© 2004 Foundation for Promotion of Cancer Research
A Phase II Study of Paclitaxel plus Cisplatin Chemotherapy in an Unfavourable Group of Patients with Cancer of Unknown Primary Site
Department of Internal Medicine, Korea Institute of Radiological and Medical Sciences, Seoul, Korea
For reprints and all correspondence: Yeon Hee Park, Division of Medical Oncology, Korea Cancer Center Hospital, 215-4, Gongneung-Dong, Nowon-ku, Seoul 139-706, Korea. E-mail: yhpark{at}kcch.re.kr
Received June 24, 2004; accepted September 23, 2004
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Abstract |
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Objective: We evaluated the efficacy and toxicity of combined paclitaxel and cisplatin chemotherapy in patients with cancer of unknown primary site (CUP). Efficacy was evaluated in terms of response rate, progression-free survival and overall survival.
Methods: Thirty-seven patients with CUP were enrolled between January 2001 and September 2003 at Korea Cancer Center Hospital. The patients received 21-day cycles of paclitaxel (175 mg/m2 i.v.) with cisplatin (60 mg/m2 i.v.) given on the first day.
Results: Of the 37 patients, 31 had adenocarcinoma subtypes. The overall response rate of 26 patients with measurable lesions was 42% [95% confidence interval (CI) 23–61%]. Stable disease was seen in six patients and progressive disease in nine. Median time to progression was 4 months (95% CI 1.3–6.8). Median overall survival was 11 months (95% CI 8.3–13.5). The major toxicities were neuropathy and neutropenia. Grade 4 neutropenia occurred in 10 patients, but febrile neutropenia was seen in four.
Conclusions: This combined paclitaxel and cisplatin regimen was well tolerated with an encouraging level of effectiveness for patients with CUP.
Key Words: carcinoma of unknown primary site (CUP) • cisplatin • paclitaxel
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INTRODUCTION |
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Cancer of unknown primary site (CUP) constitutes a heterogeneous group of tumours, which have acquired the capacity to metastasize before the development of a clinically evident primary lesion (1). They represent about 2–4% of all malignancies (1). Notable advances have been made over the past years in the treatment of well-defined clinical subgroups of CUP, such as women with peritoneal carcinomatosis and young adults with poorly differentiated carcinomas of midline distribution (2–6), but for most patients the prognosis remains poor (1). Previous chemotherapy trials using a variety of regimens have produced partial response rates of <30% and have had questionable benefits in prolonging median survival (7).
Several new antineoplastic agents, such as paclitaxel and docetaxel, have a relatively wide spectrum of clinical activity and have broadened the possibilities for treating patients with CUP (8–11). In this study, we tested a combination of paclitaxel and cisplatin. An additional objective was to determine whether there were other subgroups with good prognoses among patients with CUP. Clinical data have shown that this combination exhibits significant clinical effects in treating various common malignant tumours, including those of the lung, breast, stomach, oesophagus, ovary, and head and neck (12–16).
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PATIENTS AND METHODS |
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ELIGIBILITY CRITERIA
Patients were eligible if they had a histologically confirmed metastatic carcinoma of unknown primary site. CUP was diagnosed if the following evaluations did not reveal a primary site for each patient: complete history; physical examination including ears, nose and throat, and for women a gynaecological examination; blood and urine chemistry profile; chest X-ray, computed tomography (CT) of the abdomen and pelvis; gastrofibroscopy; mammography for women, and directed work-up of any symptomatic areas. Each metastatic tumour type was diagnosed by light microscope pathology as follows: well differentiated adenocarcinoma; poorly differentiated adenocarcinoma (PDA); poorly differentiated carcinoma (PDC); and squamous cell carcinoma.
Patients were included as having CUP if they were not in the following subsets: women with an adenocarcinoma involving only axillary lymph nodes; women with an adenocarcinoma involving only the peritoneal cavity; patients with a squamous cell carcinoma involving only cervical lymph nodes or inguinal lymph nodes; patients with a PDC consistent with a germ cell tumour involving isolated midline structures or with elevated levels of human chorionic gonadotrophin or alpha-fetoprotein, or patients with a single, small, potentially resectable tumour.
Patients were eligible if they were between 18 and 70 years of age. Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status 
2, and adequate cardiac function; adequate bone marrow function (leukocyte count 
3500/µl, absolute neutrophil count (ANC) 1500/µl and platelet count 100 000/µl), adequate renal function (serum creatinine <1.5 mg/dl) and adequate liver function [serum bilirubin <2 mg/dl and serum aspartate aminotransferase to alanine aminotransferase (AST/ALT) ratios more than twice the upper normal limit in patients without a liver metastasis, and less than five times the upper normal limit in patients with a liver metastasis].
Many of the patients have non-measurable disease, especially in the unfavourable group. Therefore, we included these non-measurable patients in this study, and analysed survival.
Patients were excluded if they had another uncontrolled serious illness, a history of previous malignancy within 5 years with the exception of a skin carcinoma or a cervical carcinoma in situ, and brain or meningeal metastases. Female patients were excluded if they were pregnant or lactating.
The protocol was approved by the institutional review board of the Korea Institute of Radiological and Medical Sciences, and all patients gave written informed consent before enrolment.
TREATMENT
The treatment regimen was as follows: paclitaxel (175 mg/m2 in 500 ml normal saline) intravenous (i.v.) infusion for 3 h on the first day, cisplatin (60 mg/m2 in 250 ml normal saline) i.v. infusion for 15 min on the first day, after completion of the paclitaxel infusion. The treatment was given every 3 weeks. Adequate pre-medication for paclitaxel (antihistamines, steroids), hydration for cisplatin and anti-emetics were given. Treatments were given every 3 weeks and evaluated for response every two courses. Patients with response or stable disease were planned to receive four courses. However, patients were allowed to receive eight cycles if they wished. In patients who had a response after chemotherapy, radiation to a known single-site residual tumour was allowed. Choice of management after progression was left to the discretion of the attending physician.
TOXICITY MONITORING, SCHEDULE AND DOSAGE MODIFICATION
Toxicities were graded according to WHO criteria (Clinical Toxicity Criteria, version 2.0). Repeated treatment cycles were given if there was a complete haematological recovery by day 22 (ANC 1500/µl and platelet count 100 000/µl). Treatment was delayed for a maximum of 14 days, or until full recovery, for patients who did not show haematological recovery at day 22. For patients experiencing grade III–IV haematological toxicity, there was a 25% reduction in the dose of paclitaxel in the next cycle. Modification of the dose of cisplatin to minimize renal toxicity was based on serum creatinine (Cr) concentration just before each cycle: if Cr was less than 1.5 mg/dl, patients received the full dose of cisplatin; for concentrations between 1.5 and 2.5 mg/dl there was a 50% reduction in the dose; if Cr was 2.5 mg/dl or greater, we discontinued use. If patients developed neuropathy of grade 3–4, treatment was discontinued and it was recorded as a treatment failure. For non-haematological toxicity other than renal or neurological toxicity, treatment was delayed until recovery to at least toxicity grade 1. Patients with significant hypersensitivity reactions to paclitaxel were withdrawn from the study. Complete response, partial response, stable disease and progressive disease were defined according to RECIST criteria (17). At initial evaluation, tumour markers [carcinoembryonic antigen (CEA), CA19-9, CA 125] were measured. Among these, elevated markers were checked every cycle.
STATISTICAL ANALYSIS
All patients were entered prospectively. The planned evaluable patient accrual was 40 patients. However, after the 37th patient was enrolled, we had to finish our study because donation of half the paclitaxel was stopped. Data were evaluated with intent-to-treat analysis. Survival curves, constructed with the date of first chemotherapy as the starting point, were computed using the Kaplan–Meier method, and differences in survival were compared using log-rank tests. Survival data were modelled using Cox regression analysis to identify prognostic factors and the risks associated with them. Categorical variables, including response rates, were compared using Chi-squared or Fisher's exact tests for univariate analysis, and logistic regression for multivariate analysis.
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RESULTS |
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Thirty-seven patients with CUP were treated from January 2001 to September 2003. Among these, 31 (84%) had adenocarcinoma subtypes. Three had squamous cell carcinomas and the other three patients had PDCs. The patient characteristics are listed in Table 1. Initial presentations were cervical lymphadenopathy, peritoneal carcinomatosis, liver mass, pelvic mass, metastatic bone tumour and pleural effusion. Many of the patients (60%) had three or more sites of disease. The total number of chemotherapy cycles was 138, with a median of four cycles per patient. The median age of the patients was 53 years. The male-to-female ratio was 1.2:1.
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EFFICACY
Among the total 37 evaluable patients, the number of patients with measurable disease was 26. Of these 26 patients who were measurable, there was a complete response in one, and a partial response in 10. The overall response rate was 42% [95% confidence interval (CI) 23–61%]. Stable disease was seen in six patients and progressive disease in nine. The median time to progression was 4 months (95% CI 2.4–5.7), and overall median overall survival was 11 months (95% CI 8.3–13.4; Figs 1 and 2). The 1-year survival rate was 38% and the 2-year survival rate was 11%.
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The efficacy in the patients with non-measurable diseases was analysed by survival (Fig. 3).
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Twelve patients had received second-line cisplatin-based chemotherapy while 15 patients had received palliative radiation therapy.
The lactate dehydrogenase (LDH) data were available in 36 patients. The range was from 284 to 2131 U/l and the median level was 540 U/l (reference value 313–618 U/l). No prognostic factor was identified by univariate or multivariate analyses. However, patients with good performance status (PS) and patients with normal CEA concentrations showed a trend towards differences in progression-free survival (good PS versus poor PS, 5.2 versus 2.7 months; P = 0.065) (normal CEA versus elevated CEA, 5.2 versus 1.9 months; P = 0.066).
TOXICITY
A total of 138 treatment cycles (median 4, range 1–8) were administered. The major toxicities were myelosuppression and neuropathy (Table 2). Grade 4 neutropenia occurred in 10 patients. No grade 4 thrombocytopenia or anaemia occurred. Nausea and vomiting occurred in 81% of patients, myalgia in 28%, and arthralgia in 42%. Grade 1 or 2 sensory neuropathy occurred in 59% of patients. This toxicity was cumulative and became progressively more severe with each treatment course (first course, 5/37 patients; second course, 10/31; third course, 12/22; fourth course, 9/15, including three patients with grade 2 toxicity). No hypersensitivity reaction associated with paclitaxel was found. Treatment delay was reported in 10 patients. Relative dose intensities of each drug were 0.82 for paclitaxel and 0.88 for cisplatin. No treatment-related deaths were observed during the study.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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This phase II study showed the combination of paclitaxel and cisplatin to have encouraging efficacy and feasibility for treating chemotherapy-naïve patients with CUP and poor prognoses. These results are similar to other phase II trials, most of which contained various new agent combinations (18–22). Our additional objective was to find other good prognostic subgroups among patients with CUP. However, we did not find any favourable subgroups in this trial. The clinical presentations in our patients were variable. Among these, the patient who achieved complete response had adenocarcinoma in both inguinal lymph nodes. Three male patients with peritoneal carcinomatosis had relatively long progression-free survival of 12–15 months, similar to female patients with this tumour (4). The three patients with disseminated lymphadenopathy with an adenocarcinoma had poor outcomes. None of the patients showed a response, and they had short survival times (2.5–3.3 months). However, this study could not differentiate specific subgroups with homogeneous disease courses, as the study population was too small to analyse the various forms of this disease with statistical power. We can confirm that CUP represents a group of various heterogeneous tumours, which share the unique clinical characteristic of metastatic disease. Nonetheless, we found that paclitaxel plus cisplatin combination chemotherapy could be used for patients with CUP, even though they may be in unfavourable subsets. With the exception of the subsets of patients with clinical and pathological features requiring specific guidelines that may translate into prolonged survival (23), to our knowledge no chemotherapy has been firmly established as the standard, first-line regimen for patients with CUP. However, anticancer treatment might provide small but definite benefits (24). Therefore, the design of a treatment plan in this setting remains a daily challenge and it is still important to differentiate specific subgroups that can explain the disease course.
We have compared these results with the other cisplatin, etoposide, 5-fluorouracil, and leucovorin (PEFL) combination chemotherapies that have been undergoing clinical trials for treating patients with CUP in our institute (25). However, this phase II clinical trial included favourable groups of patients. The response rate in that study was 37%, median progression-free survival was 5 months, and overall survival was 9.5 months. Although it is impossible to compare this paclitaxel plus cisplatin combination chemotherapy with PEFL combination chemotherapy directly, the present results showed sufficiently encouraging activity for unfavourable groups of patients with CUP. The toxicity profile suggested that this combination chemotherapy is safe for such patients.
Recently, several phase II studies reported that new agent combination chemotherapy showed encouraging results for CUP (18–20,22,26) (Table 3). However, despite these encouraging results, further study to identify the origin and nature of these unfavourable subgroups is needed. There are few data for new molecular targeted agents in this area, though such data would be of great benefit if they are shown to be applicable to CUP. Further efforts should also be made to define the biology and pathogenesis of CUP. These approaches combined will contribute to defining the biology and improving the management of CUP.
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Acknowledgments |
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We thank Bristol-Meyer Squibb, Korea, for donating half the paclitaxel used in this study, as the cost of this drug is not covered by medical insurance. This work was published in the proceedings of the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, USA, 5–8 June 2004.
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References |
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