[MOL] Advances in the treatment of GI cancer.... [00518] Medicine On Line

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[MOL] Advances in the treatment of GI cancer....

Advances in the Treatment of GI Cancer

Peter O'Dwyer, MD

The studies presented Tuesday (September 14) had no breakthrough findings. Rather, many of these intriguing small and pilot studies provided clues to ways of improving treatment of esophageal, gastric, pancreatic, and other GI malignancies, especially with additions to accepted combinations.

Advances in Esophageal and Gastric Cancer

The Royal Marsden (London) group has previously demonstrated the superiority of epirubicin, cisplatin, 5-fluorouracil (ECF) to a doxorubicin-containing regimen in patients with both esophageal and gastric cancers.[1] Because myelosuppression with epirubicin precluded dose-intensification of 5-FU, mitomycin-C was substituted for epirubicin. The resulting MCF regimen contained a daily dose of 5-FU of 300 mg per m2 versus 200 mg per m2in ECF. Ross presented the results of a randomized trial of the two regimens in 580 patients with both esophageal and gastric cancers.[2] Response rates were similar for both ECF and MCF (40% and 42%), 8% of which were complete responders in each arm. Progression-free survival was 7 months on each arm, and overall survival 9.0 and 8.7 months, respectively (P =.6). A quality of life (QOL) analysis showed consistently better results for ECF at all times measured. Thus, with equal efficacy and superior QOL, retention of ECF as a standard regimen is favored. In the discussion, the role of epirubicin in the combination was questioned: an important question remains concerning its contribution to the known active 5-FU/cisplatin combination. Similar response rates and survival were obtained irrespective of the primary site in this large study.

In esophageal cancer, a novel regimen of infusional 5-FU and cisplatin with hydroxyurea and leucovorin was presented by Taieb (Paris).[3] Eighty-one patients with locally advanced (37 patients) or metastatic (44 patients) disease were treated, and a response rate of 57% was observed, of whom 7% were complete responders. Median disease-free survival was 9 months, and overall survival 17 months.

Both of these studies support the continued use of the core combination of infusional 5-FU (either continuous or for 48 hours every 2 weeks) with cisplatin in esophageal and gastric cancers, and provide renewed stimulus for the integration of novel agents.

Such integration has been achieved for treatment of gastric cancer, as reported by Roth, for the Swiss Group for Clinical Cancer Research (SAKK).[4] Taxotere is active against gastric cancer, alone and with cisplatin.[5] In a phase I-II study in 43 patients, infusional 5-FU had been added to yield the regimen TCF (taxotere 85 mg per m2/day 1, cisplatin 75 mg per m2/day 1, 5-FU 300 mg per m2/days 1 to 14, repeated every 3 weeks). Grade 3-4 neutropenia is tolerable (23%) with this regimen, and a response rate of 50% has been observed. Overall survival at 9.3 months is comparable to other regimens in gastric cancer. A phase III study is planned.

In discussion, there emerged a clear consensus that cisplatin with an infusional 5-FU regimen remains the mainstay for therapy of both esophageal and gastric cancers, but beyond this, no "gold standard" has been established.

Resectable Gastric Cancer

In resectable gastric cancer, a study presented by Skoropad[6] (Obninsk, Russia) generated substantial interest. Eighty-five patients were randomized to receive a regimen including hyperfractionated external beam radiation (27 Gy) followed immediately by gastrectomy and intraoperative radiation therapy (IORT) (20 Gy) or surgery alone. While survival was not significantly different for the whole group, subgroup analysis revealed a potential benefit in patients with T3/T4 or N1/N2 disease. Controversial in the light of negative results from other randomized trials, the study was viewed as provocative, with the potential to rekindle interest in this modality, especially in combination with external beam radiation.

Advances in Pancreatic Cancer

The role of cisplatin in the treatment of advanced pancreatic cancer has been reevaluated recently, with potentially interesting results from combination phase II studies with 5-FU and with gemcitabine. Decreux and colleagues (Paris) reported a multicenter phase III trial in which 5-FU (daily x5 bolus) was compared with cisplatin in combination with 5-FU (5-day infusion).[7] Results were as follows:

  n N/V Neutropenia PR SD TTP (weeks) OS (weeks) % 1 yr
5-FU 103 4% 6% 0 10% 8.4 14.6 9%
5-FU/DDP 104 16% 22% 10% 20% 10.4 16 18%
N/V = nausea/vomiting; PR = partial response; SD = stable disease; TTP = time to progression (weeks); OS = overall survival; DDP = cisplatin

These survival values are somewhat lower than those reported from other randomized studies.[8] The authors' conclusion was that while a benefit from cisplatin is demonstrated, it is marginal, and the regimen is not construed as a new standard. However, they proposed that these data may permit the development of strategies to integrate platinum compounds in the treatment of advanced pancreatic cancer.

In locally advanced pancreatic cancer, combination studies of radiation and chemotherapy were presented. Preoperative 5-FU/MMC was shown by Brunner[9] (Erlangen) to be well-tolerated in a group of 37 patients, all unresectable at diagnosis, 10 of whom could subsequently be resected. Four of these are free of disease at a median of 12 months' follow-up. The toxicity of the treatment was less than that reported by Hoffman previously,[10] and caution will be required before its application in a multi-institutional setting.

In a pilot study, Antonisse and colleagues (Amsterdam) presented a poster describing the successful integration of gemcitabine with radiation.[11] The latter was an unconventional hypofractionated weekly regimen for 3 weeks (8 Gy per dose), with gemcitabine 300 mg per m2 given with the radiation, and continued at full dose following the radiation. Among 21 patients, a reduction in the level of tumor marker CA19.9 was noted in over 80%, and median survival was 16 months.

Biological Advances

The impetus to apply biological advances to clinical medicine was continued at Tuesday's meeting. Johnston and Danenberg have published extensively on the predictive value of thymidylate synthase (TS) expression in defining the outcome and response to therapy of colon cancer in both the advanced and adjuvant setting.[12] Larsson and colleagues (Goteburg) used RT-PCR and an enzymatic assay to quantitate TS from fresh colon tumor tissue of 61 patients, all of whom were operable. Dukes' stages were A, 4; B, 26; C, 17; and D, 13 patients.[13] No correlation of the RT-PCR-derived mRNA expression and the TS enzymatic assay data were obtained, and no relationship to outcome could be demonstrated. The discussion reflected the attention to methodologic detail that is required for these assays and the continued need to apply the techniques in large studies.

A very valuable application of biological analyses was provided by Kubicka (Hannover).[14] Patients with primary sclerosing cholangitis (PSC) are at increased risk of cholangiocarcinoma. Small tumors are often identified at transplantation and may contraindicate this otherwise curative procedure. Ideally, one would like to identify at-risk patients as early as possible. K-ras mutation has previously been reported in 10 of 17 patients with cholangiocarcinoma. Using a sensitive PCR-RFLP (polymerase chain reaction - restriction fragment length polymorphism) method, biliary washings from 56 PSC patients and 20 controls were analyzed. None of the controls, but 17/56 (30%) of the PSC patients, were positive for the K-ras mutation. After 30 months of further follow-up, only one patient without a K-ras mutation had developed neoplastic change, and this was dysplasia. Of the patients positive for the mutation, 4 had developed cholangiocarcinoma and 2 dysplasia. Clearly, these results indicate that surveillance for the K-ras mutation will be valuable in the long-term management of PSC, and may have the potential to permit interventions in time to prevent the development of cancer.

References

  1. Waters JS, Norman A, Cunningham D, et al. Long-term survival after epirubicin, cisplatin and fluorouracil for gastric cancer: results of a randomized trial. Br J Cancer. 1999 Apr;80(1-2):269-72.
  2. Ross P, Cunningham D, Scarffe H, et al. Results of a randomised trial comparing ECF with MCF in advanced oesophago-gastric cancer. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 496.
  3. Taieb J, Artru P, Louvet C, et al. Advanced esophageal cancer patients treated with hydroxyurea, leucovorin, 5-fluorouracil and cisplatin (HLFP regimen). Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 504.
  4. Roth AD, Maibach R, Fazio N, et al. 5FU as protracted continuous IV infusion (5Fupiv) can be added to full dose taxotere-cisplatin (TC) in advanced gastric carcinoma (AGC). Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 506.
  5. Einzig AI, Schuchter LM, Recio A, Coatsworth S, Rodriquez R, Wiernik PH. Phase II trial of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy: the Eastern Cooperative Oncology Group (ECOG) results of protocol E1293. Med Oncol. 1996 Jun;13(2):87-93.
  6. Skoropad V, Berdov B. Randomized trial of preoperative (PRT) and intraoperative (IORT) radiotherapy versus surgery alone in resectable gastric cancer. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 508.
  7. Decreux M, Douillard JY, Pignon JP, et al. Efficacy of 5FU + cisplatin (FUP) compared to bolus 5FU (FU) in advanced pancreatic carcinoma (APC). Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 497.
  8. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol. 1997 Jun;15(6):2403-2413.
  9. Brunner TB, Grabenbauer GG, Kasti S, et al. Locally advanced pancreatic carcinoma: Neoadjuvant radiochemotherapy (RCT) with f-fu and mitomycin c. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 498.
  10. Hoffman JP, Cooper HS, Young NA, Pendurthi TK. Preoperative chemotherapy of chemoradiotherapy for the treatment of adenocarcinoma of the pancreas and ampulla of Vater. J Hepatobiliary Pancreat Surg. 1998;5(3):251-254.
  11. Antonisse IE, van Groeningen CJ, Langendijk JA, et al. A phase II study of hypofractionated radiotherapy in combination with Gemcitabin in the palliative treatment of advanced pancreatic carcinoma. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 514.
  12. Leichman CG, Lenz HJ, Leichman L, et al. Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin. J Clin Oncol. 1997 Oct;15(10):3223-3229.
  13. Larsson P-A, Odin E, Wettergren Y, et al. Basal level gene expression of thymidylate synthase (TS) in colorectal cancer and normal colon mucosa - No evidence of relation to disease course. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 501.
  14. Kubicka S, Meier P, Flemming P, et al. High incidence of K-Ras mutations in the bile fluids of patients with primary sclerosing cholangitis. Abstracts and Proceedings from ECCO 10. Sept 12-16, 1999; Vienna, Austria. Abstract 499.
Warmly, lillian
 
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