 5-FU (2300 mg/m2)/LV (30 mg) and alternating OHP (7085 mg/m2, days 1 and 15) and CPT-11 (80140 mg/m2, days 8 and 22) repeated every 5 weeks. OHP and CPT-11 were escalated in cohorts of three to six patients.
Results:: Thirty patients received a median of five cycles. Dose-limiting toxicity occurred at dose level 3, and the recommended dose was OHP 70 mg/m2, CPT-11 100 mg/m2, LV 30 mg and 5-FU 2300 mg/m2/24 h. Grade 3 toxicities were diarrhea 23%, neutropenia 20%, fatigue 7%, and neurologic 7%. Two febrile neutropenia episodes (one fatal) were recorded. Among 28 patients with measurable disease (90%), we observed two complete and 20 partial responses; overall RR was 78% (95% CI, 59% to 92%). Median time to progression and overall survival were 9.5 and 25.4 months, respectively. Seven patients underwent liver metastases resection.
Conclusion:: OCFL is an overall well tolerated regimen with very high efficacy, which makes it most suitable for tumour control before surgery of metastatic disease.
Key words: colorectal cancer, irinotecan, oxaliplatin, triplet regimen
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Introduction |
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In patients with liver metastases only, these high response rates have allowed for resection of initially inoperable disease [11]. In order to increase the response rate further and to consider subsequent curative intent resection of liver metastases, we aimed to develop a five-drug combination regimen using all known active agents concomitantly and alternately. In a disease-specific phase I/II trial design we administered weekly infusional 5-FU/leucovorin (LV) in combination with either CPT-11 or oxaliplatin.
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Patients and methods |
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Study design and treatment scheme
The treatment consisted of weekly administration of a 24-h infusion of 5-FU (2300 mg/m2), LV 30 mg i.v. on days 1, 8, 15 and 22, escalating doses of OHP (7085 mg/m2) on day 1 and 15, and CPT (80100 mg/m2) on days 8 and 22, as shown in Figure 1. Treatment cycles were repeated every 5 weeks. Dose levels and escalation scheme are presented in Table 1. A minimum of three patients were to be treated at the same dose level. If no dose limiting toxicity (DLT)defined as grade 4 haematological toxicity with fever (single oral temperature >38.5 °C, or three elevations to 38 °C during a 24-h period) and/or grade 3 toxicity of any other kind apart from alopeciaoccurred during the first cycle of treatment, the next three patients were treated at the next higher dose level. If one DLT occurred in cycle 1, three additional patients had to be treated at the same dose level. If two or more DLTs occurred at a given dose level, this would define the maximally tolerated dose (MTD) and the dose just below would be considered the recommended dose for future phase II trials.
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Administration of treatment
Patients were treated through an implantable central venous device in an outpatient setting. OHP was given as a 2-h i.v. infusion on days 1 and 15, and CPT-11 as a 30-min i.v. infusion on days 8 and 22, always followed by 5-FU as a continuous infusion over 24 h. Patients received standard antiemetic premedication, including 5-hydroxytryptamine 3 receptor antagonists and steroids. In order to prevent a cholinergic syndrome, on the days of CPT-11 administration, patients received atropin 0.25 mg s.c. Patients were instructed to manage late diarrhoea by loperamide and nausea and vomiting with metoclopramide. No granulocyte colony stimulating factors were to be used except for febrile neutropenia.
Toxicity assessment, dose reductions and evaluation of response
Physical examination and blood cell counts were performed weekly and biochemistry at the beginning of each cycle. Adverse reactions were graded according to the WHO common toxicity criteria with specific scales to assess plantarpalmar syndrome and OHP-related neuropathy. In case of grade 3 neutropenia or thrombocytopenia or for any grade 34 non-haematological toxicity, doses of all cytotoxic agents were reduced by 25% for the subsequent courses. OHP was to be discontinued if peripheral neuropathy grade 3 or other severe neurotoxicity were observed. A maximum of a 1-week delay (14 days between two treatments) was allowed for severe toxicity. Responses were assessed according to the WHO criteria at the end of every two cycles of treatment. The main goal of the trial was to determine the MTD of the regimen under investigation. Statistical analysis was descriptive and survival was calculated according to the KaplanMeier method.
The trial was approved by the ethics review boards of all participating institutions. All patients gave informed written consent.
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Results |
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At dose level 2 (OHP 70 mg/m2 and CPT-11 100 mg/m2), six patients were initially entered. One patient developed non-haematological DLT consisting of grade 3 nausea/vomiting and grade 3 fatigue. After determining this dose level as the recommended dose, an additional five patients were treated without severe toxicity.
At dose level 3 (OHP 85 mg and CPT-11 100 mg/m2) two out of six patients developed grade 3 diarrhoea. Thus, this dose level was considered to be the MTD and dose level 2 the recommended phase II dose.
Because of delayed reporting of the second DLT in level 3, one patient started therapy at dose level 4 (OHP 85 mg/m2 and CPT-11 120 mg/m2). No significant toxicity was observed during four cycles at this dose level before undergoing curative resection of liver metastasis.
Toxicity assessment
The toxicity analysis is based on 30 patients and 135 cycles of treatment. Overall this regimen was well tolerated and a median of 4 cycles/patient was administered (range 29). Treatment delays were required in 12% of cycles (16 patients). Twelve patients completed 6 or more cycles of treatment, and five patients with responding tumours discontinued therapy early in order to undergo surgery and resection of their liver metastases. Reasons for treatment discontinuation were tumour progression in five patients (17%), toxicity also in five patients [grade 3 neurotoxicity after 4 cycles (one patient), grade 3 diarrhoea after 2 cycles (one patient), ileus or pulmonary embolism after cycle 2 (two patients), fatal fungal septicaemia at the end of the second cycle (one patient)], and personal treatment unrelated reasons in three patients.
Details on the treatment-related worst toxicity are reported in Tables 4 and 5. Grade 3/4 toxicity was infrequent, grade 3/4 diarrhoea occurred in seven patients (23%) and 8% of all treatment cycles. Grade 3/4 neutropenia was observed in 20% of patients and 6% of cycles, but only two febrile episodes, although one fatal fungal infection.
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Discussion |
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Our trial only included patients who had not received prior chemotherapy for metastatic disease. This allowed us to assess the activity of this regimen. The observed response rate of 78% is amongst the highest response rates ever reported for metastatic colorectal cancer [12, 13
, 17
, 18
] and almost identical to the reported 71% by Falcone et al. [12
] with the concomitant biweekly association of 5-FU/LV, CPT11 and oxaliplatin. Similarly, the time to progression and overall survival are also comparable between the two studies (9.5 and 25.4 months, respectively, in our study compared with 10.5 and 26.5 months).
High response rates and a short time to response make these triplet regimens especially suited for patients planning surgical resection of metastases, in particular liver metastases initially considered unresectable. In our trial, seven patients (23%) with a diagnosis of unresectable liver metastases underwent curative-intent resection of the residual disease after an initial response to chemotherapy. Similarly, in the trial reported by Falcone, 25% of patients underwent subsequent surgery.
The occurrence of severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy has recently been reported in patients with metastatic colorectal cancer [19]. Liver surgery is more difficult and prone to complications in this situation. The dose of oxaliplatin per cycle (140 mg/m2) in our OCFL regimen is lower than in other triplet regimens and thus less likely to induce such liver lesions.
In conclusion, OCFL is an efficient and, overall, usually well-tolerated outpatient regimen. It is associated with high response rates and most suitable for tumour control before surgical treatment of metastatic disease.
Received for publication November 6, 2004. Revision received December 22, 2004. Accepted for publication December 27, 2004.
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References |
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