Combined radiotherapy and chemotherapy (cisplatin and 5-fluorouracil) as palliative treatment for localized unresectable or adjuvant treatment for resected pancreatic adenocarcinoma: results of a feasibility study

doi:10.1016/S0360-3016(99)00478-2

International Journal of Radiation OncologyBiologyPhysics

Volume 46, Issue 4, 1 March 2000, Pages 903-911

https://doi.org/10.1016/S0360-3016(99)00478-2 Get rights and content

Abstract

Purpose: To evaluate a cisplatin-containing chemoradiotherapy (CRT) regimen followed by chemotherapy for unresectable (locally advanced group, n = 32) and resected (adjuvant group, n = 10) pancreatic adenocarcinoma. The quality of palliation and percentage of secondary resections were also studied for unresectable disease.

Methods and Materials: The protocol comprised CRT (45 Gy over 5 weeks), combined with 5-fluorouracil and cisplatin during the first and fifth weeks, followed, 3 weeks later, by 4 cycles of the same chemotherapy plus leucovorin.

Results: All patients completed CRT but only 50% of each group finished the entire protocol. Gastrointestinal toxicity and weight loss were the major side effects during CRT. Enhanced hematological toxicity limited the post-CRT chemotherapy. For the locally advanced group, median survival was 9 months; 1- and 2-year survival rates were 31 and 12.5%, respectively. The overall response rate was 16% and 50% had stable disease. A lasting palliative effect defined as improved performance status and decreased analgesic consumption, was recorded for 43% of the patients. Only three secondary resections have been performed. For the adjuvant group, median survival was 17 months.

Conclusions: Although toxic in advanced disease, this regimen significantly lowered pain and analgesic consumption, but had poor impact on secondary resectability. In an adjuvant setting, although equally toxic, this series was too small to allow conclusions to be drawn.

Introduction

Adenocarcinoma of the pancreas is a rapidly fatal malignancy that ranks fourth or fifth among the leading causes of cancer death. Despite important advances in surgical procedures, radiation and chemotherapy, the prognosis of this cancer remains dismal. Survival at 5 years is <5% and surgery is considered to be the only curative modality (1). Resectability criteria are increasingly being obtained by noninvasive procedures, such as helical computed tomography (CT) and magnetic resonance imaging. The disease is deemed resectable when there is no extrapancreatic disease, and an absence of direct tumor extension to the superior mesenteric blood vessels, celiac axis and portal vein (2). However, one-half of the patients have detectable metastatic disease at the time of diagnosis, and 20–30% have unresectable locally advanced disease without detectable metastases; thus only 10–20% have resectable tumors. Substantial regression of locally advanced disease with vascular involvement obtained with presurgical treatment could potentially allow some rare patients to undergo curative resection 3, 4, 5.

After complete resection alone, the median survival ranged from 10 to 19 months, and the 5-year survival rate varied between 12 and 24% 4, 6, 7, 8. Up to 85% of these patients will have a local relapse as the first sign of progression (9), rapidly associated with the appearance of hepatic and peritoneal metastases (10). Therefore, to date, most of the approaches designed to increase local-regional control have failed to substantially prolong survival due to metastasis development.

Clear improvement of local control by pre- or postresection chemoradiotherapy (CRT) has been demonstrated 10, 11, with unsurprisingly controversial impact on survival 12, 13. The low response rate induced by chemotherapy has been discouraging so far, and among the few postresection adjuvant chemotherapy trials that have been conducted, only one (14) suggested an advantage for survival.

Local-regional progression of disease causes symptoms, such as pain, malnutrition and bowel or biliary obstruction. Therefore, local control of the disease appears to be the first challenge for the quality of life (QOL) for patients with either resected or unresected tumors, and pain, nutritional and performance status (PS) should be reliable QOL criteria.

Non-surgical treatments tested so far are chemotherapy, radiotherapy and CRT. The most widely used regimens combine radiotherapy and 5-fluorouracil (5-FU). In vitro and invivo studies have provided evidence that leucovorin (LV) 15, 16 and cisplatin (17) enhance the cytotoxic effects of 5-FU. A role for cisplatin in combination with 5-FU in either chemotherapy or CRT regimens for advanced pancreatic adenocarcinoma was suggested by phase II trials 4, 18 and confirmed by a phase III chemotherapy study (19).

The objectives of this trial were: (i) to assess the acute and late toxicities of a single CRT regimen (45 Gy plus 5-FU and cisplatin) followed by 4 cycles of chemotherapy (5-FU, LV and cisplatin) used either as palliative treatment for localized unresectable or adjuvant treatment for resected pancreatic adenocarcinoma; (ii) to evaluate, for patients with locally advanced unresectable disease, the quality of palliation and the percentage of secondary pancreatic resections after this regimen; (iii) to describe the relapse patterns in both populations; (iv) to determine the median survival as well as the 1- and 2-year overall survival rates for both populations.

Section snippets

Methods and materials

The Bioethics Committee (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale) of Saint-Antoine Hospital, Paris, approved the protocol.

Patient eligibility and characteristics, treatment feasibility

From May 1993 to June 1997, 10 and 32 patients were included, respectively, in the adjuvant group and locally advanced group, and their respective characteristics are reported in Table 1, Table 2 . All patients included in this study had been referred by surgeons. All but 1 patient with locally advanced mucinous cystadenocarcinoma were diagnosed as having histologically proven ductular adenocarcinoma of the pancreas. All patients completed CRT, 37 (88.1%) in the planned time (5 weeks) and 5

Discussion

Few clinical trials have studied the combination of cisplatin and 5-FU as part of CRT for pancreatic cancer. To date, this modality has been reported only for locally advanced tumors 3, 4 and never as adjuvant or neo-adjuvant treatment for resectable tumors. Kamthan et al. treated 35 patients with unresectable, locally advanced pancreatic carcinomas, with CRT combining continuous infusion of 5-FU, streptozotocin and cisplatin with split-course radiotherapy (4). The median survival of 15 months

Acknowledgements

Supported by Amis du Centre des Tumeurs de Tenon. The authors express their profound gratitude to J. Jacobson for editorial assistance.

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¹: The first two authors have contributed equally to this work.

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Clinical InvestigationsCombined radiotherapy and chemotherapy (cisplatin and 5-fluorouracil) as palliative treatment for localized unresectable or adjuvant treatment for resected pancreatic adenocarcinoma: results of a feasibility study

Abstract

Introduction

Section snippets

Methods and materials

Patient eligibility and characteristics, treatment feasibility

Discussion

Acknowledgements

Int J Radiat Oncol Biol Phys

Eur J Cancer

Pharmacol Ther

Ann Oncol

Ann Oncol

Ann Oncol

Eur J Cancer

Radiother Oncol

Lancet

Cancer of the pancreas. 50 years of surgery

Cancer

Thin-section, contrast-enhanced computed tomography accurately predicts the resectability of malignant pancreatic neoplasm

Am J Surg

Multimodality protocol for locally advanced carcinoma of the pancreasa pilot program

Proc Am Soc Clin Oncol

Combined modality therapy for stage II and stage III pancreatic carcinoma

J Clin Oncol

Neoadjuvant therapy for unresectable pancreatic adenocarcinoma

Arch Surg

Collective review of small carcinomas of the pancreas

Ann Surg

Survival after pancreaticoduodenectomy

Ann Surg

Results of resection for cancer of the exocrine pancreasa study from the French Association of Surgery

Br J Surg

Clinical Investigations
Combined radiotherapy and chemotherapy (cisplatin and 5-fluorouracil) as palliative treatment for localized unresectable or adjuvant treatment for resected pancreatic adenocarcinoma: results of a feasibility study