Carcinoma of unknown primary site: Phase II trials with docetaxel plus cisplatin or carboplatin

Annals of Oncology 11: 211-215, 2000. © 2000 Kluwer Academic Publishers. Primed in the Netherlands.

Original article Carcinoma of unknown primary site: Phase II trials with docetaxel plus cisplatin or carboplatin F. A. Greco,1 J. B. Erland,1 L. H. Morrissey,1 H. A. Burris III,1 R. C Hermann,2 R. Steis,3 D. Thompson,1 J. Gray,1 & J. D. Hainsworth 1

Sarah Cannon—Minnie Pearl Cancer Center and Tennessee Oncology; 2Northwest Georgia Oncology Centers, PC, Marietta, Georgia; ^Atlanta Cancer Care. Atlanta. Georgia, USA

vomiting. In study B, 9 of 40 assessable patients (22%) had a major response to therapy. Median survival was eight months Purpose: To evaluate the toxicity, response rate and short-term and one-year survival 29%. Toxicity associated with this regisurvival associated with the chemotherapy combinations of men was predominantly myelosuppression. Comparisons of docetaxel plus cisplatin or carboplatin when used for the treat- the two sequential trials showed no differences in response ment of patients with metastatic carcinoma of unknown rates or survivals (P - 0.75). primary site. Conclusions: Docetaxel and cisplatin (study A) is an active Patients and methods: Twenty-six patients were treated with combination in carcinoma of unknown primary site, but assodocetaxel 75 mg/m2 i.v. and cisplatin 75 mg/m2 i.v. given every ciated with substantial gastrointestinal toxicity. A combination three weeks (study A) and subsequently, 47 patients were of docetaxel plus carboplatin (study B) is better tolerated and treated with docetaxel 65 mg/m2 and carboplatin (AUC dose produced a similar response rate, median survival and one= 6) every three weeks (study B). Stable or responding patients year survival. Comparative phase III trials will be necessary to received a maximum of eight courses of therapy. Patients who unequivically prove a survival advantage for any form of were known to be in treatable subset groups were excluded therapy in these patients. However, the survival for patients from these trials. The majority of patients had two or more with carcinoma of unknown primary site receiving docetaxelsites of metastasis; about 45% had adenocarcinoma and 50% based chemotherapy is comparable to the survivals for several other groups of advanced cancer patients, such as non-small poorly differentiated carcinoma. Results: In study A, 6 of 23 (26%) assessable patients had a cell lung cancer, receiving various types of chemotherapy. major response to therapy. The median survival was eight months and one-year survival 42%. Seven patients were Key words: docetaxel in unknown primary, therapy of removed from the study early for grade 3 or 4 nausea and unknown primary cancer, unknown primary cancer Summary

Introduction

Carcinomas of unknown primary site represent a relatively confusing and heterogeneous group of patients who have historically been very difficult to characterize or treat effectively. Of all advanced cancers, these patients make up about 4%, a number which is probably artificially underrepresented due to the fact that many of these patients are arbitrarily given diagnoses such as lung or colon cancer for other reasons, rather than specific and definitive information concerning a primary tumor. We have been involved in the study of these patients for more than two decades and believe that there are now reasonable and relatively logical approaches to classify various subsets of patients, some of which have highly treatable neoplasms [1-6]. Certainly patients with poorly differentiated carcinoma contain various subsets which can be effectively treated, often with observations of complete response and long-term survival in a fraction of these patients.

Traditionally those patients with well differentiated adenocarcinoma of unknown primary site have done very poorly, although there are also recognized subsets in this large group who can be managed in a more effective fashion [1, 2, 6]. Recently, in a phase II study utilizing the new agent paclitaxel in combination with carboplatin and oral etoposide, we observed unexpected activity with nearly 50% of all patients responding [7]. This included a 45% response rate in those with well differentiated adenocarcinoma. Median survival was approximately 13 months and most of the responding patients obtained excellent palliation. Based upon these findings we turned our attention to the other new taxane, docetaxel, and have studied this drug initially in combination with cisplatin and subsequently in combination with carboplatin. This report details the results of these two sequential phase II studies.

212 Table 1. Patient characteristics. Characteristic

Number of patients (%) Study A (TI = 26) Study B (n = 47) docetaxeldocetaxelcisplatin carboplatin

Age (year) Median Range

60 34-74

56 23-76

Sex (male/female)

13/13

25/22

13(50) 11 (43)

18(38) 28 (60)

2(7) 0

0 1(2)

ECOG performance status 0 1 2

10(38) 10(38) 6(24)

9(19) 26(55) 12(26)

Number of metastatic sites 1 2 >2

7(27) 14(54) 5(19)

15(32) 20 (43) 12(25)

Pre-treatment weight loss (>5%)

14(54)

24(51)

Histology Adenocarcinoma PDC or PDA Neuroendocrine carcinoma (poorly differentiated) Squamous

liver function (bilirubin level ^ 1.5 mg/dl; not greater than two times normal SGPTand SGOT) and normal renal function (creatinine < 1.5 mg/dl). Measurable lesions were not required. Patients were excluded from these studies if they had any of the following features or history: recent myocardial infarction, congestive heart failure or other severe coexistant medical illnesses; brain or meningeal metastasis; a history of previous malignancy within five years with the exception of skin cancer or cervical carcinoma in situ; pregnant or lactating women. These studies were approved by the Institutional Review Board at Centennial Medical Center and patients were required to give written informed consent. All patients were assigned a response category based on standard definitions. Complete response required a total disappearance of all clinically and radiographically detectable disease for at least four weeks. Partial response required at least a 50% reduction in the size of all measurable lesions as measured by the product of the greatest length and greatest width with no new lesions appearing Patients with stable disease had reduction of < 50% or increase of < 25% in the size of measurable disease with no lesions appearing. Patients with progressive disease had the appearance of any new lesion or an increase of ^25% in the size of any existing measurable lesion. Toxicity was graded according to the World Health Organization Common Toxicity Criteria. After completion of all treatments, patients were monitored at one to two month intervals until tumor progression occurred. Treatment at the time of tumor progression was at the discretion of the treating physician. Followup evaluation was performed on all patients until the time of death. Duration of tumor response was measured from the first day of therapy until tumor progression was documented. Survival curves from the first day of therapy for all patients entered into these trials were constructed using the method of Kaplan and Meier [8], and survival curves were compared by log-rank analysis.

Patients and methods

Study A - docetaxel plus cisplatin

The first phase II study (study A) was started in November of 1996 and the second phase II study (study B) in September of 1997. These studies were done by the Minnie Pearl Cancer Research Network, a community-based cooperative group (see Appendix). Patients with histologically confirmed metastatic carcinoma greater than age 20 were eligible if clinical evaluation did not reveal a primary tumor site. The following evaluation was required: complete history, physical examination, chemistry profile, chest X-ray, computer tomography (CT) of the abdomen, and directed workup of any symptomatic areas. Patients with the following light microscopic diagnoses were eligible: well differentiated adenocarcinoma, poorly differentiated adenocarcinoma (PDA), poorly differentiated carcinoma (PDC), poorly differentiated neuroendocrine carcinoma, and squamous cell carcinoma. Patients that were known to be in a better prognostic subset with specific well-defined treatments available were excluded from these studies. These subsets included women with adenocarcinoma that involved only axillary lymph nodes or peritoneal cavity, patients with squamous cell carcinoma that involved only cervical or inguinal lymph nodes, patients with midline carcinoma highly suggestive of a germ cell tumor [1, 2] or those with a single, small potentially resectable tumor. All patients with PDC required specific pathologic study to exclude other neoplasms. Immunoperoxidase staining for leucocyte common antigen (LCA) was required of all tumors to exclude lymphoma. Additional stains including epithelial markers, neuroendocrine markers, and melanoma markers were also routinely performed. For men with adenocarcinoma. staining for prostate-specific antigen was performed when clinical features suggested the possibility of prostate cancer. Specific neoplasms identified by special stains made the patient ineligible for these trials. Previous chemotherapy was allowed as long as patients had not received any of the drugs in this study regimen or previous paclitaxel. Other entry criteria included Eastern Cooperative Oncology Group (ECOG) performance status 0,1. or 2; adequate bone marrow function (white blood cell count > 4,000 ul. platelet count > 100.000 '(il). normal

Patients were treated with the combination of docetaxel 75 mg/m2 i.v. over one hour followed by cisplatin 75 mg/m2 i.v. over one hour given every three weeks as previously described [9]. Patients were evaluated for response after the first two courses of therapy. In responding patients and those with stable lesions and/or improved symptoms, additional treatment to a maximum of eight courses was administered. Patients were reevaluated after the completion of therapy and assigned a final response category. During treatment, white blood counts, differential and platelet counts were monitored on a weekly basis. Serum creatinine, bilirubin, alkaline phosphatase. SGPT, and SGOT were measured every three weeks before therapy. All patients were premedicated with dexamethasone 8 mg p.o. twice daily for three consecutive days starting one day prior to each treatment cycle. Patients received at least 2 liters of saline hydration with each course of therapy as well as either ondansetron 32 mg i.v. or granisetron 10 ug/kg i.v. 15 minutes before cisplatin. Dexamethasone 20 mg i.v. was also suggested 15 minutes before cisplatin. In an attempt to prevent delayed nausea and vomiting, ondansetron was given 8 mg p.o. three times daily forfivedays beginning on the second day after treatment. Cytokines were not given after thefirstcourse of chemotherapy, but were allowed in the second course without dose reduction for those who experienced grade 4 neutropenia with fever. If grade 4 neutropenia or leukopenia recurred with fever, then a 25% dose reduction of both drugs was required. Grade 4 thrombocytopenia (< 25.000/ \i\) required a 25% dose reduction of both drugs for the next course. For grade 3 neurotoxicity. therapy would be stopped, and for grade 2, treatment could continue after a two-week rest with 25% dose reduction of both drugs. For grade 4 nausea and vomiting, a 25% dose reduction of both drugs was required for the next course. For nephorotoxity. cisplatin was reduced by 50% for a calculated creatinine clearance of <54. but >45. and was withheld if <45. Severe hypersensitivity reactions required discontinuation of docetaxel. Liver function tests were monitored and in patients who developed abnormalities, docetaxel was modified as follows: elevated bilirubin or > 5 times elevation of

213 alkaline phosphatase or SGOT required a three-week rest, and if recovery, then docetaxel reduced by 25%; normal bilirubin and elevated alkaline phosphatase ( < 5 times) and elevated SGOT ( < 5 times) required a 25% dose reduction of docetaxel.

Study B - docetaxel plus carboplatin Patients were treated with docetaxel 65 mg/m 2 i.v. over one hour followed by carboplatin at a calculated area under the curve (AUC) dose of 6.0 i.v. over twenty minutes every three weeks as previously described [10]. Patients were evaluated for response after two courses and if stable or responding, additional treatment to a maximum of eight courses was administered. Patients were reevaluated after 4-8 courses of therapy and assigned a final response category. The premedication was as described in study A. but no i.v. hydration was required. Decadron was used after chemotherapy as per study A, but no medication was routinely given for delayed nausea and vomiting. Blood tests were also obtained as in study A. The use of cytokines was not allowed during the first course, but could be used subsequently as in study A. Dose modifications for other toxicities were also as in study A, except for nephrotoxicity, which would automatically adjust carboplatin total dose by AUC dosing.

Figure 1. The actuarial survival curves for study A (docetaxel-cisplatin) and study B (docetaxel-carboplatin). Twenty-three patients remain alive on both studies ranging from 11-33 months. There is no difference when comparing the two curves (P = 0.75 by log-rank analysis). Table 2. Characteristics of patients surviving longer than two years (study A). Sex

Metastatic sites

Histology

Response

Survival (months)

Female

Nodes mediastinum, supraclavicular

Poorly differentiated carcinoma

Partial

33+

Female

Nodes — supraclavicular pericardial effusion

Adenocarcinoma

Complete

31 +

Female

Lung

Adenocarcinoma

Partial

30+

Female

Liver, lung

Poorly differentiated neuroendocrine carcinoma

Stable

30+

Female

Adrenal, supraclavicular nodes

Adenocarcinoma

Not evaluable

28+

Male

Nodes - neck, abdomen, skin

Adenocarcinoma

Partial

27+

Female

Nodes abdomen, retroperitoneum, neck

Poorly differentiated carcinoma

Partial

25+

Results Study A - docetaxel plus cisplatin Between November 1996 and August 1997, 26 patients entered this trial. Patient characteristics are listed in Table 1 (for both study A and B). Nineteen patients were treated at the Sarah Cannon Center and seven patients were treated at the affiliated oncology practices or institutions of the Minnie Pearl Cancer Research Network (see Appendix). Well differentiated adenocarcinoma was the most common histologic diagnosis and 19 patients had multiple sites of metastatic disease. All the patients with one site of tumor had multiple metastatic lesions within that site (5 visceral, 1 bone, 1 lymph node). Twenty-three of twenty-six patients were assessable for response. Two patients did not complete two courses of therapy (severe toxicity) and one patient had no evaluable tumor. All patients were evaluable for toxicity and survival. A total of 86 courses were administered and the median number of courses received was three. Dose reductions were required during therapy in 14 patients, usually during the second or third courses of treatment. Efficacy Six of twenty-three (26%) assessable patients had major response to therapy (95% confidence interval (95% CI): 10%-48%) with one complete response (4.5%). Five patients (21%) had stable disease and 12 (52%) had progressive tumor. The numbers are too small to compare the response rates of histologic types, but 4 of 10 patients with well differentiated adenocarcinoma responded to therapy. Figure 1 shows the actuarial survival curve for all 26 patients in study A (study B also shown). The median survival was eight months, and seven patients (27%) remain alive (range 25-33 months, see Table 2). Five patients remain free of progressive tumor (three respond-

ing patients and two stable patients) with follow-up ranging from 16-33 months. Three responding patients developed disease progression at three, five and six months, while three patients remain in remission at twenty, twenty-five, and thirty months and one patient without assessable tumor is progression-free at 26 months. There were no differences in median survival or one-year survival for patients with well differentiated adenocarcinoma compared to patients with PDC and PDA. Toxicity The treatment was associated with considerable severe gastrointestinal toxicity. Eight patients (30%) experi-

214 enced grade 3 or 4 gastrointestinal toxicity primarily related to nausea and vomiting, and seven patients abandoned the study early (two not assessable for response) because of severe nausea and vomiting. Grade 3 or 4 leukopenia occurred during 17 courses of treatment (20%) in 14 patients (54%). Three patients required hospitalization for treatment of fever associated with neutropenia. There were no treatment-related deaths. Grade 3 or 4 thrombocytopenia was uncommon (2% of treatment courses). Two patients received cytokines. Other grade 3 and 4 toxicities with the exception of alopecia were uncommon and included peripheral neuropathy (two patients), arthralgia/myalgia syndrome (one patient), and fatigue (four patients). No patient experienced severe edema (grade 2 or 3). The degree of gastrointestinal toxicity seen and the fact that seven patients had their therapy prematurely discontinued prompted us to end the study and begin the second phase II trial (study B).

adenocarcinoma compared to patients with PDC and PDA. Comparisons of the survival curve for study A with study B showed no significant difference (P - 0.75). Toxicity Five patients were removed from study early because of treatment-related toxicity (two septic deaths, two hypersensitivity reactions, one severe fatigue). Twenty-four patients (50%) experienced grade 3-4 leukopenia (20 grade 3; 4 grade 4). Forty-five courses (30%) were associated with grade 3-4 leukopenia (41 grade 3; 4 grade 4). There were seven hospitalizations for neutropenia and fever (six patients). Only two patients had grade 3-4 thrombocytopenia. Other grade 3-4 toxicity was uncommon, including nausea and vomiting (four patients), fatigue (four patients) and neuropathy (three patients). There was no severe myalgia or arthralgia and no patient developed severe edema (grade 2 or 3). Four patients received cytokines.

Study B - docetaxel plus carboplatin Discussion Between September 1997 and October 1998, 47 patients entered this trial. Patient characteristics are listed in Table 1. Twenty-one patients were treated at the Sarah Cannon Cancer Center and twenty-six patients were treated at the affiliated oncology practices or institutions of the Minnie Pearl Cancer Research Network (see Appendix). Poorly differentiated carcinoma (PDC and PDA) was the most common histologic diagnosis and 32 patients had multiple sites of metastatic disease. Fifteen patients had a single site of tumor, but all had multiple metastasis at that site (8 visceral, 6 lymph nodes, 1 soft tissue). No patient had a specific treatable subset as previously described. Forty of forty-seven patients were assessable for response. Six patients did not complete two courses of therapy (two off study due to hypersensitivity reactions; two early deaths; two requested therapy be stopped before evaluation) and one patient had no evaluable tumor. The median number of courses received was four, and 178 courses of therapy were administered.

The taxanes, docetaxel and paclitaxel, produce objective tumor shrinkage, and clinical benefit for patients with a variety of common neoplasms. The taxanes are appropriate drugs to test in patients with metastatic carcinomas of unknown primary site. Our initial experience with paclitaxel in combination with carboplatin and extended schedule oral etoposide [7] was encouraging with noteable responses and survival in this group of patients with a historically poor prognosis. The two phase II studies reported here evaluated doxetaxel with cisplatin or carboplatin. The initial study with cisplatin (study A) proved to be associated with considerable gastrointestinal toxicity, particularly nausea and vomiting, prompting premature discontinuation of therapy in nearly 25% of the patients. The 26% response rate was disappointing, but given the heterogeneity of this patient population and the 95% CI, the response rate may be similar to the 48% response rate seen with our previously reported paclitaxel-carboplatin-oral etoposide regimen [7]. The median survival Efficacy Nine of forty assessable patients (22%) had a major was eight months in both of the docetaxel-based trials response to therapy (95% CI: 11%—38%). There were no reported here, compared to about 13 months in the complete responses. Seventeen patients (42%) had stable paclitaxel-based trial [7]. Complete responses were also disease and fourteen patients (35%) progressive disease rare, occurring in only 1 of 63 (1.5%) assessable patients at the final time of evaluation. There were no differences in the two docetaxel trials reported here, in contrast to in response comparing well differentiated adenocarci- seven of 53 patients (13%) on the previously reported paclitaxel-based trial [7]. These differences, as well as all noma (4 of 17) versus PDC and PDA (4 of 22). Figure 1 shows the actuarial survival curve for all 47 others between these trials, may not represent true patients in study B (study A also shown). The median differences, since these trials were sequential and nonsurvival was 8 months and 16 patients (39%) remain randomized; however, the apparent difference in complete alive (range 10-23 months). Three patients remain free response rate is noteworthy. Although fewer patients of progressive tumor with follow-up ranging from 11-20 in the docetaxel trials are disease-free compared to the months. All the patients with an objective response pro- earlier paclitaxel-based trial [7], there does not appear to be a major difference in survival, and several patients gressed after a median duration of seven months (range who received the docetaxel combinations remain alive 3-14 months). There was no difference in median survival for more than 15 months. Furthermore, the one-year or one-year survival for patients with well differentiated

215 survival for patients receiving docetaxel-cisplatin was 42%, and similar to that seen in the earlier study with paclitaxel-based therapy [7]. The one-year survival of 29% seen with the docetaxel-carboplatin regimen was not significantly different. The use of docetaxel in combination with cisplatin necessitated a compromise in docetaxel dose intensity, and may have reduced the efficacy of this regimen. The dose of docetaxel was reduced even further when coupled with carboplatin. It is doubtful that the dose of docetaxel could be safely increased without the prophylactic administration of cytokines, given the frequency of severe myeolosuppression associated with this regimen. The severe gastrointestinal toxicity seen with the docetaxel-cisplatin combination and the response rate seen in the small phase II trial reported here, argue against further therapy with this regimen for these patients. The docetaxel-based combinations may be less active than the triplet combination of paclitaxel, carboplatin, and oral etoposide, but the survival of the patients appears similar. Docetaxel may be a very useful drug for patients with carcinoma of unknown primary site, and combinations with other agents (e.g., gemcitabine, etoposide, etc.) may prove to be superior than with either of the platinums. It is also possible that a substitution of docetaxel for paclitaxel in the triplet regimen may prove equally or more effective, but determining an appropriate dose for docetaxel would require further study. Future trials may clarify these issues. The treatment for patients with unknown primary carcinoma is improving. For patients with poor prognostic features such as those with well differentiated adenocarcinoma and multiple metastatic sites, therapy remains particularly difficult. However, even for these patients a substantial number attain clinical benefit from taxane-based therapy. The median survival (8-13 months) and one-year survival (29%-50%), as observed in the trials reported here and in our previous trial [7], are now comparable to the survivals of several other groups of advanced carcinoma patients receiving various types of chemotherapy, including non-small-cell lung cancer. Appropriate chemotherapy should now be offered to many patients with unknown primary carcinoma.

Acknowledgements Supported in part by grants from Rhone-Poulenc Rorer and The Minnie Pearl Cancer Foundation. Appendix Minnie Pearl Cancer Research Network Contributors Tennesse Oncology, PLLC, Nashville, TN; Comprehensive Cancer Institute, Huntsville, AL; Oncology/Hematology Group of South

Florida. Miami, FL; Graves-Gilbert Oncology Clinic. Bowling Green, KY; The Center for Cancer Care. Huntsville, AL: Mary Bird Perkins Cancer Center. Baton Rouge. LA: Grand Rapids CCOP. Grand Rapids. MI: Montgomery Cancer Center. Montgomery. AL: Northwest Georgia Oncology Centers. Marietta. GA: Northwest Alabama Cancer Center. Muscle Shoals, AL: Atlanta Cancer Care. Atlanta. GA: Earle A. Chiles Research Institute. Portland, OR: Winter Park Memorial Hospital, Winter Park, FL; Consultants in Blood Disorders and Cancer, Louisville. KY; The Medical Oncology Gioup, Gulfport, MS: Spartanburg, CCOP. Spartanburg. SC; McLeod Cancer and Blood Center, Johnson City. TN; Greenview Regional Hospital, Bowling Green, KY: Terrebonne General Cancer Center. Houma. LA; Mercy Hospital. Miami, FL; Jackson Oncology Associates, Jackson, MS; Oncology/Hematology Associates of Southwest Virginia, Roanoke, VA; New Mexico Oncology Hematology, Albuquerque. NM, USA.

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Correspondence to: F. A. Greco, MD Sarah Cannon-Minnie Pearl Cancer Center 250 25th Avenue, North, Suite 412 Nashville, TN 37203 USA