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© 2002 American Society for Clinical Oncology Gemcitabine, Carboplatin, and Paclitaxel for Patients With Carcinoma of Unknown Primary Site: A Minnie Pearl Cancer Research Network StudyByFrom the Sarah Cannon Cancer Center and Tennessee Oncology, Professional Limited Liability Corperation, Centennial Medical Center, Nashville, TN; Upstate Carolina Community Clinical Oncology Program, Spartanburg, SC; Oncology and Hematology Associates of Southwest Virginia, Inc, Roanoke, VA; and Consultants in Blood Disorders and Cancer, Louisville, KY. Address reprint requests to F. Anthony Greco, MD, Sarah Cannon Cancer Center, 250 25th Ave North, Suite 412, Nashville, TN 37203; email: fgreco{at}tnonc.com
PURPOSE: To evaluate the efficacy and toxicity of the novel chemotherapy combination that includes gemcitabine, carboplatin, and paclitaxel in the treatment of patients with carcinoma of unknown primary site. PATIENTS AND METHODS: One hundred twenty patients were treated with the following regimen, administered every 21 days for a planned four courses: gemcitabine 1,000 mg/m2 intravenously (IV) on days 1 and 8, carboplatin at an estimated area under the concentration-time curve of 5 mg min/mL IV on day 1, and paclitaxel 200 mg/m2 IV on day 1. After four courses, stable and responding patients were given weekly paclitaxel 70 mg/m2 IV for 6 weeks for three 8-week courses. All patients had relatively poor prognostic features. Sixty-three patients had well-differentiated adenocarcinoma, 56 patients had poorly differentiated carcinoma, and 104 patients had performance status of 0 or 1. RESULTS: Twenty-eight (25%) of 113 assessable patients (95% confidence interval, 22% to 30%) had major objective responses to treatment. Response rates were similar in the two major histologic types. Response rate did not seem to be improved by continued therapy with weekly paclitaxel. The median progression-free survival time was 6 months. Median survival for the entire group was 9 months, and the actuarial survival at 1 and 2 years was 42% and 23%, respectively. CONCLUSION: Combination chemotherapy with gemcitabine, carboplatin, and paclitaxel followed by weekly paclitaxel is an active and tolerable treatment for patients with carcinoma of unknown primary site. The survival seen in this poor-prognosis group of patients in this multicenter community-based trial is notable and similar to other taxane-based regimens for these patients. Study of additional combinations or sequences of newer drugs, as well as the exploration of targeted biologic agents for patients with an identified target in their tumors, is warranted.
OUR UNDERSTANDING of the various clinical and pathologic features represented by patients with carcinoma of unknown primary site continues to evolve.1 Several subsets of patients are known to have a better prognosis, and others have tumors that are much more resistant to various forms of cytotoxic therapy. Recently, some patients with poor prognostic features have responded favorably to taxane/platinum-based combination chemotherapy.2-5 Furthermore, long-term follow-up of patients who received the combination of paclitaxel, carboplatin, and oral etoposide has shown continued benefit for a small minority for several years.3 Subsequent studies, including the use of docetaxel with cisplatin or carboplatin,4 demonstrated similar median and 2-year survival rates. Gemcitabine, an active drug in several solid tumors, has also found to be useful as secondary therapy for some patients with carcinoma of unknown primary site.6 We therefore designed a phase II study using gemcitabine, carboplatin, and paclitaxel for patients with previously untreated carcinoma of unknown primary site. Our previous experience with this combination in patients with advanced non–small-cell lung cancer7 also encouraged us to use this therapy for patients with carcinoma of unknown primary site. The study reported here is a phase II trial by the Minnie Pearl Cancer Research Network, a community-based cooperative group.
Patients who had histologically confirmed metastatic carcinoma were eligible for the present study if the following evaluations had not revealed a primary site: complete history, physical examination, chemistry profile, chest x-ray, computed tomography scan of the chest, abdomen, and pelvis, mammography in women, and directed workup of any symptomatic areas. Patients were eligible who had light microscopic pathologic diagnoses, as follows: well-differentiated adenocarcinoma, poorly differentiated adenocarcinoma (PDA), poorly differentiated carcinoma (PDC), and squamous cell carcinoma. Serum markers were not required to enter patients on the trial, except B-human chorionic gonadotrophin in those with PDC and prostate-specific antigen in men. Some patient subsets known to have good prognostic features were excluded from this study. These subsets included women with adenocarcinoma involving only axillary lymph nodes or the peritoneal cavity, patients with squamous cell carcinoma involving only cervical lymph nodes or inguinal lymph nodes, patients with poorly differentiated carcinoma consistent with a germ cell tumor (ie, isolated midline structures, multiple pulmonary nodules, or elevated levels of beta-human chorionic gonadotropin or alpha-fetoprotein), men with prostate-specific antigen elevated in their plasma or stained in their tumor, patients with a single, small, potentially resectable tumor, patients with neuroendocrine carcinomas, and patients with poorly differentiated neoplasms not otherwise classified. Specific pathologic study was required for patients with the initial diagnosis of PDC to exclude other neoplasms. Immunoperoxidase staining for leukocyte common antigen was required in all patients to exclude lymphoma. Additional immunoperoxidase stains, including epithelial markers (cytokeratins), neuroendocrine markers (neuron-specific enolase and chromogranin), and melanoma markers (S-100, Hmb-45) were also performed routinely. For men with adenocarcinoma, staining for prostate-specific antigen was performed when clinical features suggested prostate carcinoma. Patients with specific neoplasms identified by special stains were excluded. The pathology reports were reviewed on every patient by two of the authors (F.A.G. and J.D.H.), but no central pathology review was done.
Previous chemotherapy was not allowed. Other entry criteria included an Eastern Cooperative Oncology Group performance status of 0, 1, or 2, adequate bone marrow function (WBCs Patients were treated as outpatients with the following chemotherapy regimen: paclitaxel 200 mg/m2 by 1-hour intravenous (IV) infusion, day 1; carboplatin at area under the concentration-time curve 5.0 x 20- to 30-minute IV infusion, day 1; and gemcitabine 1,000 mg/m2 IV days 1 and 8. All patients received premedication with IV corticosteroids, diphenhydramine (50 mg), and cimetidine (300 mg) given 30 minutes before paclitaxel administration. The carboplatin dose was calculated by the Calvert formula, as follows:
The glomerular filtration rate (GFR) was calculated by the Cockroft and Gault method using the following serum creatinine measurement:
Treatment courses were repeated every 3 weeks. Patients were reevaluated for response after the first two courses. Patients whoresponded to treatment and those who had stable lesions and improved symptoms received additional courses for a planned total of four courses of treatment. Patients were restaged after completion of four courses. Those with responses or stable disease were given weekly paclitaxel 70 mg/m2 for 6 weeks followed by 2 weeks rest for three 8-week courses. In patients who had partial or stable responses after chemotherapy, radiation to a known single-site residual tumor was encouraged. During therapy, blood counts were monitored on a weekly basis. The blood counts on day 1 of each course were used to modify doses in the subsequent course as follows: if leukocyte count was 2,500/µL or higher and platelet count was 75,000/µL or higher, all drugs were given at full dose; if leukocyte count was lower than 2,500/µL or platelet count was lower than 75,000/µL, treatment was delayed 1 week or until leukocyte count was 3,000/µL or higher and platelet count was 100,000/µL or higher, and then patients were treated again with a full dose of all agents. Patients who were hospitalized for treatment of neutropenia and fever received 75% doses of all drugs. The blood counts on day 8 were used to modify the gemcitabine dose if necessary. Dose reductions based on the day-8 blood counts were as follows: if leukocyte count was 2,000/µL or lower or platelet count was 75,000/µL or lower, gemcitabine was omitted. During weekly paclitaxel administration, doses were modified as follows: if leukocyte count was 2,000/µL or higher or platelet count was 75,000/µL or higher, the patient was given a full dose; if leukocyte count was lower than 2,000/µL or platelet count was lower than 75,000/µL, dose was omitted; levels were rechecked in 1 week. In any patient experiencing grade 3 or 4 neuropathy, the therapy was stopped. Cytokines were not used prophylactically during the first course of treatment of any patient. Subsequent use of cytokines was at the discretion of the treating physician. In particular, if it was deemed important to continue treatment on schedule in a patient who had demonstrated an early response to therapy, cytokines could be used prophylactically to maintain dose and schedule. Paclitaxel was discontinued in patients who experienced a severe acute hypersensitivity reaction, and other drugs were continued on schedule. Patients experiencing other grade 3 or 4 nonhematologic toxicity (with the exception of nausea, vomiting, and alopecia) had treatment withheld until the toxicity decreased to grade 1 or less and then received 75% doses of the agent responsible. Quality of life end points and cost analyses were not included as part of this phase II trial. After two courses of therapy and at the completion of therapy, all studies that were abnormal at the beginning of treatment were repeated. All patients were assigned a response category based on standard definitions. The complete response category required the total disappearance of all clinically and radiologically detectable disease for at least 4 weeks. The partial remission category required at least a 50% reduction in the size of all measurable lesions as measured by the product of the greatest length and the greatest width, with no new lesions appearing. Patients in the stable disease category had a reduction of less than 50% or increase of less than 25% in the size of measurable lesions, with no new lesions appearing. Patients assigned to the progressive disease category had development of any type of new lesions or an increase of 25% or more in the size of any existing measurable lesion. Toxicity was graded according to the World Health Organization common toxicity criteria. After completion of all treatment, patients were followed up at 1- to 2-month intervals until tumor progression occurred. Treatment at the time of tumor progression was at the discretion of the treating physician.
Statistical Considerations All patients were followed up until the time of progression or death. Duration of tumor response or freedom from progression (in stable patients) was measured from the first day of therapy until tumor progression was documented. Actuarial survival curves were constructed using the Kaplan-Meier method.9 All patient data (including copies of all primary source documents) were reviewed at the data center of the Minnie Pearl Cancer Research Network at the Sarah Cannon Cancer Center. All response and toxicity validations were done by reviewing primary source documents for every patient.
One hundred twenty patients were treated on the present study between December 1998 and August 2000. Patient characteristics are listed in Table 1. Patients were treated at the Sarah Cannon Cancer Center and 25 affiliate members of the Minnie Pearl Cancer Research Network. Well-differentiated adenocarcinoma was the most common histologic diagnosis, and almost two thirds of patients had multiple sites of metastasis. Patients with involvement of a single organ system usually had multiple metastases at that site.
One hundred thirteen (94%) of 120 patients were evaluated for tumor response. Of the seven patients not evaluated, one patient did not complete two courses of therapy (intercurrent illness), two had severe paclitaxel hypersensitivity reactions, two refused additional therapy, one died of unrelated cause, and one had a treatment-related death (sepsis). Of the 89 patients with partial response or stable tumor after two courses of combination chemotherapy, only 48 (59%) began weekly paclitaxel after the four courses of combination chemotherapy. Most of the 41 patients who did not receive weekly paclitaxel developed progressive cancer during the third or fourth course of combination chemotherapy and were removed from study. A total of 395 courses of gemcitabine/carboplatin/paclitaxel was administered. During these treatment courses, 92% of the intended day-1 chemotherapy doses and 85% of the day-8 gemcitabine doses were administered. During treatment with weekly paclitaxel, the drug was administered at 90% of the planned dose.
Efficacy
No additional responses followed the administration of weekly paclitaxel in the 48 patients receiving this agent. Only 24 patients completed all three planned courses without evidence of tumor progression or excessive toxicity.
Figure 1 illustrates the actuarial survival curve for all 120 patients. The minimum follow-up was 8 months (range, 8 to 27 months). The median survival was 9 months. The 1- and 2-year actuarial survival rates were 42% and 23%, respectively. The median progression-free survival time of the 89 responding or stable patients was 6 months. When subsets were compared, there were no apparent survival differences based on performance status (0 or 1 v 2), number of metastatic organ sites (one or two v
Toxicity Table 3 outlines the grade 3 and 4 toxicities seen in the 120 patients receiving this therapy. Three hundred ninety-five courses of chemotherapy were administered (median, four courses). Myelosuppression was the most common toxicity and was usually moderate. Severe leukopenia (grade 3 or 4) occurred in 46% of patients. However, only 12 patients (10%) required hospitalization for treatment of fever associated with neutropenia, and there was one treatment-related septic death. Grade 3 or 4 thrombocytopenia occurred in 43% of patients, but only two patients required platelet transfusions. Other grade 3 or 4 toxicities were uncommon and included fatigue in 22 patients (18%), peripheral neuropathy in nine patients (7%), and arthralgia/myalgia syndrome in nine patients (7%).
Combination chemotherapy with gemcitabine, carboplatin, and paclitaxel followed by weekly paclitaxel in responding and stable patients is active against carcinoma of unknown primary site. One fourth (n = 28) of all patients showed an objective response to treatment, and 61 other patients remained stable or had less than a partial response for at least 2 months. In the 89 responding or stable patients, the median progression-free survival time was 6 months, with 18% and 10% of patients progression-free for 1 and 2 years, respectively. Early progressive disease at the time of initial response evaluation was seen in only 20% of this patient population and is consistent with our previous phase II trials using taxane-based chemotherapy.2-5 The survival did not vary when considering well-differentiated adenocarcinoma versus other carcinomas. This three-drug regimen was relatively well tolerated, with infrequent grade 4 toxicity and only one treatment-related death. The toxicity was similar to our previous experience with this regimen in the treatment of patients with advanced non–small-cell lung cancer.7 The survival observed in these 120 patients was similar to that seen in our three previous sequential phase II trials of taxane-based chemotherapy with similar entry requirements,2-5 which included a total of 144 patients (Fig 2). Median survival in all four of these studies (264 patients) has ranged from 9 to 11 months. The 1-year survival is approximately 40%, and 2-year survival is approximately 20%. The patients in the phase II trial reported here had a median survival of 9 months, a 1-year survival rate of 42%, and a 2-year survival rate of 23%. The projected long-term survival results of this trial and the long-term survival of patients on our previous three trials2-4 are encouraging, because long-term survival (> 2.5 years) has been reported only rarely in patients with well-differentiated adenocarcinoma of unknown primary site treated in prospective chemotherapy trials.5 Median, 1-year, and 2-year survivals are likely more important than response rates in evaluating the efficacy of therapy for these patients. It is difficult to determine the precise contribution of each of the components of therapy included in this treatment regimen. It is unlikely that continued therapy with weekly paclitaxel for patients who are in remission or stable results in any meaningful improvement in response rate or survival. Certainly there does not seem to be any difference in overall survival when comparing the large phase II trial reported here with results of other taxane-based regimens that have not included maintenance therapy.2-5 However, these comparisons of sequential series of nonrandomized phase II trials, even when differences are not apparent, may be spurious. We are encouraged, however, by the fact that long-term follow-up of our initial phase II trial patients using taxane-based chemotherapy has been reported as 48% at 1 year, 20% at 2 years, and 14% at 3 years, respectively.3 The similar median survival and 1-year survival seen in our subsequent three phase II trials, including the study reported here, suggest that long-term follow-up may also be similar. Gemcitabine seems to be active against carcinoma of unknown primary site even in some patients who have progressed after therapy with other taxane-based treatment.6 It is possible that gemcitabine contributed to the results seen in this trial even though there does not seem to be any difference in survival when comparing the results of the four consecutive phase II trials we have conducted in these patients. There are inherent problems in adequately comparing sequential studies; therefore, definitive phase III studies should be considered. It is important to pursue additional therapeutic trials in this diverse and heterogeneous group of patients. Several of the newer targeted biologic agents presently being evaluated and used for patients with various solid tumors may have a role for selected patients with carcinoma of unknown primary site, particularly if the target can be identified in the tumors of these patients. Some of these approaches could include treatment with the antibody directed against HER2/neu (trastuzumab)10 and treatment with various epidermal growth factor receptor inhibitors. The use of antiangiogenic agents with chemotherapy should also be considered. A more thorough understanding of the biology of these tumors should be forthcoming, particularly with the successful development and implementation of gene expression profiling. It is likely that this technique will allow us to determine the primary site and perhaps the biology of many of these tumors in the future.
Minnie Pearl Cancer Research Network Participating Sites:Tennessee Oncology, PLLC, Nashville, TN; Northeast Arkansas Clinic, Jonesboro, AR; Southeast Florida Hematology Oncology Group, Ft Lauderdale, FL; Oncology Hematology Group of South Florida, Miami, FL; Florida Oncology Associates, Orange Park, FL; Winter Park Memorial Hospital, Winter Park, FL; Atlanta Cancer Care, Atlanta, GA; Northeast Georgia Medical Center, Gainesville, GA; Northwest Georgia Oncology Centers, P.C., Marietta, GA; Graves Gilbert Oncology Clinic, Bowling Green, KY; Greenview Regional Hospital, Bowling Green, KY; Consultants in Blood Disorders and Cancer, Louisville, KY; Oncology Associates of Western Kentucky, Paducah, KY; Mary Bird Perkins Cancer Center, Baton Rouge, LA; Terrebonne General Medical Center, Houma, LA; Louisiana Oncology Associates, Lafayette, LA; Grand Rapids CCOP, Grand Rapids, MI; Hattiesburg Clinic, Hattiesburg, MS; The Hematology Oncology Clinic, Hattiesburg, MS; Jackson Oncology Associates, Jackson, MS; Upstate Carolina CCOP, Spartanburg, SC; University Oncology, Chattanooga, TN; Thompson Cancer Center, Knoxville, TN; Cancer Outreach Associates, Abbingdon, VA; and Oncology and Hematology Associates of Southwest Virginia, Inc, Roanoke, VA.
Supported in part by grants from Eli Lilly, Indianapolis, IN, Bristol Myers-Squibb, Princeton, NJ, and the Minnie Pearl Cancer Foundation, Nashville, TN.
1. Greco FA, Hainsworth JD: Cancer of unknown primary site, in DeVita VT Jr, Hellman S, Rosenburg SA (eds): Cancer: Principles and Practice of Oncology (ed 6). Philadelphia, PA, Lippincott, 2001, pp 2537-2560
2.
Hainsworth JD, Erland JB, Kalmn CA, et al: Carcinoma of unknown primary site: Treatment with one-hour paclitaxel, carboplatin and extended schedule etoposide. J Clin Oncol 15: 2385-2393, 1997 3. Greco FA, Burris HA, Erland JB, et al: Carcinoma of un-known primary site: Long-term follow-up after treatment with paclitaxel, carboplatin, and etoposide. Cancer 89: 2655-2660, 2000[CrossRef][Medline]
4.
Greco FA, Erland JB, Morrissey LH, et al: Phase II trials with docetaxel plus cisplatin or carboplatin in carcinoma of unknown primary site. Ann Oncol 11: 211-215, 2000 5. Greco FA, Gray J, Burris HA, et al: Taxane-based chemotherapy for patients with carcinoma of unknown primary site. Cancer J 7: 203-212, 2001[Medline] 6. Hainsworth JD, Burris HA, Calvert SW, et al: Gemcitabine in the second-line therapy of patients with carcinoma of unknown primary site: A phase II trial of the Minnie Pearl Cancer Research Network. Cancer Invest 19: 335-339, 2001[CrossRef][Medline] 7. Hainsworth JD, Burris HA, Erland JD, et al: Phase I/II trial of paclitaxel by 1-hour infusion, carboplatin and gemcitabine in the treatment of patients with advanced non-small cell lung carcinoma. Cancer 85: 1269-1276, 1999[CrossRef][Medline] 8. Simon R: How large should a phase II trial of a new drug be? Cancer Treat Rep 71: 1079-1084, 1987[Medline] 9. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am State Assoc 53: 457-481, 1958
10.
Hainsworth JD, Lennington WJ, Greco FA: Overexpression of Her-2 in patients with poorly differentiated carcinoma or poorly differentiated adenocarcinoma of unknown primary site. J Clin Oncol 18: 632-635, 2000 Submitted August 13, 2001; accepted November 14, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
4,000/µL and platelets 
1.5 mg/dL), and normal renal function (creatinine 
