Role of Radiation Therapy in the Management of the Patient With Pancreatic Cancer

September 1, 1996

Most patients who have pancreatic cancer present with advanced disease that is not amenable to surgery. For patients whose disease is amenable to surgery and who are managed with surgical resection alone, local

ABSTRACT: Most patients who have pancreatic cancerpresent with advanced disease that is not amenable to surgery.For patients whose disease is amenable to surgery and who aremanaged with surgical resection alone, local recurrence ratesare high and long-term survival rates are low. The use of radiationtherapy to treat pancreatic cancer has been studied in variousclinical contexts. Preoperative radiation therapy for resectableor borderline unresectable disease may benefit some patients butis not used routinely. For patients with resected disease, datafrom the Gastrointestinal Tumor Study Group (GITSG) trials supportthe use of adjuvant chemoradiation. For patients with locallyunresectable disease, the use of radiation therapy plus chemotherapyprovides modest benefit, as suggested by the clinical trials ofthe GITSG and other groups. Additional studies employing modifiedradiation therapy techniques and improved chemotherapeutic regimens,with enhanced radiosensitization and direct cytotoxicity, areneeded to optimize treatment regimens for patients with this disease.[ONCOLOGY 10(Suppl):13-17, 1996]

Introduction

Treatment strategies for patients with pancreatic cancer differbased on disease stage. Standard treatment strategies for patientswith T1-T2,NX,M0 disease include surgical resection and adjuvantor, less commonly, neoadjuvant chemoradiation, whereas therapyfor unresectable presentations includes surgical bypass procedures,radiation therapy, and/or chemotherapy [1].

Pancreatic cancer is particularly challenging for the radiationoncologist because of the limited radiation tolerance of adjacentorgans in the upper abdomen, including the kidney, liver, stomach,small bowel, and spinal cord [2]. The radiotherapy technique usuallyused to treat pancreatic cancer is conventional external-beamradiotherapy (EBRT), although more specialized techniques, suchas intraoperative radiotherapy (IORT) and brachytherapy, havebeen described. Intraoperative radiotherapy involves the applicationof a single high dose of radiation during a surgical procedure,while brachytherapy entails the interstitial implantation of radioactivesources [1,3].

Radiation therapy can be potentiated with the use of radiosensitizingchemotherapeutic agents. One such agent, fluorouracil (5-FU),has been shown to be a radiosensitizer in vitro [4]. More recently,in vitro experiments reported by Shewach and Lawrence showed thatthe chemotherapeutic agent gemcita-bine (Gemzar), a deoxycytidineanalog, produced increased radiation sensitivity in human coloncarcinoma (HT-29) cells [5].

Resectable or Borderline UnresectableDisease

Preoperative Radiation Therapy

Pilepich and Miller examined preoperative (neoadjuvant) radiationtherapy as a means of improving the efficacy of surgical resectionin patients with borderline resectable or locally unresectabledisease [6]. In this study, patients received 4,000 to 5,000 cGyover a 4.5- to 5-week period and were evaluated for surgery 6weeks after radiotherapy. Of 17 patients, 11 were selected forlaparotomy. At surgery, 4 of the 11 patients had metastatic disease,1 patient was determined to be locally unresectable, and 6 patientsunderwent resection. Only 1 of the 6 patients experienced a clearconversion from unresectable to resectable disease. The authorsconcluded that radical resection was possible after preoperativeradiation in some patients but that a significant number of patientsshould be expected to develop metastatic disease during or shortlyafter the radiotherapy course [6].

Ishikawa et al conducted a retrospective review of the use ofpreoperative irradiation in 18 patients with resectable or borderlineresectable disease [7]. Patients received fractionated radiationto 5,000 cGy, terminating about 1 month prior to exploratory surgery.Measurable tumor shrinkage was noted in all 18 patients, and 16patients underwent pancreatic resection [7]. Although these resultsindicate that preoperative radiation is feasible, it is not usedroutinely [8].

Resectable Disease

Postoperative Radiation Therapy

Historically, surgery alone has had disappointing results in patientswith pancreatic cancer. For example, Tepper et al showed thatsurgery for resectable disease was associated with a 5-year crudesurvival rate of 15% and a local recurrence rate of 50% [9]. Similarresults were reported by Griffin et al [10]. Based on these findings,it was suggested that postoperative radiation therapy might reducethe incidence of local failure after radical surgery [9,10].

A National Cancer Institute (NCI) study compared IORT with standardpostoperative radiation therapy in patients with locally confinedpancreatic cancer who were undergoing either total or regionalpancreatectomy [11]. Patients were randomized to receive eitherpostoperative IORT (2,000 cGy using 9 to 12 MeV to the tumor bedand regional nodal basins) or postoperative EBRT (5,000 cGy overa period of 5 to 6 weeks). Although overall survival was similarbetween the treatment groups, disease-free survival and localdisease control were better in the IORT-treated patients thanin the EBRT-treated patients. These results suggested that IORTmay provide some benefit in patients with locally confined pancreaticcancer [11].

More recently, a retrospective study by Zerbi et al examined theimpact of IORT following surgical resection [12]. Patients eitherunderwent resection alone (47 patients) or resection and IORTat a dose of 12.5 to 20 Gy (43 patients). Whereas 1-, 2-, and3-year survival rates and median disease-free survival did notdiffer significantly between the treatment groups, local recurrencewas significantly reduced in patients who underwent resectionplus IORT (27% of patients), as compared with those who had aresection only (56% of patients; P less than .01 by the chi-squareand Mantel-Cox tests).

Although these results provide some support for the concept ofadding of IORT to surgical resection to enhance local control,it should be noted that no survival benefit was observed. Selectionfactors may have contributed to the improved local control observed,and IORT remains investigational in this context [12].

Postoperative Radiation Therapy Plus Chemotherapy

In 1985, the Gastrointestinal Tumor Study Group (GITSG) reportedthe results of a randomized trial that compared surgical resectionalone (N = 22) with surgical resection followed by radiation therapyplus chemotherapy (N = 21) [13]. Postoperative radiation therapy(EBRT) consisted of 4,000 cGy given in two courses of 2,000 cGyeach, and chemotherapy consisted of IV 5-FU at 500 mg/m²daily during the first 3 days of each 2,000-cGy course of radiation.One month after the completion of radiation therapy, chemotherapywas continued weekly for up to 2 years or until recurrence.

Accrual into the trial was slow due to the concern that patientswould not tolerate surgery plus radiation and chemotherapy [14].Nevertheless, this study demonstrated that surgery plus adjuvantradiation and chemotherapy significantly improved survival comparedwith surgery alone (median survival, 20 vs 11 months; P = .03using a one-sided log-rank test) [13].

The results of the initial GITSG trial led to the design of aconfirmatory trial in which an additional 30 patients receivedsurgery plus radiation and chemotherapy [15]. Median survivalwas 18 months, which was similar to that observed for the adjuvanttherapy group (20 months) in the initial trial. Two-year actuarialsurvival was 46% for the confirmatory trial patients who receivedadjuvant therapy, 43% for the initial trial patients who receivedadjuvant therapy, and only 18% for the initial trial patientswho received surgery alone (Figure 1). The results of both studiessupported the benefit of surgery plus radiation and chemotherapyin patients with resected pancreatic cancer [16].

The GITSG concluded that "... the combined use of radiationtherapy and fluorouracil as adjuvant therapy after curative resectionis effective and is preferred to no adjuvant therapy [15]."However, the use of adjuvant radiation therapy and chemotherapyhas been slow to gain acceptance. Reluctance to use this treatmentregimen reflects a variety of concerns, including the possibilitythat patients with positive surgical margins may not benefit fromthis treatment regimen [17], and doubt surrounding the GITSG studyresults due to the low patient numbers (N = 43) and lengthy recruitmenttime [2].

However, more-recent data continue to support the GITSG results[18]. In addition, efforts at improving postoperative adjuvantradiation therapy by using hepatic radiation and continuous-infusion5-FU have been initiated, but whether these efforts will resultin improved outcomes with acceptable toxicity is unknown [19].Decisions about whether or not to use adjuvant therapy for patientswith resectable pancreatic cancer should be made on a case-by-casebasis [1].

Locally Unresectable Disease

Radiation Therapy

Haslam et al examined the impact of radiation administered to29 patients with unresectable pancreatic cancer [20]. Radiotherapygenerally consisted of 6,000 cGy given in three sequential treatmentsof 2,000 cGy in 10 fractions over 2 weeks, followed by 2-weekintervals of rest. Fifteen of these patients also received chemotherapy,and some patients underwent palliative bypass procedures.

Good palliation was achieved in 45% of these patients. At 2.5years after diagnosis, 21% of the patients were alive. Althoughthis study suggested that radiation therapy may be advantageousfor patients with locally unresectable disease, it was limitedby its retrospective design and indiscriminate use of chemotherapyand bypass procedures [20].

In a study reported by Dobelbower et al, 40 patients with locallyunresectable pancreatic cancer received radiation therapy (5,900to 7,000 cGy over a 7- to 9-week period) [21]. Twelve of the patientsalso received chemotherapy. The projected 1-year survival ratewas 49%, similar to that for patients with resectable diseasewho were treated with surgery of curative intent.

Shibamoto et al reported that radiation therapy confers a survivaladvantage [22]. In patients with unresectable lesions but no distantmetastases, survival was longer in patients who received radiationthan in historical controls who did not (P = .00003).

The decision as to whether to use radiation therapy in the patientwith locally unresectable disease should include considerationof the extent of the tumor, the extent of normal tissue exposureto the radiation fields, and the patient's baseline medical andnutritional status [1]. Specialized and experimental radiationtherapy techniques, including hyperfractionated EBRT, IORT, brachytherapy,high-linear-energy-transfer radiation, and charged-particle irradiation,have been considered [23-30]. The extent to which these approachesmay be helpful will depend on whether they enhance locoregionalcontrol with acceptable morbidity to normal tissues and whethersuch enhanced control results in improved survival and qualityof life.

Radiation Therapy Plus Chemotherapy

Combining 5-FU with radiation therapy may augment the effectsseen with radiation therapy alone [31]. A GITSG study comparedthe effectiveness of radiation alone (6,000 cGy), radiation (4,000cGy) plus 5-FU, and radiation (6,000 cGy) plus 5-FU in 194 patientswith locally unresectable pancreatic cancer [32,33]. Fluorouracilwas administered at a dosage of 500 mg/m² IV on each of thefirst 3 days of the radiation therapy course and was subsequentlycontinued indefinitely.

After 106 patients were randomized, the radiation-therapy groupwas discontinued because it was found to have a significantlyinferior survival rate than survival in either group that receivedradiation plus 5-FU (P less than .01 by the log-rank test; Figure2). Therefore, all remaining patients were randomized to one ofthe radiation-chemotherapy groups.

When survival was analyzed for the second phase of the study,the higher radiation dose plus 5-FU appeared to be superior tothe lower radiation dose plus 5-FU; however, this difference wasnot statistically significant (P = .19 by the log-rank test).In fact, at 15 months the survival curves for these two treatmentregimens overlapped. This study demonstrated the benefits of combinedradiation and 5-FU therapy compared with radiation alone in patientswith pancreatic cancer confined to the pancreas and peripancreaticarea [32,33].

Klaassen et al of the Eastern Cooperative Oncology Group (ECOG)studied 5-FU alone (600 mg/m² IV weekly) vs 5-FU plus radiationtherapy (4,000 cGy) in patients with locally unresectable disease[34]. Median survival was equivalent for the two treatment groups.In the 91 patients analyzed, median survival was 8.2 months with5-FU (N = 44) vs 8.3 months with 5-FU plus radiation (N = 47).These results suggested that patients with locally unresectablepancreatic cancer should receive 5-FU alone, because this regimenproduced results similar to those obtained with 5-FU plus radiation.

A subsequent study by the GITSG disputed the results of Klaassenet al and confirmed the advantage of radiation plus chemotherapyover chemotherapy alone [35]. This study compared radiation pluscombination chemotherapy (streptozocin, mitomycin, and 5-FU [SMF])with combination chemotherapy alone. Radiation plus chemotherapyresulted in a 1-year survival rate of 41%, as compared with 19%for chemotherapy alone (P less than .02) [35].

As a result of the GITSG trial and other studies, radiation therapyplus chemotherapy has been used to improve local control and influencesurvival in patients with locally unresectable pancreatic cancer.

Future Directions

Novel combinations and means of administering radiation therapyand chemotherapy may yield better local control and survival forpatients with resectable and locally unresectable disease [36,37].Recent studies suggest that preoperative administration of radiationplus chemotherapy may be of benefit in selected patients [38-40],but additional study is needed to confirm these results. Chemotherapeuticagents other than 5-FU that may provide synergistic effects whencombined with radiation include mitomycin and cisplatin (Platinol).In addition, gemcitabine, a deoxycytidine analog currently inclinical trials,* has produced increased radiation sensitivityin human colon carcinoma cells [5].

Pancreatic cancer remains difficult to treat. Current data supportthe use of adjuvant radiation plus chemotherapy following surgicalresection. For patients with locally unresectable pancreatic cancer,data from the GITSG and other groups also support the use of radiationplus chemotherapy for palliation. Continued research into therole of radiation therapy in the treatment of pancreatic canceris clearly warranted.

References:

1. Brennan MF, Kinsella TJ, Casper ES: Cancer of the pancreas,in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles& Practice of Oncology, 4th ed, pp 849-882. Philadelphia,JB Lippincott, 1993.

2. Abrams RA, Grochow LB: Adjuvant therapy with chemotherapy andradiation therapy in the management of carcinoma of the pancreatichead. Surg Clin North Am 75:925-938, 1995.

3. Heijmans HJ, Hoekstra HJ, Mehta DM: Is adjuvant intra-operativeradiotherapy (IORT) for resectable and unresectable pancreaticcarcinoma worthwhile? Hepatogastroenterology 36:474-477, 1989.

4. Nakajima Y, Miyamoto T, Tanabe M, et al: Enhancement of mammaliancell killing by 5-fluorouracil in combination with X-rays. CancerRes 39:3763-3767, 1979.

5. Shewach DS, Lawrence TS: Radiosensitization of human tumorcells by gemcitabine in vitro. Semin Oncol 22:68-71, 1995.

6. Pilepich MV, Miller HH: Preoperative irradiation in carcinomaof the pancreas. Cancer 46:1945-1949, 1980.

7. Ishikawa O, Ohhigashi H, Teshima T, et al: Clinical and histopathologicalappraisal of preoperative irradiation for adenocarcinoma of thepancreatoduodenal region. J Surg Oncol 40:143-151, 1989.

8. Evans DB, Rich TA, Byrd DR, et al: Adenocarcinoma of the pancreas:Current management of resectable and locally advanced disease.South Med J 84:566-570, 1991.

9. Tepper J, Nardi G, Suit H: Carcinoma of the pancreas: Reviewof MGH experience from 1963 to 1973. Analysis of surgical failureand implications for radiation therapy. Cancer 37:1519-1524, 1976.

10. Griffin JF, Smalley SR, Jewell W, et al: Patterns of failureafter curative resection of pancreatic carcinoma. Cancer 66:56-61,1990.

11. Sindelar WF, Kinsella TJ: Randomized trial of intraoperativeradiotherapy in resected carcinoma of the pancreas (abstract).Proceedings of the 28th Annual ASTRO Meeting 12:148, 1986.

12. Zerbi A, Fossati V, Parolini D, et al: Intraoperative radiationtherapy adjuvant to resection in the treatment of pancreatic cancer.Cancer 73:2930-2935, 1994.

13. Kalser MH, Ellenberg SS: Pancreatic cancer: Adjuvant combinedradiation and chemotherapy following curative resection. ArchSurg 120:899-903, 1985.

14. Douglass HO: Current approaches to multimodality managementof advanced pancreatic cancer. Hepatogastroenterology 40:433-442,1993.

15. Gastrointestinal Tumor Study Group: Further evidence of effectiveadjuvant combined radiation and chemotherapy following curativeresection of pancreatic cancer. Cancer 59:2006-2010, 1987.

16. Douglass HO, Stablein DM, Kalser MH, et al: Confirmation bythe gastrointestinal tumor study group that survival followingpotentially curative resection of pancreatic cancer is improvedby multidisciplinary postoperative therapy, in Salmon SE (ed),Adjuvant Therapy of Cancer V, p 525. Orlando, Florida, Grune &Stratton, 1987.

17. Willett CG, Lewandrowski K, Warshaw AL, et al: Resection marginsin carcinoma of the head of the pancreas: Implications for radiationtherapy. Ann Surg 217:144-148, 1993.

18. Yeo CJ, Cameron JL, Lillemoe KD, et al: Pancreaticoduodenectomyfor cancer of the head of the pancreas: 201 patients. Ann Surg221:721-733, 1995.

19. Carducci MA, Abrams RA, Yeo CJ, et al: Early evaluation ofabdominal/hepatic irradiation and 5-fluorouracil/leucovorin infusionafter pancreaticoduodenectomy. Int J Radiat Oncol Biol Phys 35:143-150,1996.

20. Haslam JB, Cavanaugh PJ, Stroup SL: Radiation therapy in thetreatment of irresectable adenocarcinoma of the pancreas. Cancer32:1341-1345, 1973.

21. Dobelbower RR Jr, Borgelt BB, Strubler KA, et al: Precisionradiotherapy for cancer of the pancreas: Technique and results.Int J Radiat Oncol Biol Phys 6:1127-1133, 1980.

22. Shibamoto Y, Manabe T, Baba N, et al: High dose, externalbeam and intraoperative radiotherapy in the treatment of resectableand unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys19:605-611, 1990.

23. Leichman L, Seydel HG, Stablein D, for the GastrointestinalTumor Study Group: Continuous hyperfractionated radiation + 5-fluorouracil(5FU) followed by streptozotocin, mitomycin-C and 5FU for patientswith localized unresectable cancer of the pancreas: A GITSG pilot-trial(abstract). Proc Am Assoc Cancer Res 25:195, 1984.

24. Roldan GE, Gunderson LL, Nagorney DM, et al: External beamversus intraoperative and external beam irradiation for locallyadvanced pancreatic cancer. Cancer 61:1110-1116, 1988.

25. Abe M, Takahashi M, Yabumoto E, et al: Clinical experienceswith intraoperative radiotherapy of locally advanced cancers.Cancer 45:40-48, 1980.

26. Shipley WU, Wood WC, Tepper JE, et al: Intraoperative electronbeam irradiation for patients with unresectable pancreatic carcinoma.Ann Surg 200:289-296, 1984.

27. Rich TA: Radiation therapy for pancreatic cancer: Eleven yearexperience at the JCRT. Int J Radiat Oncol Biol Phys 11:759-763,1985.

28. Mohiuddin M, Cantor RJ, Biermann W, et al: Combined modalitytreatment of localized unresectable adenocarcinoma of the pancreas.Int J Radiat Oncol Biol Phys 14:79-84, 1988.

29. Thomas FJ, Krall J, Hendrickson F, et al: Evaluation of neutronirradiation of pancreatic cancer. Am J Clin Oncol 12:283-289,1989.

30. Linstadt D, Quivey JM, Castro JR, et al: Comparison of helium-ionradiation therapy and split-course megavoltage irradiation forunresectable adenocarcinoma of the pancreas: Final report of anorthern California oncology group randomized prospective clinicaltrial. Radiology 168:261-264, 1988.

31. Moertel CG, Childs DS Jr, Reitemeier RJ, et al: Combined 5-fluorouraciland supervoltage radiation therapy of locally unresectable gastrointestinalcancer. Lancet 2:865-867, 1969.

32. Gastrointestinal Tumor Study Group: Comparative therapeutictrial of radiation with or without chemotherapy in pancreaticcarcinoma. Int J Radiat Oncol Biol Phys 5:1643-1647, 1979.

33. Moertel CG, Frytak S, Hahn RG, et al: Therapy of locally unresectablepancreatic carcinoma: A randomized comparison of high dose (6000rads) radiation alone, moderate dose radiation (4000 rads + 5-fluorouracil),and high dose radiation + 5-fluorouracil. Cancer 48:1705-1710,1981.

34. Klaassen DJ, MacIntyre JM, Catton GE, et al: Treatment oflocally unresectable cancer of the stomach and pancreas: A randomizedcomparison of 5-fluorouracil alone with radiation plus concurrentand maintenance 5-fluorouracil--an Eastern Cooperative OncologyGroup Study. J Clin Oncol 3:373-378, 1985.

35. Gastrointestinal Tumor Study Group: Treatment of locally unresectablecarcinoma of the pancreas: Comparison of combined-modality therapy(chemotherapy plus radiotherapy) to chemotherapy alone. J NatlCancer Inst 80:751-755, 1988.

36. Rich TA, Evans DB, Curley SA, et al: Adjuvant radiotherapyand chemotherapy for biliary and pancreatic cancer. Ann Oncol5(suppl 3):S75-80, 1994.

37. Komaki R, Wilson JF, Cox JD, et al: Carcinoma of the pancreas:Results of irradiation for unresectable lesions. Int J RadiatOncol Biol Phys 6:209-212, 1980.

38. Yeung RS, Weese JL, Hoffman JP, et al: Neoadjuvant chemoradiationin pancreatic and duodenal carcinoma. Cancer 72:2124-2133, 1993.

39. Coia L, Hoffman J, Scher R, et al: Preoperative chemoradiationfor adenocarcinoma of the pancreas and duodenum. Int J RadiatOncol Biol Phys 30:161-167, 1994.

40. Hoffman JP, Weese JL, Solin LJ, et al: A pilot study of preoperativechemoradiation for patients with localized adenocarcinoma of thepancreas. Am J Surg 169:71-78, 1995.