Chemotherapy for pancreatic cancer

10

Chemotherapy for pancreatic cancer SUSAN G. A R B U C K

THE CLINICAL PROBLEM The incidence of pancreatic cancer has been increasing internationally (Brennan et al, 1989). It is the fifth most common cause of cancer death in the United States (Silverberg et al, 1990). Based on current trends in the USA in 1990, 28 100 new cases will be diagnosed and 25 000 patients will die. At diagnosis, fewer than 20% of patients have disease that is macroscopically confined to the pancreas. Forty percent of patients present with locally advanced disease involving regional lymph nodes and/or tissues adjacent to the pancreas. Although these patients should be considered candidates for curative resection, fewer than 5% will survive five years. Forty percent of patients have visceral metastases at the time of diagnosis, particularly involving the liver and peritoneum. Widespread metastasis also occurs to other abdominal viscera, the lungs and bone. Radiotherapy in combination with 5-fluorouracil (5-FU) has demonstrated some benefit in patients with locally advanced disease and as adjuvant therapy following surgical resection (Gastrointestinal Tumor Study Group (GITSG), 1981, 1987). Most patients, however, will have metastatic disease at some time during the course of their illness. It is this last group of patients who pose the greatest challenge for systemic treatment. An effective therapy may be defined as one that results in a significant number of complete responses or prolonged survival for the treated population (both responders and non-responders) (Anderson et al, 1983), or one that prolongs survival for even a small proportion of patients. Such a benefit might be identified as a plateau on the tail of the survival curve of treated patients. In order to identify an effective treatment and to discard ineffective or dangerous ones, strict clinical trial methodology is required. CLINICAL TRIAL METHODOLOGY It is important that any new treatment is evaluated in a well-defined patient population that is sufficiently homogeneous to allow the effects of treatment to be identified against a background of patient variability (Simon, 1990). The methods for patient selection should not lead to biased results. The patients studied should be representative of the group to whom therapy Baillibre's Clinical Gastroenterology--

Vol. 4, No. 4, December1990 ISBN0-7020-1470-2

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might be given. Eligibility criteria must be clearly stated so as to allow physicians and surgeons to judge to what extent the results are applicable to their own patients. The objective of a phase II clinical trial is to determine whether a new treatment has some minimally acceptable level of activity in a particular tumour type which would justify additional investigation. Patients who are entered into phase II trials of anticancer drugs should be previously untreated and have a good performance status. Such studies in debilitated patients or those who have had several treatments beforehand are of no research value and unlikely to benefit the patient (Simon, 1990). Whilst appropriate eligibility criteria have been applied in more recent trials, they were not applied in many of the older phase II studies. All entered patients including those who are ineligible, drop out, or have incomplete follow-up must be accounted for in the final results. It is generally accepted that these patients should comprise less than 15% of the study population (Simon and Wittes, 1985). The definitions of endpoints must be precise and preferably standardized for similar studies. The primary study endpoint should be a direct measure of patient benefit. Most frequently, response is used as the primary endpoint in phase II trials of new treatments. The following definitions are commonly used. A complete response requires disappearance of all previously detectable tumour and symptoms, and a return to normal laboratory tests. A partial response occurs when there is reduction by at least 50% of the sums of the product of the longest perpendicular diameters of all measurable tumours. There should be no increase in the size of any lesion and no new areas of malignant disease. An objective response should be maintained for a minimum of four weeks. Progressive disease is defined as a 25% increase in any measurable lesion or the appearance of new areas of malignancy. Symptomatic deterioration of the performance status requires a careful search for progressive disease. Patients have stable disease when criteria for response or progression are not met. A response rate should be reported with its confidence interval (Simon, 1986). A confidence interval is a range of values of the true response rate that are consistent with the observed response rate. The degree of consistency is determined by the confidence level, normally given as 95%. Although achievement of a complete response is frequently associated with prolonged survival, achievement of a partial response does not have proven benefit. Physicians frequently associate a partial tumour response with symptomatic improvement but other factors must be considered when evaluating efficacy including treatment toxicity and duration of response. A partial response of brief duration and at the cost of significant toxicity may be of little or no value to the patient. Identification of a treatment resulting in a partial response may, however, provide information that aids the development of a more efficacious regimen (Simon, 1990). Comparison of survival duration for responding and non-responding patients is not a valid method of analysis (Anderson et al, 1983) and is now rarely reported in reputable journals. Prolonged survival should be demonstrated for the entire treated population or for a specific subgroup of

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patients. In the latter instance, an alteration in the tail of the survival curve should be clearly identifiable. SPECIAL PROBLEMS IN PATIENTS WITH PANCREATIC CANCER Patients with pancreatic cancer present some special problems which must be considered when evaluating results of clinical trials. Although response is frequently the reported endpoint, evaluation of response requires identification of clearly and reproducibly measurable disease. Patients without measurable disease using currently available imaging techniques, often have large volumes of turnout found at surgery. Such patients are not candidates for studies that use response as the primary endpoint. The North Central Cancer Treatment Group (NCCTG) uses survival as the primary endpoint and includes patients with non-measurable disease in its trials (Cullinan et al 1985, 1989). Response is documented in the small proportion of the study population with measurable disease. The primary pancreatic lesion, although often measurable on computerized tomography (CT), frequently contains many inflammatory and connective tissue cells and stromal tissue that contribute to 'tumour' size. The Gastrointestinal Tumor Study Group (GITSG) has reported that response of the primary pancreatic lesion correlated with prolonged survival in a small group of patients. They suggested that the primary pancreatic lesion could be used as a measurable disease indicator (Barkin et al, 1986). Studies that correlate response of the primary with metastatic lesions would also be helpful. It is important that measurable disease is clearly defined, since this will affect determination of response, the study endpoint. Other factors may contribute to the difficulty in enrolling patients on clinical trials and completing the planned treatment. The median survival of patients with pancreatic cancer is very brief and measured in weeks. Fewer than 10% of patients are alive at one year. At presentation, patients are frequently malnourished due to mechanical obstruction of the gastrointestinal tract and varying degrees of malabsorption. Patients often have impaired liver function due to hepatic metastases or biliary tract obstruction. In addition, hypoalbuminaemia, ascites and other problems which may alter drug distribution, metabolism and pharmacodynamics, are frequent. Few investigators describe administered dose intensity (mg/m ~per week), a measure of the ability to administer full drug doses on schedule (Hryniuk, 1987). This measure is altered by dose reductions and delays required for recovery from toxicity (Hryniuk, 1987). Owing to physiological problems that are not infrequent in patients with pancreatic cancer, it may be that adequate drug doses are not delivered. Thus, administered dose intensity should be described in published reports. SINGLE-AGENT CHEMOTHERAPY FOR ADVANCED PANCREATIC CANCER For more than three decades efforts have been made to identify active

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agents for treatment of pancreatic carcinoma. Of more than 30 agents tested, only 5-FU resulted in a response rate with 95% confidence intervals greater than 20% (Brennan et al, 1989) (Table 1). In a collected series of 212 patients treated before 1975, response rates varying from 0 to 67% and an Table 1. Collected results of single-agent chemotherapy for pancreatic cancer. Drug

No. patients

Response rate + 95% CI

212 53 27 91 31 28 117

28 + 6 21 + 6 11 + 6 4+ 2 0 7+ 5 12 + 6

5-FU Mitomycin-C Streptozotocin MethyI-CCNU BCNU Doxorubicin Ifosfamide*

CI, confidence interval; 5-FU, 5-fluorouracil; CCNU, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea; BCNU, 1,3-bis(2-chloroethyl)- 1-nitrosourea. * Studies by Bruhl et al (1976) and Gad-E1-Mawla and Zeigler (1981) were omitted because criteria for response were not well defined. See Table 2. Adapted from Brennan et al (1989). Table 2. Results of phase II studies of ifosfamide for pancreatic cancer.

Drug regimen

No. Response patients %

CI +95%

Median survival (months)

Reference

60 mg/kg × 5 days or 30 mg/kg × 10 days + 5 Gy pretreatment

13

77

46-94

NR

Bruhl et al (1976)

2 g/m 2 x 5 days

10

60

2%86

NR

Gad-EI-Mawla and Ziegler (1981)

1.25-1.5 g/m 2 × 5 days to maximum 2 g/m 2 per day Uroprotection: NAC

28

21

9-41

6

Loehrer et al (1985)

1.75 g/m2 x 5 days to maximum 2 g/m 2 per day Uroprotection: Mesna

30

10

2-28

2.8

GITSG (1989)

2 g/m 2 x 5 days Uroprotection: Mesna

30

7

1-22

3

Ajani et al (1988)

1.25 g/m 2 x 5 days to maximum 2 g/m: per day Uroproteetion: NAC

29

3

0-20

NR

Bernard et al (1986) (MAOP preliminary)

CI, confidence interval; NR, not reported; NAC, N-acetylcysteine; Mesna, 2-mercaptoethane sulphonate; GITSG, Gastrointestinal Tumor Study Group; MAOP, Mid-Atlantic Oncology Program.

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overall response rate of 28% were reported (Carter and Comis, 1975). The last authors suggested that this response rate of 28% was an overestimate of 5-FU activity. In most of these trials minor variations of the 5-FU loading regimen were used. Although treatment regimens differed, different response rates were more likely due to differences in patient selection, such as extent of the tumour, performance status and prior treatment, as well as criteria for tumour response. In addition, because small numbers of patients were treated in many of these uncontrolled trials, the response rates have large confidence limits. Evaluation of these results illustrates many of the methodological problems already described. Interest in alkylating agent therapy of pancreatic cancer increased following reports of high response rates obtained with ifosfamide (Table 2) (Bruhl et al, 1976; Gad-EI-Mawla and Ziegler, 1981). In these studies criteria for response were poorly defined. Following a subsequent study with carefully defined response criteria, Loehrer et al (1985) reported five partial responses and one complete response in 28 patients, (response rate 21%, 95% confidence interval 6-38%). Unfortunately, these results have not been confirmed in subsequent trials (Bernard et al, 1986; Ajani et al, 1988; GITSG, in press). An overall response rate of 10% (12 out of 117 patients) in the four American studies with well-defined response criteria indicates that ifosfamide does not have significant activity in pancreatic carcinoma. Other commonly used drugs for the treatment of pancreatic cancer include mitomycin-C, streptozotocin and doxorubicin. Although they are used frequently in combination regimens for pancreatic carcinoma, the response rates with single-agent streptozotocin and doxorubicin in small numbers of patients, are low (Table 1). The partial responses seen with single-agent chemotherapy are usually brief and rarely associated with clinical benefit. COMBINATION REGIMENS FOR ADVANCED PANCREATIC CANCER

Many phase II and III studies of combination chemotherapy have been performed in advanced pancreatic cancer (Tables 3-5). The Southwest Oncology Group (SWOG) compared 5-FU and mitomycin to streptozotocin, 5-FU and mitomycin (Bukowski et al, 1983) (Table 5). Although the response rate for the streptozotocin-containing combination was significantly higher than for the two-drug regimen (34 vs 8%), the median survivals did not differ (18 vs 17 weeks). In a similarly designed study by the Eastern Cooperative Oncology Group (ECOG), streptozotocin was added to 5-FU and methylCCNU (Horton et al, 1981). Neither response rate nor median survival was improved by the addition of streptozotocin. The most frequently used combinations for advanced pancreatic carcinoma have been the FAM (5-FU, doxorubicin and mitomycin-C) and SMF (streptozotocin, mitomycin and 5-FU) regimens which were developed at Georgetown University (Tables 3 and 4) (Bitran et al, 1979; Bukowski et al, 1980; Smith et al, 1980; GITSG, 1986; Oster et al, 1986; Wiggins et al, 1987;

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C u l l i n a n et al, 1989). I n g e n e r a l , the higher r e s p o n s e rates r e p o r t e d in initial p h a s e II trials were n o t c o n f i r m e d by the C o o p e r a t i v e G r o u p s , n o r were r e s p o n s e rates i n c r e a s e d with the a d d i t i o n of o t h e r m a r g i n a l l y active or inactive drugs ( K o v a c h et al, 1974; B u k o w s k i et al, 1982; K a r l i n et al, 1982; S m i t h et al, 1982). I n r a n d o m i z e d trials that c o m p a r e d the two r e g i m e n s , t h e r e was n o significant difference in m e d i a n survival (Table 5). I n a n i m p o r t a n t study, the N o r t h C e n t r a l C a n c e r T r e a t m e n t G r o u p ( N C C T G ) c o m p a r e d single-agent 5 - F U , 5 - F U a n d d o x o r u b i c i n , a n d the Table 3. 5-FU and adriamycin combinations for pancreatic cancer.

Drug regimen

No. patients

Response %

CI + 95%

Median survival (months) References

FAM Smith et al Bitran et al (modified 42 day schedule) CALGB NCCTG GITSG

27 15

37 40

20-58 17-67

6* 3.7

Smith et al (1980) Bitran et al (1979)

65 13 29

14 8 3

7-25 0-40

6.5 4.3t 3

Oster et al (1986) Cullinan et ai (1985) GITSG (1986)

4-drug FAM combinations FAM-STZ FAM-chlorzotocin FAM-Me FAP

25 23 23 29

48 13 22 21

28-68 3-35 8--44 9--40

7.5 6.4 7.4 4

Bukowskiet al (1982) Smith et al (1982) Karlin et al (1982) Moertel et al (1986)

* Median survival of 39 patients, 12 of whom did not have measurable disease; t median survival of 50 patients, 37 of whom did not have measurable disease. CI, confidenceinterval; CALGB, Cancer and Leukemia Group; NCCTG, North CentralCancer Treatment Group; GITSG, Gastrointestinal Tumor Study Group; FAM, 5-fluorouracil, doxorubicin, mitomycin-C; STZ, streptozotocin; Me, methyl-CCNU; FAP, 5-fluorouracil, doxorubicin, cisplatin. Table 4. Results ofstreptozotocin, 5-fluorouraciland mitomycin-C(SMF) for pancreatic cancer.

References Wiggins et al (1987) Bukowski et al (1980) SWOG (Bukowski et al, 1983) CALGB (Oster et al, 1986) GITSG (1986) SMF I SMF II

Median survival (months)

No. patients

Response %

CI + 95%

23 22 56 68

43 32 34 4

24--65 12-50 22-48 1-13

6 6 4.3 4.5

28 29

14 15

5-34 5-33

4.5* 3.8t

* Median survival for 48 patients, 20 of whom had prior treatment; t median survival for 44 patients, 15 of whom had prior treatment. CI, confidence interval; SWOG, Southwest Oncology Group; CALGB, Cancer and Leukemia Group B; GITSG, Gastrointestinal Tumor Study Group. SMF I: streptozotocin I g/m2 and 5-FU 600 mg/m2 days 1, 8, 29, 36, and mitomycin-C 10 mg/m2 day I of an 8 week schedule. SMF II: streptozotocin 350 mg/mz and 5-FU 300-350mg/m2 days 1-5 every 5 weeks, and mitomycin-C 10 mg/m2 day 1 of a 10 week schedule.

CHEMOTHERAPY

959

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standard FAM combination in patients with pancreatic carcinoma (Table 5) (Cullinan et al, 1985). Neither response rates nor median survival differed significantly but more toxicity and higher costs were associated with the combination regimens. Since there are no trials comparing 5-FU with no active drug treatment (support care), the therapeutic benefit from 5-FU is unknown. Differences in patient selection may account for the small prolongation of median survival in patients treated with 5-FU compared with untreated patients in historical series. Patients enrolled in clinical trials may be in better condition than untreated patients included in older series describing the natural history of advanced pancreatic cancer (O'Connell, 1985). In 1980, results of a randomized trial comparing supportive care only with a programme of induction 5-FU, methotrexate, vincristine and cyclophosphamide followed by continuing treatment with 5-FU and mitomycin-C were reported (Mallinson et al, 1980). Objective response rates were not included; the median survival of the treated group, however, was significantly longer than the control group (44 vs 9 weeks). Of note, 14 of the 40 patients did not have histologically confirmed pancreatic cancer. Moreover, the induction programme included only one drug with demonstrated activity in advanced pancreatic carcinoma. The NCCTG was unable to confirm these results in a phase III trial with 172 previously untreated patients (CuUinan et al, 1989). Patients were randomized to receive 5-FU (500 mg/m2 per day for 5 days every 5 weeks) or the Mallinson regimen, or 5-FU, doxorubicin and cisplatin (FAP). Previously Moertel et al (1986) had reported a 21% response rate and a median survival of four months with the FAP regimen. Survival was the endpoint of the phase III NCCTG trial. The median survival for the Mallinson regimen was only 4.5 months and was not significantly different from that obtained with the other regimens. Since the Mallinson and FAP regimens were more toxic than single-agent 5-FU, neither of the former regimens was recommended. On the basis of demonstrated drug synergy and long-term survival in the DUPAN-1 nude mouse model of human pancreatic cancer, a phase II trial combining cisplatin, high-dose cytosine arabinoside (Ara-C) and caffeine was performed at the Memorial Sloan-Kettering Cancer Center (Kyriazis et al, 1985; Dougherty et al, 1988). A 39% response rate was reported in 18 patients. This combination was compared with the standard SMF combination in a randomized trial. Cisplatin, Ara-C and caffeine was more toxic and had no therapeutic advantage over the SMF combination (Hurdis et al, 1990). Biochemical modulation of 5-FU

5-FU is metabolized to the active metabolite fluorodeoxyuridylate (FdUMP), which binds to and inhibits thymidylate synthetase. Thymidylate synthetase is required for production of thymidylate, an essential precursor of DNA. In the presence of higher concentrations of reduced folates, thymidylate synthetase inhibition is prolonged and cytotoxicity is enhanced in some tumour cell systems (Evans et al, 1981; Arbuck, 1987). This

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provides the rationale for using leucovorin (folinic acid) in conjunction with 5-FU. Seven prospective randomized phase III trials comparing 5-FU with 5-FU and leucovorin have been completed in patients with advanced, previously untreated colorectal cancer. The use of 5-FU in combination with leucovorin resulted in higher response rates than 5-FU alone in five out of seven of these trials (Arbuck, 1989). On the basis of results in colorectal cancer, Bruckner et al (1988) treated a small selected group of eight patients with pancreatic cancer every two to four weeks with leucovorin, at a dose of 100 to 200 mg over 10 minutes, and 30 mg/m 2 of 5-FU one hour later. Patients had early metastatic disease, defined as 'small lesions that were not immediately life threatening in a physiologically intact patient'. Four patients had occult primary lesions or small metastatic disease at the time they initiated treatment. In this highly selected population, three complete responses and one partial response were seen. The complete responses were maintained for 17, 22 and >30 months. A preliminary report from Roswell Park Cancer Institute and the DanaFarber Cancer Center, described results in a more typical population of 27 previously untreated patients with histologically documented, measurable, locally unresectable or metastatic pancreatic carcinoma (DeCaprio et al, 1989). Most patients in this study were also asymptomatic; the median ECOG performance status was 0. Nevertheless only 8% of patients had objective partial responses. Toxicity was similar to that reported for the 5-FU/leucovorin combination in other tumour types and one toxic death occurred. Since the response rate of 8% is no better than that described in prior phase II studies with 5-FU alone, 5-FU and leucovorin cannot be recommended for the treatment of pancreatic carcinoma outside of a clinical trial. Recently, phase II studies have suggested that other 5-FU based regimens may also have increased efficacy in advanced colorectal carcinoma. These include 5-FU/a-interferon, 5-FU/N-(phosphonacetyl)-L-aspartate (PALA) and continuous infusion 5-FU-based regimens. Sufficient benefit was suggested in the phase II studies to move these regimens into phase III evaluation in colorectal cancer and into phase II evaluation in pancreatic cancer. In a murine model, interferon provided a host-protective effect by decreasing toxicity and permitting increased 5-FU dose intensity over that which could be achieved with 5-FU alone (Stolfi et al, 1983). In addition to many other effects, interferon also inhibits thymidine incorporation into DNA (Elias and Crissman, 1988). Such an effect could potentiate 5-FU cytotoxicity. A 63 % response rate in 32 patients with advanced colorectal cancer treated with 5-FU and a-interferon has been reported (Wadler and Schwartz, 1990). One of six pancreatic cancer patients responded to the same regimen (Wadler et al, 1989). Accrual has increased to 15 patients but no additional responses have been seen (Wadler, personal communication 1990). In another preliminary report using 5-FU and ~/-interferon, no benefit was reported (Roh et al, 1986).

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PALA is an inhibitor of aspartate transcarbamylase, one of the initial enzymes for de novo biosynthesis of pyrimidines. This depletion results in greater utilization of 5-fluorouridine triphosphate (FUTP) and increased FUTP incorporation into RNA. PALA has been reported to potentiate 5-FU activity in preclinical models (Grem et al, 1988). In colorectal cancer, initial studies of the combination have been sufficiently promising that this regimen is being evaluated in phase III trials. In a preliminary report, three responses were described in 16 evaluable patients with pancreatic cancer (Schilder et al, 1990). This combination is undergoing additional evaluation. Recent studies in colorectal cancer have indicated that biochemical modulation of 5-FU can result in increased response rates. Although further study is warranted, it does not appear that improved efficacy in one relatively chemoresistant disease will translate easily into benefit in another. Progress may be forthcoming with additional understanding of both the underlying disease and the biochemical mechanisms of drug action and drug resistance. COMBINED MODALITY THERAPY: RADIOTHERAPY AND 5-FU FOR LOCALLY ADVANCED PANCREATIC CARCINOMA In 1958, the addition of 5-FU to radiotherapy was shown to enhance regression of certain transplanted animal tumours (Heidelberger et al, Table 6. Results of randomized trials of single treatment vs combined treatment for pancreatic cancer. Median No. survival Statistical patients (months) analysis

Treatment regimens

References

Locally advanced disease Mayo Clinic 35-40 Gy + placebo 35--40 Gy + 5-FU

32 32

6.3 10.4

GITSG 60 Gy 40 Gy + 5-FU followed by 5-FU 60 Gy + 5-FU followed by 5-FU

25 83 86

5.5 10.5 10

GITSG SMF 54 Gy + 5-FU followed by SMF

21 22

8 10.5

p < 0.02

ECOG 5-FU 40 Gy + 5-FU followed by 5-FU

41 47

8.2 8.3

NS

p < 0.05

Moertel et al (1969); Childs et al (1965) GITSG (1981)

p < 0.01

GITSG (1988)

Klaassen et al (1985)

Adjuvant GITSG Surgery alone 40 Gy + 5-FU

randomized registered

22 21 24

11 20 19

p = 0.03

Kaiser & Ellenberg (1985); GITSG (1987)

GITSG, Gastrointestinal Tumor Study Group; ECOG, Eastern Cooperative Oncology Group; NS, not significant; SMF, streptozotocin, mitomycin-C, 5-fluorouracil.

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1958). Other investigators have reported similar results. On the basis of these studies, investigators at the Mayo Clinic evaluated radiotherapy in combination with 5-FU in patients who had locally unresectable pancreatic carcinoma, and in whom all tumour could be encompassed by a 20 × 20 cm radiotherapy port (Childs et al, 1965; Moertel et al, 1969). Patients were randomized to receive either radiotherapy (35-40 Gy) plus 5-FU (15 mg/kg on days 1, 2 and 3) or radiotherapy plus saline placebo (Table 6). The median survival of the 5-FU group was 10.4 months vs 6.3 months for the placebo group which was statistically significant. A GITSG study (1981) confirmed the benefit of radiotherapy combined with 5-FU for locally advanced pancreatic carcinoma. They evaluated 5-FU (500 mg/m 2 for the first three days of each 20 Gy course) in combination with a split course of radiotherapy (40 vs 60 Gy) vs treatment with a split course of radiotherapy alone (60 Gy). Patients on the combined treatment arms also received weekly courses of 500 mg/m 2 5-FU beginning one month after completion of radiotherapy. Chemotherapy was continued for two years or until progression was documented. Radiotherapy alone was inferior and was discontinued after accrual of only 25 patients (median survival of 5.5 months). More than 80 patients were entered on each of the other two arms (median survival 10 months). Forty percent of patients treated with the combined regimens were alive at one year compared with only 10% of those treated with radiotherapy alone. There was no survival advantage for the higher radiation dose. 5-FU did not decrease the frequency with which distant metastases were observed as the first evidence of progressive disease. This finding suggested that benefit was due to enhancement of the local effect of radiotherapy by 5-FU (GITSG, 1981). Two groups have compared chemotherapy alone to combined modality treatment. A GITSG study (1988) randomized patients to treatment with SMF combination chemotherapy vs radiotherapy (54Gy) with 5-FU, followed by SMF (Table 6). Again, survival at 12 months was significantly longer for the combined vs the single modality programme (41 vs 19%). Since the number of local failures was similar in both groups, the radiotherapy may have delayed but did not prevent local disease progression. This study demonstrated that combined modality treatment, already proven to be better than radiotherapy alone, was superior to combination chemotherapy. No survival advantage was demonstrated for pancreatic cancer patients treated with combined modality therapy in an ECOG study (Klaassen et al, 1985). Patients received 5-FU alone (600 mg/m 2 weekly) or radiotherapy (40 Gy) with the same 5-FU dose administered on the first three days of radiotherapy and weekly beginning on the day radiotherapy was completed. The ECOG patient selection criteria differed from the GITSG trial. Patients were entered with locally advanced disease at diagnosis o r at the time of local recurrence. An unacceptably high 22% of patients with gastric and pancreatic cancer were ineligible or failed to complete the treatment programme. The ECOG combined modality regimen had a higher 5-FU dose and was more toxic than the Mayo or GITSG programmes, but the number of patients who were able to complete radiotherapy was not

964

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reported. Although it suggests lack of benefit for combined modality therapy, there are several other reasons why this study may not have demonstrated that combined modality treatment was better than treatment with 5-FU alone. When therapeutic benefit of combined modality treatment was demonstrated, the benefit was not large, particularly since the programme added additional weeks of radiation treatment and additional toxicity. Both the Mayo Clinic and GITSG investigators urged that their regimens should not be adapted as standard treatment but instead provide the impetus for additional research (Moertel et al, 1969; GITSG, 1981).

ADJUVANT COMBINED MODALITY THERAPY WITH RADIOTHERAPY AND 5-FU Since combined modality treatment improved survival of patients with locally advanced disease, in 1974 the GITSG began an adjuvant trial. Surgery alone was compared with surgery followed by radiotherapy (40 Gy) plus 5-FU (Kaiser and Ellenberg, 1985). This study was terminated prematurely after entry of only 43 patients because of an unacceptably low accrual rate and the observation of increasingly large survival differences between the study arms. The median survival of the treatment group (20 months) was significantly longer than that observed for the control group (11 months). Four of 43 patients in the treatment group and one in the control group survived 5 years or longer following surgery. At the time of the most recent report no control patients were alive. Treated patients were alive at 5.1, 9, 10.2 and 11.2 years after surgery. On the basis of this result, an additional 24 patients were registered and received the same combined modality regimen (GITSG, 1987). As shown in Table 6, the results in those registered to combined modality treatment were similar to those who were randomized to the same treatment programme. Median survival was twice as long in patients whose tumours were confined to the pancreas compared with those whose tumours had spread to contiguous structures. At this time, radiotherapy in combination with 5-FU should be considered standard treatment for patients who undergo curative resection of disease that is confined to the pancreas. Such treatment results in some long-term survivors of greater than five years who may be cured of their disease. FUTURE STRATEGIES FOR CHEMOTHERAPY OF

PANCREATIC CANCER Laboratory studies should be done to explore further the basis of drug resistance in pancreatic carcinoma. Approaches to reverse multidrug resistance are being studied. Human pancreatic tumours should be evaluated to determine whether the p-glycoprotein or other markers of drug resistance are associated with chemoresistance of this disease. New approaches to

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treatment may evolve as understanding of the aetiology and growth regulation of pancreatic cancer increases. Development of such strategies will require leads from basic research groups. The initial studies of combined modality treatment used what are now considered relatively unsophisticated radiation techniques. These delivered an uneven radiation dose to the pancreas and CT was not available to aid in tumour localization. The ideal dose and schedule of 5-FU in combination with radiotherapy were not determined and currently used treatment regimens were developed empirically. Techniques for radiotherapy have improved since studies demonstrating an advantage for combined modality therapy were performed. Continuous development of multimodality treatment programmes including neoadjuvant treatment followed by surgery for locally advanced disease is needed (Weese et al, 1990). Such programmes may increase the small benefit already demonstrated in locally advanced disease and following curative resection. SUMMARY

To date, no satisfactory treatment has been developed for treatment of patients with advanced pancreatic carcinoma. The median survival of these patients is only three to six months. Of more than 30 agents evaluated over the past three decades, only 5-FU results in a response rate with 95% confidence intervals greater than 20%. Most responses are partial, of short duration, and of questionable clinical benefit. To date, efforts to improve response rates by biochemical modulation of 5-FU have been unsuccessful but additional studies are warranted and are ongoing. Although improved response rates have been reported with some drug combinations, such as streptozotocin, mitomycin and 5-FU (SMF), median survival for combination therapy is no better than that attained with single-agent therapy. Current therapeutic options for patients with advanced disease include 5-FU, supportive care, or investigational treatment in a clinical trial. In three out of four studies, patients with locally advanced pancreatic carcinoma who received combined modality therapy (radiation in combination with 5-FU) survived significantly longer than those treated with either radiation or chemotherapy alone. The brief survival advantage, however, must be considered in the context of the additional toxicity and treatment time required for the combined modality treatment. Radiotherapy in combination with 5-FU should be considered standard adjuvant therapy for patients with completely resected disease. The median survival of treated patients was 20 months and significantly longer than the surgery alone control group (11 months) (Kalser and Ellenberg, 1985; GITSG, 1987). Of greatest significance is the tail-end plateau on the survival curve suggesting that approximately 18% of patients who received combined modality therapy were cured. The results with currently available treatment for all stages of disease are poor; therefore, patients should be informed about ongoing clinical trials which may someday improve the prognosis for pancreatic cancer.

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Acknowledgement The assistance of Pat Beers in preparation of this manuscript is gratefully acknowledged.

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