Clinical investigation: gallbladder
Adjuvant external beam radiation therapy with concurrent chemotherapy in the management of gallbladder carcinoma

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Abstract

Purpose: This study was performed to evaluate the outcome of patients with gallbladder cancer who received postoperative concurrent chemotherapy and radiation therapy.

Methods and Materials: Curative resection followed by adjuvant combined modality therapy with external beam radiation therapy (EBRT) and chemotherapy was attempted in 21 consecutive gallbladder carcinoma (GBC) patients at the Mayo Clinic from 1985 through 1997. All patients received concurrent 5-fluorouracil during EBRT. EBRT fields encompassed the tumor bed and regional lymph nodes (median dose of 54 Gy in 1.8–2.0-Gy fractions). One patient received 15 Gy intraoperatively after EBRT. A retrospective analysis was performed for the end points of local control, distant failure, and overall survival.

Results: After maximal resection, 12 patients had no residual disease on pathologic evaluation, 5 had microscopic residual disease, and 4 had gross residual disease. One patient had Stage I disease, and 20 had Stage III–IV disease. With median follow-up of 5 years (range: 2.6–11.5 years), 5-year survival for the entire cohort was 33%. The 5-year survival rate of patients with Stage I–III disease was 65% vs. 0% for those with Stage IV disease (p < 0.02). For patients with no residual disease, 5-year survival was 64% vs. 0% for those with residual disease (p = 0.002). The median survival was 0.6, 1.4, and 5.1 years for patients with gross residual, microscopic residual, and no residual disease, respectively (p = 0.02). The 5-year local control rate for the entire cohort was 73%. Two-year local control rates were 0%, 80%, and 88% for patients with gross residual, microscopic residual, or no residual disease, respectively (p < 0.01). Five-year local control rates were 100% for the 6 patients who received total EBRT doses >54 Gy (microscopic residual, 3 patients; gross residual, 1 patient; negative but narrow margins, 2 patients) vs. 65% for the 15 who received a lower dose (3, gross residual; 2, microresidual; 10, negative margins).

Conclusion: Patients with completely resected (negative margins) GBC followed by adjuvant EBRT plus 5-fluorouracil chemotherapy had a relatively favorable prognosis, with a 5-year survival rate of 64%. These results seem to be superior to historical surgical controls from the Mayo Clinic and other institutions, which report 5-year survival rates of approximately 33% with complete resection alone. Both tumor stage and extent of resection seemed to influence survival and local control. More aggressive measures using current cancer therapies and integration of new cancer treatment modalities will be required to favorably impact on the poor prognosis of patients with Stage IV or subtotally resected GBC. Additional investigation leading to earlier diagnosis is warranted, because most patients with GBC present with advanced disease.

Introduction

Gallbladder carcinoma (GBC) is the sixth most common gastrointestinal malignancy in the United States and continues to increase in incidence; more than 6,900 new cases were estimated for 2000 (1). In general, the prognosis of patients diagnosed with GBC is poor, with an expected overall 5-year survival rate of less than 10% and a median survival of 6 months (2). The poor survival rate results from 50–70% of patients presenting with advanced disease (Stage III, IV), because the onset of symptoms is insidious, occurring over a period of weeks to months 2, 3. Of the patients who ultimately succumb to GBC, 86% have advanced local-regional disease (4).

Complete surgical resection is the most effective treatment for Stage 0–I GBC, but it offers little chance of durable local control or improved survival in Stage II–IV GBC. The reported 5-year survival rates are as follows: Stage 0–I, 33–100%; Stage II, 9–33%; Stage III, 0–25%; and Stage IV, 0–5% 5, 6, 7, 8, 9, 10, 11, 12.

Attempts have been made to improve local control and survival using adjuvant radiotherapy alone or in combination with chemotherapy. There have been conflicting reports regarding the value of postoperative adjuvant radiotherapy 13, 14, 15, 16, 17, 18, 19. Given the small number of reported series, the benefit of adjuvant radiotherapy has been difficult to assess, because of the different patient selection factors, staging systems, extent of resection, radiation therapy technique, and chemotherapy regimes used in the different series.

Based on the poor overall survival rate and high local recurrence rates after surgery alone, a prospective treatment approach was developed at our institution in an attempt to improve outcome after curative resection, with a combined modality approach of radiation therapy plus concurrent 5-fluorouracil (5-FU) chemotherapy. This report analyzes this multimodality approach to GBC.

Section snippets

Methods and materials

A comprehensive review of the tumor registry within the division of radiation oncology at the Mayo Clinic in Rochester, MN identified 21 patients from 1985 through 1997 with GBC who received adjuvant external beam radiation therapy (EBRT) with concurrent 5-FU-based chemotherapy after an attempt at curative resection. The medical records of these 21 patients were examined in detail as to the individual patient characteristics, tumor stage, pathology, surgical resection, radiation therapy,

Clinicopathologic characteristics

Of the 21 patients evaluated, 15 were female and 6 were male. The median age at diagnosis was 62.4 years and ranged from 45.6 to 78.8 years. Presenting symptoms or signs included the following: pain in 18 of 21 patients (85.7%), jaundice in 5 (23.8%), pruritis in 2 (9.5%), palpable mass in 2 (9.5%), and weight loss of >10% body weight in 1 (4.8%). The median duration of symptoms or signs before diagnosis was 1.8 weeks and ranged from 0.1 to 52.7 weeks.

The extent of surgical resection was

Surgery alone: survival and patterns of relapse

In general, the prognosis of patients diagnosed with gallbladder malignancies is poor, and the overall 5-year survival rate is less than 5–10% (15). The majority of patients, 50–70%, diagnosed with gallbladder malignancies present with advanced disease, Stage III–IV (3). As diagnostic imaging has improved, GBC has been detected at earlier, resectable stages more frequently, and the role of surgical treatment has evolved toward more extensive and radical resections 4, 10, 22, 23, 24, 25.

Conclusion

Based upon the findings of this study and those of the literature, it can be concluded that gallbladder carcinoma is associated with a generally poor prognosis. It is possible that the previous dismal outcome could be improved by noting the factors associated with favorable outcomes and applying these findings to patient care strategies. Surgical resection alone has resulted in relatively poor survival rates. However, performing a complete resection with negative margins seems critical to

Acknowledgements

The authors thank Ms. Lynn Taraski for preparing the manuscript and overseeing the tables and figures.

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