Chemotherapy for oligodendroglioma. Progress report.
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Antineoplastic Combined Chemotherapy Protocols↗
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Radiation recall supraglottitis. A hazard in head and neck chemotherapy.
The enhanced effects of chemotherapy on previously irradiated tissue have been well demonstrated. When chemotherapy is given some time after irradiation and elicits a tissue reaction in the radiation field, the reaction is termed radiation recall. We review known interactions between chemotherapy and radiotherapy and report, to our knowledge, the first case of a supraglottitis radiation recall reaction. Familiarity with this phenomenon and potential complications of chemotherapy following head and neck irradiation may expedite early diagnosis and appropriate lifesaving treatment.
Cytarabine↗
Gastrointestinal cancer. Treatment with fluorouracil-nitrosourea combinations.
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Carmustine↗
Thymosin fraction V and intensive combination chemotherapy. Prolonging the survival of patients with small-cell lung cancer.
Patients with small-cell bronchogenic carcinoma who received intensive remission-induction chemotherapy randomly received either thymosin fraction V, 60 mg/sq m or 20 mg/sq m twice weekly, or no thymosin treatment during the initial six weeks of chemotherapy. Chemotherapy was then continued for two years. Thymosin administration did not increase the complete response rate. Patients receiving thymosin, 60 mg/sq m, had significantly prolonged survival times relative to the other treatment groups. This benefit was due to prolonged relapse-free survival in complete responders to treatment. The mechanism by which thymosin increased survival duration is unclear but may relate to restoration of immune deficits due to disease or treatment.
Antineoplastic Agents↗
Ototoxicity in children with malignant brain tumors treated with the "8 in 1" chemotherapy protocol.
BACKGROUND: Adjuvant chemotherapy has improved the outcome of childhood malignant brain tumors in large randomized trials. With increasing survival rates, treatment toxicity has become a matter of concern. Radiation therapy and cisplatinum are known to be ototoxic. METHODS: We evaluated the incidence and factors predisposing to ototoxicity in children treated with the "8 in 1" chemotherapy protocol in Finland during 1986--1993. Thirty-five of the 82 children survived for at least 1 year after diagnosis. Thirty of these children were old enough to have an audiogram. RESULTS: Seventeen of the 30 children had normal hearing, seven had hearing loss at high frequencies, and six (20%) had severe hearing loss in the speech range. The risk factors for severe hearing loss were young age, a high cumulative dose of cisplatinum, and deteriorating renal function. In the presence of these factors, the risk of severe hearing loss was over 50%. Hearing loss at high frequencies could occur after low cumulative doses of cisplatinum, but severe hearing loss correlated with high cumulative doses. CONCLUSIONS: Cisplatinum-induced hearing loss at high frequencies is common, but hearing loss in the speech range also occurs, particularly in children with predisposing factors, and may progress insidiously and rapidly. Therefore a hearing test before each "8 in 1" course is important.
Adolescent↗
Intracranial Hodgkin's disease in two patients with familial Hodgkin's disease.
Intracranial Hodgkin's disease is very rare and is often a terminal event. The case of a 33-year-old man who relapsed in the anterior pituitary gland without other evidence of disease 6 months after extended field radiation therapy for Stage IIA Hodgkin's disease is presented. He remains well with no evidence of disease five years after surgery and chemotherapy for intracranial relapse. The case of a 16-year-old boy with a dural relapse of Hodgkin's disease associated with positive cerebrospinal fluid cytology is also presented. These two patients are members of different families each with multiple cases of Hodgkin's disease. Central nervous system involvement with Hodgkin's disease may be more frequent in familial Hodgkin's disease in which immune deficiency is common.
Adolescent↗
Combined radiation and chemotherapy for advanced undifferentiated nasopharyngeal carcinoma in children.
Five children, 11-16 years of age at diagnosis, with advanced (stage IV) undifferentiated nasopharyngeal carcinoma, are reviewed. All had radiotherapy and chemotherapy, four at first treatment, are disease free in 3 months, 6, 10, and 13 years from diagnosis. One patient who had radiotherapy only as primary treatment and chemotherapy for metastases, died 15 months from diagnosis. One patient who received 60 Gy and chemotherapy according to the BACON protocol had severe early toxicity and severe late sequelae of treatment. Three patients who received chemotherapy according to a modified UICC-2 protocol for nasopharyngeal carcinoma and 50 to 54 Gy to the primary site had only mild early toxicity and mild late effects of treatment. With lower radiation doses, adjusted to the effect of preradiation chemotherapy, complete tumor control was achieved and acute and long-term morbidity reduced.
Adolescent↗
Hodgkin disease in children: results of a prospective randomized trial in a single institution in Argentina.
PURPOSE: To compare prospective treatment strategies in childhood Hodgkin disease to the following subsets of patients: a) Favorable prognostic group: these patients were randomized to receive 6 vs. 3 CVPP chemotherapy cycles without radiotherapy (CVPP: cyclophosphamide, vinblastine, procarbazine, and prednisone. The scheme was repeated every 28 days). b) Intermediate prognostic group: these patients were randomized to receive 6 cycles of CVPP or AOPE (AOPE: Adriamycin, vincristine, prednisone, and etoposide). Between the third and fourth cycles, all patients in this group received radiotherapy (RT)(30-40 Gy to initially involved areas). c) Unfavorable prognostic group: those patients received a single arm regimen of 6 cycles of CCOPP/CAPTe (3 of each combination) every 28 days. All these patients received radiotherapy (30-40 Gy to initially involved areas). RESULTS: From October 1987 to December 1994, a total of 114 children and adolescents were evaluated. Mean age was 9 (range 2-17) years. There were 72 boys and 42 girls. With a median follow-up of 5 (range 1.5-8.7) years, at 80 months event-free survival (EFS) and overall survival (OS) for the whole cohort are 0.809 (SE: 0.04) and 0.873 (SE: 0.04), respectively (SE: Standard Error). Favorable prognostic group (n = 26) EFS is 0.831 (0.09) (Arm CVPP x 3:0.857 (0.13) and Arm CVPP x 6: 0.875 (0.08); p = non significant). Intermediate prognostic group (n = 64) EFS is 0.806 (0.05) (Arm CVPP x 6 + RT: 0.872 (0.05) and Arm AOPE x 6 + RT: 0.667 (0.10); p = 0.04). Unfavorable group (n = 24) EFS is 0.829 (0.07). CONCLUSIONS: Results of treatment for the whole group are satisfactory. However, 3 cycles of CVPP without radiotherapy obtain equal EFS than 6 cycles without radiotherapy in the favorable prognostic group. In the intermediate prognostic group, 6 cycles of CVPP plus radiotherapy obtain a superior EFS than 6 cycles of AOPE plus radiotherapy. With the success of treatment for Hodgkin disease in children, future research needs to be focused in reducing toxicity without altering the excellent actual outcome.
Adolescent↗
Sensitivity to DNA cross-linking chemotherapeutic agents in mismatch repair-defective cells in vitro and in xenografts.
Together with tolerance to killing induced by methylating agents, loss of mismatch repair (MMR) has previously been found to be associated with hypersensitivity to the DNAcross-linking agent 1-(2-chloroethyl)-3-cyclohexyl-nitrosourea(CCNU) in several human tumor cell lines (Aquilina et al., 1998). Here, we have investigated whether MMR might act as an efficient repair pathway and provide protection against the clastogenicity induced by CCNU and whether the hypersensitivity of MMR-defective cells is extended to other cross-linking agents. An increase in cell killing and in the frequency of micronuclei was observed after CCNU exposure in 2 hPMS2-defective clones (clones 6 and 7) compared with the parental HeLa cells. Introduction of a wild-type copy of chromosome 7 in clone 7 led to re-expression of the hPMS2 protein and brought survival and chromosomal damage upon CCNU exposure to parental levels. Our data indicate that MMR protects against the clastogenic damage induced by this drug. The hPMS2-defective HeLa cells were also hypersensitive to killing by mitomycin C. Mitomycin C sensitivity was confirmed in an hMLH1-defective clone derived from Raji cells and in msh2-defective mouse embryo fibroblasts derived from knock-out mice. hPMS2-defective and parental HeLa cells were transplanted into nude mice, and the animals were treated with mitomycin C. While parental cell growth rate was unaffected, the growth of MMR-defective tumor was significantly reduced. Our results indicate that the in vitro hypersensitivity to mitomycin C conferred by loss of MMR is paralleled in vivo and may have implications for the chemotherapy of MMR-defective tumors.
Adenosine Triphosphatases↗
Mutational specificity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea in Escherichia coli: comparison of in vivo with in vitro exposure of the supF gene.
Forward mutations induced by 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in the supF gene of Escherichia coli were recovered from bacteria deficient in nucleotide excision repair and in DNA-alkyltransferase activity. Bacteria were exposed to 0.4 mM CCNU (in vivo supF mutagenesis), increasing the overall mutation frequency 15.7-fold above the spontaneous value. A total of 73 independent supF- mutants were sequenced. The resulting mutation spectrum was compared with those obtained in bacteria and mammalian cells following the classical shuttle-vector approach (in vitro supF mutagenesis). In vivo CCNU mutagenesis in E. coli yielded a large number of deletions (20/73), in agreement with mammalian data but distinct from in vitro bacterial spectra, which are almost exclusively composed of G:C-->A:T transitions. A substantial proportion (6/18) of CCNU-induced deletions (> 3 bp) involved repeated DNA sequences, suggesting a contribution of a slippage-misalignment process in the generation of this mutation class. Substitutions occurred primarily at G:C base pairs (44/53) and were predominantly G:C-->A:T transitions (39/53). This mutational change was attributed to the mispair potential of the O6-chloroethylguanine lesion with thymine. Most G:C-->A:T transitions (34/39) were located at three 5'-GG-3' hotspot sites (positions 123, 160, and 168). The distribution of hotspot sites for G:C-->A:T substitutions differed as a function of the in vivo or in vitro chemical modification of the supF-bearing plasmids and revealed significant differences in the DNA strand distribution of this mutational event. Our data suggest that the transcriptional status of the target gene has strong influence on the probability of O6-chloroethylguanine formation, reducing its incidence in the transcribed DNA strand.
Base Composition↗
Phase II study of procarbazine, CCNU, and vincristine combination chemotherapy in the treatment of malignant brain tumors.
Forty-eight patients with primary or metastatic malignant tumors of the central nervous system (CNS) were treated with combination chemotherapy, consisting or procarbazine (100 mg/m2 X 14 days), CCNU (75 mg/m2), and vincristine (1.4 mg/m2 X 2, 1 week apart) (PCV) every 4 weeks. Most patients had undergone initial resection of primary tumors, postoperative radiotherapy, and a post irradiation interval of 3 months or more. Other patients harbored unbiopsied, newly-discovered primary or metastatic tumors. All patients were deteriorating neurologically when treatment began. Overall response rate for PCV combination therapy was 44%, no better than results obtained with single agent procarbazine or BCNU, the most effective drugs used alone in previous brain tumor chemotherapy studies.
Brain Neoplasms↗
Clinical management of advanced gastrointestinal cancer.
Although advanced gastrointestinal cancer is the most commonplace problem encountered by the medical oncologist, this group of diseases has proved exceedingly resistant to past chemotherapy efforts. 5-Fluorouracil (5-FU), accepted by some as standard treatment, had provided only infrequent, incomplete, and fleeting antitumor effects, which are probably more than counterbalanced by its gastrointestinal, mucocutaneous, and hematologic antihost effects. There is no evidence that any manipulation of route or schedule of administration provides any improvement in the therapeutic ratio of 5-FU. There is no evidence that this drug contributes to patient survival when used at any stage of any type of gastrointestinal carcinoma. The search for alternative single drugs to 5-FU has been disappointing. The nitrosoureas and Mitomycin C produce occasional regressions, but they do not match the meager effectiveness of 5-FU; and they, in addition, present the difficult problem of cumulative bone marrow suppression. Recent trials with combination regimens have given some indication that the long stalemate in chemotherapy of gastrointestinal cancer may be breaking. Substantial improvements in frequency of tumor regression have been recorded for gastric carcinoma with combinations of 5-FU and BCNU, 5-FU and methyl CCNU, and 5-FU, Mitomycin C, and cytosine arabinoside; for colorectal carcinoma, with the combination of 5-FU, methyl CCNU, and vincristine; and for carcinoid tumors and islet cell carcinomas, with the combination of 5-FU and Streptozotocin. There are also suggestion that such combination chemotherapy with response rates in the 30 to 50% range may produce increased survival when compared to the untreated patient and patients treated with single-drug regimens. While the accomplishments of chemotherapy for the gastrointestinal cancer patient remain less than spectacular there is nevertheless realistic hope that a respectable contribution can now be made to multidisciplinary efforts applied at a stage of disease with minimal tumor burden.
Adenoma, Islet Cell↗
Growth rate of pulmonary metastases in human sarcomas.
The growth rate of spherical pulmonary metastases was studied in 15 patients with osseous and soft tissue sarcoma. The median volume doubling time (Dt) was 25 days. The time from diagnosis of the primary tumor to occurrence of pulmonary metastases correlated directly with the length of Dt. No correlation between Dt and tumor histology was observed. The effect of therapy on the tumor growth curve was studied in 1 patient. The therapeutic implications derived from the quantitative evaluation of tumor growth rate are discussed.
Adolescent↗
Hypercalcemia in small cell (oat cell) carcinoma of the lung. Coincident parathyroid adenoma in one case.
Hypercalcemia is very uncommon in small cell (oat cell) carcinoma of the lung. Two cases of this neoplasm associated with symptomatic hypercalcemia are described. Despite normal skeletal roentgenograms, metastatic bone disease was demonstrated by abnormal bone scans and bone biopsies in both patients. The combination of conventional antihypercalcemia therapy, cytotoxic cancer chemotherapy, and synthetic salmon calcitonin corrected the hypercalcemia despite progression of the small cell carcinoma. One patient with elevated serum immunoreactive parathyroid hormone (PTH) had a parathyroid adenoma at autopsy. This association emphasizes that in cases of bronchogenic small cell carcinoma with hypercalcemia, conincidental primary hyperparathyroidism should be considered.
Adenoma↗
Clinical comparison of the nitrosoureas.
The nitrosourea group of antitumor agents was developed by the Division of Cancer Treatment of the National Cancer Institute. Three nitrosoureas (BCNU, CCNU, MeCCNU) have undergone extensive clinical trials, and two of them (BCNU, CCNU) will soon become commercially available. This paper briefly considers the preclinical development of the nitrosoureas and provides an overview and comparison of the extensive clinical data. Information is given regarding any clinical differences. We discuss general conclusions drawn from the nitrosourea development.
Animals↗
Treatment of grade III and IV astrocytoma with dimethyl triazeno imidazole carboxamide (DTIC, NSC-45388) alone and in combination with CCNU (NSC-79037) or methyl CCNU (MeCCNU, NSC-95441).
The effectiveness of DTIC in the treatment of Grade III and IV astrocytomas was analyzed in two phases. In the first phase, 14 patients (Group A) with progressive neurologic dysfunction following primary treatment were treated with DTIC alone (8 patients) or in combination with CCNU or methyl CCNU (6 patients) and evaluated for change in neurologic status. Five of the 8 treated with DTIC responded symptomatically for a median duration of 18 weeks, and 3 of 6 treated with the combination of drugs responded for a median duration of 12 weeks. In the second phase, 15 patients (Group B) were treated within 4 weeks of surgical resection with radiation therapy and adjuvant chemotherapy with DTIC and/or MeCCNU. These patients were followed for survival and compared to a historical control group of 15 patients (Group C) treated with surgery and radiation only. The drug-treated group had a median survival of 55 weeks, compared to 35 weeks for the control group. Hematologic toxicity was life threatening in 2 of 14 patients treated with combination drugs, but mild with DTIC alone. DTIC appears to be active against malignant astrocytomas. Survival may be lengthened by combining chemotherapy with surgery and radiation therapy.
Adult↗
BACON (bleomycin, adriamycin, CCNU, oncovin and nitrogen mustard) in squamous lung cancer. Experience in fifty patients.
Fifty patients with inoperable squamous carcinoma of the lung. 38 with extensive, and 12 with limited disease, were treated with BACON. Tumor regression greater than 50% was observed in 17 patients (45%) with extensive, and four patients (33%) with limited disease. Stabilization of disease for greater than or equal to 8 weeks was seen in four extensive and eight limited patients, and had the same prognostic importance with regard to survival as response: in extensive disease, responding and stable patients had median survival (MST) of 26 weeks from start of therapy, while MST for non-responders was 9 weeks. MST in limited disease (all patients responding or stable) was 32 weeks. Analysis of survival in extensive disease by performance status showed improvement in each category over historical control results for supportive care alone. BACON was better tolerated and probably more effective when CCNU was given every 8 weeks, rather than every 4 weeks.
Bleomycin↗
Chemotherapy of invasive thymoma.
Despite conventional therapy, including surgery and radiation, 5-year survival for invasive thymoma remains poor. Chemotherapeutic agents, including cisdiamminedichloroplatinum, prednisone, adriamycin and nitrogen mustard-vincristine-vinblastine-procarbazine, and bleomycin-adriamycin-CCNU-vincristine have produced short-term remissions. In view of the small number of cases seen in any one institution, a cooperative study to evaluate chemotherapeutic efficacy in malignant thymoma would seem worthwhile.
Adolescent↗