Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double-blind, placebo-controlled study.

Cisplatin-induced toxicities are mainly caused by the formation of free radicals, leading to oxidative organ damage. Plasma concentrations of antioxidants decrease significantly during cisplatin chemotherapy for cancer. Forty-eight cancer patients treated with cisplatin-based chemotherapy were randomised in a double-blind manner to receive either supplementation with vitamin C, vitamin E and selenium dissolved in a beverage or to receive a placebo beverage. Primary outcome measures were the amount of nephrotoxicity and ototoxicity induced by cisplatin. No significant differences were found between the two study groups with respect to these primary outcome measures. However, patients who achieved the highest plasma concentrations of the three antioxidant micronutrients had significantly less loss of high-tone hearing. In addition, significant correlations were found between the reduced/oxidised vitamin C ratio and malondialdehyde (MDA), markers of oxidative stress, and cisplatin-induced ototoxicity and nephrotoxicity. The lack of protection against cisplatin-induced toxicities in patients in the intervention arm may be related to poor compliance and/or inadequate supplementation. Supplementation with a higher dose (intensity) and in combination with other antioxidants should be investigated further.

Positron-emission tomography with [18F]fluorodeoxyglucose. Part I. Biochemical uptake mechanism and its implication for clinical studies.

Over the past decades, Positron Emission Tomography has opened a new field of imaging. Nowadays, this technique is being used for diagnosing, staging disease as well as for prognostic stratification and monitoring therapy. In this respect, [18F]fluorodeoxyglucose (FdGlc) is by far the most commonly used PET agent. Many factors have been identified being responsible for a high uptake of this agent in malignancy. However, additional factors such as tumour treatment may interfere with the uptake mechanism. Knowledge of all these factors is a prerequisite for an optimal interpretation of PET studies and, consequently, for a reliable judgement of tumour status. In this article, a review is given of the factors influencing FdGlc uptake and the implications for clinical studies.

Thromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature.

PURPOSE: To evaluate the risk of major thromboembolic complications in male germ cell cancer patients receiving cisplatin-based chemotherapy and to review the literature on this subject. PATIENTS AND METHODS: One hundred seventy-nine germ cell cancer patients treated between January 1979 and May 1997 in our hospital were analyzed with respect to risk factors for developing thromboembolic events, such as baseline tumor characteristics, prior tumor therapy, administration of cytostatic agents, and the use of antiemetic drugs. The patients were treated with a variety of combination chemotherapy regimens, primarily cisplatin-containing combination regimens. RESULTS: Of the 179 patients, 15 patients (8.4%) were identified who developed a total of 18 major thromboembolic complications in the time period between the start of chemotherapy and 6 weeks after administration of the last cytostatic drug in first-line treatment. Of these 18 events, three (16.7%) were arterial events, including two cerebral ischemic strokes, and 15 (83. 3%) were venous thromboembolic events, including 11 pulmonary embolisms. One (5.6%) of the 18 events was fatal. Liver metastases (odds ratio, 4.9; 95% confidence interval, 1.1 to 20.8) and the administration of high doses of corticosteroids (>/= 80 mg dexamethasone per cycle; odds ratio, 3.5; 95% confidence interval, 1. 2 to 10.3) as antiemetic therapy were identified as risk factors for the development of major thromboembolic complications. CONCLUSION: Germ cell cancer patients who receive chemotherapy, in particular those who have liver metastases or receive high doses of corticosteroids, are at considerable risk of developing thromboembolic complications.

Vaccination of melanoma patients with an allogeneic, genetically modified interleukin 2-producing melanoma cell line.

Thirty-three metastatic melanoma patients were vaccinated according to a phase I-II study with an allogeneic melanoma cell line that was genetically modified by transfection with a plasmid containing the gene encoding human interleukin 2 (IL-2). The cell line expresses the major melanoma-associated antigens and the HLA class I alleles HLA-A1, -A2, -B8, and Cw7. All patients shared one or more HLA class I alleles with this cell line vaccine. Patients were immunized by three vaccinations, each consisting of 60 x 106 irradiated (100 Gy) melanoma cells (secreting 120 ng of IL-2/10(6) cells/24 hr) administered subcutaneously at weekly intervals for 3 consecutive weeks. Side effects of treatment consisted of swelling of locoregional lymph nodes and induration at the site of injection, i.e., a delayed-type hypersensitivity (DTH) reaction. In three patients, vaccination induced inflammatory responses in distant metastases containing necrosis or apoptosis along with T cell infiltration. Apoptosis occurred only in Bcl-2-negative areas, not in Bcl-2-expressing parts of the metastases. Two other patients experienced complete or partial regression of subcutaneous metastases. Seven patients had protracted stabilization (4 to >46 months) of soft tissue metastases, including one patient who developed vitiligo after vaccination. Immune responses to the vaccine could be detected in 67% of the 27 patients measured. Vaccination was shown to induce a variable change in the number of anti-vaccine cytotoxic T lymphocytes (CTLs) in peripheral blood, which did not correlate with response to treatment. However, in two of five patients the frequency of anti-autologous tumor CTLs measured was significantly higher than before vaccination. This study demonstrates the feasibility, safety, and therapeutic potential of vaccination of humans with allogeneic, gene-modified tumor cells, and that frequencies of vaccine-specific CTLs among patient lymphocytes can be determined by using a modified limited dilution analysis (LDA).

[Results of 15 years of treatment of nonseminoma testicular cancer: 84% 5-year survival rate]. / Resultaten van 15 jaar behandeling van niet-seminomateuze testiscarcinomen: 84% 5-jaarsoverleving.

OBJECTIVE: To review the results 5 years after treatment of patients with testicular non-seminoma. DESIGN: Retrospective, descriptive. METHOD: The records were studied of the 146 patients treated in Leiden University Hospital, the Netherlands, in 1979-1993 for non-seminoma of the testicle. The median age was 27 years (range: 16-76). The median follow-up duration was 65 months (range: 4-172). The Kaplan-Meier method was used to calculate the recurrence and survival rates. RESULTS: In all, 21 of the 146 patients died (5-year survival rate: 84%). Five patients died as a result of treatment. A relapse occurred in 14 of the 49 stage I patients after frequent controls according to the European Organization for Research and Treatment of Cancer (EORTC) standards. One of these patients died after he refused further treatment for his relapse (5-year survival rate: 96%), 92 patients, including 13 from the stage I group, were treated according to protocol with chemotherapy because of metastatic disease, of whom 51 underwent surgery following primary treatment. The histology of the resected material showed vital tumour tissue in 14 of the 51 patients (27%). Seven patients never reached complete remission after chemotherapy and died. In 12 of the 92 patients a relapse occurred after chemotherapy; seven of these died despite further treatment. The 5-year survival rate of the 92 patients with metastatic disease was 82%. None of the surviving patients developed a second primary or major pulmonary, renal or auditory problem. CONCLUSION: The chance of cure and survival in patients suffering from testicular non-seminoma with the help of chemotherapy and surgery is over 80%. In stage I patients intensive surveillance, and chemotherapy in case of a relapse, is effective. Even patients with metastatic disease have a high probability of being cured with few long-term side effects.

Cisplatin combination chemotherapy induces a fall in plasma antioxidants of cancer patients.

BACKGROUND: Antioxidants protect the body against cellular oxidative damage and thus some of the adverse effects induced by cisplatin and other cytostatic drugs. PATIENTS AND METHODS: The effect of cisplatin-combination chemotherapy on concentrations of plasma antioxidants was studied in 36 cancer patients, including osteosarcoma and testicular carcinoma patients. RESULTS: Eight to 15 days after the start of each cytostatic drug infusion concentrations of various plasma antioxidants were measured and compared to pretreatment values: vitamin C and E, uric acid and ceruloplasmin levels fell significantly (P < 0.01-0.005) and returned to baseline levels before the start of the next chemotherapy cycle. Levels of the antioxidants bilirubin albumin and the ratio vitamin E/cholesterol + triglycerides measured three weeks after the start of chemotherapy significantly decreased compared to pretreatment levels and remained low thereafter (P < 0.001-0.002). Dietary intake of antioxidants and anthropometric measurements, evaluated in 14 patients did not change during the whole treatment period. CONCLUSIONS: Cisplatin-combination chemotherapy induces a fall in plasma antioxidant levels, that may reflect a failure of the antioxidant defense mechanism against oxidative damage induced by commonly used anticancer drugs. This probably results from consumption of antioxidants caused by chemotherapy induced-oxidative stress as well as renal loss of water-soluble, small molecular weight antioxidants such as uric acid.

Does supportive pamidronate treatment prevent or delay the first manifestation of bone metastases in breast cancer patients?

The effect of pamidronate treatment on the first development of bone metastases was investigated in 124 patients with breast cancer, with either locally advanced disease (n = 33) or extraskeletal metastases (n = 91), but no bone metastases in a randomised, multicentre, open controlled study. Patients were assigned to treatment with oral pamidronate, 300 mg/day, (n = 65) or to a control group (n = 59). Tumour therapy was freely allowed. A first clinical event of skeletal morbidity occurred in 22% pamidronate and 20% control patients; unequivocal first radiological manifestation of bone metastases was found in 36% pamidronate and 27% control patients (n.s.). The actuarial risk of a first skeletal event was similar in both groups. Quality-of-life measurements of bone metastases-related aspects showed no differences between the two groups. 19 patients withdrew from the study because of gastrointestinal complaints attributed to pamidronate. We conclude that supportive oral pamidronate treatment (300 mg/day) does not prevent nor delay the development of bone metastases in breast cancer patients at risk.

The diagnostic utility of somatostatin receptor scintigraphy in oncology.

Somatostatin receptor scintigraphy (SRS) with the diethylenetriaminopentaacetic-acid-conjugated somatostatin analogue [111In-DTPA-D-Phe1] octreotide, also known as 111In-pentetreotide, is a new non-invasive modality for the evaluation of tumours that express receptors for somatostatin. These receptors are present on neuroendocrine and other tumours, including lymphomas and some breast cancers. In oncology SRS is a promising diagnostic tool for localizing primary tumours, staging, control and follow-up after therapy, and for identification of patients who may benefit from therapy with unlabelled octreotide or, in the future, with radiolabelled octreotide. In the past few years many small and large studies investigating various aspects of SRS have been reported. In this review the value of SRS in the management of individual tumour types is explored. For many tumours the best sensitivity in lesion detection is only achieved by very careful imaging after the administration of at least 200 MBq 111In-pentetreotide. On the basis of the current experience the main value of SRS in oncology is in the staging and evaluation of gastroenteropancreatic tumours, paragangliomas, small-cell lung cancer and lymphomas. Promising areas for SRS are the evaluation of breast cancer, non-medullary thyroid cancer and melanoma, and initial results with targeted radionuclide therapy using radiolabelled octreotide have been reported.

Age at diagnosis as an indicator of eligibility for BRCA1 DNA testing in familial breast cancer.

We searched for criteria that could indicate breast cancer families with a high prior probability of being caused by the breast/ovarian cancer susceptibility locus BRCA1 on chromosome 17. To this end, we performed a linkage study with 59 consecutively collected Dutch breast cancer families, including 16 with at least one case of ovarian cancer. We used an intake cut-off of at least three first-degree relatives with breast and/or ovarian cancer at any age. Significant evidence for linkage was found only among the 13 breast cancer families with a mean age at diagnosis of less than 45 years. An unexpectedly low proportion of the breast-ovarian cancer families were estimated to be linked to BRCA1, which could be due to a founder effect in the Dutch population. Given the expected logistical problems in clinical management now that BRCA1 has been identified, we propose an interim period in which only families with a strong positive family history for early onset breast and/or ovarian cancer will be offered BRCA1 mutation testing.

Ifosfamide treatment as a 10-day continuous intravenous infusion.

Experimental and clinical studies on ifosfamide indicate that fractionated treatment regimens have a higher efficacy compared to a single short-term infusion. In addition, protracted continuous infusion, in general, is often less toxic without loss of antitumour activity. To study the toxicity of a 10-day continuous infusion at increasing dosages of ifosfamide and mesna, 24 patients with a variety of advanced cancers (colon 10, pancreas 5, adenocarcinoma with unknown primary 5, and 4 others) received a total of 60 cycles (range 1-6 cycles, median 2) at 3 to 4 week intervals. The ifosfamide and mesna doses ranged from 654 mg m-2 day-1 to 1562 mg m-2 day-1 for a total of ten doses. Twenty-two patients were chemotherapy-naive. Pharmacia-Deltec CADD-1 pumps and Port-a-Cath implantable venous access devices were used. The dose-limiting toxicity was leucopenia without thrombocytopenia. At a dose of 1300 mg m-2 day-1 in 30% of the cycles in 7 patients leucopenia of WHO grades 3 and 4 was observed, while at higher dosages this percentage increased to 73%. Haemoglobin values usually decreased during the infusion with a mean of 1 mmol/l (range 0.3-2.5 mmol/l), frequently with partial or full recovery by the next cycle. The next most disturbing side-effect was fatigue (50% of patients WHO grades 2 and 3), and nausea and vomiting requiring drug treatment in 75% of patients. Renal failure and haematuria did not occur. There were two catheter-related complications: thrombosis (1 patient) and mechanical obstruction (1 patient). One patient developed severe encephalopathy at day 6 (total dose 18 g ifosfamide) with complete recovery after cessation of the infusion. In summary, a tolerable ifosfamide dose using this regimen in this previously largely untreated patient group appears to be 1200-1300 mg m-2 day-1 for 10 days. Fatigue is a frequent complaint and might be explained as a kind of neurotoxicity. The treatment can be administered to outpatients.

Hypercalcemia in patients with breast cancer: a survival study.

In a retrospective study survival after hypercalcemia in breast cancer patients has been investigated. A group of 72 patients were treated with bisphosphonate APD [3-(amino-1,1-hydroxypropylidene)bisphosphonate] and third-generation amino-containing bisphosphonates between January 1980 and October 1992. A median survival of 4.5 months was found. In a multivariate analysis, four independent prognostic factors for survival have been found: the interval between first relapse and hypercalcemia, sites of metastases at the moment of hypercalcemia, primary treatment, and the level of serum alkaline phosphatase. Patients with a "flare" reaction on tamoxifen treatment and patients with a normal serum alkaline phosphatase level and bone metastases only had a prolonged survival. Hypercalcemia associated with visceral metastases carried a very poor prognosis. The level of serum calcium in this series of patients was no prognostic indicator for survival.

Reverse smoking as a risk factor for palatal cancer: a cross-sectional study in rural Andhra Pradesh, India.

A cross-sectional study of reverse smoking and its association with pre-malignant and malignant lesions of the palate was conducted in the north coastal areas of Andhra Pradesh, India. A total of 480 randomly selected persons were interviewed. Information about smoking status, diet and access to mass media was obtained in each case and an examination of the oral cavity was performed. Reverse smoking of chutta was practised by 33% of the total rural population. The prevalence rate of all palatal lesions was 55%. The prevalence rates of the separate lesions: leukoplakia palatii, palatal keratosis and palatal cancer, were 9.8%, 18.1% and 1.9%, respectively. The presence of these (pre-)malignant lesions was strongly associated with reverse smoking and also associated with conventional chutta smoking. Reverse smoking induced significantly more lesions than conventional chutta smoking, and was a major determinant of subsequent palatal cancer: all 9 newly diagnosed palatal cancers were observed within the group of reverse smokers. There was an inverse relationship between the incidence of palatal lesions and vitamin A intake. The study of access to mass media indicated that the most favourable medium for promoting a prevention campaign would be the cinema.

Hypothyroidism during immunotherapy with interleukin-2 is associated with antithyroid antibodies and response to treatment.

PURPOSE: We investigated whether the association of interleukin-2 (IL-2) with hypothyroidism is related to the presence of thyroid autoantibodies, dose of IL-2, and clinical effectiveness of treatment, and reviewed the literature. PATIENTS AND METHODS: Sixteen cancer patients were treated with high-dose recombinant, continuous infusion IL-2 (18 x 10(6) IU/m2/d) and lymphokine-activated killer (LAK) cells. One patient previously treated for a toxic goiter with radioactive iodine was analyzed separately. Thyroid function and levels of thyroid antibodies were determined regularly. RESULTS: Seven of 15 patients (47%) became hypothyroid with high serum thyrotropin (TSH) levels within 60 to 120 days after the start of treatment; five responded favorably to treatment (one complete remission [CR], four partial remissions [PRs]), compared with none of the other eight patients. Two hypothyroid patients developed antimicrosomal antibodies (AMAs), one showed a further increase of antithyroglobulin antibodies (TgAbs), and six developed TgAbs. Only one of eight euthyroid patients developed slightly elevated TgAb levels. Development of hypothyroidism correlated significantly with a favorable response to treatment (r = .76, P = .001). The patient, treated with radioactive iodine, also became hypothyroid with high levels of TSH and development of AMAs and TgAbs. No difference was found between the hypothyroid and euthyroid patients in mean cumulative dose of IL-2 administered within the first 60 days or total treatment period, or with the relative dose-intensity. No other autoantibodies were found and patients had normal corticotropin (ACTH) stimulation tests. CONCLUSION: The likelihood of developing (transient) hypothyroidism is higher in patients who respond to IL-2 treatment. The development of antithyroid antibodies suggests that IL-2 treatment triggers autoreactive B-cell clones or that cellular and/or cytokine-mediated thyroid destruction leads to activation of autoreactive B-cell clones.

Linkage to markers for the chromosome region 17q12-q21 in 13 Dutch breast cancer kindreds.

We have performed linkage analysis with five markers for the chromosome region 17q12-q21 in 13 Dutch breast cancer kindreds in order to find support for the claim by Hall et al. that a gene in this region, termed "BRCA1," is associated with predisposition to early-onset familial breast cancer. This work is part of a collaborative study, the results of which are published elsewhere in this issue. Best evidence for linkage was observed with the marker CMM86 (D17S74) in pedigrees with an average age at onset of < or = 47 years (LOD score = 1.77 at 1% recombination). In one breast-ovarian cancer family with a high probability of being linked to 17q, we observed one putative recombinant between D17S250 and D17S579, which suggests that BRCA1 is proximal to D17S579.

Palliative pamidronate treatment in patients with bone metastases from breast cancer.

PURPOSE: An open, randomized study was performed to assess the effects of supportive pamidronate treatment on morbidity from bone metastases in breast cancer patients. PATIENTS AND METHODS: Eighty-one pamidronate patients and 80 control patients were monitored for a median of 18 and 21 months, respectively, for events of skeletal morbidity and the radiologic course of metastatic bone disease. The oral pamidronate dose was 600 mg/d (high dose [HD]) during the earliest study years, then changed to 300 mg/d (low dose [LD]) because of gastrointestinal toxicity. Twenty-nine of 81 pamidronate (HD/LD) patients first received 600 mg/d and were then changed to 300 mg/d; 52 of 81 pamidronate LD patients received 300 mg/d throughout the study. Tumor treatment was unrestricted. RESULTS: An overall intent-to-treat analysis was performed. In the pamidronate group, the occurrence of hypercalcemia, severe bone pain, and symptomatic impending fractures decreased by 65%, 30%, and 50%, respectively; event-rates of systemic treatment and radiotherapy decreased by 35% (P < or = .02). The event-free period (EFP), radiologic course of disease, and survival did not improve. Subgroup analyses suggested a dose-dependent treatment effect. Compared with their controls, in pamidronate HD/LD patients, events occurred 60% to 90% less frequently (P < or = .03) and the EFP was prolonged (P = .002). In pamidronate LD patients, event-rates decreased by 15% to 45% (P < or = .04). Gastrointestinal toxicity of pamidronate caused a 23% drop-out rate, but other cancer-associated factors seemed to contribute to this toxicity. CONCLUSION: Pamidronate treatment of breast cancer patients efficaciously reduced skeletal morbidity. The effect appeared to be dose-dependent. Further research on dose and mode of treatment is mandatory.

Clinical heterogeneity of hereditary breast cancer and its impact on screening protocols: the Dutch experience on 24 families under surveillance.

We investigated 24 families who satisfied a set of criteria for hereditary breast cancer. Five families had only breast cancer, four a combination of breast and ovarian cancer and the remaining 15 had also a variety of other cancers. The families include 86 patients, 78 of which had a malignant tumour and the rest had a benign lesion in the breast. The median age at diagnosis of the breast cancer was 47 years. Three of the 24 families were of a late onset variant. 58 of the 86 patients were symptomatic while 18 were identified during presymptomatic screening because of a positive family history. In 10 cases the reason for referral was not known. 56 of the symptomatic patients had a malignant breast lesion, 52% of which were with lymph node metastasis whereas 12 of the screening group had breast cancer with 2 patients showing lymph node involvement (P = 0.06). 22 of the symptomatic patients and none of the screening patients died of breast cancer after a median observation period of 6 and 7 years, respectively (P < 0.05).