Liver metastases of digestive endocrine tumours: natural history and response to medical treatment

BACKGROUND: Few data are available about the natural history of liver metastases of digestive endocrine tumours. Moreover, results of studies on treatment with intravenous chemotherapy, hepatic arterial chemoembolization and somatostatin analogues are conflicting. AIMS OF THE STUDY: To assess the progression of liver metastases of digestive endocrine tumours before antitumoral treatment, and to evaluate a stepwise therapeutic strategy in these patients. PATIENTS AND METHODS: 22 patients with histologically-confirmed liver metastases were studied. Primary tumours were carcinoids in nine, gastrinomas in five, non-functioning pancreatic tumours in six and calcitonin-secreting tumours in two patients. The progression of liver metastases was assessed according to the World Health Organization criteria in 10 patients before treatment, and during treatment in all patients. Intravenous (i.v.) chemotherapy with streptozotocin and 5-fluorouracil was used in patients with more than 25% progression in tumour size or with more than 50% liver involvement. Hepatic arterial chemoembolization was performed if i.v. chemotherapy failed, or as a first-choice treatment after 1993. The somatostatin analogues octreotide or lanreotide were used as a third-choice treatment. RESULTS: Progression (+90%, range 28-600%) of liver metastases was identified in the 10 patients studied before treatment, after a median follow-up of 11.5 months. Objective and minor responses were obtained in 2/10 patients (20%) and 1/10 patients (10%) receiving i.v. chemotherapy. Corresponding figures were 3/7 (43%) and 2/7 (29%) for hepatic arterial chemoembolization. No objective response was observed with somatostatin analogues, although 2 patients experienced a minor response. CONCLUSION: Untreated liver metastases of digestive endocrine tumours show an objective increase (their size approximately doubles after 1 year of follow-up). Among the currently available therapeutic modalities, hepatic arterial chemoembolization provides the highest response rates. An increase in patient survival as a result of this procedure remains to be determined.     

Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver

PURPOSE: Extrahepatic metastasis represents a frequent pattern of disease progression when fluorodeoxyuridine (FUDR) is given by the intraarterial route for the treatment of unresectable colorectal liver metastases. Systemic fluorouracil (5-FU) plus leucovorin was added to intrahepatic FUDR to prolong the duration of disease control. METHODS: Only patients with colorectal cancer who had evidence of unresectable metastases confined to the liver were eligible. Laparotomy was performed to establish arterial perfusion of the liver. Cycles of intrahepatic FUDR followed by a 1-week rest period then intravenous chemotherapy with 5-FU plus leucovorin were administered until maximal regression of hepatic metastases. Maintenance chemotherapy with 5-FU plus leucovorin was then given until disease progression. RESULTS: Fifty-seven patients entered this trial; four patients (7%) were ineligible and 13 (23%) did not receive any chemotherapy on study because of findings at laparotomy. The 40 eligible patients who began chemotherapy are included in the statistical analyses. Twenty-five patients (62% of those who received chemotherapy) experienced regression of liver metastases. The median time to tumor progression was 9 months, but only 3% remained progression-free at 24 months. The median survival duration was 18 months. Toxicity was tolerable with no cases of biliary sclerosis. One treatment-related fatality due to sepsis was observed. CONCLUSION: Although short-term treatment results appear to be somewhat better than we have previously observed with intrahepatic FUDR alone, the sequential regimen did not have an impact on long-term, progression-free survival in patients with unresectable liver metastases. We are now investigating this regimen as surgical adjuvant therapy in selected patients following hepatic metastasectomy where this aggressive approach might have a greater therapeutic effect in the minimal residual disease setting.     

Internal radiation therapy for patients with primary or metastatic hepatic cancer: a review

BACKGROUND: The limited efficacy of current approaches to the treatment of patients with hepatic cancer, including external beam radiation therapy and cytotoxic chemotherapy, has reawakened interest in the use of internal radiation therapy. METHODS: The authors reviewed series of patients with liver metastases or hepatocellular carcinoma (HCC) treated with 1) interstitial irradiation and direct intratumoral injection of 90Y microspheres, 2) intraarterial infusion of (131)I-Lipiodol, 3) intraarterial infusion of 90Y microspheres, or 4) parenteral administration of radiolabeled monoclonal antibodies. RESULTS: High dose rate interstitial irradiation with afterloading of (192)Ir resulted in local control of hepatic metastases for a median of 8 months and complete tumor eradication in 2 patients. Direct intratumoral injection of 90Y microspheres reduced the size of 90.6% of tumors and completely destroyed them in 8 patients. Treatment with arterial (131)I-Lipiodol resulted in a 17-92% response rate as well as a case of complete remission of unresectable HCC. It was found to be most effective against small tumors. No response was observed with liver metastases from colorectal carcinoma. Partial response was commonly achieved when patients with unresectable liver metastases or HCC were treated with intraarterial 9OY microspheres. Among four patients whose HCC became resectable following treatment with 90Y microspheres, two cases of complete remission were documented. In a prospective randomized trial, (131)I-antiferritin combined with chemotherapy was no more effective than chemotherapy alone. CONCLUSIONS: The different approaches to internal radiation therapy that are reviewed in this article represent several ways in which radiation can be selectively targeted to hepatic tumors without undue radiation to the nontumorous liver. However, the efficacy of each of these therapies still needs to be evaluated in randomized controlled trials.     

Randomized trial of surgery versus surgery followed by adjuvant hepatic arterial infusion with 5-fluorouracil and folinic acid for liver metastases of colorectal cancer. German Cooperative on Liver Metastases (Arbeitsgruppe Lebermetastasen)

OBJECTIVE: To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases. SUMMARY BACKGROUND DATA: Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases. METHODS: Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 per day for 5 days as a short infusion), or liver resection only. RESULTS: The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients. CONCLUSION: According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated.     

Hepatic transcatheter arterial chemoembolization alternating with systemic protracted continuous infusion 5-fluorouracil for gastrointestinal malignancies metastatic to liver: a phase II trial of the Puget Sound Oncology Consortium (PSOC 1104)

We assessed a regimen of alternating regional and systemic therapy in patients with gastrointestinal malignancies with liver-dominant metastases for feasibility, toxicity, response rate, response duration, patterns of progression, and progression-free and overall survival. Regional therapy comprised selective hepatic transcatheter arterial chemoembolization (TACE) using a suspension of cisplatin and particulate polyvinyl alcohol. This procedure was delivered between cycles of protracted continuous infusion 5-fluorouracil (PCI-5FU) as systemic chemotherapy. Patient eligibility criteria included: (a) having histologically documented adenocarcinoma arising from a gastrointestinal primary site with unresectable liver metastases bidimensionally measurable on computerized tomography scan; (b) age greater than 18 years; and (c) performance status 0-2 (Zubrod). PCI-5FU (250 mg/m2/day) was administered i.v. for 28 days, followed by the first TACE (TACE 1) delivered to the hepatic artery supplying the lobe with the greatest tumor burden. Restaging was performed before TACE 2 and TACE 3, which followed at monthly intervals. PCI-5FU for 21 days was sandwiched between each of the TACE treatments. After the final TACE, maintenance PCI-5FU was given for 28 days of each 35-day cycle until toxicity or progression. Between December 23, 1991, and January 19, 1995, 32 patients were registered in this trial, of whom 27 were eligible; 20 completed one or more treatment cycles and were evaluable for radiographic response. Patients with colorectal liver metastases predominated (74%). Twelve (44%) of 27 patients had failed one or more prior treatment regimens. There were no treatment-related deaths, and hematological and hepatic toxicities were generally manageable and reversible. Two patients, however, developed hepatic abscesses requiring drainage, and one patient developed an infarcted gallbladder, which necessitated cholecystectomy. There were no patients with complete responses; there were 8 (40%) with partial responses, 4 (20%) with minor responses, 2 (10%) with stable disease, and 6 (30%) who progressed on the treatment. The median duration of response for partial responders was 4.2 months (127 days; range, 56-245 days). The median reduction in carcinoembryonic antigen for responders was 87.5%. Two patients underwent subsequent resection of residual metastases; one of them is still alive at 58.4 months follow-up. The predominant site of disease progression was the liver; 25% of the patients progressed in extrahepatic sites. The median overall survival for the whole group is 14.3 months (95% confidence interval, 7.2-16.2). Actuarial overall survival for the whole group at 1 year and 2 years is 57 and 19%, respectively. Alternating systemic PCI-5FU and regional TACE (cisplatin/polyvinyl alcohol) is an active and feasible regimen with manageable toxicities in patients with metastatic gastrointestinal malignancies with liver-dominant disease and merits further investigation. The complications seen were in line with those reported at other specialized centers.     

Assessing the reliability and responsiveness of 5 shoulder questionnaires

Inspired by the high response rates achieved with the DBCT regimen (dacarbazine [DTIC], carmustine [BCNU], cisplatin and tamoxifen [TAM]), we administered the nitrosourea compound fotemustine, cisplatin and TAM (FCT regimen) to 69 patients with metastatic melanoma. Fotemustine (100 mg/m2) and cisplatin (100 mg/m2) were administered every 4 weeks, preceded by TAM 160 mg daily for 7 days from the second course onwards. Pharmacokinetic blood sampling was performed in 14 patients during the initial two cycles to compare the pharmacokinetic behaviour of fotemustine with or without TAM. Previous chemo- or radiotherapy was allowed, and patients with brain metastases or concomitant other malignancies were included. Four complete and 11 partial responders were observed among 66 evaluable patients, yielding a response rate of 22.7% (95% confidence interval 12.9 32.5%). The median survival time was 6.4 months (range 0.1-52+ months). The main toxicities were thrombocytopenia, protracted nausea/vomiting and ototoxicity. Renal toxicity was generally mild, but possibly contributed to two deaths. Seven patients experienced deep venous thrombosis during the study. TAM had no influence on the pharmacokinetics of fotemustine. The activity of the FCT regimen was clearly inferior to that initially reported with DBCT treatment. However, a recent publication concludes that the latter achieves a considerably lower response rate when administered to a larger patient group. We believe our results reflect the true activity of FCT and similar regimens when administered routinely to unselected patients. Considering the number of potentially serious side effects, we cannot recommend the moderately active FCT regimen as a palliative treatment option for melanoma patients.     

Genetic alterations in primary and secondary hyperparathyroidism

OBJECTIVE: To evaluate treatment of patients with primary liver cancer. DESIGN: Prospective protocol including subsets of randomised studies. SETTING: University hospital, Sweden. SUBJECTS: 123 patients with primary liver cancer. INTERVENTIONS: 64 patients underwent hepatic resection, 25 were included in a trial of adjuvant chemotherapy. 24 further patients whose tumours were not resectable were included in a trial of intra-arterial infusion of doxorubicin. MAIN OUTCOME MEASURES: Survival and postoperative morbidity. RESULTS: The median survival time for patients who had had resections was 11 months (range 0-111). Twelve per cent survived more than 5 years. No prognostic factor had any significant effect on outcome. The postoperative mortality was 11% (7/64). The patients allocated to adjuvant chemotherapy survived a median of 10 months (range 1-47) and the controls 29 months (range 8-111) (p=0.04). Patients with unresectable liver cancer treated with intra-arterial doxorubicin lived no longer than untreated controls (median 8 months (range 1-56) compared with 7 months (range 1-28)). CONCLUSIONS: Treatment of patients with primary liver cancer is still an unsolved problem. Adjuvant chemotherapy with doxorubicin had no beneficial effect on survival.     

Immunochemotherapy of metastatic uveal melanoma with interferon alfa-2b, interleukin-2 and fotemustine. Case reports and review of the literature

In spite of their tumor's origin in the uveal tract, many patients suffering from advanced uveal melanoma are admitted to dermatological oncology units. Most patients with metastases from uveal melanoma receive treatments that were established for stage IV cutaneous melanoma. However, both the biology as well as the metastastic behaviour of this tumor is different from cutaneous melanoma. Lymphatic metastases do not occur, and hematogeneous metastases usually occur later and predominantly involve the liver. The prognosis is very bad ranging from 2 to 5 months. We describe three patients with advanced uveal melanoma who received immunochemotherapy containing interferon-alpha 2b, interleukin-2, and fotemustine. This therapy induced a partial response of more than 49 months duration in one patient, whereas for the remaining patients the disease progression could be stabilized for eight and 16 months, respectively. This therapeutic success is reflected by a prolonged survival of 14,43+, and 59+ months.     

Fotemustine given simultaneously with total brain irradiation in multiple brain metastases of malignant melanoma: report on a pilot study

Melanoma patients with multiple brain metastases not amenable to surgery or stereotactic radiotherapy were treated with total brain irradiation in fractions of 2.5 Gy four times weekly, up to 40 Gy. At days 1, 8, and 25100 mg/m2 fotemustine was infused 4 h before irradiation. Of 12 evaluable patients, four showed partial remission and three stabilization in the brain. The median survival in these two groups of patients was 6 months; the survival of the other patients was 2 months. Severe haematological side effects were observed in 6/13 patients. In conclusion, the combination of fotemustine and total brain irradiation seems to be more effective than either treatment alone, but bears the risk of additional bone-marrow toxicity.     

Effects of systemic and regional chemotherapy after hepatic resection for colorectal metastases

BACKGROUND: Although the survival benefit of hepatic resection for colorectal metastasis has been established, some controversy remains regarding the significance of adjuvant chemotherapy after hepatic resection. METHODS: One hundred thirty-two consecutive patients who had liver resection for colorectal metastasis at our hospital between 1980 and 1997 were studied. After curative hepatic resection, 37 patients underwent systemic chemotherapy, administered orally or intravenously, and 38 patients underwent regional chemotherapy, given intra-arterially or intraportally. Forty patients had no adjuvant chemotherapy. The chemotherapeutic agents used for oral administration were uracil and Tegafur or Tegafur alone. Mitomycin C (MMC) or 5-FU was used for IV chemotherapy. Combinations of 5-FU/leucovorin or MMC/5-FU (doxorubicin) were used for regional chemotherapy. Univariate and multivariate analyses were applied to test the significance of adjuvant chemotherapy for patient survival or disease-free survival. RESULTS: Overall 5-year survival was 42.2% (95% CL: 31.2%, 53.2%). Among the possible prognostic factors studied, univariate analysis showed a significant difference in survival based on the number of tumors and lymph node metastases in the hepatic hilum. There was a significant difference in disease-free survival based on adjuvant chemotherapy and lymph node metastasis. The multivariate analysis for patient survival selected four prognostic factors (P < .05), including adjuvant chemotherapy, lymph node metastasis, disease-free interval, and tumor size. The multivariate analysis for disease-free survival selected adjuvant chemotherapy, lymph node metastasis, and disease-free interval as significant factors. The most common recurrence site was remnant liver, regardless of adjuvant chemotherapy. CONCLUSIONS: Adjuvant chemotherapy significantly improved survival and disease-free survival after hepatic resection for colorectal metastases. It did not decrease recurrence rate in the remnant liver.     

Prognostic factors for survival in patients with brain metastases from renal cell carcinoma

BACKGROUND: Patients presenting with brain metastases from renal cell carcinoma portend a poor prognosis, with a reported median survival of 4-6 months. Given their short life expectancy, these patients generally have been excluded from clinical trials that assess the efficacy of medical treatments. However, clinical impression suggests that some patients may achieve long term palliation. METHODS: The clinical features of 68 patients who were treated at the Institut Gustave Roussy for brain metastases from renal cell carcinoma were collected retrospectively. Using univariate and multivariate analyses, a prognostic model based on independent prognostic factors was established. An external data set of 57 patients was used to validate the model. RESULTS: The median survival was 7 months. On univariate analysis survival was related significantly to the following adverse prognostic factors: no initial nephrectomy, left side and temporal location of brain metastases, presence of fever or weight loss, erythrocyte sedimentation rate > 50 mm/h, and time from initial diagnosis to brain metastases < or = 18 months. Multivariate analyses identified the previous variable as well as the presence of other visceral metastases as independent prognostic factors. Forty-four patients (65%) with no or 1 adverse prognostic factor (average risk group) had a median survival of 8 months and a 26% 1-year survival rate. Twenty-four patients (35%) with 2 adverse prognostic factors (poor risk group) had a median survival of 3 months and a 1-year survival rate of 9%. This model proved to be discriminant in an external data set; the median survival of patients assigned to the average risk group was 11 months (46% 1-year survival rate) compared with 4 months (9% 1-year survival rate) for patients assigned to the poor risk group. CONCLUSIONS: Patients presenting with brain metastases from renal cell carcinoma and poor risk prognostic factors are highly unlikely to benefit from medical treatments except symptomatic procedures. Conversely, the enrollment of patients with average risk prognostic factors into clinical trials dealing with chemotherapy or immunotherapy may be considered.     

Exposure of macrophage-like cells to titanium particles does not affect bone resorption, but inhibits bone formation

Endocrine tumours of the pancreas, even in case of liver involvement, are generally characterized by a slower evolution and a better prognosis, if compared with ductal carcinoma. This fact gives reason to a radical surgical approach, whenever possible, and to the research of any effective adjuvant treatment. For this purpose, hepatic transarterial chemoembolization (TACE) has been proposed in recent years for the treatment of metastatic endocrine tumours. Out of 80 patients suffering from endocrine tumours of the pancreas, observed between January 1985 and December 1996, 28 (35%) presented liver metastases at the time of diagnosis. Twelve of these patients were submitted to palliative resection of pancreatic tumour and one or more cycles of TACE. Overall survival was 50% (6/12); median survival was 35.4 months (range 4-75). These results suggest that chemoembolization, combined with surgical resection of primary malignancy, appears to be able to control the disease for a certain time and to increase the survival rate.     

p53 nuclear protein overexpression in colorectal cancer: a dominant predictor of survival in patients with advanced hepatic metastases

PURPOSE: To determine whether p53 protein expression is similar within primary colorectal cancer (CRC) and synchronous regional and distant metastases and to assess whether p53 nuclear protein expression could predict outcome in patients with synchronous unresectable liver metastases treated by hepatic artery infusional (HAI) chemotherapy. MATERIALS AND METHODS: Paraffin sections from tumor and corresponding normal mucosa representative of 50 consecutive advanced CRC cases were examined for p53 nuclear protein expression by immunohistochemistry using the monoclonal antibody PAb 1801. Patterns of p53 nuclear expression were correlated with standard clinicopathologic variables and outcome, including response to HAI and survival. In a subset analysis, the pattern of nuclear p53 immunoreactivity was compared between primary CRC and lymph node and liver metastases. RESULTS: Positive nuclear immunoreactivity for p53 protein was found in 72% of cases. The pattern of p53 protein expression in lymph node and liver metastases was identical to that of the primary tumor. The median survival time was 21.0 months in patients with p53-positive tumors and 53.2 months in patients with p53-negative tumors (Wilcoxon test P = .038). Two-year survival rates were 41.7% and 78.6%, respectively (P < .01). No significant difference was found in the response rates to HAI chemotherapy between the two groups. By multivariate analysis, p53 protein status was the single best predictor of survival, with a relative risk of 6.312. CONCLUSION: Our results indicate that nuclear p53 protein status in primary CRC is similar to that in metastatic sites and may be the dominant predictor of survival in patients with advanced hepatic metastases.     

Comparison of parental and health care professional preferences for the acellular or whole cell pertussis vaccine

PURPOSE: To evaluate the efficacy and toxicity of gamma knife radiosurgery in the treatment of melanoma metastases to the brain. PATIENTS AND METHODS: We retrospectively reviewed 55 patients with single or multiple intracranial melanoma metastases treated at the University of California, San Francisco, with gamma knife radiosurgery from 1991 through 1995. Sixteen patients were treated with gamma knife radiosurgery for recurrence following previous radiation therapy, 11 received radiosurgery as a boost to whole-brain radiation therapy, and 28 had radiosurgery alone for initial management of brain metastases. The median minimum radiosurgery tumor dose for 140 treated lesions was 19 Gy (range, 10-22 Gy) prescribed at the 35% to 90% isodose contour (median, 50%). The median total target volume per patient was 6.1 cc (range, 0.25-28.3 cc). RESULTS: With a median follow-up of 75 weeks in living patients, the median survival times were 35 weeks overall: 35 weeks for patients with solitary metastases versus 33 weeks for those with multiple metastases. A factor that was significant in univariate analysis of survival was total target volume treated. This parameter remained significant on multivariate analysis. The actuarial median freedom from progression analyzed by lesion for 113 lesions in 46 patients with imaging follow-up was 89 weeks with 6-month and 1-year actuarial freedom from progression rates of 89% (95% confidence interval, 80%-95%) and 77% (95% confidence interval, 62%-87%). In univariate analysis, improved freedom from progression was associated with smaller target volume treated, smaller maximum diameter, or higher prescribed dose. Four patients (7%) developed acute Radiation Therapy Oncology Group grade > or = 2 morbidity, and five patients (9%) developed late grade > or = 2 morbidity. DISCUSSION: Median survival and freedom from progression in patients treated with radiosurgery for melanoma metastatic to the brain are comparable to results in published radiosurgery series of grouped histologies. For melanoma patients, total intracranial tumor volume appears to be of greater prognostic significance than the absolute number of metastases treated. We conclude that gamma knife radiosurgery is effective and should be considered among various management strategies.     

Identification of autolysosomes directly associated with proteolysis on the density gradients in isolated rat hepatocytes

BACKGROUND: More than 40% of patients who undergo curative resection of advanced colorectal carcinoma can be expected to have recurrence of the disease. The most frequent sites of recurrence are the liver (33% of patients) and lung (22%). Interest has therefore focused on treating hepatic or pulmonary metastases, or both, to improve the outcomes of these patients. Although surgical resection has become an increasingly accepted treatment for resectable localized hepatic or localized pulmonary metastases from colorectal carcinoma, the value of aggressive surgery for the removal of both hepatic and pulmonary metastases from patients with primary colorectal carcinoma remains to be clarified. METHODS: Data on 30 patients who had undergone resection of both hepatic and pulmonary metastases from colorectal carcinoma were included in the study. RESULTS: Independent, significant prognostic features were found to be the time that hepatic or pulmonary metastases occurred and the distribution of pulmonary metastases. Median survival times were 30 months (range, 7-108 months) after resection of both hepatic and pulmonary metastases and 48.5 months (range, 11-149 months) after excision of the primary colorectal tumor. Actuarial 1-, 3-, and 5-year survival after resection of both hepatic and pulmonary metastases was 86.7%, 49.3%, and 43.8%, respectively. No perioperative mortality occurred. There were three cases of minor morbidity, which the authors considered acceptable. CONCLUSIONS: Resection of both hepatic and pulmonary metastases from colorectal carcinoma may help to prolong the survival of a small group of patients with these metastases.     

Triggering of acute myocardial infarction onset by episodes of anger. Determinants of Myocardial Infarction Onset Study Investigators

PURPOSE: We performed this study to identify prognostic factors in a subgroup of patients with carcinoma of unknown primary site treated with cisplatin combination chemotherapy. PATIENTS AND METHODS: Seventy-nine patients with poorly differentiated adenocarcinoma or undifferentiated carcinoma of unknown primary site were treated on two consecutive phase II chemotherapy protocols. The first protocol consisted of treatment with 3-week courses of cisplatin, etoposide, and bleomycin (BEP). In the second protocol, cisplatin was administered weekly combined with oral administration of etoposide (DDP/VP). To identify prognostic factors, univariate and multivariate analyses were conducted. RESULTS: In the univariate analysis, performance status, histology, liver or bone metastases, and serum levels of alkaline phosphatase and AST were significant variables to predict survival. In the multivariate analysis, performance status and alkaline phosphatase were the most important prognostic factors. CONCLUSION: Good-prognosis patients had a performance score of 0 (World Health Organization [WHO]) and an alkaline phosphatase serum level less than 1.25 times the upper limit of normal (N). These patients had a median survival duration greater than 4 years. Intermediate-prognosis patients were characterized by either a WHO performance status < or = 1 or an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of 10 months and a 4-year survival rate of only 15%. The poor-prognosis group had both a WHO performance status > or = 1 and an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of only 4 months and none survived beyond 14 months. Treatment strategies for these three groups are discussed. It is suggested that this prognostic model be validated in other patients series.     

CT of calcified liver metastases in colorectal carcinoma

PURPOSE: To assess the incidence, characteristics and prognostic significance of calcification within colorectal hepatic metastases. MATERIALS AND METHODS: A retrospective analysis of CT in 265 patients with locally advanced or metastatic cancer was performed. Four groups were defined: (a) calcification within liver metastases prior to therapy, (b) noncalcified liver metastases with development of calcification on therapy, (c) noncalcified liver metastases, and (d) advanced local tumour without liver metastases. The number of calcified deposits in each patient was documented. A marker lesion was analysed for character, distribution and percentage of calcification. Survival between the four groups was compared. RESULTS: Twenty-nine (11%) patients had calcified liver metastases at presentation and 10 (4%) developed calcification during chemotherapy. Analysis of a marker lesion showed that the most frequent characteristic was fine calcification with a variable distribution. The most frequent change on treatment was alteration in the extent of calcification. Calcification developing on treatment was usually central. There was no difference in survival between groups 1, 2 and 3, but groups 1, 2 and 3 had a shorter survival than group 4. CONCLUSION: Calcification of liver metastases shows a variable pattern and may develop or change during therapy. Liver metastatic calcification may not carry any prognostic significance in colorectal cancer.     

Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment

PURPOSE: To investigate the value of maintenance treatment for patients with metastatic breast cancer whose disease is in complete remission (CR). PATIENTS AND METHODS: One hundred ninety-five women (141 eligible) whose disease was in CR or in CR except for bone metastases following six cycles (6 months) of doxorubicin-containing induction treatment were randomized to receive cyclophosphamide, methotrexate, fluorouracil, prednisone, tamoxifen, and halotestin [CMF(P)TH] or observation. In a previous pilot study, patients in CR after 24 months of induction treatment were randomized to continue chemotherapy for 4 more years or stop chemotherapy. RESULTS: Among patients randomized to CMF(P)TH, life-threatening toxicity included leukopenia in 3%, thrombocytopenia in 3%, cardiac in 2%, and diabetes in 1%. The median time to relapse from randomization was 18.7 months on CMF(P)TH and only 7.8 months on observation (P < .0001). The median time to death was 32.2 months on CMF(P)TH and 28.7 months on observation (P=.74). Similar results were seen in the pilot study (median time to relapse, 12.6 and 6.4 months; median survival, 37.7 and 24.2 months; study too small for statistical significance). Maintenance treatment was always the most significant covariate in time-to-relapse models. CONCLUSION: There is definite toxicity associated with CMF(P)TH maintenance treatment. When CR was obtained on induction, maintenance treatment with CMF(P)TH was never significant in survival models. However, maintenance treatment was always the most significant covariate in the time-to-relapse models, which motivates its consideration for appropriately informed patients.     

Metastatic melanoma of unknown primary origin shows prognostic similarities to regional metastatic melanoma: recommendations for initial staging examinations

BACKGROUND: Metastatic melanoma of unknown primary origin accounts for approximately 2-6% of all melanoma cases. The prognostic significance of this diagnosis is still controversial. METHODS: Of 3258 patients with malignant melanoma recorded during the period 1976-1996, 2.3% had metastases of unknown primary origin. Anatomic distribution, clinical stage, and survival probabilities were evaluated. RESULTS: Thirty patients were classified as having cutaneous or subcutaneous in-transit metastases, and they showed a 5-year survival rate of 83%. Thirty-seven patients were classified as having lymph node metastasis, and their 5-year survival rate was 50%. Disseminated disease was diagnosed in only 8 patients, who had a median survival of 6 months. Comparison of survival probabilities for patients with in-transit metastases and unknown primary tumors with the probabilities for those with cutaneous primary tumors revealed a significant advantage for the former group. No significant differences were found for patients with lymph node metastasis when those with unknown primary tumors were compared with those who had cutaneous melanomas with regional lymph node metastasis. CONCLUSIONS: The clinical disease course of patients with metastatic melanoma of unknown primary origin is similar to that of patients with primary cutaneous melanoma when the same clinical stages of the disease are compared. Based on the assumption that the majority of regional metastases develop from completely regressed primary cutaneous melanoma, recommendations for initial staging examinations in patients with unknown primary tumors are given in this article.     

Detection and determination of theobromine and caffeine in urine after administration of chocolate-coated peanuts to horses

BACKGROUND AND OBJECTIVES: Most patients with colorectal liver metastases are not eligible for resection because they have multiple lesions or because of anatomical constraints. We report the use of cryotherapy to destroy residual metastases following liver resection in patients with disease too widespread for treatment by resection alone. METHODS: Twenty patients with bilobar disease confined to the liver (median 3; range 2-8 lesions) were treated in this way. Seventeen patients also received regional chemotherapy postoperatively. RESULTS: Morbidity was high, but there were no procedure-related deaths and only one patient's hospital stay exceeded 24 days. Significant destruction of tumor, as evidenced by a decline in CEA levels, occurred within 3 months of surgery in all patients (P < 0.001). Median duration of follow-up was 15 (6-53) months. Survival rates at 1 and 2 years were 88% and 60%, respectively, and median survival was 32 months. Seven patients remain well and seven are alive with recurrent liver and/or other metastases. CONCLUSIONS: Although this is not a control study, it would appear that some patients with irresectable liver metastases benefit from this multimodality approach.