Vitamin D Receptor and Role of Vitamin D Supplementation in Advanced Gallbladder Cancer: A Prospective Study from Northern India.

BACKGROUND: The proposed role of Vitamin D Receptor (VDR) in various cancers underscores the importance of vitamin D compounds as a novel therapeutic agent in the prevention of occurrence and progression of cancer. Vitamin D Receptor (VDR) expression in gallbladder cancer (GBC) has not been widely analyzed yet. In the present study, an attempt has been made to study VDR expression and the role of vitamin D supplementation during palliative chemotherapy in advanced GBC. METHODS: Expression of VDR was analyzed in benign cholecystectomy specimens (n=11), and GBC specimens (n=32). Thirty patients with advanced GBC were subjected to palliative chemotherapy. Out of them, 19 patients were supplemented with Vitamin D and 11 patients were not. Effect of vitamin D supplementation on the change in vitamin D scores and improvement in quality of life (QOL) were assessed by EORTC QLQ c30 version 3.0. and the difference in outcome between the two groups were studied. RESULTS: Mean intensity, staining and immunoreactivity scores signifying VDR expression were decreased in the studied population of GBC when compared to benign disease. In palliative setting, vitamin D supplementation significantly improved the quality of life. However, the effect on disease- specific survival, although present, was not statistically significant. CONCLUSION: VDR expression downregulation is associated with increasing malignant process. Vitamin D may act as sensitizers for tumor cell death besides downplaying potential harmful effects of palliative chemotherapy thus reducing the associated morbidity. This study assumes importance as the first clinical study reporting VDR expression in GBC tissue and the possible role of vitamin D supplementation in patients with advanced disease.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for gallbladder cancer: a retrospective review.

Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) often prolongs survival in patients with peritoneal surface disease, yet is generally avoided in patients with peritoneal spread from gallbladder cancer as a result of its aggressive biologic behavior. Therefore, we reviewed our experience with CRS/HIPEC for patients with gallbladder cancer. We retrospectively evaluated the outcomes of CRS/HIPEC procedures performed from 1991 to 2013 using a prospectively maintained database of 1069 procedures. Patient and tumor characteristics, morbidity, mortality, and survival were reviewed. CRS/HIPEC was performed six times in five patients with peritoneal spread from gallbladder cancer. Patients were young (age 28 to 54 years) without pre-existing comorbidities. Eighty per cent had an Eastern Cooperative Oncology Group score of 0 or 1. At CRS, organs resected included omentum (n = 4), liver (n = 3), colon (n = 2), ovaries (n = 1), and diaphragm (n = 1). A complete macroscopic cytoreduction of intraperitoneal disease was achieved in every case. Clavien graded major morbidity was 17 per cent. There was no observed mortality. Median and 3-year survival were 22.4 months and 30 per cent, respectively. CRS/HIPEC may be performed safely in patients with peritoneal dissemination from gallbladder cancer. Carefully selected patients with low-volume disease amenable to complete cytoreduction may experience a meaningful survival benefit.

S0941: a phase 2 SWOG study of sorafenib and erlotinib in patients with advanced gallbladder carcinoma or cholangiocarcinoma.

BACKGROUND: Gallbladder cancers and cholangiocarcinomas make up a heterogenous group of tumours with a poor prognosis in advanced stages. On the basis of evidence of dysregulation of the epidermal growth factor receptor, vascular endothelial growth factor and mitogen-activated protein kinase pathways in biliary cancers, we performed a phase 2 trial of sorafenib and erlotinib in patients with advanced biliary cancers. METHODS: Eligible patients were previously untreated in the advanced setting with adequate hepatic and bone marrow function. Sorafenib and erlotinib were administered continuously at 400 mg BID and 100 mg daily, respectively. RESULTS: Thirty-four eligible patients were recruited. The study was terminated after the first stage of accrual owing to failure to meet the predetermined number of patients who were alive and progression free at 4 months. There were two unconfirmed partial responses (6%, 95% CI: 1-20%), with a median progression-free survival of 2 months (95% CI: 2-3), and median overall survival of 6 months (95% CI: 3-8 months). Grade 3 and 4 adverse events included hypertension, AST/ALT increase, bilirubin increase, diarrhoea, hypokalaemia, hypophosphatemia and rash. CONCLUSIONS: Despite compelling preclinical rationale, the combination of sorafenib and erlotinib does not have promising clinical activity in an unselected population of patients with biliary cancers. Improved patient selection based on tumour biology and molecular markers is critical for future evaluation of targeted therapies in this disease.

Postoperative chemoradiotherapy for gallbladder cancer.

PURPOSE: The goal of this work was to analyze the outcome of adjuvant chemoradiotherapy for patients with gallbladder cancer who underwent surgical resection and to identify the prognostic factors for these patients. PATIENTS AND METHODS: Between August 1989 and November 2006, 47 patients with gallbladder cancer underwent surgical resection followed by adjuvant radiotherapy. There were 21 males and 26 females, and median age was 60 years (range 44-75 years). Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes up to 40-50 Gy at 2 Gy/fraction; 41 patients also received intravenous 5-fluorouracil as a radiosensitizer. Median follow-up duration was 48 months for survivors. RESULTS: There were 2 isolated locoregional recurrences, 14 isolated distant metastases, and 7 combined locoregional and distant relapses. The 5-year overall survival rate was 43.7%. According to the extent of resection, the 5-year overall survival rates were 52.8%, 20.0%, and 0% in R0-, R1-, and R2-resected patients, respectively (p = 0.0038). On multivariate analysis incorporating extent of resection, T stage, N stage, performance of lymph node dissection, and histologic differentiation, extent of resection was the only prognostic factor associated with overall survival (p = 0.0075). Among the 37 patients with R0 resection, there was no difference of 5-year overall survival rates in patients with N0, N1, and Nx diseases (46.2%, 60.0%, and 44.4%, respectively, p = 0.6246). As for significant treatment-related morbidity, there was only 1 patient with grade 4 gastric ulcer. CONCLUSION: Adjuvant chemoradiotherapy after R0 resection can achieve a good long-term survival rate in gallbladder cancer patients, even in those with lymph node metastases, and may play a role for patients who underwent R0 resection of primary tumor without lymph node dissection.

[Chemotherapy in gallbladder carcinoma]. / Chimiothérapie dans le cancer de la vésicule biliaire.

Gallbladder cancer is an aggressive tumor. Its incidence varies according to geography. Surgery is the standard treatment for localized stage but there is no standard treatment in metastatic or locally advanced disease. Because of the rarity of bile tract cancer (BTC) and gallblader carcinoma (GBC), most studies have grouped all BTC and GBC together, and there are very few GBC-specific studies. In addition, there is a paucity of randomized controlled studies in this disease with small numbers of patients and inclusion bias. One randomized trial ABC-02 was well conducted and showed a survival benefit in favor of gemcitabine (GEM)+cisplatin (CDDP), which can be regarded as the standard in locally advanced BTC. Adjuvant therapy after surgical resection is not validated. Understanding the molecular mechanisms of carcinogenesis of GBC has opened the way for the use of targeted therapies. This new treatment would improve survival and quality of life of our patients.

National trends in the management and survival of surgically managed gallbladder adenocarcinoma over 15 years: a population-based analysis.

INTRODUCTION: National Comprehensive Cancer Network (NCCN) guidelines recommend hepatic resection and lymphadenectomy (LND) for gallbladder adenocarcinoma (GBA). We sought to evaluate compliance with these recommendations and to assess trends in the management and survival of patients with GBA. METHODS: Using Surveillance, Epidemiology and End Results (SEER)-Medicare-linked data, we identified 2,955 patients with GBA who underwent cancer-directed surgery from 1991 to 2005. We assessed clinicopathologic data, trends in surgical management, and survival. RESULTS: From 1991 to 2005, preoperative evaluation included CT (62%), MRI (6%), and PET (2%). Only 383 (13%) patients underwent radical resection/hepatectomy with a temporal increase over the study period (1991-1995, 12%; 1996-1999, 10%; 2000-2002, 12.0%; 2003-2005, 16%; P < 0.001). For patients undergoing radical resection/hepatectomy, LND ≥ 3 nodes was performed in 96 (3%) patients. Among patients who had LND, 47% had nodal metastasis. The overall 1-, 3-, and 5-year survival was 56%, 30%, and 21%. On multivariate analysis, radical resection/hepatectomy (hazard ratio (HR) = 0.71) and LND ≥ 3 nodes (HR = 0.56) were independently associated with increased survival. There was no significant improvement in survival over time (P = 0.60). CONCLUSIONS: Compliance with NCCN guidelines for GBA remains poor. Survival of patients with surgically managed GBA has not improved over time.

Survival of a cohort of patients with Intermediate and advanced gall bladder cancer treated with a prospective therapeutic protocol / Sobrevida de uma coorte de pacientes com câncer na vesícula intermédio e avançado tratados com um protocolo terapêutico de natureza prospectiva

PURPOSE: To evaluate the results of a prospective therapeutic protocol with long-term follow up in terms of survival rates in a cohort of patients treated with Intermediate and Advanced GBC (GBC). METHODS: Prospective cohort of patients with intermediate and advanced stages of GBC treated between 1996 and 2006. All cases were treated with a partial hepatic segmentectomy on segments IVb and V and a regional lymph node dissection and six cycles of out-patient chemotherapy (5-FU and leukovorin). With an average follow-up of 31.5 months, the morbidity, operative mortality, hepatic and lymphatic infiltration and actuarial survival were measured. Descriptive statistics were applied as well as bivariate analysis applying Fisher's exact test and non-parametrical tests and Kaplan Meier survival curves. Also logistic regression and proportional risk of Cox were applied. RESULTS: 40 patients were included in this protocol, with an average age of 59.5 years (40-85 years), of which 28 were women (70 percent). Depth of wall infiltration: muscular 8 patients (20 percent), subserosal 12 patients (30 percent), serosal 12 patients (30 percent) and perivesicular adipose tissue 8 patients (20 percent). The series morbidity was 27.5 percent. There was no operative mortality. The chemotherapy was well tolerated. The overall actuarial survival in the series was 50 percent at 60 months. CONCLUSION: Our protocol treatment has morbidity, mortality and survival rates similar to previously reported series.

OBJETIVO: Avaliar os resultados de resultados da aplicação de um protocolo terapêutico de natureza prospectiva, com seguimento em longo prazo nos termos de taxas de sobrevivência em uma coorte de pacientes operados com carcinoma vesícula biliar (CVB) intermédio e avançado. MÉTODOS: A coorte prospectiva de pacientes com estágios intermediários e avançados de CVB tratados entre 1996 e 2006. Todos os casos foram tratados com uma segmentectomia hepática parcial em segmentos IVb e V e uma dissecção linfonodal regional e seis ciclos de quimioterapia de ambulatório (5-FU e leukovorin). Com um tempo de seguimento médio de 31,5 meses, a morbidade, mortalidade operatória, hepático e infiltração linfática e atuarial de sobrevida foram medidas. Estatísticas descritivas foram aplicadas, bem como análise bivariada aplicando o teste exato de Fisher, testes não-paramétricos, curvas de sobrevida Kaplan Meier e técnica de regressão logística e risco proporcional de Cox. RESULTADOS: Foram incluídos 40 pacientes neste protocolo, com uma média de idade de 59,5 anos (40-85 anos), dos quais 28 eram mulheres (70 por cento). Profundidade de infiltração parede: muscular 8 pacientes (20 por cento), subserosal 12 pacientes (30 por cento), serosas 12 pacientes (30 por cento) e perivesicular no tecido adiposo, 8 pacientes (20 por cento). A série morbidade foi de 27,5 por cento. Não houve mortalidade operatória. A quimioterapia foi bem tolerada. A sobrevida global atuarial da série foi de 50 por cento em 60 meses. CONCLUSÃO: Nosso protocolo tem tratamento morbidade, mortalidade e taxas de sobrevivência semelhantes às relatadas anteriormente série.

Survival of a cohort of patients with intermediate and advanced gall bladder cancer treated with a prospective therapeutic protocol.

PURPOSE: To evaluate the results of a prospective therapeutic protocol with long-term follow up in terms of survival rates in a cohort of patients treated with Intermediate and Advanced GBC (GBC). METHODS: Prospective cohort of patients with intermediate and advanced stages of GBC treated between 1996 and 2006. All cases were treated with a partial hepatic segmentectomy on segments IVb and V and a regional lymph node dissection and six cycles of out-patient chemotherapy (5-FU and leukovorin). With an average follow-up of 31.5 months, the morbidity, operative mortality, hepatic and lymphatic infiltration and actuarial survival were measured. Descriptive statistics were applied as well as bivariate analysis applying Fisher's exact test and non-parametrical tests and Kaplan Meier survival curves. Also logistic regression and proportional risk of Cox were applied. RESULTS: 40 patients were included in this protocol, with an average age of 59.5 years (40-85 years), of which 28 were women (70%). Depth of wall infiltration: muscular 8 patients (20%), subserosal 12 patients (30%), serosal 12 patients (30%) and perivesicular adipose tissue 8 patients (20%). The series morbidity was 27.5%. There was no operative mortality. The chemotherapy was well tolerated. The overall actuarial survival in the series was 50% at 60 months. CONCLUSION: Our protocol treatment has morbidity, mortality and survival rates similar to previously reported series.

Lymph node evaluation is associated with improved survival after surgery for early stage gallbladder cancer.

BACKGROUND: Guidelines for the current National Comprehensive Cancer Network recommend radical cholecystectomy, including hepatic resection and portal lymph node (LN) dissection, for patients with early stage gallbladder (GB) cancer. We sought to determine the survival benefit conferred by adequate LN evaluation. METHODS: We used the surveillance, epidemiology and end results (SEER) neoplasm registry to identify patients who had an operation for GB cancer between 1988 and 2004. Patients were classified by stage of disease, operative procedure performed (cholecystectomy alone or radical resection), number of LNs evaluated (0, 1, >1), and receipt of radiation (RT). We included patients with T1B, T2, and T3 neoplasms who were LN positive or negative. Patients with T4 neoplasms and those with metastatic disease were excluded. Multivariate analysis included adjustment for age, race, sex, neoplasm grade, stage, operation performed, receipt of RT, and neoplasm registry. RESULTS: We identified 4,614 patients who underwent operative treatment for stage 1-2B GB (including T1B-T3 and LN positive or negative) cancer between 1988 and 2004. Of 4,614 patients, 9.6% (442) had radical resection, whereas 90.4% (4,172) had cholecystectomy alone. Among patients undergoing radical resection, 56% had LNs evaluated as compared with 28% of patients after cholecystectomy. For patients with T1B and T2 neoplasms who underwent radical resection, pathologic evaluation of at least 1 LN was associated with a significant improvement in median overall survival (OS) compared with those who had no LN evaluated (123 months vs 22 months; P < .0001). Radical resection with no LN evaluation provided similar OS compared with cholecystectomy alone (22 months vs 23 months; P = NS). For patients with T3 neoplasms, radical resection, including pathologic evaluation of at least 1 LN, was also associated with improved OS compared with radical resection with no LN evaluation (12 months vs 7 months; P = .0014). Again, individuals who had radical resection without LN evaluation had similar OS compared with those who had cholecystectomy alone (7 months vs 6 months; P = NS). Individuals who had radical resection with LN evaluation were more likely to receive RT than those who had radical resection without LN evaluation (33.1% vs 19.1%; P = .002). In multivariate analysis (including adjustment for RT), however, LN evaluation was still associated with a decrease in mortality compared with no LN evaluated (HR = 0.611; 95% CI = 0.484, 0.770). The pathologic evaluation of additional LN (>1) did not provide any additional benefit compared with the evaluation of a single node (HR = 0.795; 95% CI = 0.571, 1.107). Radical resection alone (without LN evaluation) did not provide any benefit over cholecystectomy alone (HR = 1.098; 95% CI = 0.971, 1.241). CONCLUSION: LN evaluation is a critical component of radical resection for GB cancer. In the absence of LN evaluation, radical resection provides no benefit over cholecystectomy alone.

Adjuvant therapy for gallbladder carcinoma: the Mayo Clinic Experience.

PURPOSE: To analyze the effect of adjuvant chemoradiotherapy on gallbladder carcinoma. METHODS AND MATERIALS: We retrospectively reviewed the records from consecutive patients who underwent R0 resection of gallbladder carcinoma between January 1, 1985, and December 31, 2004. Patients had either Stage I (T1-T2N0M0) or Stage II (T3N0M0 or T1-T3N1M0) disease. Patients undergoing adjuvant therapy received 5-fluorouracil chemotherapy concurrently with radiotherapy (median dosage, 50.4 Gy in 28 fractions). Adverse prognostic factors and the effect of adjuvant treatment on overall survival (OS) were evaluated. RESULTS: A total of 73 patients were included in the analysis; of these, 25 received adjuvant chemoradiotherapy. On univariate analysis, no adverse prognostic factors for OS reached statistical significance, but trends were noted for Stage N1 vs. N0 (p = .06), Nx vs. N0 (p = .09), Stage T3 vs. T1-T2 (p = .06), and histologic findings other than adenocarcinoma (p = .13). The median OS for patients receiving adjuvant chemoradiotherapy vs. surgery alone was 4.8 years and 4.2 years, respectively (log-rank test, p = .56). However, a significantly greater percentage of patients receiving adjuvant chemoradiotherapy had Stage II disease (p <.001). In the multivariate Cox model, increasing T and N category and histologic findings other than adenocarcinoma were significant predictors of decreased OS. Additionally, adjuvant chemoradiotherapy was a significant predictor of improved OS after adjusting for these prognostic factors (hazard ratio for death, 0.3; 95% confidence interval, 0.13-0.69; p = .004). CONCLUSION: After adjusting for the stage parameters and histologic findings, our data suggest that adjuvant chemoradiotherapy might improve OS for patients with gallbladder cancer.

Gallbladder cancer (GBC): 10-year experience at Memorial Sloan-Kettering Cancer Centre (MSKCC).

BACKGROUND: The incidence of gallbladder cancer (GBC) in the US is 1.2/100,000. This report examines the patterns of presentation, adjuvant treatment and survival of a large cohort of patients with GBC evaluated at MSKCC over a 10-year period. METHODS: A retrospective analysis of patients referred to MSKCC with a diagnosis of GBC between January 1995 and December 2005 was performed. Patients were identified from the MSKCC cancer registry. Information extracted included, demographics, clinical and pathological stage, surgical management, pathology, adjuvant and palliative therapy, date of relapse, death or last follow-up. Date of diagnosis was defined as date of surgery or biopsy. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Four hundred thirty-five GBC cases were identified: 285 (65.5%) females,150 (34.5%) males. Median age 67 years (range 28-100). Pathology: 88% adenocarcinoma, 4% squamous, 3% neuroendocrine, 2% sarcoma. 36.6% presented as AJCC Stage IV. 47% were discovered incidentally at laparoscopic cholecystectomy. One hundred thirty-six of these were re-explored, of whom 100 (73.5%) had residual disease. Of those who underwent curative resections (N = 123), 8 (6.5%) received adjuvant chemotherapy, 8 (6.5%) chemoradiation alone and 8 (6.5%) both chemoradiation and systemic chemotherapy. Median overall survival for the cohort was 10.3 months (95% CI 8.8-11.8) with a median follow up of 26.6 months. The median survival for those presenting with stage Ia-III disease was 12.9 months (95% CI 11.7-15.8 months) and 5.8 months (95% CI 4.5-6.7) for those presenting with stage IV disease. Median survival was 15.7 months (95% CI 12.4-18.4) for those discovered incidentally at laparoscopic cholecystectomy. For those who underwent re-exploration, median survival was 14.6 months (95% CI 12.6-18.3) if residual disease was present, and 72 months (95% CI 34 to infinity) if no evidence of disease. The median survival for those who received adjuvant therapy was 23.4 months (95% CI 15.7-47). CONCLUSIONS: GBC is commonly diagnosed incidentally (47%). Re-exploration reveals a high incidence of residual disease (74%). Median survival is better for patients who have no evidence of disease on re-exploration (72 months) compared to those with residual disease detected (P < 0.0001). Overall prognosis is poor. Although we did not observe a survival benefit for those who received adjuvant therapy, the study did not have sufficient power to address this question. In addition, the number of patients who received adjuvant therapy was small with marked heterogeneity in clinical and therapeutic details, precluding any definitive conclusions being drawn. Prospective randomized trials of adjuvant therapy are needed in this disease.

Thermo-chemo-radiotherapy for advanced gallbladder carcinoma.

BACKGROUND/AIMS: Many gallbladder carcinomas are detected at an advanced stage, and the outcome of the patients with these tumors is dismal despite aggressive tumor removal. We have treated advanced gallbladder carcinoma with chemoradiotherapy combined with hyperthermia. In this study, clinical effectiveness of thermo-chemo-radiotherapy (TCRT) for advanced gallbladder carcinoma was evaluated in comparison with other treatment modalities. METHODOLOGY: Two hundred and seventy patients with advanced gallbladder carcinoma (Stage VI) were treated. According to treatments received, they were divided into five groups as follows: group 1; 30 patients treated with TCRT, group 2; 19 patients underwent R0-resection, group 3; 39 patients underwent R1,2-resection, group 4; 57 patients treated with chemo- and/or radiotherapy, group 5; 125 patients with only supportive therapy. RESULTS: In group 1, there were 19 objective responses (5 complete response and 14 partial response) in respect to tumor regression, and 15 (6 complete response and 9 partial response) of 20 patients with obstructed bile duct showed resolution of the bile duct. The survival rate was best in group 2. A significant improvement of long-term survival was exhibited in group 1 and 3 compared to group 4 and 5, and there was no significant difference between group 1 and 3 (p<0.01). CONCLUSIONS: TCRT can produce significant response and improvement of survival time in patients with advanced gallbladder carcinoma, and may be a favorable alternative to aggressive surgical approaches.

[Neoadjuvant chemoradiotherapy in gallbladder cancer]. / Quimiorradioterapia de neoadyuvancia en cáncer de vesícula biliar.

BACKGROUND: Gallbladder cancer is generally associated with a poor prognosis, being local recurrence the main pattern of failure. AIM: To evaluate neoadjuvant chemoradiation as a means to improve the prognosis in gallbladder cancer. PATIENTS AND METHODS: Twenty three gallbladder cancer patients were prospectively treated between June 1993 and September 1999 in the Temuco Regional Hospital. Eighteen (82%) patients had subserosal infiltration, while three (13%) had serosal and two (9%) adipose tissue infiltration. Chemotherapy was done with 5-fluorouracil in continuous infusion during 5 days at day 1 and 28 of treatment. Radiotherapy consisted in a total dose of 4500 cGy, divided in 25 sessions. Patients' survival was compared with a series of 19 patients not subjected to chemoradiation, formerly treated at the institution. RESULTS: Twenty patients had hematological problems secondary to the therapy. Leucopenia and thrombocytopenia were the most common toxic effects and eight had leucopenia under 2.0 x 10(3) during the treatment course. Chemoradiation delayed surgical treatment in eight patients. After the chemoradiation protocol, seven patients were excluded from surgical treatment and 14 patients underwent resection. Three of the latter (11%) had liver involvement and four (14%) had lymph node involvement. Among the patients who underwent resection, five are still alive with a follow up of 43.8 months. Treated patients had a worst actuarial survival than subjects not treated with chemoradiation. CONCLUSIONS: In this series of patients chemoradiation had no positive effect and a potentially detrimental effect in patients with gallbladder cancer.

Phase II trial of intravenous flourouracil and subcutaneous interferon alfa-2b for biliary tract cancer.

PURPOSE: To assess the efficacy of systemic intravenous-fluorouracil (5-FU) and subcutaneous recombinant human interferon alfa-2b (rIFN alpha-2b) in patients with measurable cancer of the biliary tree. PATIENTS AND METHODS: Thirty-five patients (25 with cholangiocarcinoma and 10 with gallbladder carcinoma) were registered onto this phase II protocol between 1992 and 1995. Patients received a continuous infusion of 750 mg/m2/d of 5-FU on days 1 through 5 through a centrally placed venous catheter and a subcutaneous injection of 5 MU/m2 of rIFN alpha-2b on days 1, 3, and 5. Treatment cycles were repeated every 14 days; one course of therapy included four treatment cycles. Disease status was assessed every 8 weeks. Dosages were lowered for grade III mucositis. Fourteen patients had prior treatment and, before initiating this therapy, 17 patients required decompression of the biliary tree. RESULTS: Eleven of 32 (34%) assessable patients had a partial response. The median time to disease progression was 9.5 months, and the median survival time 12 months. Grade III to IV toxic effects were granulocytopenia (14%), mucositis (20%), diarrhea (9%), and dermatitis (11%). Grade III to IV asthenia and fatigue were observed in 6% of patients. CONCLUSION: Drug tolerance was better among previously untreated patients. To achieve a complete response, additional chemotherapy or radiotherapy should be considered when liver resection or transplantation is not feasible. However, if these results can be reproduced by other investigators, the regimen should be studied for adjuvant treatment of gallbladder carcinoma incidentally identified in patients undergoing cholecystectomy.

[Radiotherapy for advanced carcinoma of the gallbladder: special reference to IORT and hyperthermo-chemo-radiotherapy].

The results of radiotherapy in 37 patients who were treated for carcinoma of the gallbladder from April 1975 to April 1992 are presented. To analyze the treatment results, patients were divided into four groups depending on treatment modality: intraoperative radiotherapy (IORT) with surgical resection in 9 (resection group), IORT with palliative surgery in 5 (palliative surgery group), hyperthermo-chemo-radiotherapy for inoperable cases in 11 (HCR group), external irradiation for inoperable cases in 12 (ExRT alone group). Most of the patients in the resection group received ExRT. The HCR group showed better local response than the groups treated with palliative surgery and ExRT alone. The mean length of survival in the resection, palliative surgery, HCR and ExRT alone groups was 315 days, 144 days, 246 days and 74 days, respectively. Although no statistically significant difference in survival was observed between the resection and HCR groups, the relapse-free interval of the resection group was significantly longer than that of the other groups. The application of IORT for surgically resectable tumors contributed to improved prognosis and better quality of life. Although IORT for patients with unresectable tumors had little effect on survival, it was considered to play a palliative role in improving the quality of life. The HCR group had a significantly longer survival time and relapse-free interval than the palliative surgery and ExRT alone groups. In conclusion, the application of HCR for inoperable carcinoma of the gallbladder contributed to the improvement of prognosis and quality of life.

[Efficacy of 48-hour infusion of 5-fluorouracil for gall bladder cancer].

Usefulness of an adjuvant chemotherapy for 23 patients who had undergone "non-curative" resection for adenocarcinomas of the gallbladder was investigated. Patients were divided into two groups: Group A (16 patients) was given MF (mitomycin C 6 mg/m2, 5-fluorouracil 250 mg/body) by injection on the 2nd and 9th postoperative day and received orally Tegafur 600 mg/day and PSK 3 g/day. Group B(7 patients) was treated weekly with a 48-hour infusion of 5-FU (1,000 mg/m2/24 hours), for 6 weeks and leucovorin (30 mg/body) was given for 2 hours prior to 5-FU infusion. The results were evaluated by the Kaplan-Meier method. Response rate of anti-tumor was 0% in Group A and 14.3% in Group B, including: PR, 1 and NC, 6 cases. The 50% survival time was 230 days in group A and 471 days in group B (p = 0.0008). The results suggest that treatment with 5-FU and LV is effective for gallbladder cancer.

[Prospective randomized trial comparing modified FAM (5-fluorouracil (5-FU) + adriamycin + mitomycin C) versus 5-FU alone for the treatment of non-resectable pancreatic and biliary tract carcinomas (the 1st trial in non-resectable patients). Study Group of Surgical Adjuvant Therapy for Carcinomas of the Pancreas and Biliary Tract].

The modified FAM (5-fluorouracil (5-FU) + adriamycin (ADR) + mitomycin C (MMC)) therapy (FAM group) was compared with 5-FU mono-therapy (F group) by multi-institutional randomized trial in the patients with cancer of the pancreas or the biliary tract who underwent non-resection. The patients in FAM group received 6 mg/m2 of i.v. MMC during operation, 310 mg/m2 of i.v. 5-FU for 5 days in the 1st and 3rd postoperative weeks and 12 mg/m2 of i.v. ADR in the 2nd postoperative week. Those in F group received only 5-FU course in the administration schedule of FAM group. Among the cases which completed respective whole administration schedules. 35 cases in FAM group and 36 in F group, better effect than partial response (PR) was observed in neither groups, and there was no significant difference between groups with respect to overall/each disease survival duration, progression-suppressed duration and clinical effect. Primary adverse effects were alimentary symptoms and hepatic dysfunction, neither of which was serious, and there was no difference between groups except that hair loss was observed in more cases in FAM group (p less than 0.05). Results in FAM group did not statistically surpass those in F group, but a tendency was observed that FAM group was better than F group in terms of survival duration and clinical effect for cancer of the gall-bladder.

Epidemiological survey of maintenance workers in London Transport Executive bus garages and Chiswick Works.

A mortality study of maintenance men employed for at least one year between 1 January 1967 and 31 December 1975 at 71 London Transport bus garages and Chiswick Works has been carried out. Over 97% of the population were successfully traced to determine their vital status at 31 December 1975. The mortality observed in the study population was compared with that which would be expected from the mortality rates for the all male population of England and Wales. The mortality of the study population from all causes was much lower than expected on this basis, as was the mortality from cerebrovascular disease, ischaemic heart disease, and bronchitis. Mortality from all neoplasms was slightly less than expected overall and especially in the younger age groups. The observed deaths from cancer of the lung were approximately the same as those expected on the basis of national rates. Nevertheless, a deficit of observed deaths from lung cancer was obtained after adjusting for the higher mortality from this disease in Greater London. Raised mortality was found in subgroups of the population for several malignant disease groups but these were almost all based on small numbers of deaths, making it difficult to exclude chance effects. Both the number of men and deaths in the study were limited and the follow up time was also short. Considerable extension of the study to include more men and increase the follow up time would be required for any definite mortality patterns to emerge.