Systemic And Regional Chemotherapy For Advanced Hepatobiliary Carcinomas
1983; King Faisal Specialist Hospital and Research Centre; Volume: 3; Issue: 2 Linguagem: Inglês
10.5144/0256-4947.1983.105
ISSN0975-4466
Autores Tópico(s)Viral-associated cancers and disorders
ResumoCurrent Concepts in MedicineSystemic And Regional Chemotherapy For Advanced Hepatobiliary CarcinomasA Progress Report Agop Y. BedikianMD, FACP Agop Y. Bedikian Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Centre Search for more papers by this author Published Online:1 Apr 1983https://doi.org/10.5144/0256-4947.1983.105SectionsPDF ToolsAdd to favoritesDownload citationTrack citations ShareShare onFacebookTwitterLinked InRedditEmail AboutINTRODUCTIONPrimary hepatic cancer is a common disease in several countries in the African and Asian continents. Among certain African tribes, especially the Bantus, hepatoma accounts for 30 to 50 percent of all cancers. The incidence of hepatoma in Saudi Arabia is several times higher than that in the United States. The experience at the Oncology Department of the King Faisal Specialist Hospital and Research Centre shows that about 20 percent of all patients with malignant neoplasms arising from organs of the digestive system are diagnosed as having primary hepatic cancer, compared with an incidence of 2 percent in the United States.1 In our institution it is second only to esophageal cancer as the leading cancer affecting the organs of the digestive system. Carcinoma of the biliary system, on the other hand, is rare, with an incidence of 9 percent. The prognosis of patients with hepatobiliary cancer is poor with an average survival duration of 5 to 7 months from onset of symptoms. Occasionally, a patient will survive 5 years. Only a few patients have surgically resectable tumors at diagnosis.1HepatomaPatients with surgically nonresectable primary hepatic cancer will be primarily treated with systemic chemotherapy, except for a small proportion of patients with good general health and tumors limited to the liver who are also candidates for regional chemotherapy. Comparison of efficacy of treatment regimens is difficult because of inadequate characterization of patient populations included in the chemotherapy studies. Patient characteristics that have been shown to influence survival duration significantly include the pre-treatment performance status, jaundice, sex, and race.2 These factors must be kept in mind when comparing the efficacy of the different chemotherapy regimens.SYSTEMIC CHEMOTHERAPYSingle-Agent TreatmentThe use of cytotoxic agents in the treatment of hepatomas has been under investigation for the past two decades. Important clinical antitumor activity has been documented for only a few agents. The cumulative result of single-agent treatment of hepatomas has been recently reviewed3 (Table 1). The efficacy of Adriamycin (doxorubicin) has been shown in multiple studies. Olweny et al. administered Adriamycin at the dose of 75 mg/m2 every 3 weeks to 14 patients and achieved three complete and eight partial remissions with a median survival duration of 8 months.4 Subsequent studies in the United States confirmed this activity of Adriamycin, although with lower response rates. Adriamycin at 60 mg/m2 every 3 weeks resulted in objective tumor regression in 32 percent of 44 patients, with 5 patients achieving complete remission and surviving 12 to 24 months.5 However, the overall median survival duration was only 14 weeks. Vogel et al. treated 41 patients and observed correlation between the Adriamycin dose tolerated and the response rate. The good risk patients who received Adriamycin 75 mg/m2 had a higher response rate than poor risk patients requiring dosage reduction because of the presence of jaundice (16 percent versus 8 percent respectively).6 In a large, randomized, clinical trial conducted by the Eastern Cooperative Oncology (Group (ECOG) and Falkson, Adriamycin resulted in three responses in 36 patients (31 with no prior therapy).2 In addition, 23 percent of the 26 patients who received Adria-mycin after failing on the other treatments that included either 5-fluorouracil (5-FU), 5-FU/streptozotocin or 5-FU/methyl CCNU responded. In this trial 5-FU was given orally. The cumulative results of single-agent treatment of hepatoma resulted in a 19 percent response rate in 165 patients.3,7 The response rate was higher in African patients (16 of 47 versus 15 of 118 patients respectively).Table 1. Hepatoma: cumulative data on systemic chemotherapyTable 1. Hepatoma: cumulative data on systemic chemotherapyFive-fluorouracil has shown very limited activity in several studies. Despite the high response rate (40 percent) reported by Livingston and Carter based on the collected cases from English medical literature, and 50 percent response rate in 12 patients treated with 5-FU administered orally reported by Kennedy et al., most clinical trials show 5-FU to be ineffective against hepatoma.8,9 Link et al. in a prospective study randomly assigned patients with biopsy-proven hepatoma to receive 5-FU either orally or intravenously. No responses were observed.10 Similarly, no responses were seen in 48 patients treated with 5-FU administered by mouth in a large study by ECOG and Falkson.2 The overall success of 5-FU against hepatoma is about 10 percent, the response rate to 5-FU administered intravenously being only slightly higher.3The majority of reported clinical trials using other antitumor agents have been too limited to permit a definite conclusion about their effectiveness. Of the new anticancer drugs, only neocarzinostatin, a polypeptide antibiotic isolated from Streptomyces carzinostaticus, has been adequately evaluated. Review of clinical trials in hepatoma completed in Japan and the United States indicates a response rate of about 20 percent in 52 patients.11,12 Less conclusive studies include trials with etoposide (VP-16-213), a podophyllotoxin derivative, which was recently evaluated for activity against hepatoma.13 It has shown activity when administered by the intravenous or the oral route.14,15 The overall response rate stands at 19 percent in 32 patients treated thus far. In 28 patients entered in four studies, mitomycin C has produced a 25 percent response rate.3,16 Limited evaluation of dichlormethotrexate and AMSA (4-9[acridinylamino]-methane-sulfon-M-anisidide) has resulted in no responses in 16 and 9 patients respectively.Multidrug Combination ChemotherapyClinical trials with multidrug regimens in patient: with hepatoma have also been limited. Only a few have adequate patient entry to permit specific statements about their effectiveness. Five-FU/methyl CCNU (semustine), Adriamycin/bleomycin, 5-FU/Adriamycin, and 5-FU/strepto-zotocin two-drug regimens have been evaluated in more than 30 patients each and given response rates ranging from 5 to 23 percent (Table 1). In the ECOG-South African multi-institutional randomized study, 5-FU was administered by mouth in combination with either methyl CCNU or streptozotocin.2 The low response rates, 5 percent and 12 percent respectively, could have been due to poor absorption of 5-FU when administered orally. Five-FU/mitomycin C gave responses in 39 percent of 13 patients. The addition of Adriamycin to the combination did not improve the efficacy of the combination.20 In a small group of patients, the Adriamycin/mitomycin two-drug regimen gave responses in four of seven patients.7 Despite the higher response rates reported with some of these multidrug regimens, a significant survival advantage over Adriamycin has not been documented.INTRA-ARTERIAL REGIONAL THERAPYBecause hepatoma at times is detected at a stage limited to the liver, albeit the surgically unresectable stage, chemotherapy administered via the hepatic artery is considered a logical alternative therapy for these patients. Floxuridine (FUDR), dichlormethotrexate, mitomycin C, and Adriamycin have been administered by this route and resulted in prolonged survival in a few patients. El Domeiri et al. treated six patients with either 5-FU or methotrexate and observed survivals ranging from 4 months to 3 years.22 Five patients treated with intra-arterial methotrexate survived longer than four patients treated with intra-arterial 5-FU in Geddes' study (median 9.5 versus 3 months).23 Sundqvist et al. treated 46 patients with primary and secondary liver cancer (including 11 with hepatoma) with intra-arterial 5-FU. The median survival duration was 7 months and the 1-year survival rate was 27 percent. Unfortunately, the data on survival of hepatoma patients were not reported separately.24 Reed et al. treated 13 patients with hepatoma with intra-arterial FUDR and observed clinically significant tumor regression in 9 and overall median survival duration of 7 months.25 In a randomized clinical trial that included 81 patients, Ong and Chan observed no survival advantage for patients randomized for hepatic arterial infusion of 5-FU, hepatic de-arterialization plus portal vein infusion, or hepatic dearterialization plus radiotherapy over patients who were randomized for no treatment.26Despite the numerous reports of the efficacy of Adriamycin administered intravenously, data on its efficacy against hepatoma when given via the hepatic artery are very scanty. Responses were observed in four of six patients who were included in two studies employing Adriamycin administered through the hepatic artery.27,28 Matsu-moto et al. treated patients with mitomycin C given weekly through the hepatic artery (8 patients) or every 2 to 4 months through the celiac artery (13 patients). The median survival was longer for patients treated through the celiac artery (median 178 versus 130 days).29 Kinami and Miyazaki reported objective tumor regression in 7 of 14 patients with intra-arterial mitomycin C. The median survival in the overall group was 7.1 months.30 Patt et al. treated 10 patients with hepatoma confined to the liver with FUDR. Adriamycin, and mitomycin C administered through the hepatic Artery. Six patients achieved a partial remission and two other patients had minor responses. The treatment was well tolerated and associated with little morbidity.31Thus, several antitumor agents have been delivered intra-arterially with some success. It is difficult to compare these results with those observed in patients treated with intravenous chemotherapy because of the marked differences in the selection criteria. The superior response rates and survival duration obtained with hepatic arterial treatment regimens could as well be due to selection of patients with better prognostic factors in these studies.Gallbladder and Bile Duct CarcinomasGallbladder cancer and bile duct carcinomas constitute about 9 percent of all gastrointestinal malignant neoplasms seen in the Oncology Department at King Faisal Specialist Hospital and Research Centre. They constitute 3 to 6 percent of all gastrointestinal malignancies in the United States.32,33 Of the 75 patients with gallbladder cancer seen at M. D. Anderson Hospital, the median survival duration was 5.2 months.32 Only 5 percent of the patients had curative resection for malignancy limited to the gallbladder. Of 47 patients with carcinoma of the extrahepatic bile ducts, more than half had either direct invasion into the liver or metastasis to nearby organs, including the pancreas and small bowel.34 The overall median survival duration was 8 months, with 15 percent of the patients surviving more than 2 years. Only 16 percent of the patients were found to have limited tumors and underwent curative surgical resection.The information about the efficacy of anticancer drugs in the management of these malignancies has been hampered by the absence of chemotherapy trials designed to evaluate efficacy of anticancer drugs against these malignancies separately and the difficulty in obtaining objective measurement of tumor response. Researchers conducting early studies relied upon symptomatic improvement and survival duration to evaluate response to treatment. The introduction of computed tomographic (CT) scan and sonography has made possible objective evaluation of the efficacy of antitumor agents against these malignancies.SYSTEMIC CHEMOTHERAPYSingle-Agent TreatmentReports of efficacy of chemotherapy against gallbladder cancer are scanty mainly because these results are reported in combination with those of bile duct cancer. In a retrospective case review, Perpetuo et al. observed no response in 36 patients treated with 5-FU, Adriamycin, or nitrosourea-containing regimens.32 In another series, the median survival duration of 23 patients with gallbladder cancer treated with 5-FU was 4 months. The 1-year survival rate was only 17 percent.35 Three patients with biliary tract tumors in this series survived 1.5, 10, and 13 months. Retrospective analyses of cases of bile duct cancer treated at M. D. Anderson Hospital and Tumor Institute showed six partial remissions among 21 patients treated with chemotherapy.34 The responding patients survived significantly longer than nonresponding patients (median 8.5 versus 2 months, p = 0.005). The cumulative results of single-agent treatment of gallbladder and bile duct cancers have been recently reviewed3 (Table 2). The effective antitumor agents include 5-FU, mitomycin C, nitrosoureas, and DTIC (dacarbazine). Of the new anticancer agents, only neocarzinostatin has had some evaluation.Table 2. Biliary tract carcinoma: cumulative data on systemic chemotherapyTable 2. Biliary tract carcinoma: cumulative data on systemic chemotherapyMultidrug Combination ChemotherapyIn spite of limited data on single-agent activity of the above antitumor agents, several multidrug regimens have been designed and evaluated. The 5-FU/Adriamycin/mitomycin C (FAM) regimen has been evaluated in 17 patients with intrahepatic or extrahepatic cholangiocarcinomas and resulted in three responses among 14 patients with measureable disease.20 One of the three patients without measureable disease was alive after 46 months. The overall median survival was 8 months. In a smaller series, ftorafur/Adriamycin/BCNU, a three-drug combination, resulted in two complete and one partial response in seven evaluable patients.36 Information about survival duration was not provided. The reported experience with other regimens is too fragmentary to enable any conclusion.INTRA-ARTERIAL CHEMOTHERAPYExperience with intra-arterial chemotherapy for the carcinomas of the gallbladder and bile duct is very fragmentary. The number of patients with these tumors entered into regional chemotherapy protocols is too small to give any idea about the efficacy of this approach. However, Reed et al. reported on 10 patients with gallbladder and bile duct cancer treated with FUDR administered through the hepatic artery.25 They observed objective tumor regression in eight of nine patients who had adequate trials with this treatment. In several patients, the response lasted more than 7 months. The responders survived significantly longer than nonresponders (median 6 versus 1 month). Misra et al. treated 13 patients with advanced gallbladder cancer using intrahepatic arterial infusion with 5-FU and mitomycin C.38 Nine of 13 patients had an objective response defined as at least 50 percent decrease in the liver size and in the abnormal levels of serum alkaline phosphatase and glutamic oxaloacetic transaminase and near normal levels of serum bilirubin for a minimum period of 2 months. Their survival periods ranged from 4.6 to 14 months.CONCLUSIONPending the discovery of methods leading to early diagnosis, the majority of patients with hepatobiliary carcinomas will continue to present with advanced stages of disease. Although the available chemotherapy regimens are only modestly effective, in the past few years there has been renewed interest in new therapies that have led to the discovery of new drugs and multidrug regimens with encouraging activity. At the present time there is no conclusive evidence that patients with hepatobiliary carcinomas survive longer when treated with hepatic artery infusions than when treated with systemic chemotherapy. Similarly, the advantage of multidrug regimens over Adriamycin alone remains debatable. The discovery of new and more effective drugs offers the best hope for these patients.ARTICLE REFERENCES:1. Moertel CG: The liver. In: Holland JF, Frei E, eds: Cancer Medicine. Philadelphia, Lea and Febiger; 1974 p 1541. 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Hall SW, Benjamin RS, Murphy WKet al..: "Adriamycin, BCNU, Ftorafur chemotherapy of pancreatic and biliary tract cancer" . Cancer 44(6):20081979. Google Scholar37. Karlin DA, Stroehlein JR, Bennetts RW, et al..: "Combination 5-Fluorouracil, Adriamycin, mitomycin-C and methyl CCNU (FAMMe) chemotherapy for advanced gastrointestinal cancer" . Proc AACR and ASCO 22:2641981. Google Scholar38. Misra NC, Jaiswal MS, Singh RV, et al..: "Intrahepatic arterial infusion of combination of mitomycin-C and 5-fluorouracil in treatment of primary and metastatic liver carcinoma" . Cancer 39(4):14251977. Google Scholar Previous article Next article FiguresReferencesRelatedDetails Volume 3, Issue 2April 1983 Metrics History Published online1 April 1983 KeywordsBile duct neoplasms—Drug therapyGallbladder neoplasms—Drug therapyHepatoma—Drug therapyInformationCopyright © 1983, Annals of Saudi MedicinePDF download
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