Reduced combined radiotherapy and chemotherapy for Hodgkin's disease--risk-adapted treatment approach.
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Adolescent↗
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Results and prognostic factors following optimal treatment of advanced Hodgkin's disease.
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Adult↗
Aggressive oligodendroglioma: a chemosensitive tumor.
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Alkylating Agents↗
Effects of antimetastatic, antiinvasive and cytotoxic agents on the growth and spread of transplantable leukemias in mice.
The effects of cytotoxic (cyclophosphamide, CCNU, GANU), antiinvasive (vincristine, vinblastine) and antimetastatic (ICRF-159, DM-COOK) agents have been compared in mice-bearing P388 and L1210 leukemias, and TLX5 lymphoma. The drugs tested increase the survival time of the treated mice in a manner consistent with a cytotoxic action in the case of cyclophosphamide, CCNU, GANU, vincristine and vinblastine. Leukemic infiltration of the brain after i.p. tumor implantation has been determined by bioassay of this organ, and is reduced by treatment with all of the drugs tested, with the exception of ICRF-159. DM-COOK appears to increase the life-span of the treated animals by the inhibition of leukemic spread rather than by a cytotoxic action. The marked cytotoxicity of vincristine and vinblastine is sufficient to account for failure to detect any antimetastatic effects of these agents. The lack of antidisseminative effect observed for ICRF-159 under the experimental conditions employed might be connected with the observation that the antimetastatic action of this drug on solid tumors is due to its effects on tumor blood vessels.
Animals↗
Potentiation of CCNU activity by misonidazole in metastases.
The KHT sarcoma is a model system in which metastases can be studied in multiple organs without prior clonal selection. The present series of experiments were designed to evaluate and compare the extent of potentiation of chemotherapeutic agent activity by radiosensitizers when KHT sarcoma cells were grown in different anatomical sites. In these studies the effect of combining misonidazole (MISO) and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) on KHT lung nodules and ovarian metastases was determined. Ovarian metastases were a consequence of the direct spread of tumor cells growing as lung nodules. Once established, KHT cells in the lungs and ovaries grew with a similar doubling time (1-2 days). Response of tumors at either site to chemotherapy in the presence or absence of a sensitizer was assessed using an in vivo to in vitro excision assay. MISO (1.0 mmol/kg) was administered simultaneously with a range of CCNU doses and survival of clonogenic tumor cells was measured 24 h after treatment. The results demonstrate that the addition of MISO to CCNU treatment potentiated the action of this chemotherapeutic agent at both tumor sites although greater cell kill enhancement occurred in the ovarian metastases. In the lung nodules, when combined with CCNU, a 1.0 mmol/kg dose of MISO was found to yield a dose modifying factor (DMF) of approximately 1.3. The same combination resulted in a DMF of approximately 1.8 in the ovarian metastases. This difference in DMF was not a result of an intrinsic difference in sensitivity to CCNU since cells grown at either site gave rise to the same dose response curve. Rather the difference in dose modification by MISO appears to be a consequence of the larger fraction of radiobiologically hypoxic cells in the ovarian tumors (approximately 50 per cent) than in the lung nodules (approximately 5 per cent) at the time of treatment. These findings suggest the use of drug-sensitizer combinations to treat disseminated disease and provide further evidence for the requirement of hypoxia in chemopotentiation by radiosensitizers.
Animals↗
Postoperative radiotherapy and radiotherapy combined with CCNU chemotherapy for treatment of brain gliomas.
A prospective, randomized trial evaluates the effects of two postoperative treatment regimens on survival in 198 adult patients with supratentorial gliomas. All patients were irradiated with 6,000 rads after possibly radical removal of tumors. CCNU administration in the doses of 100 mg/sq m of body surface every 6-8 weeks following surgery proved to have no significant effect on the survival of patients. The median survival time in patients receiving radiation therapy alone was 61 +/- 7 weeks, while in those receiving additional chemotherapy was 56 +/- 4 weeks. Tumor histological malignancy and patients age were found to be the only important prognostic factors, irrespective of the treatment modality.
Adolescent↗
The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group.
Fifty-eight patients with high-grade astrocytoma were treated by members of the Childrens Cancer Study Group in a prospective randomized trial designed to study the effectiveness of chemotherapy as an adjuvant to standard surgical treatment and radiotherapy. Following surgical therapy, patients were assigned randomly to radiotherapy with or without chemotherapy consisting of chloroethyl-cyclohexyl nitrosourea, vincristine, and prednisone. Treatment with chemotherapy prolonged survival and event-free survival. Five-year event-free survival was 46% for patients in the radiotherapy and chemotherapy group, and 18% for patients in the radiotherapy-alone group. Five-year survival was similarly improved. The differences in outcome due to treatment were statistically significant after correcting for imbalances in important prognostic factors (event-free survival, p = 0.026; survival, p = 0.067). The presence of mitoses or necrosis in the tumor specimen was associated with poorer outcome. Patients whose initial surgery was limited to biopsy, and patients with basal ganglia lesions, also had significantly worse outcome. Chemotherapy administered at the time of recurrence in a small number of patients did not produce any long-term survivors. This study is to our knowledge the only randomized trial to investigate effectiveness of chemotherapy in the treatment of high-grade astrocytoma in children.
Adolescent↗
Supraophthalmic carotid infusion for recurrent glioma: rationale, technique, and preliminary results for cisplatin and BCNU.
The chemotherapeutic agents 1-3 bis(2-chloroethyl)-1-nitrosourea (BCNU) and cis-diamminedichloroplatinum II (cisplatin) have both shown activity against malignant glioma, especially when given by arterial infusion. The combination of these agents given by this method is logical because their individual major toxicities are directed at different organ systems, and because of their differences in restriction by the blood-brain barrier. Both agents are toxic to the eye, and infusion of both agents simultaneously into the internal carotid artery would deliver doses of the drug to the eye which should be associated with an unacceptable level of ocular toxicity. We have developed a technique utilizing a flexible flow-directed catheter with a tip which is manipulated by hydraulic forces for delivery of the drug into the intracranial carotid artery above the origin of the ophthalmic artery, thus sparing the eye from the high concentration of drug during the first pass through the arterial circulation. In 13 patients with recurrent malignant glioma treated by arterial infusion of both agents (cisplatin 150-200 mg, BCNU 300 mg fixed dose), we have had no damage to the ipsilateral eye. Preliminary results of treatment appear to be good, with definite tumor regression following arterial infusion in 10 of 12 radiographically evaluable cases. Median survival to date is 11 months with 3 patients still surviving. The longest survival is 24 months. The supraophthalmic infusion technique protects the eye and the combination of drugs given by arterial infusion produces a high tumor response rate.
Adult↗
Randomized comparisons of radiotherapy and CCNU versus radiotherapy, CCNU plus procarbazine for the treatment of malignant gliomas following surgery. A Southwest Oncology Group Report.
One hundred and fifteen eligible patients with histologically verified malignant gliomas (astrocytoma grade III-IV) were randomized to receive either radiotherapy 6 000 rads/7 week plus CCNU 130 mg/M2 every 6 weeks (treatment 1) or radiotherapy 6 000 rads/7 weeks plus CCNU 75 mg/M2 day 1 plus procarbazine 100 Mg/m2 days 1-14 every 6 weeks (treatment 2) within 4 weeks following surgical resection. The response rates showed no statistically significant differences between treatment 1 CR/PR - 24/17% and treatment 2 CR/PR - 14/14% (P-value = 0.31). The median survival was also not significantly different: 55 and 50 weeks for treatments 1 and 2, respectively. The most important prognostic parameter identified was age with younger patients showing higher response rates and longer survival. Patients' performance status was also a useful prognostic parameter for response and survival. Neither the extent of surgical resection nor the tumor grade correlated significantly with the outcome. Further studies are needed to identify active chemotherapeutic agents for the treatment of brain tumors.
Brain Neoplasms↗
2-Nitroimidazole potentiation of nitrosourea induced cytotoxicity in subcutaneous implants of rat 9L brain tumor cells.
To determine if the 2-nitroimidazole (2-NI) and the nitrosourea (NU) in a brain tumor chemopotentiation trial should be selected on the basis of known structure-activity relationships (electron affinity, lipophilicity, alkylating activity, carbamoylating activity), s.c. implants of rat 9L brain tumor cells were treated with combinations of misonidazole (MISO) or etanidazole (SR-2508) administered under oxic and hypoxic conditions, and BCNU, CCNU or chlorozotocin (CLZ) administered under oxic conditions. Cell kill was assessed by an in vivo to in vitro colony formation assay. To mimic the 'preincubation effect', the 2-NI was injected i.p., and 30 min later the tumor was clamped. After 2 hr, the clamp was released, and the NU administered immediately. MISO (2.5 mmole/kg) and SR-2508 (3.75 mmole/kg) reached the same peak tumor concentration in 30 min. Both 2-NIs were metabolized at the same rate in the clamped tumors; however, metabolism of the 2-NIs by hypoxic cells over the 2 hr clamping period did not produce any measurable s.c. 9L cell kill. The relative effectiveness of the NUs for killing oxic s.c. 9L tumor cells was: BCNU greater than CCNU greater than CLZ. Clamping the tumor prior to NU administration did not change the NU cytotoxicity. No potentiation of the NU cytotoxicity by the 2-NIs was observed in oxic tumors. Although metabolism of MISO by hypoxic cells did not result in potentiation of CLZ cytotoxicity at any dose, it resulted in potentiation of BCNU cytotoxicity at all doses and CCNU cytotoxicity at high doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Increasing radiation dose intensity using hyperfractionation in patients with malignant glioma. Final report of a prospective phase I-II dose response study.
We attempted to show a dose effect relationship for radiation therapy by treating patients harbouring malignant glioma with increasing doses of radiation in a step-wise fashion. We postulated that no increase in delayed toxicity would be seen because we used hyperfractionation technique. Between January 1981 and December 1988 we treated 280 patients three times daily at 4 hour intervals. 100 patients received a total dose of 6141 cGy, 73 patients received 7120 cGy, and 107 patients received 8000 cGy. CCNU was given at the time of tumor progression following radiotherapy. Median time to tumor progression was 28 weeks for patients who received 6141 cGy, 27 weeks for patients who received 7120 cGy and 36 weeks for patients who received 8000 cGy. Median survival was 46 weeks for patients who received 6141 cGy, 38 weeks for patients who received 7120 cGy and 45 weeks for patients who received 8000 cGy. There was no statistically significant difference in either time to tumor progression or survival among the three treatment arms and no dose response effect was seen. There was no increase in delayed radiation toxicity when the total radiation dose was increased up to 8000 cGy.
Adolescent↗
Primary central nervous system lymphoma: a role for adjuvant chemotherapy.
Sixteen immunocompetent patients, 10 of whom were previously reported, with primary non-Hodgkins lymphoma of the central nervous system (PCNSL) were treated and followed longitudinally by the Neuro-oncology Service at the University of California, San Francisco (UCSF) and the University of California, San Diego (UCSD). After undergoing surgery (biopsy or resection), these patients received radiation therapy (RT) with hydroxyurea (HU) followed by adjuvant chemotherapy with the combination of procarbazine, CCNU, and vincristine (PCV) as previously reported. All patients ultimately died of progressive recurrent PCNSL. Toxicity using the HU + RT followed by PCV schedule was tolerable. Median and quartile survival data (41 and 65 months, respectively) suggest efficacy for this chemotherapy schedule and further emphasizes a role for adjuvant chemotherapy in the primary treatment of PCNSL.
Adolescent↗
Efficacy of '8-drugs-in-one-day' combination in treatment of recurrent GBM patients.
Thirty-five adult recurrent GBM patients, divided randomly in two groups of 19 and 16 cases, had been treated with two regimens of chemotherapy: a) 'eight-drugs-in-one-day'; b) procarbazine + CCNU + vincristine (PCV) respectively. Chemotherapy was planned at the tumour relapse and delivered as long as tolerated without irreversible sequelae or until the CT scan showed tumor progression. Multiple agents are used simultaneously in the therapeutic approach using 'eight-in-one' to kill as many heterogeneous cells of malignant glial tumor as possible and minimize the emergence of cellular resistance to chemotherapy. Rate response to chemotherapy and the median adjunctive survival time (6.5 and 6 months, respectively) are not significantly different in the two arms of this study. Our experience with such an aggressive multi-drugs combination 'eight-in-one-day' was disappointing if compared with less toxic, better tolerated and easy delivered (PCV) regimen.
Antineoplastic Combined Chemotherapy Protocols↗
Enhancement of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) toxicity by acetohydroxamic acid analogues of 3-nitropyrazole in vitro.
A series of acetohydroxamic acid derivatives of 3-nitropyrazole were synthesized and evaluated for their ability to potentiate (chemosensitization) the activity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) against EMT-6 mouse mammary tumor cells in vitro. The compounds were designed to test the hypothesis that the chemosensitizing activity of the analogues would be proportional to the rate of isocyanate formation via a Lossen rearrangement, in part a function of the leaving group at the N terminus of each acetohydroxamate. Substitution of acetohydroxamic acid side chains at the N-1 position of the parent 3-nitropyrazole resulted in compounds which were preferentially toxic to cells treated under hypoxic conditions, and which were capable of enhancing the toxicity of CCNU in hypoxia. As was observed for cytotoxicity, the enhancement of CCNU toxicity by these sensitizing agents was significantly reduced under aerobic treatment conditions. A strong correlation was established between hypoxic toxicity and chemosensitizing potency. The activity of the analogue, however, was not proportional to their excepted rates of Lossen rearrangement. Nevertheless, several potent chemosensitizing compounds were identified; some of which were 10-50 X's more potent on a molar basis than Misonidazole, the reference chemosensitizing compound.
Cell Survival↗
Postoperative radiotherapy and radiotherapy combined with CCNU chemotherapy for treatment of brain gliomas.
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Antineoplastic Agents↗
Misonidazole and CCNU chemotherapy for recurrent primary brain tumor.
CCNU chemotherapy prolongs survival of patients with primary brain tumor when given at the time of tumor progression following radiation therapy. Used as single agent, response rates of 30 to 80 per cent have been reported with median response durations of five to six months. Experimentally, tumor cytotoxicity is enhanced using the combination of misonidazole and CCNU, without increasing myelotoxicity. In this phase I/II study, 23 patients with primary brain tumor which progressed following radiation therapy were treated with combined CCNU and misonidazole. In all patients either the diagnosis of high grade glioma was made at the time of initial diagnosis prior to radiation therapy or the tumor transformed from low grade to high grade glioma at the time of progression following radiation therapy. CCNU 120 mg/M2 was given four hours following misonidazole 3.5 g/M2 every six weeks, with dosage adjustments for myelotoxicity. Treatment was continued for one year or until tumor progression. Of the 17 patients in the study for one year or more, 11 (65 per cent) survived for one year, and six (35 per cent) remained free of tumor progression for one year. Median time to tumor progression from start of CCNU plus misonidazole chemotherapy was 27 weeks and median survival was 80 weeks. No severe complications resulted from myelotoxicity. One patient developed mild peripheral neuropathy which disappeared following discontinuation of misonidazole.
Adult↗
Normalization of defective monocyte chemotaxis during chemotherapy in patients with small cell anaplastic carcinoma of the lung.
Monocyte chemotactic responsiveness (MCR) in 14 patients with small cell anaplastic bronchogenic carcinoma was depressed before treatment compared with the MCR in 28 normal controls (P = 0.00004). MCR was subsequently monitored during combination chemotherapy and after 6 months the MCR had become normalized compared with pretreatment values (P = 0.00006). In addition, chemotactic factor inhibitor (CFI) activity in plasma was measured before treatment and after 6 months. When incubated with plasma before treatment casein had 62% of normal activity and when incubated with plasma after chemotherapy, 81% of normal activity (P = 0.0009). CFI activity decreased by greater amounts in patients in complete remission than in patients in partial remission or in non-responders (P = 0.01). This study supports the concept that cancer patients have depressed monocyte function. Chemotherapy seems to enhance monocyte chemotaxis in vitro and to decrease CFI activity in plasma.
Adult↗
Correlations between experimental chemotherapy in the murine glioma and effectiveness of clinical therapy regimens.
Intracerebral murine glioma 26 was used as a model system for evaluating two-drug combinations of antitumor agents, BCNU was combined with either procarbazine, dianhydrogalactitol, or ellipticine. CCNU was combined with procarbazine. All combinations were more active than the individual drugs alone. The most potent combinations achieved 85-100% tumor "cure" at 120 days, with combined toxicity indices of 0.25 (CCNU-procarbazine) to 1.30 (NCNU-dianhydrogalactitol). The experimental data were compared to clinical studies with CCNU, procarbazine, and vincristine, and BCNU-procarbazine.
Animals↗