M. Hejna

The role of chemotherapy and radiation in the management of biliary cancer : a review of the literature

Carcinoma of the biliary tract is a rare tumour. To date, there is no therapeutic measure with curative potential apart from surgical intervention. Thus, patients with advanced, i.e. unresectable or metastatic disease, face a dismal prognosis. They present a difficult problem to clinicians as to whether to choose a strictly supportive approach or to expose patients to the side-effects of a potentially ineffective treatment. The objective of this article is to review briefly the clinical trials available in the current literature utilising non-surgical oncological treatment (radiotherapy and chemotherapy) either in patients with advanced, i.e. locally inoperable or metastatic cancer of the biliary tract or as an adjunct to surgery. From 65 studies identified, there seems to be no standard therapy for advanced biliary cancer. Despite anecdotal reports of symptomatic palliation and survival advantages, most studies involved only a small number of patients and were performed in a phase II approach. In addition, the benefit of adjuvant treatment remains largely unproven. No clear trend in favour of radiation therapy could be seen when the studies included a control group. In addition, the only randomised chemotherapeutic series seemed to suggest a benefit of treatment in advanced disease, but due to the small number of patients included, definitive evidence from large, randomised series concerning the benefit of non-surgical oncological intervention as compared with supportive care is still lacking. Patients with advanced biliary tract cancer should be offered the opportunity to participate in clinical trials.

Two consecutive phase II studies of 5-fluorouracil/leucovorin/mitomycin C and of gemcitabine in patients with advanced biliary cancer.

Introduction: Carcinoma of the biliary system is a rare tumor entity, and patients with advanced disease face a dismal prognosis. Because of the absence of standard chemotherapy for advanced biliary carcinoma, we have performed two consecutive studies to evaluate the clinical potential of 5-fluorouracil, leucovorin and mitomycin C as well as the novel antimetabolite gemcitabine in this disease. Patients and Methods: A total of 39 consecutive patients suffering from locally inoperable or metastatic biliary cancer were enrolled in the study between March 1994 and October 1997. Twenty patients were treated with leucovorin 200 mg/m2 and 5-FU 400 mg/m2, both given as intravenous bolus on days 1–4, and mitomycin C 8 mg/m2 on day 1 (group A). Treatment cycles were repeated every 28 days. The second cohort included 19 patients, who received gemcitabine 1200 mg/m2 on days 1, 8 and 15 with a 2-week interval before the next treatment cycle (group B). Treatment was continued for a maximum of 6 cycles in the absence of progressive disease in both groups, and endpoints of the study were responses rates, survival and toxicity. Results: In group A, 5 patients (25%) had a partial response (PR), 6 additional patients (30%) had stable disease (SD) and 9 patients (45%) progressed during treatment. The median survival was 9.5 months (range, 3–14.5) with the median time to progression being 4 months (range, 3–9). In group B, 3 patients achieved a PR (16%), 4 showed SD (21%), while the remaining 12 patients had progressive disease. A median survival of 6.5 months (range, 2–11.5) was obtained, and the median time to progression was 2.5 months (range, 1–6+). Toxicity was generally mild in both treatment arms, 6 patients in group A required dose reductions, while no dose adaptation had to be performed for gemcitabine. Conclusion: Our data suggest that treatment of advanced biliary cancer is feasible and can be safely performed with both regimens applied in our study. While administration of gemcitabine has resulted in only mild toxicities, its exact impact on the management of advanced biliary cancer should be evaluated in a controlled trial.

Value of Peptide Receptor Scintigraphy Using 123I-Vasoactive Intestinal Peptide and 111In-DTPA-D-Phe1-Octreotide in 194 Carcinoid Patients: Vienna University Experience, 1993 to 1998

PURPOSE To report our experience with both (123)I-vasoactive intestinal peptide (VIP) and (111)In-DTPA-D-Phe(1)-octreotide for imaging to identify primary and metastatic tumor sites in carcinoid patients. PATIENTS AND METHODS One hundred ninety-four patients with a verified or clinically suspected diagnosis of a carcinoid tumor were injected with (111)In-DTPA-D-Phe(1)-OCT for imaging purposes, while 133 patients underwent scanning with both (123)I-VIP and (111)In-DTPA-D-Phe(1)-OCT in random order. Imaging results were compared with computed tomography scans, results of conventional ultrasound, endosonography, and endoscopy, and results of surgical exploration in case of inconclusive conventional imaging. RESULTS Primary or recurrent carcinoid tumors could be visualized with (111)In-DTPA-D-Phe(1)-OCT in 95 (91%) of 104 patients; metastatic sites were identified in 110 (95%) of 116 patients. In 11 (51%) of 21 patients with suggestive symptoms but without identified lesions by conventional imaging, focal tracer uptake located the carcinoid tumor. In addition, metastatic disease was demonstrated in three patients after resection. In a direct comparison in the 133 patients who underwent both imaging modalities, (111)In-DTPA-D-Phe(1)-OCT was found to be superior to (123)I-VIP, with 35 (93%) of 38 versus 32 (82%) of 38 scans being positive in primary or recurrent tumors, 58 (90%) of 65 versus 53 (82%) of 65 being positive in patients with metastatic sites, and seven (44%) of 16 versus four (25%) of 16 being positive in patients with symptoms but otherwise negative work-ups. Overall, additional lesions not seen on conventional imaging were imaged in 43 (41%) of 158 versus 25 (25%) of 103 scans with (111)In-DTPA-D-Phe(1)-OCT and (123)I-VIP, respectively. CONCLUSION Both peptide tracers have a high sensitivity for localizing tumor sites in patients with ascertained or suspected carcinoid tumors, with (111)In-DTPA-D-Phe(1)-OCT scintigraphy being more sensitive than (123)I-VIP receptor scanning. Both, however, had a higher diagnostic yield than conventional imaging, as verified by surgical intervention or long-term follow-up. The combination of both peptide receptor scans does not seem to further enhance diagnostic information.

Successful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide

Treatment options for hepatocellular cancer apart from surgical resection are limited because of the drug-refractory nature of this disease. Little is known about the role of somatostatin-receptors in hepatocellular cancer, and somatostatin analogs have not been investigated for treatment of this malignancy. We present the case of a 68-yr-old male, who was successfully treated with the long-acting somatostatin analog lanreotide.

Placebo-Controlled Trial of Medroxy – progesterone Acetate in Gastrointestinal Malignancies and Cachexia

Background: Cancer cachexia is a common and serve medical problem in the management of patients with cancer, and its treatment remains a therapeutic challenge. Medroxyprogesterone acetate (MPA), which

Treatment of advanced pancreatic cancer with epirubicin, 5-fluorouracil and l-leucovorin: A phase II study

BACKGROUND Preclinical data suggest that the levorotatory isomer of leucovorin (1-LV) can augment the cytotoxic effects of 5-fluorouracil (5-FU) more effectively than racemic LV. A phase II study was initiated to evaluate the effect of a combination of the pure L-isomer of LV and 5-FU along with epirubicin in patients with advanced pancreatic cancer. PATIENTS AND METHODS Twenty-eight consecutive, previously untreated patients with measurable metastatic adenocarcinoma of the pancreas were enrolled in this study. Treatment consisted of epirubicin 50 mg/m2 on day 1 and 5-FU 400 mg/m2 plus 1-LV 100 mg/m2 both administered on days 1 to 5. Treatment cycles were repeated every four weeks for a total of six months unless progressive disease was documented earlier. The study endpoints were survival, toxicity, objective response as well as palliative beneficial effects of the regimen in terms of performance status, body weight and pain. RESULTS Six patients had a partial response (21%; 95% CI, 8% to 44%) and 10 (36%) stable disease (35%), while the remaining 12 patients (43%) progressed during treatment. The median time to treatment failure was 2.9 months (range 1.2-13.7 months), and the median survival time was six months (range 1.8-19 months), with three patients (11%) being alive after one year. Beneficial palliative effects in terms of performance status, body weight and/or pain were seen in 12 of 28 patients (43%): an improvement in performance status was recorded in four patients, pain was attenuated and/or analgetic consumption reduced by > or = 50% in eight patients, and five patients had weight gain of > 5% of their pretreatment body weight. Treatment-associated side effects were generally mild to moderate. Severe adverse reactions included (asymptomatic) granulocytopenia in five, mucositis and/or diarrhea WHO grade 3 in four patients. CONCLUSION Our data suggest that epirubicin plus 5-FU and 1-LV is a tolerable regimen that has some positive effects in the treatment of pancreatic cancer. Since this regimen, however, is unlikely to offer any major therapeutic advantage compared to monochemotherapy or other combination regimens, the search for novel and more effective cytotoxic agents must continue.

Mitomycin C, Vinorelbine, Carboplatin plus Granulocyte-Macrophage Colony-Stimulating Factor for Treatment of Advanced Non-Small Cell Lung Carcinoma

Background: The therapeutic potential of chemotherapy in the treatment of recurrent or metastatic non-small cell lung carcinoma (NSCLC) seems modest. Thus, the search for novel agents and combination regimens with a superior therapeutic index has a high priority. The present combination regimen consisting of mitomycin C, vinorelbine, carboplatin and granulocyte-macrophage colony-stimulating factor (GM-CSF) was chosen because of the known activity of these agents in NSCLC and their potential drug synergism without (nonhematologic) cross-toxicity. To prevent/counteract neutropenia that was assumed to represent the dose-limiting toxicity, the hematopoietic growth factor GM-CSF was routinely adminstered. The objective of our trial was to determine the antitumor efficacy and tolerance of this combination regimen in patients with advanced NSCLC. Patients and Methods: Forty consecutive patients with nonresectable, measurable NSCLC (stage IIIB, 7; stage IV, 33) were treated with an intravenous combination chemotherapy regimen consisting of mitomycin C 8 mg/m2 on day 1, vinorelbine 40 mg/m2 on days 1 and 21, and carboplatin 250 mg/m2 on days 1 and 21; GM-CSF 5 µg/kg was administered subcutaneously on days 2–8 and 22–28. Treatment cycles were repeated every 6 weeks. All patients are evaluable in terms of toxicity and response assessment. A total of 123 courses was administered. Results: Objective tumor response was notes in 16 patients (40%; 95% confidence interval 24.9–56.7%), including 3 (7.5%) complete and 13 partial responses. There was no change in 12 (31.5%) patients, and 12 had progressive disease. Median duration of response was 6 (range 3–15) months, the median time to progression for all patients was 6.2 (range 1–17.5) months, and the projected median survival time was 8.7 (range 1–23.3) months; the 1-year survival rate was 27.5%. Myelosuppression was the most frequently encountered adverse reaction; WHO grade 3 or 4 granulocytopenia and/or thrombocytopenia occurred in 42.5 and 12.5%, respectively. Other toxicities were generally mild to moderate, and always fully reversible. Conclusion: With a 40% major response rate and disease stabilization in one additional third of our patients, this drug combination seems to have significant activity against advanced metastatic NSCLC. Due to its subjective tolerance and ease of administration, further investigation of this regimen in the palliative-intent care setting seems warranted.

Treatment of advanced gastric cancer with oral etoposide, leucovorin and tegafur: experience with an oral modification of the etoposide, leucovorin and 5-fluorouracil (ELF) regimen.

Recent data have suggested enhanced therapeutic activity with prolonged administration of both etoposide as well as fluoropyrimidines in the treatment of gastrointestinal malignancies. Based on this rationale, we investigated the clinical effectiveness and tolerance of an oral modification of the widely applied etoposide, leucovorin and 5-fluorouracil (ELF) regimen in patients with advanced gastric cancer. 32 patients with advanced gastric cancer were treated with oral etoposide (100 mg), leucovorin (3 x 100 mg), and tegafur (3 x 200 mg) over 14-21 days for a maximum of six cycles. Objective response was seen in only 5 patients (16%), stable disease was documented in 7 (22%), while the remaining patients progressed during therapy. The median time to progression was 2.8 months (range 0.7-12 months) and median overall survival was 6 months (range 1-18+ months). Due to grade 3 nausea/emesis, 8 patients discontinued treatment prematurely, while 12 patients experienced anorexia and progressive weight loss. Haematological toxicity was modest, with 4 patients developing asymptomatic grade 3-4 granulocytopenia. We conclude that this oral combination regimen cannot be recommended for the treatment of advanced gastric cancer.

Tolerance of the Novel Chemosensitizer Dexverapamil in Combination with Anthracycline Chemotherapy: a Prospective Toxicity Analysis in Advanced Gastrointestinal Cancer

Background: A prospective clinical study was performed to determine the incidence and severity of cardiovascular and other systemic toxicities associated with the novel chemosensiti

Brief Case ReportSuccessful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide

Treatment options for hepatocellular cancer apart from surgical resection are limited because of the drug-refractory nature of this disease. Little is known about the role of somatostatin-receptors in hepatocellular cancer, and somatostatin analogs have not been investigated for treatment of this malignancy. We present the case of a 68-yr-old male, who was successfully treated with the long-acting somatostatin analog lanreotide.