Hereditary persistence of alpha-fetoprotein. Case report and review of the literature.

Persistently elevated alpha-fetoprotein (AFP) levels of 24 to 30 micrograms/ml (normal < 10 micrograms/ml) were found in a 38-year-old healthy man. Subsequently, AFP was found to be elevated in another five out of 13 family members within three generations. The pedigree is consistent with an autosomal dominant inheritance pattern. No discernible disease and no functional abnormality appears to be associated with this clinically benign disorder which has been recorded in the literature on four occasions to date. The reported AFP levels in these other cases ranged from 18 to 198 micrograms/ml. Physiologically, AFP is mainly produced in the liver and the yolk sac of human fetuses more than four weeks old, with peak values of up to 4 mg/ml at 12 to 16 weeks of gestation. After birth, AFP levels usually fall, within eight to 12 months, to a very low concentration of < 10 micrograms/ml and persist at low levels throughout life. However, AFP levels can rise above normal in both children and adults in distinct conditions and diseases which will be discussed. Hereditary persistence of alpha-fetoprotein (HPAFP) should be considered in both children and adults with unexplained and persistent elevation of AFP e.g., those screened for hepatocellular carcinoma or diagnosed for germ cell tumor. It should also be recognized in AFP screening for neural tube defects or Down's syndrome during pregnancy. Hereditary persistence of AFP can be easily confirmed by analyzing AFP levels in family members.

Neuropharmacology of emesis and its relevance to anti-emetic therapy. Consensus and controversies.

Recent great advances in the neuropharmacology of the emetic pathways have led to better therapy and improved insight into pathophysiological processes in patients undergoing chemo- and radiotherapy. This article gives an overview of the area, outlines current controversies and makes recommendations for future clinical studies.

Initial prognostic factors in small-cell lung cancer patients predicting quality of life during chemotherapy. Swiss Group for Clinical Cancer Research (SAKK).

The question of whether initial prognostic factors in small-cell lung cancer patients have a predictive value for patients' quality of life (QL) during chemotherapy is addressed in the context of a randomised clinical trial comparing early and late alternating chemotherapy (SAKK protocol 15/84). The relative impact of initial tumour stage and performance status, previous weight loss, sex and age on patient-rated QL was analysed over six chemotherapy cycles in 124-130 patients (according to available QL data) with more than 400 questionnaires. Fatigue/malaise, personal functioning, emotional and general well-being were prospectively selected as QL indicators. Predefined summary measures (average QL score over chemotherapy cycles, 'minimum', 'maximum' and 'final' improvement) were analysed separately by scale in various patient groups. General linear models adjusted for treatment arm and response were used to confirm the univariate findings. Within the overall sample, the average QL scores over six cycles were predicted by initial prognostic factors. Patients with poor prognostic factors reported worse QL. Within a limited sample (with baseline QL), patients with poor prognostic factors reported worse QL at baseline and greater improvement under treatment. Graphical comparison of QL patterns over cycles showed permanent discrimination by levels of prognostic factors. The impact of initial prognostic factors was consistently confirmed in the three analyses. Levels of performance status and weight loss best discriminated QL. Initial tumour stage, performance status and previous weight loss can predict QL in small-cell lung cancer during chemotherapy, even after controlling for response to treatment. Our results may contribute to clinical decision-making with regard to the intensity of chemotherapy and QL outcome, especially in patients with extensive disease.

Early versus late alternating chemotherapy in small-cell lung cancer. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: From 1984 to 1989, the Swiss Group for Clinical Cancer Research (SAKK) performed a randomized phase III trial comparing early versus late alternating chemotherapy in patients with small-cell lung cancer. PATIENTS AND METHODS: 406 eligible patients were entered into the trial. Regimen A consisted of PAV (cisPlatin, Adriamycin, VP 16-213, and Regimen B of CyMOC (Cyclophosphamide, Methotrexate, Oncovin, CCNU). Cycles were repeated as rapidly as possible. patients were randomized to receive either ABABAB (early alternating chemotherapy) or AAABBB (late alternating chemotherapy). After six cycles patients with limited disease in complete or partial remission and those with extensive disease in complete remission received irradiation to the primary (45 Gy) and the CNS (36 Gy). RESULTS: The overall remission rate was 87% with 31% complete remissions. The median survival of all 406 eligible patients was 346 days with 15% of the patients alive at two years. The overall remission rate, the rate of complete remission, the median survival and the rate of long-term survival were not significantly different in the two treatment arms. In limited disease the estimated percentages of survival at 2 years were 33% in the early and 24% in the late alternating chemotherapy arms. Patients with extensive disease survived significantly longer with late alternating chemotherapy than on the early alternation regimen (median survival 336 days versus 301 days, p = 0.01). In the latter patients the received dose intensities (RDI) of cisplatin, adriamycin and etoposide were significantly higher in the late-alternation arm. Patients treated with early alternating chemotherapy rated their tumor symptoms, functional states, fatigue/malaise and restriction of social activity significantly better, reflecting an improved subjective adjustment. CONCLUSIONS: Alternating chemotherapy with PAV-CyMOC plus consolidating radiotherapy is a feasible and effective treatment for small-cell lung cancer, with acceptable toxicity. Whereas patients with early alternating chemotherapy achieve a better subjective adjustment, late alternating chemotherapy allows for a higher RDI of cisplatin, adriamycin and etoposide, which results in a significantly longer median survival of patients with extensive disease.

Quality versus quantity of life in the treatment of patients with advanced small-cell lung cancer? A randomized phase III comparison of weekly carboplatin and teniposide versus cisplatin, adriamycin, etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: Based on a promising pilot study with weekly carboplatin and teniposide (CBDCA/VM) the Swiss Group for Clinical Cancer Research (SAKK) performed a randomised phase III trial in patients with extensive-disease small-cell lung cancer aimed at the development of an effective palliative treatment with low subjective toxicity. PATIENTS AND METHODS: From September 1989 to September 1991 patients were randomised to a weekly regimen of CBDCA/VM or to our 'standard chemotherapy' of cisplatin, adriamycin and etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine (PAV-CyMOC). RESULTS: The trial was closed before the planned accrual of 140 evaluable patients due to a significant survival difference shown by an interim analysis. Of the 61 patients 59 were eligible and included in the final analysis. The results achieved with the PAV-CyMOC regimen were significantly better than those observed in patients treated with weekly CBDCA/VM (remission rate of 65% vs. 29%; p = 0.006). The median survival of patients treated with the PAV-CyMOC combination was significantly longer than that of patients receiving weekly CBDCA/VM (260 days vs. 147 days; p = 0.0035). The 1-year survival rate was 30% in the PAV-CyMOC arm compared to 4% in the CBDCA/VM-treated patients. As expected, side effects including myelosuppression, alopecia and mucositis were significantly more pronounced in patients treated with the PAV-CyMOC regimen. No significant difference was found in patient-rated tumor symptoms and general quality-of-life categories. CONCLUSION: Contrary to our initial expectation that we would achieve similar therapeutic results with less subjective toxicity, in this randomised prospective trial the results achieved by weekly carboplatin and teniposide were significantly inferior in terms of remission rate and survival to those of our 'standard regimen' of cisplatin, adriamycin and etoposide alternating with cyclophosphamide, methotrexate, vincristine and lomustine. The weekly regimen was less toxic than the standard chemotherapy. Whether patients are willing to accept a significant trade-off between quantity and quality of life remains to be evaluated.

Combined-modality treatment of small-cell lung cancer: randomized comparison of three induction chemotherapies followed by maintenance chemotherapy with or without radiotherapy to the chest. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: From 1980 to 1983 the Swiss Group for Clinical Cancer Research (SAKK) performed a randomised phase III trial in patients with small-cell lung cancer with the objective of improving the results of induction chemotherapy and defining the role of consolidating chest irradiation. PATIENTS AND METHODS: Patients were initially randomised to induction arms AVP (adriamycin, etoposide and cisplatin given every four weeks for four cycles), EVA (cyclophosphamide, etoposide and adriamycin given every four weeks for four cycles) or MOC/AVP (methotrexate, vincristine, cyclophosphamide alternating with adriamycin, etoposide and cisplatin given for two cycles). All patients received prophylactic cranial irradiation with 30 Gy, and after four months of induction chemotherapy were randomized to maintenance chemotherapy with or without consolidating chest irradiation. The patients in the combined-modality maintenance arm first received radiation therapy to the chest (45 Gy) followed by MOC/EVA chemotherapy. RESULTS: 266 patients were eligible and evaluable. An overall response rate of 70% with 21% of complete remissions, a median survival of 9.3 months and survival of 8% of the patients at two years were observed. The highest objective response rate was achieved with the AVP-induction chemotherapy with an 80% response rate and 32% complete remissions. Similar results were achieved with the alternating regimen of MOC/AVP. In contrast, patients treated with the EVA induction regimen had significantly lower overall remission (56%) and complete remission rates (7%). The role of consolidating chest irradiation could not be clarified in limited-disease patients due to the small number of them who were randomised to the maintenance part of the study. However, in patients with extensive disease in partial remission after induction treatment, combined maintenance therapy had a more significant adverse effect on survival than maintenance chemotherapy alone (median survival in the maintenance phase of 148 days versus 239 days, p = 0.011). CONCLUSION: We conclude that the combination of adriamycin, etoposide and cisplatin is an active induction treatment. Consolidating chest irradiation is contraindicated in patients with extensive disease in partial remission after induction when given in a sequential manner, as in our trial.

Ondansetron plus dexamethasone is superior to ondansetron alone in the prevention of emesis in chemotherapy-naive and previously treated patients. Swiss Group for Clinical Cancer Research (SAKK).

BACKGROUND: This prospective, randomized, double-blind study assessed whether the addition of dexamethasone to ondansetron leads to improved control of chemotherapy--induced emesis, both in patients undergoing their first course of highly emetogenic chemotherapy and in chemotherapy-pretreated patients refractory to standard anti-emetics. PATIENTS AND METHODS: Patients were randomized to receive either 20 mg dexamethasone as an intravenous infusion or placebo plus ondansetron 8 mg 15 minutes prior to and 4 and 8 hours after the administration of chemotherapy. According to the randomisation code patients received from day 2 to day 5 either ondansetron 8 mg p.o. + placebo p.o., three times daily, or ondansetron 8 mg p.o. + dexamethasone 4 mg p.o., three times daily. Patients undergoing multiple-day treatment received intravenous study treatment on the days of chemotherapy and thereafter oral treatment as outlined above. RESULTS: A total of 215 patients were entered into the study. Of these, 207 were evaluable (111 previously-untreated and 96 previously-treated patients). In the chemotherapy-naive patients the combination of ondansetron plus dexamethasone was significantly superior to ondansetron plus placebo in protecting the patients completely from emesis (retching and vomiting) (81% versus 64%, p = 0.04). The mean number of vomiting episodes was significantly lower in the ondansetron-plus-dexamethasone-treated patients than in those receiving ondansetron plus placebo (0.8 versus 2.1, p = 0.03). In this group of patients there was significantly superior protection from emesis on the second day (p-value = 0.04), and a trend towards a better protection on the third and fourth days. On each day the active combination offered better protection from nausea with an approximately 20% difference in favor of ondansetron plus dexamethasone. In the group of established vomiters the combination of ondansetron plus dexamethansone was superior to ondansetron plus placebo in protecting the patients from acute emesis, with 70% versus 48% of the patients being completely protected (p = 0.03). The mean number of vomiting episodes was significantly lower in the ondansetron-plus-dexamethasone-treated-patients than in those receiving ondansetron plus placebo (0.9 versus 2.1, p = 0.02). In the ondansetron-plus-dexamethasone arm 55% of the patients had complete protection from nausea, retching and vomiting compared to 35% in the ondansetron-plus-placebo-treated group (p = 0.05). Overall 22% of the patients (20% in the ondansetron-plus-placebo and 25% in the ondansetron-plus-dexamethasone arm) experienced at least one, usually mild, adverse event. More patients in the ondansetron-plus-dexamethasone arm complained of epigastric pain or burning (8/101 versus 4/112, p-value = 0.16). The difference in patients reporting constipation (6/101 versus 0/112) was highly significant at a p-value of 0.008. CONCLUSIONS: The combination of dexamethasone plus ondansetron is more effective in protecting chemotherapy-naive patients undergoing their first course of highly emetogenic chemotherapy with cisplatin and chemotherapy-pretreated patients refractory to standard antiemetics from chemotherapy-induced nausea and vomiting compared to ondansetron plus placebo.

Effect of thoracic radiotherapy on mortality in limited small cell lung cancer. A meta-analysis of 13 randomized trials among 2,140 patients.

This meta-analysis was designed to evaluate the hypothesis that thoracic radiotherapy contributes to a moderate increase in overall survival in limited small-cell lung cancer. We collected individual data on all patients enrolled before December 1988 in randomized trials comparing chemotherapy alone with chemotherapy combined with thoracic radiotherapy. The study included 13 trials and 2140 patients with limited disease. A total of 433 patient with extensive disease were excluded. Overall, 1862 of 2103 patients who could be evaluated died; the median follow-up period for the surviving patients was 43 months. The relative risk of death in the combined therapy group as compared with the chemotherapy group was 0.86 (95 percent confidence interval, 0.78 to 0.94; P = 0.001), corresponding to a 14 percent reduction in the mortality rate. The benefit in terms of overall survival at three years (+/- SD) was 5.4 +/- 1.4 percent. Indirect comparison of early with late radiotherapy and of sequential with non-sequential radiotherapy did not reveal any optimal time for treatment. There was a trend toward a larger reduction in mortality among younger patients. In conclusion, thoracic radiotherapy moderately improves overall survival in patients with limited small-cell lung cancer who are treated with combination chemotherapy.

Oral ondansetron in the prophylaxis of nausea and vomiting induced by cyclophosphamide, methotrexate and 5-fluorouracil (CMF) in women with breast cancer. Results of a prospective, randomized, double-blind, placebo-controlled study.

BACKGROUND: The combination of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) is a widely used chemotherapy regimen in breast cancer patients. However, the control of nausea and vomiting induced by oral CMF is a rarely examined problem. Therefore we felt a randomized, placebo controlled study justified in order to improve currently available antiemetic therapy. SUBJECTS AND METHODS: In a randomised double-blind trial ondansetron given orally, 8 mg three times a day for 15 days, was compared with placebo in 82 breast cancer patients receiving chemotherapy with CMF (cyclophosphamide 100 mg/m2 orally days 1-14, methotrexate 40 mg/m2 i.v. days 1 and 8 and 5-fluorouracil 600 mg/m2 i.v. days 1 and 8). The patients recorded nausea and the number of vomits and retches daily on diary cards. Forty-two patients received ondansetron and 40 received placebo. RESULTS: Significantly more patients who received ondansetron experienced neither vomiting nor retching (emesis) compared to those receiving placebo over a 15 day treatment period (60% vs. 35%, p = 0.027). The difference, with 95% confidence limits, was estimated at 25 (4.45%). Furthermore, there was a trend in favour of ondansetron in the control of nausea. Ondansetron was well tolerated, with 25 patients (59%) reporting at least 1 adverse event compared to 18 patients (45%) receiving placebo (p = 0.191). CONCLUSION: The results indicate that ondansetron given orally for 15 days is safe and effective in the control of emesis induced by CMF. It is however too early to recommend ondansetron as standard antiemetic therapy for oral CMF, as the treatment of nausea and vomiting in this setting has not been studied thoroughly enough.

Clinical studies with granisetron, a new 5-HT3 receptor antagonist for the treatment of cancer chemotherapy-induced emesis. The Granisetron Study Group.

Granisetron (BRL 43694A) is a novel, selective 5-hydroxytryptamine-3 (5-HT3) receptor antagonist developed for the prophylaxis and treatment of cytostatic drug-induced emesis. After a brief review of the preclinical evaluation of granisetron the clinical findings with this novel compound are summarised. From the data of large randomised trials one can conclude that granisetron is an active antiemetic, both as a prophylactic and an intervention agent, to an extent which is superior or at least equal to the best available antiemetic combination regimens, having a major efficacy ranging from 74 to 92%. Granisetron may be given as a single, 5-min infusion before chemotherapy and is thus more convenient to administer than many antiemetic regimens. The adverse event profile of granisetron is favourable with a wide therapeutic margin. The only consistent side-effects attributable to granisetron are headache in about 14% of the patients and constipation in about 4% of the patients. Headache induced by granisetron was generally mild and resolved spontaneously or was promptly relieved with standard analgesics. No extrapyramidal side-effects were observed with granisetron.

A meta-analysis of thoracic radiotherapy for small-cell lung cancer.

BACKGROUND: In spite of 16 randomized trials conducted during the past 15 years, the effect of thoracic radiotherapy on the survival of patients with limited small-cell lung cancer remains controversial. The majority of these trials did not have enough statistical power to detect a difference in survival of 5 to 10 percent at five years. This meta-analysis was designed to evaluate the hypothesis that thoracic radiotherapy contributes to a moderate increase in overall survival in limited small-cell lung cancer. METHODS: We collected individual data on all patients enrolled before December 1988 in randomized trials comparing chemotherapy alone with chemotherapy combined with thoracic radiotherapy. Trials that included only patients with extensive disease were excluded. RESULTS: The meta-analysis included 13 trials and 2140 patients with limited disease. A total of 433 patients with extensive disease were excluded. Overall, 1862 of 2103 patients who could be evaluated died; the median follow-up period for the surviving patients was 43 months. The relative risk of death in the combined-therapy group as compared with the chemotherapy group was 0.86 (95 percent confidence interval, 0.78 to 0.94; P = 0.001), corresponding to a 14 percent reduction in the mortality rate. The benefit in terms of overall survival at three years (+/- SD) was 5.4 +/- 1.4 percent. Indirect comparison of early with late radiotherapy and of sequential with non-sequential radiotherapy did not reveal any optimal time for treatment. There was a trend toward a larger reduction in mortality among younger patients: the relative risk of death in the combined-therapy as compared with the chemotherapy group ranged from 0.72 for patients less than 55 years old (95 percent confidence interval, 0.56 to 0.93) to 1.07 (0.70 to 1.64) for patients over 70. CONCLUSIONS: Thoracic radiotherapy moderately improves survival in patients with limited small-cell lung cancer who are treated with combination chemotherapy. Identification of the optimal combination of chemotherapy and radiotherapy will require further trials.

Prevalence of the Rhesus-negative phenotype in Caucasian patients with small-cell lung cancer (SCLC).

We report that the Rhesus (Rh)-negative phenotype is more prevalent in patients with small-cell lung cancer (SCLC) than in the normal Caucasian population (SCLC: 25% Rh-negative vs. 15% expected, p less than 0.0001). This finding has been validated for a Central and a Northern European population (Switzerland and UK). In contrast, the Rh-negative phenotype is no more frequent in non-small-cell lung cancer patients or in heavy smokers with coronary heart disease than in the general population. There was a normal distribution of the ABO blood group phenotype in all patients studied. Whilst the significance of this observation is unclear, we hypothesize that a genetic predisposition to the development of SCLC may be linked to a hitherto unidentified gene on chromosome 1p near the Rh locus. Our observation may perhaps allow further progress to be made in understanding genetic mechanisms of SCLC carcinogenesis.

Phase II study of continuous subcutaneous interferon-alfa combined with cisplatin in advanced malignant melanoma.

Interferon-alfa (IFN-alpha) and cisplatin have shown synergism in vitro against tumour cell lines and optimal effects were observed with continuous and high IFN concentration. 20 patients with advanced malignant melanoma were treated with 10 MU IFN subcutaneously continuously, daily, plus cisplatin 50 mg/m2 intravenously on days 8 and 9. Cisplatin was repeated every 4 weeks. The main toxic effects were myelosuppression, fatigue and weight loss. Toxicities always resolved completely after reduction/interruption of IFN and no life-threatening infection was observed. There were 1 complete and 6 partial responses. 6 patients had stable disease. Median time to progression was 7 months with a range of 16 to 2 months. The combined regimen of IFN-alpha and cisplatin is active in patients with multiple visceral and skeletal sites.

[Syndrome of inappropriate ADH secretion (SIADH) in small-cell bronchus carcinoma]. / Das Syndrom der inadäquaten ADH-Sekretion (SIADH) beim kleinzelligen Bronchuskarzinom.

Based upon the pertinent literature, the paraneoplastic syndrome of inappropriate antidiuretic hormone secretion (SIADH) in patients with small cell lung cancer is reviewed. Small cell lung cancer is a distinct tumor with neuroendocrine features capable of producing peptide hormones amongst which the antidiuretic hormone (ADH, arginine vasopressin) is one of the most frequent. Paraneoplastic SIADH may result from ectopic ADH production or from other tumor-related mechanisms leading to increased pituitary ADH secretion. The overt SIADH is characterized by neurological and psychiatric symptoms attributable to cerebral edema. Pooled published data suggest that the average incidence of clinically manifest SIADH in patients with newly diagnosed small cell lung cancer is 4%. Cases without clinical symptoms, detectable by laboratory tests only, are more frequent: hyponatremia, serum hypoosmolality and urine hyperosmolality are present in 14%, and an inappropriately elevated level of immunoreactive ADH in 38% of all patients respectively. Successful treatment of the underlying tumor, accompanied by a restricted fluid intake in severe cases, will usually result in prompt disappearance of the paraneoplastic SIADH. During and after the tumor treatment, plasma ADH may be useful as a tumor marker.

[Preventive and therapeutic measures in cytostatic-associated toxicity]. / Prophylaktische und therapeutische Massnahmen bei zytostatika-assoziierter Toxizität.

Strategies (both prophylactic and therapeutic) to reduce side effects of chemotherapy are reviewed. In particular, issues concerning proper patient information are discussed which should help to increase patient compliance. Chemotherapy, especially regimens with a curative intent, must normally be administered under the guidance of an oncologist. However, close cooperation with the general practitioner is essential in order to ensure high quality counselling and treatment of the outpatient.

Combination chemotherapy with mitomycin, vindesine, and cisplatin for non-small cell lung cancer. Association of antitumor activity with initial tumor burden and treatment center.

From 1984 through 1986, 205 patients with non-small cell lung cancer were entered into a group-wide trial of the Swiss Group for Clinical Cancer Research (SAKK). This trial evaluated the combination of mitomycin (8 mg/m2 intravenously [IV] on day 1), vindesine (3 mg/m2 IV on days 1 and 8), and cisplatin (60 mg/m2 IV on day 1) with forced diuresis, repeated every 4 weeks (MiViP regimen). One hundred eighty-three patients were evaluable. Six complete and 69 partial responses were documented for an overall response rate of 41% (95% confidence interval, 34% to 50%). In the multivariate analysis the strongest predictors for response were the participating institution and the number of initially involved organ sites. The estimated median time to progression for patients with a complete response, partial response, or stable disease was 155 days (estimated inter-quartile range, 99 to 258 days). In the multivariate analysis the time to progression was significantly associated with the number of involved organ sites (P = 0.041). The estimated median survival time for the 183 evaluable patients was 239 days (estimated inter-quartile range, 137 to 436 days). In univariate and multivariate analyses performance status, number of involved organ sites, pretreatment status with radiation therapy, and participating institution were all significantly associated with survival. The principal toxicities were myelosuppression and nausea and vomiting with 16% of the patients refusing further treatment after a median of four cycles of chemotherapy. In conclusion, the MiViP regimen was an active combination chemotherapy in patients with non-small cell lung cancer in a large trial performed by the SAKK. The prognostic value of the participating institution and the number of organ sites involved by metastatic deposits in non-small cell lung cancer needs further investigation.

The symptomatic control of cytostatic drug-induced emesis. A recent history and review.

This article outlines the historical development of anti-emetic therapies and reviews the pathophysiology and clinical aspects of cytostatic drug-induced vomiting. The methodology and the factors affecting the results of clinical trials with anti-emetics are discussed. Advances in knowledge of the role of 5-hydroxytryptamine in cytostatic drug-induced vomiting have improved current anti-emetic therapy with the development of 5-HT3 receptor antagonists such as granisetron. Early trials show granisetron to be a very effective anti-emetic and suggest useful advantages over the regimens currently considered to be standard therapy for prophylaxis and treatment of cytostatic drug-induced emesis.