Abstract
Background: The combination of cisplatin and etoposide is effective in the treatment of small cell lung carcinomas and other high-grade neuroendocrine tumors (NET). This combination has been considered as a default treatment for patients with high-grade NET of the colon and rectum (CRC). No formal series has yet described the activity of this regimen in this patient population. A retrospective study assessing the efficacy of cisplatin plus etoposide in metastatic CRC (MCRC) NET is reported. Patients and Methods: MCRC NET patients treated with cisplatin and etoposide were identified through the use of pharmacy and tumor registry records from a single institute for the period of 2003-2010. Responses of the identified patients were categorized using RECIST 1.1 (revised response evaluation criteria in solid tumors) guidelines. Results: Eight patients were identified with high-grade CRC NET who had been treated with cisplatin plus etoposide. One patient had a radiographic complete response and four had a partial response. The median progression-free survival was 4.5 months (2-9 months) and the median overall survival was 9.5 months (3.5-17 months). Conclusion: Patients with high-grade CRC NET have a high response rate to cisplatin and etoposide, which in most patients is short-lived, and the survival is limited to less than 1 year.
Neuroendocrine tumors (NET) of the colon and rectum (CRC) are divided into three categories by the WHO classification: carcinoid tumors/well-differentiated NET with low-grade atypia and malignancy, malignant carcinoid/well-differentiated neuroendocrine carcinomas (NEC)-with intermediate features and poorly differentiated NET or small cell carcinoma with high-grade atypia and malignancy. Colorectal small cell carcinomas comprise 0.2-0.8% of all colorectal tumors (1, 2). The incidence of CRC NETs is rising in the United States, primarily as a result of increased incidental detection on screening. Symptoms of colorectal NETs include hematochezia, pain and change in bowel habits (3, 4).
Pathologically, high-grade CRC NETs are poorly differentiated carcinomas with distinctive cytoarchitectural features and are often immunoreactive for markers of neuroendocrine differentiation (5). The prognosis for high-grade CRC NET is poor, as most patients have metastatic disease at the time of diagnosis (6). In 2008, Landry et al. (7, 8) reported a 5-year survival rate of 17-20% and median survival of 20-31 months for CRC NET (stage IV) after study of 4,710 rectal NETs and 2,459 colon NETs. However, the SEER-based (Surveillance, Epidemiology and End Results database) data did not stratify outcome of stage IV CRC NET based on tumor grade or by treatment. The treatment of high-grade CRC NET remains largely non-standardized. Several studies have confirmed that combined chemotherapy with cisplatin and etoposide is the standard regimen in the treatment of small cell lung cancer. Because of the overlap in the genetic, pathological and clinical features of poorly differentiated extra-pulmonary NET with small cell lung cancer (9-11), the same regimen has been advocated for extra-pulmonary high-grade NET.
The aim of this report was to review the outcome of metastatic high-grade CRC (MCRC) NET tumors treated in a single-institute with cisplatin and etoposide.
Patients and Methods
A review of the Roswell Park Cancer Institute (RPCI) tumor registry and pharmacy records was performed for the period of 2003-2010. Only patients with a diagnosis of MCRC NET who were treated with cisplatin and etoposide at RPCI were eligible for analysis. All the staging radiographic studies were retrieved and re-evaluated. Objective responses, progression-free survival (PFS) and OS were determined based on RECIST 1.1 criteria.
Patient demographics and NET site.
Statistical analysis was performed by use of the Kaplan-Meier method for estimating survival curves.
Results
Patient demographics. Eight patients with high-grade MCRC NET treated with first-line cisplatin and etoposide were identified. The median age was 64 years (31-83 years). All the patients had evidence of metastatic disease to the liver at presentation. One patient had concurrent lung metastases, two patients had concurrent distant lymph node involvement and one patient had concurrent lung, bone and distant lymph node involvement. Pathology was reported as poorly differentiated or high-grade in all eight patients. The patient demographics are detailed in Table I.
Treatment summary. All the patients received 21-day cycles of cisplatin plus etoposide. Cisplatin was administered at 80 mg/m2 on day 1 and etoposide was administered at 80 mg/m2/day on days 1-3. The median number of cycles administered was 5 per patient (range 2-12 cycles). Two patients received second-line therapy with cisplatin and irinotecan upon progression. (Table II)
Treatment efficacy. All eight patients were evaluable for radiographic response. One patient had a complete response (Figure 1a and b), four patients had a partial response and two patients had stable disease. One patient had progressive disease at 2 months. The median PFS was 4.5 months and median OS was 9.5 months (Table II, Figure 2a and 2b). The 12-week and 18-week PFS rates were 7/8 patients and 6/8 patients, respectively.
Treatment and patient outcomes.
Discussion
MCRC NET treatment with cisplatin plus etoposide resulted in an objective response in five out of eight patients, a median PFS of 4.5 months and an OS of 9.5 months. The response was short-lived and most patients died within a year from diagnosis. The main limitation of this study was the small sample size.
Two prior studies on cisplatin and etoposide in advanced NET have been reported and the overall response rates were 42 and 67% and the median survival was 15 and 19 months, respectively (12, 13). However, these two reports combined included only 5 patients with-high grade CRC NET. Bernick et al. studied 36 cases of colorectal/anal NETs (25 with stage IV), and the OS of this population was 10.5 months, confirming the poor prognosis of this group (5). Despite recommending cisplatin and etoposide, the outcome with this combination was not described in this series (5).
a: CAT scan at a baseline of patient 7. b: CAT scan at complete response of patient 7.
a: Overall survival. b: Progression-free survival.
Despite the small number of patients included in the present series, we believe that it represents the largest cohort of patients with high-grade MCRC NET treated with cisplatin and etoposide. The frequent objective responses associated with this combination support its use in this subgroup of patients.
- Received November 27, 2010.
- Revision received February 18, 2011.
- Accepted February 19, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
In this issue
Jump to section
Related Articles
Cited By...
- Current Treatment Options in Gastroenteropancreatic Neuroendocrine Carcinoma
- High-Grade Gastrointestinal Neuroendocrine Carcinoma Management and Outcomes: A National Cancer Database Study
- Medical Management of Gastroenteropancreatic Neuroendocrine Tumors: Current Strategies and Future Advances
- Mixed Adenoneuroendocrine Carcinoma of the Colon: Molecular Pathogenesis and Treatment