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© 2003 American Society for Clinical Oncology Cisplatin in Combination With Either Gemcitabine or Irinotecan in Carcinomas of Unknown Primary Site: Results of a Randomized Phase II Study—Trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01)
From the Centre Val d’Aurelle, Montpellier; Centre P. Papin, Angers; Institut C. Regaud, Toulouse; Institut G. Roussy, Villejuif; Centre Hospitalier, La Roche/Yon; Centre A. Vautrin, Nancy; Centre E. Marquis, Rennes; Centre A. Lacassagne, Nice; Centre G.F. Leclerc, Dijon; Centre R. Gauducheau, Nantes; Centre Hospitalier Universitaire, Besançon; Centre F. Baclesse, Caen; Centre R. Huguenin, Saint-Cloud; and Centre L. Bérard, Lyon, France. Address reprint requests to Stéphane Culine, MD, PhD, Department of Medical Oncology, Centre Régional de Lutte Contre le Cancer, Val d’Aurelle, Parc Euromédecine, 34298 Montpellier Cedex 5, France; e-mail: stculine{at}valdorel.fnclcc.fr.
Purpose: To evaluate the efficacy and toxicity of novel chemotherapy combinations including cisplatin with gemcitabine (GC) or irinotecan (IC) for patients with carcinomas of an unknown primary site. Patients and Methods: Eighty patients were randomly assigned to receive GC or IC. In the GC arm, chemotherapy consisted of cycles combining gemcitabine 1,250 mg/m2 intravenously (IV) on days 1 and 8, and cisplatin 100 mg/m2 IV on day 1 at 3-week intervals. Patients in the IC arm originally received 3-week cycles of irinotecan 200 mg/m2 IV on day 1 and cisplatin 80 mg/m2 IV on day 1. After the inclusion of 15 patients in that arm, the toxicity profile required the irinotecan doses to be reduced to 150 mg/m2 per cycle. Independent histologic and radiologic reviews were done. Results: A total of 78 patients were assessable for efficacy and toxicity. The median number of cycles was four in each arm. Objective responses were observed in 21 patients (55%) in the GC arm (95% CI, 34% to 66%) and in 15 patients (38%) in the IC arm (95% CI, 23% to 54%). Treatment had to be stopped because of toxicity in seven patients in the GC arm and in eight patients in the IC arm. With a median follow-up of 22 months, the median survivals were 8 and 6 months in the GC and IC arms, respectively. Conclusion: This study demonstrates the activity of both the GC and IC regimens. There was toxicity associated with both regimens. Additional studies of combination chemotherapy regimens are required.
CARCINOMAS OF unknown primary site (CUP) represent a group of heterogeneous tumors that share the unique clinical characteristic of metastatic disease with no identifiable origin at the time of therapy. Despite advances in tumor imaging and pathology, patients with metastatic carcinomas from an unidentified primary site still account for 5% to 10% of all cancer patients.1 Because outcome is poor, with a median survival time of about 6 to 12 months, the benefit of chemotherapy compared with best supportive care is still unclear. Moreover, the optimal chemotherapy remains to be determined.2 The recent introduction of several new cytotoxic agents with broad spectra of clinical activity (such as gemcitabine, irinotecan, and taxanes) has created opportunities for the empiric treatment of CUP. We report here on the results of a randomized phase II study assessing the efficacy in terms of objective response rates, and the toxicity of two novel combination regimens including cisplatin plus gemcitabine (GC arm) or cisplatin plus irinotecan (IC arm).
Eligibility Criteria The Trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01) study was approved by the Board for the Protection of Persons Subjected to Biomedical Research of Montpellier and was conducted in 14 French cancer centers from August 1999 to November 2000. Eligibility criteria included age older than 18 years; histologically confirmed CUP; no previous chemotherapy; Eastern Cooperative Oncology Group performance status of 0, 1, or 2; measurable disease; absolute neutrophil count  1,500/µL, platelet count 100,000/µL, serum creatinine concentration  1.25 x upper normal limit, or creatinine clearance more than 60 mL/min; normal function tests for liver (serum bilirubin level 1.25 x upper normal limit); and cardiac ejection fraction greater than 50% by echocardiographic or radionuclide cineangiography. Patients were excluded if they had any of the following features: inclusion in subsets with specific well-defined treatment (ie, women with adenocarcinoma that involved only axillary lymph nodes, women with papillary serous carcinoma of the peritoneum, patients with squamous carcinoma that involved only cervical or inguinal lymph nodes, carcinomas with neuroendocrine features, and patients with carcinoma that involved a single potentially resectable tumor site), symptomatic brain metastases, history of previous malignancy with the exception of skin cancer or cervical carcinoma-in-situ, pregnant or lactating women, or severe coexistent medical illnesses. All patients provided written consent.
Pretreatment Evaluation
Chemotherapy and Patient Monitoring A complete reassessment of all metastatic sites was planned every two cycles of chemotherapy. Patients were assigned a response category on the basis of WHO standard definitions.3 Complete response required the total disappearance of all clinical and radiologically detectable disease for at least 4 weeks. Partial response was defined as a greater than 50% reduction in the product of the bidimensional measurements for a minimum of 1 month, with no new lesions appearing. Progressive disease was defined as a greater than 25% increase in tumor size or the appearance of any new lesion. Responding patients or those with nonprogressive lesions could receive additional courses according to the discretion of the treating physician. After completion of therapy, patients were monitored at 3-month intervals until progression of disease. Follow-up evaluation was performed in all patients until the time of death. Responses to treatment were initially assessed by the investigators. Responses and stabilizations were reviewed centrally and blindly by an independent radiologist expert. If an assessment discordance occurred between the investigator and the radiologist expert, a second independent radiologist expert was asked to review the case blindly and the second reviewer’s expertise was considered for final assessment.
Statistical Design
Patient Characteristics Fourteen centers enrolled 80 patients onto the study. Forty patients were randomly assigned to receive the GC regimen. One patient died as a result of progressive disease before the start of therapy and data from another patient could not be collected. Therefore, initial characteristics were described for 39 patients, and 38 patients in that arm were assessable for efficacy and toxicity, respectively. Forty patients were allocated to receive the IC regimen. All of these patients were assessable for efficacy and toxicity. In general, patients were well matched with respect to initial characteristics (Table 1  ). Pathologic review was performed on 75 specimens (samples from one patient were not collected and four patients had cytopathologic diagnosis only). Well-differentiated adenocarcinoma was the most common histologic diagnosis. About one fourth of patients had only one site of metastatic disease. Bone, lung, and liver were the dominant visceral sites of disease, whereas mediastinum was the most frequent location of lymph node involvement. A majority of patients had a performance status of 0 or 1. According to the prognostic model developed by our group,7 49 patients (60%) had poor-risk characteristics (Eastern Cooperative Oncology Group performance status of 2 or elevated serum lactate dehydrogenase level) at entry onto the study (27 and 22 patients in the GC and IC arms, respectively).
Treatment Delivery The median number of cycles was four in each treatment arm. In the GC arm, two patients received only one cycle because of early progressive disease (one patient) and grade 2 renal toxicity (one patient), whereas 14, one, and two patients were treated with six, seven, and eight cycles, respectively. In the IC arm, four patients received only one cycle, whereas eight, two, two, and one patient were treated with six, seven, eight, and 12 cycles, respectively. Chemotherapy was stopped after the first cycle because of early progressive disease in three patients and pulmonary embolism in one patient. From cycle 1 to 6, the median delay between cycles was 21 days in both arms. Cisplatin was discontinued in four patients (two in each arm) before the end of treatment schedule because of grade 2 ototoxicity.
Toxicity
Efficacy Forty patients were enrolled in each arm because six ORs (one complete and five partial responses) and five ORs (five partial responses) were observed at the end of the first stage in the GC and IC arms, respectively. The final results are summarized in Table 3 . Objective responses were observed in 21 patients (55%) in the GC arm (95% CI, 34% to 66%) and in 15 patients (38%) in the IC arm (95% CI, 23% to 54%). With a median follow-up of 22 months, the median survivals were 8 and 6 months in the GC and IC arms, respectively.
The design of treatment plans for patients presenting with CUP clearly remains a daily challenge for physicians. To improve the poor outcome of patients, studies in recent years have focused on the introduction of new cytotoxic agents with broad spectra of clinical activity, such as gemcitabine or taxanes. The use of paclitaxel in combination with carboplatin seemed to provide promising results in two independent studies, with reported median survivals ranging from 11 to 13 months.8,9 In a more recent experience published by the Minnie Pearl Cancer Research Network with a combination of paclitaxel, carboplatin, and gemcitabine, the median survival was only 9 months.10 In this study, both the GC and IC regimens satisfied the two-step design that demonstrates antitumor efficacy. However, median survivals were short and suggest that the new drugs studied so far have demonstrated no clear influence on the management of CUP patients. In addition, significant toxicities required the discontinuation of therapy in approximately 25% of patients in each arm. An important point to consider while one assesses the results of phase II trials is related to the prognostic features of enrolled patients. Indeed, some discrepancies are more likely related to the inclusion of a higher proportion of patients with poor prognostic features rather than to an effective difference in anticancer activity of regimens. Because no simple or reliable prognostic model has been reported so far for the design of clinical trials in the disease, our group recently demonstrated the independent adverse prognostic value of a poor performance status and elevated serum lactate dehydrogenase levels on survival of CUP patients.7 In this study, 60% of patients had poor prognostic features. This observation could explain the short median survivals of patients in both arms. Additional prospective trials led by the French National group will be designed using our prognostic model.7 In good-risk patients, the next trial will compare the impact of single-agent cisplatin (100 mg/m2 every 3 weeks) to the GC combination on survival (GEFCAPI 02 trial). The GC combination was selected to retain cisplatin dose-intensities in both arms. In patients with poor-risk disease, low-toxicity chemotherapy will be challenged with best supportive care only (GEFCAPI 03 trial). Concomitantly, a better understanding of the biology might lead to targeted therapies. An Her-2 overexpression has been reported in some patients with poorly differentiated adenocarcinoma and predominant tumor location above the diaphragm.11 Our basic research program includes identification studies of new molecular targets, establishment of animal models of CUP, and microarray analyses of CUPs compared with neoplasms with a known primary site. It is hoped that this approach will be the first step of new progress in the management of patients with CUP.
The authors indicated no potential conflicts of interest.
Supported in part by grants from Aventis France, Eli Lilly France, the Association pour la Recherche contre le Cancer, and the Ligue Nationale contre le Cancer.
1. Hainsworth JD, Greco FA: Treatment of patients with cancer of an unknown primary site. N Engl J Med 329:257–263, 1993 2. Sporn JR, Greenberg BR: Empirical chemotherapy for adenocarcinoma of unknown primary tumor site. Semin Oncol 20:261–267, 1993[Medline] 3. Miller AB, Hoogstraten B, Staquet B, et al: Reporting results of cancer treatment. Cancer 47:207–214, 1981[CrossRef][Medline] 4. Simon R: Optimal two-stage designs for phase II clinical trials in oncology. Control Clin Trials 10:1–10, 1989[Medline] 5. Kaplan EL, Meier P: Non parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 6. Rothman KJ: Estimation of confidence limits for the cumulative probability of survival in life table analysis. J Chronic Dis 31:557–560, 1978[CrossRef][Medline]
7. Culine S, Kramar A, Saghatchian M, et al: Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site. J Clin Oncol 20:4679–4683, 2002 8. Greco FA, Burris HA, Erland JB, et al: Carcinoma of unknown primary site: Long term follow-up after treatment with paclitaxel, carboplatin and etoposide. Cancer 89:2655–2660, 2000[CrossRef][Medline]
9. Briasoulis E, Kalofonos H, Bafaloukos D, et al: Carboplatin plus paclitaxel in unknown primary carcinoma: A phase II Hellenic Cooperative Oncology Group study. J Clin Oncol 18:3101–3107, 2000
10. Greco FA, Burris HA, Litchy S, et al: Gemcitabine, carboplatin, and paclitaxel for patients with carcinoma of unknown primary site: A Minnie Pearl Cancer Research Network study. J Clin Oncol 20:1651–1656, 2002
11. Hainsworth JD, Lennington WJ, Greco FA: Overexpression of Her-2 in patients with poorly differentiated carcinoma and poorly differentiated adenocarcinoma of unknown primary site. J Clin Oncol 18:632–635, 2000 Submitted December 17, 2002; accepted June 28, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
