A phase II study of mitomycin C, cisplatin and protracted infusional 5-fluorouracil in advanced pancreatic carcinoma: efficacy and low toxicity

R. D. Petty1,4,+, M. C. Nicolson1, S. Skaria1, T. S. Sinclair2, L. M. Samuel1 and M. Koruth3

Departments of 1 Oncology (ANCHOR Unit), 2 Gastroenterology and 3 Surgery, Aberdeen Royal Infirmary, Aberdeen; 4 Department of Medicine and Therapeutics (Oncology), University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, UK

Received 8 January 2003; accepted 5 March 2003


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background:

The effective treatment of unresectable pancreatic carcinoma represents a formidable challenge. There is a need to develop systemic therapies which combine efficacy with acceptable toxicity. The current ‘gold standard’ gemcitabine gives an objective response rate of the order of 20% and median survival up to 6 months. Here we have evaluated the efficacy and toxicity of mitomycin C, cisplatin and protracted infusional 5-fluorouracil (MCF).

Patients and methods:

Forty-five patients with locally advanced (13 patients) or metastatic (32 patients) pancreatic carcinoma were treated with mitomycin C 7 mg/m2 6 weekly, cisplatin 60 mg/m2 3 weekly and protracted venous infusion 5-FU 300 mg/m2/day. Patients were evaluated for response after three cycles and received six cycles in total in the absence of progressive disease or poor tolerance. Median age was 62 (45–75) years; 41 patients were World Health Organization performance status 0–1.

Results:

Treatment was well tolerated with 36 (84%) patients completing three or more cycles. Grade 3 or 4 toxicities were uncommon: anaemia in three patients (7%), mucositis in two (5%), nausea and vomiting in three (7%) and diarrhoea in one (1%). An objective response was seen in 21 (46%) patients. There was one complete response. The median survival overall was 7.1 months and 10.5 months in responders. The median duration of response was 4.3 months. One-year survival was 29%, 2-year survival was 18%.

Conclusions:

MCF combines efficacy with low toxicity in the treatment of advanced pancreatic carcinoma. The efficacy is at least comparable and may be superior to single-agent gemcitabine and MCF may therefore provide a cost-effective alternative.

Key words: chemotherapy, cisplatin, 5-fluorouracil, mitomycin C, pancreatic cancer


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Pancreatic carcinoma represents a significant healthcare problem and presents a formidable challenge to oncologists. There are 7000 new cases diagnosed annually in the UK and 5500 present with locally advanced or metastatic disease [1]. The median survival for untreated advanced pancreatic cancer is about 3 months [1]. In addition, disease-related symptoms—pain, anorexia, obstructive jaundice, fatigue and gastric outlet obstruction—result in a complex clinical syndrome which can prove difficult to palliate effectively.

Despite a prolonged period of pessimism it is now clear that systemic chemotherapy can benefit a significant proportion of patients with advanced pancreatic cancer through prolongation of survival, symptom control and improved quality of life [233]. Patient selection is undoubtedly important but data from phase II and phase III trials have shown that response rates of 15–30%, median survival of 5–9 months and 1-year survival of 15–25% can be achieved [233]. The use of the composite end point of clinical benefit response (CBR), involving measurements of pain, Karnofsky performance status and weight, has revealed that up to 60% of patients may benefit from chemotherapy.

Several agents alone and in combination have been evaluated. Most comprehensive data exists for gemcitabine. In the cardinal study by Burris et al., 126 patients were randomised to gemcitabine or weekly bolus 5-fluorouracil (5-FU) [2]. CBR was seen in 24% of gemcitabine patients as compared to 5% of 5-FU treated and median survivals (5.7 versus 4.4) and 1-year survivals (18% versus 2%) were significantly improved with gemcitabine. Gemcitabine was well tolerated compared with 5-FU in this study with grade 3 or 4 neutropenia in 19% and 7%, thrombocytopenia in 10% and 0%, anaemia in 7% and 3%, nausea and vomiting in 10% and 3% and diarrhoea in 2% and 0%, respectively. Smaller studies have reported similar efficacy and toxicity for single-agent gemcitabine [3]. Consequently many authorities regard single-agent gemcitabine as the standard of care for first-line chemotherapy in advanced pancreatic cancer. Despite encouraging results from phase II trials, phase III studies to date have not shown a consistent clinically significant benefit for combination chemotherapy over single-agent chemotherapy [4, 5].

Here we present the results of a phase II study of mitomycin C, cisplatin and protracted venous infusion 5-FU (MCF) in advanced pancreatic cancer. The rationale for this was the observed single-agent activity of each drug in pancreatic carcinoma, combined with the observation of synergy between 5-FU and cisplatin, and 5-FU and mitomycin C in a number of clinical and preclinical settings [3436]. A phase II study of cisplatin and 5-FU in advanced pancreatic cancer demonstrated good efficacy and acceptable toxicity [6]. Phase II studies of MCF in carcinoma of unknown primary and gastric carcinoma have shown this regimen to be well tolerated [37, 38].


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Patients presenting between January 1996 and February 2001 were eligible following clinical and radiological diagnosis of locally advanced or metastatic carcinoma of the pancreas. Forty-five patients were enrolled after informed consent. A biopsy was performed in 37 patients (84%) and was successful in 29 (64%). Only one attempt at biopsy was made. In those patients without a histological diagnosis entry into the study was approved only after review of their clinical and radiological features in the multidisciplinary setting.

Eligible patients had not received prior chemotherapy or radiotherapy, were over 18 years of age, had no central nervous system metastases, no uncontrolled infection and a life expectancy of more than 3 months. Adequate bone marrow function (absolute neutrophil count 1.5 x 109, platelets >100 x 109), renal function [serum creatinine less than upper limit of normal (ULN) and calculated clearance by Cockcroft–Gault formulae of >50], hepatic function (serum billirubin BR <1.5 ULN, serum transaminases <1.5 ULN) were assessed. Pain and biliary obstruction were controlled in all patients before entry into the study. The trial was approved by institutional ethics committee.

Treatment and evaluation schedule
MCF consisted of mitomycin C 6 mg/m2 administered as an intravenous bolus every 6 weeks, cisplatin 50 mg/m2 infusion with hydration (0.9% sodium chloride 1000 ml with potassium chloride 10 mmol and magnesium sulphate 8 mmol over 2 h pre- and post-cisplatin and 0.9% sodium chloride 500 ml post-cisplatin) 3 weekly and 5-FU administered as protracted infusion at 300 mg/m2/day via indwelling central venous catheter in the subclavian or internal jugular vein. Prophylactic warfarin 1 mg o.d. was given to all patients. If toxicity of the National Cancer Institute–Common Toxicity Criteria (NCI–CTC) grade 2 or greater was observed the subsequent cycle was delayed until the toxicity was resolved and a 20% dose reduction in mitomycin and cisplatin instigated. Toxicities specifically related to 5-FU (mucositis, Palmar Planter Erythema (PPE) and diarrhoea) of grade 2 or worse resulted in the interruption of the protracted venous infusion until resolution and recommencement at 20% dose reduction.

Assessment of efficacy and toxicity
All patients had a baseline computed tomography (CT) scan. Patients were assessed clinically for response and toxicity weekly during treatment. Toxicity and performance status were recorded on each occasion (NCI–CTC grade). Treatment was continued for 9 weeks after which response was assessed by CT scan. If stable disease or better was recorded treatment continued for a further 9 weeks to complete 18 weeks of treatment. Treatment was discontinued at any time if there was clinical, biochemical or radiological evidence of disease progression or if in the opinion of the investigator or patient unacceptable toxicity was encountered.

Response was assessed according to the World Health Organization criteria. All responses were confirmed by second CT scan at least 4 weeks after the CT documenting the response.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Forty-five patients referred to the Department of Oncology at Aberdeen Royal Infirmary between January 1996 and February 2001 were included. Twenty-nine patients had a confirmed histological diagnosis. There were no significant differences in age, sex, performance status, site or stage of disease between those with or without a histological diagnosis (data not shown). The patient characteristics are summarised in Table 1.


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Table 1. Patient characteristics
 
Dose intensity
Treatment was well tolerated with 175 cycles delivered overall with a median of four cycles (12 weeks) per patient. Thirty-eight patients (84%) received three or more cycles and 14 (31%) received full dose intensity (mitomycin C 2.2 mg/m2/week, cisplatin 20 mg/m2/week and 5-FU 2100 mg/m2/week).

Toxicity
Toxicities are recorded in Table 2. With the exception of nausea, vomiting and mucositis toxicity was uncommon and in particular grade 3 or 4 toxicity was infrequent: anaemia grade 3 and 4 occurred in 2% and 4% of patients, respectively, mucositis grade 3 occurred in 7% of patients and diarrhoea grade 3 occurred in 2% of patients. No grade 3 or 4 neutropenia or thrombocytopenia was recorded.


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Table 2. Toxicity (NCI–CTC grade, 45 patients)
 
Six patients (13%) had thromboembolic events; in three cases (7%) these were related to Hickman line catheters. There were no deaths related to chemotherapy.

Efficacy
Efficacy data are summarised in Table 3. One patient had a complete response. Twenty partial responses were recorded. The overall objective response rate was 46%. All responses were confirmed with CT at least 4 weeks after the initial responding scan. Stable disease was recorded in a further seven patients.


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Table 3. Efficacy
 
With a median follow-up of 36 months all but two patients have died. Median survival overall was 7.1 months. In those patients with an objective response it was 10.5 months, in non-responders 4.9 months (P <0.05). Median duration of response was 4.3 months.

The 1-year and 2-year survival rates were 29% and 18%, respectively. In patients with an objective response to chemotherapy 1-year survival was 62% and 2-year survival was 38%.

Response rate and survival were not significantly different in those patients with a histological diagnosis compared to those without (1-year survival 52% and 37%, P = 0.12, respectively, and median survival 6 months versus 4 months, P = 0.122, respectively, for histologically proven versus not histologically proven).

Interestingly, all patients with an objective response responded within the first 9 weeks (three cycles) of treatment and none progressed before completion of 18 weeks (six cycles) of treatment. No patients with stable disease after 9 weeks of treatment subsquently responded with further treatment.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The results of this single-centre phase II trial of MCF in advanced pancreatic carcinoma have shown this regimen to have significant efficacy and low toxicity. The demonstrated efficacy and tolerability is superior to that reported for single-agent gemcitabine in this setting both in terms of objective response rate and 1-year survival.

Twenty-nine out of the 45 cases (64%) were confirmed histologically. Biopsy was attempted in 85%. In this group of patients with advanced disease, often difficult symptom control problems and poor prognosis it was deemed appropriate to make only one attempt at biopsy. However, careful review of the clinical and radiological features of each case in the multidisciplinary setting (involving medical oncologists, radiation oncologists, hepatobiliary surgeons and gastroenterologists) combined with observation of the natural history of all cases in this study (own recorded observations—clinical and radiological) leaves no doubt as to the diagnosis of pancreatic carcinoma in all patients. This is supported by the lack of significant difference in response rate and median survival between patients with and without a histological diagnosis. Furthermore, in a cohort of 186 patients with a clinical and radiological diagnosis of pancreatic cancer but no histological diagnosis with long-term follow-up only 13 (6.9%) had a benign cause [39].

The overall objective response rate was 46%. This compares favourably to those rates published for gemcitabine and gemcitabine-based combinations [25, 733]. The difficulties in evaluating reponse in advanced pancreatic cancer are well documented [39]. In particular, the often intense desmoplastic reaction associated with the primary tumour can make measurement difficult and subjective. Independent review of the radiological response data was not performed in this study. Therefore while the reported response rate is encouraging the 1-year and 2-year survival data provide more convincing evidence of the efficacy of this regimen. Again these data compare favourably with the published data for 1-year and 2-year survival for gemcitabine and gemcitabine-based combinations [25, 733].

Single-agent chemotherapy with gemcitabine is considered by many oncologists to represent the ‘gold standard’ for first-line chemotherapy in advanced pancreatic cancer [2]. Ongoing phase III studies are addressing the issue of whether gemcitabine-based combination chemotherapy can provide superior efficacy without acceptable additional toxicity [35]. Table 4 summarises all the published phase II/III studies of gemcitabine and gemcitabine-based combinations in advanced pancreatic cancer patients (all studies had at least 30 patients). The studies are arranged in descending order based upon reported median survival. Clearly the results for many of these studies will be influenced by patient selection and prognostic factor distribution within the treated groups, so that comparison should be made with caution. Nevertheless, the results from this study lie within the middle of the range reported for gemcitabine-based chemotherapy and therefore suggest that MCF has comparable efficacy.


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Table 4. Gemcitabine-based chemotherapy in advanced pancreatic carcinoma by descending median survival
 
Further confirmation of these results involving a larger multicentre investigation with external radiological review and clinical benefit response analysis is necessary if the efficacy and low toxicity of MCF is to be validated. However, a more appropriate regimen may be MCX (mitomycin C, cisplatin and Xeloda/capecitabine). Capecitabine has proven efficacy in advanced pancreatic cancer comparable to 5-FU and avoids the inconvenience and complications of indwelling central venous catheters and ambulatory chemotherapy. Furthermore the documented induction of thymidine phosphorylase by mitomycin C provides a mechanism for possible synergy with capecitabine [40].

In conclusion, MCF is an effective, well-tolerated, cost-effective regimen in patients with advanced pancreatic cancer. The efficacy appears to be at least comparable and may be superior to single-agent gemcitabine with similar toxicity. Further studies are ongoing but MCF may provide a cost-effective alternative for the management of advanced pancreatic carcinoma.


    Acknowledgements
 
We acknowledge the help of J. C. A. P. and J. C. P. in the manuscript preparation.


    Footnotes
 
+ Correspondence to: Dr R. Petty, Department of Medicine and Therapeutics (Oncology), University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZN, UK. Tel: +44-1224-553061; Fax: +44-1224-553766; r.d.petty{at}abdn.ac.uk Back


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