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Phase II Trial of Paclitaxel, Carboplatin, and Etoposide in Advanced Poorly Differentiated Neuroendocrine Carcinoma: A Minnie Pearl Cancer Research Network Study

John D. Hainsworth, David R. Spigel, Sharlene Litchy, F. Anthony Greco

From the Sarah Cannon Research Institute; and Tennessee Oncology, PLLC, Nashville, TN

Address reprint requests to John D. Hainsworth, MD, Sarah Cannon Research Institute, 250 25th Avenue N, Ste 110, Nashville, TN 37203; e-mail: jhainsworth{at}tnonc.com

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: To evaluate the efficacy of chemotherapy with paclitaxel, carboplatin, and etoposide in advanced adult poorly differentiated neuroendocrine carcinomas.

PATIENTS AND METHODS: Patients eligible for this multicenter, phase II trial had metastatic poorly differentiated neuroendocrine carcinoma and had received no previous treatment. Patients with a variety of known primary sites (excepting small-cell lung cancer) and patients with unknown primary site were eligible. Patients received four courses of chemotherapy with paclitaxel, carboplatin, and etoposide, administered at 3-week intervals. After completing four courses of treatment, patients with objective response or stable disease received three courses (24 weeks) of weekly paclitaxel.

RESULTS: Seventy-eight patients were treated; 62% had unknown primary site. Forty-one patients (53%) had major responses (complete response rate, 15%), and five patients remain disease free from 18 to 66 months after therapy. Response rates were similar regardless of histology (small-cell v poorly differentiated carcinoma) or primary site. The median, 2-year, and 3-year survivals for the entire group were 14.5 months, 33%, and 24%, respectively. Myelosuppression was the major toxicity, as has been reported previously with this regimen.

CONCLUSION: This prospective phase II trial provides additional evidence that this family of relatively uncommon carcinomas is initially chemosensitive, with a high overall response rate to combination chemotherapy and a minority of complete responses. The three-drug regimen evaluated in this trial is moderately toxic, and has no obvious efficacy advantages when compared with standard platinum/etoposide regimens. Treatment for advanced poorly differentiated neuroendocrine carcinoma should parallel treatments used for small-cell lung cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Neuroendocrine carcinomas are a family of neoplasms that share similar immunohistochemical staining characteristics (chromogranin, synaptophysin) and ultrastructural features (neurosecretory granules). Despite these shared features, these neoplasms are widely diverse in their biologic behavior and clinical features. Poorly differentiated neuroendocrine (PDNE) carcinomas have been described arising from a wide variety of primary sites, including the bladder, prostate, cervix, esophagus, larynx, kidney, and others.^1-7 Some of these neoplasms appear histologically similar to small-cell lung cancer, and have been termed extrapulmonary small-cell carcinomas. Other PDNE neoplasms do not have small-cell features by light microscopy, and are identified as neuroendocrine carcinomas only after immunoperoxidase staining or electron microscopy demonstrate typical features.

Anecdotal reports have documented the chemosensitivity of PDNE carcinomas arising at various sites.^2-4,6-11 In addition, we previously recognized a group of PDNE carcinomas of unknown primary site that were highly responsive to cisplatin-based regimens.¹² In our initial report, 18 (72%) of 25 such patients responded to cisplatin-based chemotherapy, with 24% complete responders and a minority (15%) having long-term disease-free survival.

At the time this study was designed, several of the newer chemotherapeutic agents (taxanes, topotecan, irinotecan) had demonstrated single-agent activity in the treatment of small-cell lung cancer.^13-17 Combination regimens containing these agents were being compared with standard platinum/etoposide regimens. We had previously documented a high level of activity with a regimen containing paclitaxel, carboplatin, and etoposide in patients with small-cell lung cancer,¹⁸ and studies comparing the efficacy of three-drug versus two-drug regimens were ongoing. Previous trials had suggested a benefit of extended treatment with etoposide-containing therapy,^19,20 and follow-up treatment with other drugs (topotecan, paclitaxel) was being evaluated. Our own experience with the paclitaxel, carboplatin, and etoposide regimen also included a phase II trial in patients with carcinoma of unknown primary site;²¹ in that trial, two patients had neuroendocrine carcinoma, and both had complete responses.

In this multicenter phase II study, we further investigated the efficacy of paclitaxel, carboplatin, and etoposide in the treatment of patients with PDNE carcinomas. Patients with known primary sites (with the exception of small-cell lung cancer) as well as patients with PDNE carcinoma of unknown primary site were eligible for inclusion. Patients who had objective response or stable disease after four courses of combination therapy continued treatment with weekly paclitaxel, in an attempt to prolong the duration of response.

	PATIENTS AND METHODS

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Patient enrollment in this multicenter, phase II study was initiated in January 1999. This study was conducted in the Minnie Pearl Cancer Research Network, a community-based, collaborative clinical trials group.

Patient Eligibility
All patients were required to have advanced, histologically-proven PDNE carcinoma. Specifically, the following histologic diagnoses were eligible: poorly differentiated (or anaplastic) small-cell carcinoma with neuroendocrine features, and poorly differentiated carcinoma with neuroendocrine features identified by either immunoperoxidase staining (positive chromogranin and/or synaptophysin) or by electron microscopic findings (neurosecretory granules). Patients with PDNE carcinoma of unknown primary site were eligible, as were patients with various known primary sites. Additional eligibility criteria included: Eastern Cooperative Oncology Group performance status 0, 1, or 2; measurable disease; no previous chemotherapy; adequate bone marrow function (WBC 4,000/µL or higher and platelets 100,000/µL or higher; serum bilirubin 1.5 mg/dL or less, and serum creatinine 1.5 mg/dL or less).

Patients were excluded if they had well-differentiated neuroendocrine carcinomas of the carcinoid or islet cell type. In addition, patients with small-cell lung cancer (small or intermediate cell subtype), as evidenced by a suggestive lung mass and/or positive bronchial biopsy, were excluded. However, patients with large-cell neuroendocrine carcinoma of the lung were eligible. Additional exclusion criteria included: age younger than 18 years; pregnant or lactating women; recent myocardial infarction or congestive heart failure; history of allergic reaction to drugs mixed with Cremophor stabilizer (Cremophor EL; BASF Aktiengesellschaft, Ludwigshafen, Germany); any other medical conditions considered likely to preclude administration of this chemotherapy regimen. All patients were required to sign written informed consent before study entry. This clinical trial was approved by the institutional review board of Centennial Medical Center (Nashville, TN), and by the institutional review boards of participating network sites.

Pretreatment Evaluation
Before beginning therapy, all patients were to be evaluated with routine history, physical examination, chemistry profile, and CBC counts. Tumor staging with computed tomography scans of the chest and abdomen was required. Computed tomography or magnetic resonance imaging scan of the head was also required.

Treatment Plan
All patients received combination chemotherapy with paclitaxel 200 mg/m², administered by 1-hour intravenous (IV) infusion, day 1; carboplatin at an area under the concentration-time curve 6.0 IV, day 1; and etoposide 50 mg alternating with 100 mg orally, daily, days 1 to 10. Treatment courses were repeated at 21-day intervals. Cytokines were not administered with the first course of treatment. Prophylactic granulocyte colony-stimulating factor for patients experiencing febrile neutropenia was permitted at the discretion of the treating physician, but was not to substitute for mandated dose reductions. Routine premedications for paclitaxel hypersensitivity were administered intravenously 30 minutes before paclitaxel. The carboplatin dose was calculated using the method described by Calvert et al.²²

After the completion of two courses of chemotherapy, patients were evaluated for response. Patients who had objective response or stable disease after completing two courses of therapy received two additional courses. Patients were re-evaluated 6 weeks later, after the completion of four courses. This re-evaluation served as the confirmation of response required by the WHO response criteria.

Patients who had objective response or stable disease after the completion of paclitaxel, carboplatin, and etoposide received continued treatment with weekly paclitaxel (70 mg/m², 1-hour IV infusion for 6 consecutive weeks, followed by 2 weeks without treatment). Three such courses (total 24 weeks) of weekly paclitaxel were administered.

Patients remaining in remission after completion of weekly paclitaxel were observed without additional treatment, with re-evaluation at 2-month intervals.

Dose Modifications
During treatment with paclitaxel, carboplatin, and etoposide, CBC counts were to be obtained on a weekly basis. Patients received full doses of paclitaxel and carboplatin if the WBC count was 2,500/µL or higher and the platelet count was 75,000/µL or higher. If the WBC count was less than 2,500/µL or the platelets were less than 75,000/µL, treatment with paclitaxel and carboplatin was delayed 1 week, or until the WBC had risen to higher than 3,000/µL and platelets had risen to higher than 100,000/µL; treatment was administered at full dose.

Any patient who experienced an episode of neutropenia and fever during treatment received 75% doses of all three drugs during subsequent courses. Patients who developed grade 3 or 4 nonhematologic toxicity had treatment withheld until the toxicity resolved to less than grade 2; treatment was then resumed using 75% doses of the offending agents.

Definition of Treatment Response
All patients were assigned a response category based on WHO criteria. Complete remission required the total disappearance of all clinically and radiologically detectable disease for at least 4 weeks. Partial remission required a reduction of more than 50% in the size of all measurable lesions, as measured by the product of greatest length and maximum perpendicular width, with no new lesions appearing, and persisting for at least 4 weeks. Stable disease was defined as a decrease of less than 50% or an increase of less than 25% in size of existing lesions, as measured by the products of perpendicular diameters, with no new lesions appearing. Patients with progressive disease had an increase by more than 25% in the size of previously existing lesions, or the appearance of any new lesions.

Statistical Considerations
When this trial was designed in 1998, clinical data regarding treatment of PDNE carcinomas (other than small-cell lung cancer) were limited to results in small, usually retrospective, groups of patients. Although it was presumed that various neuroendocrine tumors shared sensitivity to platinum/etoposide regimens, demonstration in prospective clinical trials was sparse. Therefore, the goals of this clinical trial were to verify the activity of a platinum/etoposide-based regimen in the treatment of PDNE carcinoma; to further test the hypothesis that PDNE carcinomas of various primary sites (or of unknown primary site) shared chemosensitivity to the same chemotherapy regimens; and to obtain specific information regarding the efficacy and toxicity of the paclitaxel, carboplatin, and etoposide regimen.

Based on previous reports containing small numbers of patients, we estimated the response rate with a platinum/etoposide regimen to be approximately 50%. Therefore, a response rate of 50% or more with this regimen would confirm the chemosensitivity of PDNE carcinomas to platinum/etoposide-based therapy. Since the similar response rates of patients with unknown primary site versus PDNE carcinomas of various known primary sites was presumed but not well documented, we chose to include two groups of patients. The inclusion of 45 patients in each group allowed the determination of a response rate for each group within confidence limits of ± 7%. Achievement of a response rate of 70% or higher would suggest, with alpha and beta confidence limits of .1, that the paclitaxel, carboplatin, and etoposide regimen was more active than previous reports with platinum/etoposide, and indicate further development of the regimen to be appropriate.

Progression-free survival for these patients was measured from the date of first treatment until the date tumor progression was documented. Overall survival was measured from the date of first treatment until the date of death. Survival curves were constructed using the Kaplan-Meier method.²³

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Patient Characteristics
Between January 1999 and March 2005, 78 patients were enrolled by 15 participating sites in the Minnie Pearl Cancer Research Network (Appendix). Due to the relatively slow enrollment of these uncommon patients we chose to stop enrollment without achieving our original goal of 90 patients. Patient characteristics are summarized in Table 1. Patients in this trial had a median age of 58 years; the large majority had good performance status. Twenty patients (26%) had small-cell neuroendocrine features by light microscopy (four of these patients were given the diagnosis of Merkel cell carcinoma); the remaining 58 patients had poorly differentiated carcinoma, with neuroendocrine origin confirmed by immunohistochemistry (54 patients) or electron microscopy (four patients). Forty-eight patients (62%) had PDNE carcinoma of unknown primary site. A wide variety of primary sites were represented in the remaining 30 patients (Table 1). The majority of patients (73%) had metastases at more than one site. Even when only one site was involved, 19 (90%) of 21 patients had multiple metastases at that site. Only two patients (3%) had involvement limited to a single lymph node group.

Response to Treatment
The responses of the 78 patients enrolled in this trial are shown in Table 2. Forty-one (53%) of 78 patients had major responses to treatment (partial response, 29; complete response, 12). Overall response rates in the subgroups with unknown versus known primary cancers were similar (55% v 50%, respectively). Response rates were similar regardless of histology (small-cell v PDNE carcinoma; 58% v 51%) and number of metastatic sites (> 1 v 1; 53% v 52%).

View larger version (13K): [in this window] [in a new window]   Fig 1. Progression-free survival (PFS) for the entire group (N = 78). The median PFS was 7.5 months (95% CI, 6.4 months to 10.5 months).

View larger version (13K): [in this window] [in a new window]   Fig 2. Overall survival for the entire group. Median survival was 14.5 months (95% CI, 9.5 months to 18.5 months).

View larger version (12K): [in this window] [in a new window]   Fig 3. Comparison of progression-free survival in patients with unknown primary site (N = 48) versus known primary site (N = 30).

View larger version (12K): [in this window] [in a new window]   Fig 4. Comparison of overall survival in patients with unknown primary site versus known primary site.

Weekly paclitaxel was relatively well tolerated. Grade 3/4 neutropenia occurred in only two (5%) of 38 patients, and there were no hospitalizations for neutropenia/fever. Grade 3/4 neuropathy developed in one patient.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
PDNE carcinomas in adults are a diverse, relatively uncommon group of cancers. With the exception of small-cell lung cancer, few prospective therapeutic trials have been conducted, although anecdotal reports in small patient series have documented the chemosensitivity of tumors in this family.^1-12 The results of this relatively large, prospective phase II trial confirm previous reports and further document the chemosensitivity of these uncommon neoplasms. In a group of 78 patients with advanced PDNE carcinoma, treatment with paclitaxel, carboplatin, and etoposide produced an overall response rate of 53%, and a complete response rate of 15%. Although the contribution of subsequent weekly paclitaxel cannot be definitively assessed, its value is doubtful, because no patients had improved responses, and almost one half of the patients who began this treatment had tumor progression before finishing. The median survival for the entire group was 14.5 months, and 24% of patients were alive at 3 years. Five of the complete responders remain disease-free after follow-up ranging from 16 months to 66 months.

Although all patients in this study had advanced, PDNE carcinoma, their clinical features were diverse. Forty-eight patients (62%) had metastatic carcinoma of unknown primary site, while 30 patients (38%) had known primary site at various locations (11 primary sites represented). Although some of these patients with known primary sites fall in to the general classification of extrapulmonary small-cell carcinoma, the majority did not have recognized small-cell features histologically, and are better described as PDNE carcinoma. Despite the variety of patients included, it is clear that all of these neuroendocrine carcinomas share a similar chemosensitivity. The response rates were similar in the group of patients with unknown primary site versus the group with known primary site.

The selection of the chemotherapy regimen in this trial was based on our previous clinical experience with this three-drug regimen in small-cell lung cancer and carcinoma of unknown primary site.^18,21 While this regimen is clearly active in patients with PDNE carcinoma, previous results with platinum/etoposide regimens have been comparable.^12,24,25 In a retrospectively identified group of 41 patients, treatment with cisplatin/etoposide had similar efficacy (response rate, 41.5%; median survival, 15 months) with less grade 3/4 neutropenia (60% v 82%).²⁴ This experience is similar to results of several trials comparing three- versus two-drug regimens in patients with advanced lung cancer. Although occasional trials have demonstrated improved efficacy with three- or four-drug regimens,²⁶ the majority of trials have shown no significant survival benefits,^27-30 and all trials have shown increased toxicity. In the absence of clear demonstration of superiority, this three-drug regimen cannot be recommended in favor of a better tolerated platinum/etoposide regimen.

At present, it seems reasonable to treat patients with metastatic PDNE tumors according to guidelines established for small-cell lung cancer. This recommendation would apply to patients with unknown primary carcinoma as well as those with a variety of primary sites. A platinum/etoposide regimen of brief duration (ie, four to six courses) is probably the best tolerated of the current common regimens for small-cell lung cancer. In the unusual patient with only one site of tumor involvement, the addition of local radiation therapy should be considered, although the added benefit of this modality is not proven in these relatively rare tumors.

Because PDNE carcinomas are frequently chemosensitive, accurate initial diagnosis of these patients is important. Poorly differentiated carcinomas of unknown primary site should always be tested for the neuroendocrine markers chromogranin and synaptophysin. In addition, poorly differentiated carcinomas with known primary site exhibiting unusual biologic behavior (eg, early widespread metastasis, unusual metastatic sites) should be evaluated for the possibility of neuroendocrine features. In this study, a number of patients with colorectal carcinoma presented with poorly differentiated carcinoma and diffuse liver and lung metastases at the time of diagnosis. This unusual clinical behavior led to immunoperoxidase staining for chromogranin and synaptophysin; only when these stains were positive was the neuroendocrine nature of these tumors appreciated.

Although PDNE carcinomas as a family share a high initial level of chemosensitivity, the benefits of treatment remain transient for the large majority of patients. Further improvement in this group of carcinomas, including small-cell lung cancer, will probably require the successful targeting of tumor specific cellular abnormalities, in addition to the currently available cytotoxic agents. Possible therapeutic targets include vascular endothelial growth factor and the vascular endothelial growth factor receptor, bcl-2, the m-TOR/Akt pathway, and somatostatin receptors. Future improvements in the treatment of PDNE carcinomas of unknown primary site, and various other rare neuroendocrine carcinomas, will probably parallel improvements in the treatment of small-cell lung cancer. The shared chemosensitivity of this family of carcinomas argues for the empiric application of improved therapies for small cell lung cancer to this group of rare neuroendocrine carcinomas.

	Appendix

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
Minnie Pearl Cancer Research Network Participating Sites
Tennessee Oncology, Professional Limited Liability Corporation, Nashville, TN; Comprehensive Cancer Institute, Huntsville, AL; Upstate Carolina Community Clinical Oncology Program, Spartanburg, SC; Atlanta Cancer Care, Atlanta, GA; Northeast Georgia Oncology Centers, Marietta, GA; Grand Rapids Community Clinical Oncology Program, Grand Rapids, MI; Terrebonne General Medical Center, Houma, LA; Medical Oncology, Limited Liability Corporation, Baton Rouge, LA; Cancer Outreach Associates, Professional Corporation, Abingdon, VA; University of Tennessee Cancer Institute/Boston Baskin Cancer Group, Professional Liability Corporation, Memphis, TN; South Texas Oncology and Hematology, PA, San Antonio, TX; University Oncology and Hematology Associates, Chattanooga, TN; Medical Consultants, LTD, Milwaukee, WI; Columbia Oncology, Columbia, TN; and the Northeast Alabama Medical Center, Anniston, AL.

	Authors' Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following author or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other F. Anthony Greco Bristol-Myers Squibb (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-$99,900 (C) $100,000 (N/R) Not Required

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: John D. Hainsworth, F. Anthony Greco Provision of study materials or patients: John D. Hainsworth, David R. Spigel, F. Anthony Greco Collection and assembly of data: John D. Hainsworth, Sharlene Litchy Data analysis and interpretation: John D. Hainsworth, Sharlene Litchy, F. Anthony Greco Manuscript writing: John D. Hainsworth Final approval of manuscript: John D. Hainsworth, David R. Spigel, Sharlene Litchy, F. Anthony Greco

 

	NOTES

 
Supported by grants from Bristol-Myers Squibb and The Minnie Pearl Foundation.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Appendix Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted November 28, 2005; accepted April 27, 2006.

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