Radiotherapy Plus Procarbazine,Lomustine, and Vincristine Versus Radiotherapy Plus Temozolomide for IDH-Mutant Anaplastic Astrocytoma: A Retrospective Multicenter Analysis of the French POLA Cohort

Background IDH‐mutant anaplastic astrocytomas (AAs) are chemosensitive tumors for which the best choice of adjuvant chemotherapy between procarbazine, lomustine, and vincristine (PCV) or temozolomide (TMZ) after radiotherapy (RT) remains unclear.MethodsIn a large cohort of patients with histologically proven 2016 World Health Organization classification AA with IDH1/2 mutations included in the French national POLA cohort (n = 355), the primary objective was to compare progression‐free survival (PFS) between the two treatment regimens (n = 311). Secondary endpoints were overall survival (OS), progression type, pseudoprogression rate, and toxicity.ResultsThe 4‐year PFS in the RT + PCV arm was 70.8% versus 53.5% in the RT + TMZ arm, with a hazard ratio (HR) of 0.58 (95% confidence interval [CI], 0.38–0.87; p = .0074) in univariable analysis and 0.63 (95% CI, 0.41–0.97; p = .0348) in multivariable analysis. The 4‐year OS in the RT + PCV arm was 84.3% versus 76.6% in the RT + TMZ arm, with an HR of 0.57 (95% CI, 0.30–1.05; p = .0675) in univariable analysis. Toxicity was significantly higher in the RT + PCV arm with more grade ≥3 toxicity (46.7% vs. 8.6%, p < .0001).ConclusionRT + PCV significantly improved PFS compared with RT + TMZ for IDH‐mutant AA. However, RT + TMZ was better tolerated.Implications for PracticeIn the absence of fully conducted randomized trials comparing procarbazine, lomustine, and vincristine (PCV) with temozolomide (TMZ) in adjuvant treatment after radiotherapy (RT) for the management of IDH‐mutant anaplastic astrocytoma (AA) and a similar level of evidence, these two chemotherapies are both equally recommended in international guidelines. This study in a national cohort of IDH‐mutant AA defined according the 2016 World Health Organization (WHO) classification shows for the first time that the RT + PCV regimen significantly improves progression‐free survival in comparison with the RT + TMZ regimen. Even if at the time of analysis the difference in overall survival was not significant, this result provides new evidence for the debate about the chemotherapy regimen to prescribe in adjuvant treatment to RT for WHO 2016 IDH‐mutant AA.     

Procarbazine for non-Hodgkin's lymphoma

Procarbazine hydrochloride is an oral alkylating agent with activity against lymphoma. It is most commonly used in the treatment of Hodgkin's disease. The use of procarbazine-containing chemotherapeutic regimens in non-Hodgkin's lymphoma fell out of favor with the advent of CHOP. We report two patients with relapsed and/or refractory follicular lymphoma that achieved a complete and durable remission with a prolonged course of daily procarbazine.     

Unscheduled DNA synthesis in the testis,a secondary test for the evaluation of chemical mutagens

DNA damage induced by methylmethane sulfonate, cyclophosphamide, doxorubicin and procarbazine in male germ cells was assessed in rabbits by the demonstration of unscheduled DNA synthesis (UDS), in meiotic and postmeiotic phases of maturation. Immediately after treatment by the intravenous route tritiated thymidine was injected into both testicles. Subsequently, rabbits were ejaculated serially, sperm heads were isolated and assayed for radioactivity by liquid scintillation counting. Dose-dependent UDS was demonstrated in late spermatocytes and early spermatids. High doses of hycanthone also induced UDS, but isoniazid and metronidazole had no effect. The rabbit testis UDS test takes into account metabolic and pharmacokinetic aspects of the test substances and provides information about their penetration through the blood-testicular barrier. It is therefore useful for secondary evaluation of potential mutagens. UDS induced by procarbazine was abolished by simultaneous treatment with Ara-C. Thus, the test also recognizes substances that inhibit DNA repair synthesis.     

Feasibility and response to 1-(4-amino-2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride chemotherapy with pre-treated procarbazine for elderly patients with newly diagnosed glioblastoma

Purpose To evaluate the feasibility of 1-(4-amino- 2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) of pre-treated procarbazine for elderly patients with newly diagnosed glioblastomas. Patients and methods From January 2004 to March 2005, 7 patients with glioblastoma were enrolled. After maximal surgical resection, patients were treated with two to four cycles of procarbazine (100 mg/m² for day 1 to 5), ACNU (80 mg/m²/day¹ for day 5), cepharantine (70 mg for day 5 and 12) and vincristine (1.4 mg/m² for day 5 and 12). Results Significant toxicities of this regimen, including infectious toxicities, are described. Among the 7 patients enrolled, there were 6 patients were died, and one was still alive with disease at 13 months. The 6-month progression-free survival and 1-year overall survival are 29% (95% CI, 16% to 73%) and 29% (95% CI, 16% to 73%), respectively. Conclusion The chemotherapy regimen is active but too toxic for elderly patients with newly diagnosed glioblastoma.     

Action of N-isopropyl-α-(2-methylhydrazino)-p-toluamide hydrochloride (procarbazine hydrochloride) in the germ tissue of mice: dominant lethal effects

A study was carried out on the effects of N-isopropyl--(2-methylhydrazino)-p-toluamide (procarbazine, Natulan^®) in the dominant lethal test in the mouse. Male mice were dosed once and mated with fresh virgin females each week. The utilization of sperm, treated as spermatids or testicular sperm with 100–800 mg/kg, resulted in significant post-and pre-implantation death of embryos. Fertility was markedly reduced after the injection of 200 mg/kg of procarbazine and over. This is probably due to a cell killing effect, the most sensitive stages being differentiating spermatogonia, type A spermatogonia and resting primary spermatocytes. Total sterility was induced for several weeks with doses of 600 and 800 mg/kg. Up to 12 weeks after treatment the number of females with implants was still significantly lower than controls indicating a severe depletion of spermatogonial cells. The spectrum of effects correlates well with the drug's effect on nucleic acid and protein synthesis.     

The mouse spot test: Results with a new cross

The fertility and sensitivity of a new cross using male PDB (a/a b/b d/d p/p) and non-agouti female NMRI (a/a c/c) mice have been assessed. This cross results in embryos which are heterozygous at the same coat colour loci as are present in the embryos from the classical TxC57Bl/6 cross, commonly used in the mammalian spot test.The fertility of this new cross reflects the good breeding performance of the NMRI females. The typical litter size at the age when the F₁ are examined for coat colour mosaics is 9–10, and this, together with the high pregnancy rate, results in substantial economies in the number of treated animals. The sensitivity of the cross to treatment with ethylnitrosourea, procarbazine, isoniazid, cyclophosphamide and 4-nitroquinoline oxide has been shown to compare well with other published results. If further evaluation of this cross confirms these preliminary results, then the cross can be used to reduce numbers of experimental animals without loss of sensitivity.     

Effect of Sexual Maturity on Testicular Injury Subsequent to Procarbazine Administration in Rats

The present study examined the effect of age on various aspects of Leydig cell and Sertoli cell function in Sprague-Dawley rats administered procarbazine. Procarbazine was administered intraperitoneally to Sprague-Dawley rats aged 14, 24, and 60 days in 3 weekly injections of 200 mg/kg. Animals were sacrificed 1 week after the last injection. Severe impairment of spermatogenesis was evident in all animals. Sertoli cell function, as assessed by total testicular ABP content, was not significantly different between procarbazine-treated animals and controls in any age group. On the other hand, procarbazine administration resulted in a 60% reduction in total intratesticular testosterone content in the 14-day-old rats but not in the 24- or 60-day-old animals. Serum testosterone was significantly reduced by 50% in the group of 14-day-old animals but not in the other age groups. Serum LH values were not significantly changed from control levels in any age group. Testicular content of Fe, Zn, Mn, and Cn were unaltered by procarbazine administration in any age group. Since serum LH and testicular cation content were not affected by procarbazine treatment, the significant decreases in serum and testicular testosterone in 14-day-old animals after procarbazine administration may indicate a direct age-dependent effect of procarbazine on Leydig cell function.     

A phase II study of intensified chemotherapy alone as initial treatment for newly diagnosed anaplastic oligodendroglioma: an interim analysis

Background Anaplastic oligodendrogliomas (AO) and anaplastic oligoastrocytomas (AOA) are currently treated with a combination of surgery, radiotherapy and chemotherapy. Myeloablative therapy with autologous peripheral blood progenitor cell rescue (APBPCR) is one strategy to exploit the chemosensitivity of these tumors while deferring cranial radiation in an effort to avoid radiation-related neurotoxicity. Methods Twenty patients (16 AO, 4 AOA) with a median age of 46 years (range, 19-60) and KPS of 90 (range, 70-100) were treated with 4 cycles of procarbazine, Lomustine (CCNU) and vincristine (I-PCV) every six weeks. Responding patients were eligible for myeloablative therapy with busulfan and thiotepa followed by APBPCR. 1p and 19q chromosomes were analyzed prospectively but patients were enrolled without regard to deletion status. Results Fifteen patients (75%) had a response to I-PCV and 14 underwent transplant. Median disease-free and overall survival of the transplanted patients has not been reached but is at least 36 months. No patients required dose reduction or termination of I-PCV due to toxicity. Hepatic veno-occlusive disease (VOD) was a complication of transplant in three patients and resulted in one death. Patients with and without deletions of 1p and 19q had durable responses. Conclusions This regimen conferred durable responses in more than one-half of patients, allowing deferral of radiotherapy for three years or longer. The major limitation of this approach is the acute toxicity associated with both the induction and consolidation regimens; temozolomide has replaced I-PCV for the current trial and the incidence and severity of VOD is being followed closely.     

Teratogenicity induced in cultured rat embryos by the serum of procarbazine treated rats

Male rats were injected with single intraperitoneal doses of 50–200 mg/kg of procarbazine hydrochloride (P). Their undiluted serum was then used as the culture medium for 9.5-day-old embryos to evaluate its teratogenic and toxic potential in vitro. A 48-h exposure to this medium resulted in a variety of dysmorphogenic effects. Somite, limb bud and otic vesicle deformities were seen at all dose levels, and neural tube and optic vesicle abnormalities were frequently observed in the 150 and 200 mg/kg groups. Embryonic growth and differentiation were only moderately affected at any dose levels.In a second set of experiments, embryos were directly exposed to 100–150 μg/ml P combined with a liver enzymatic activating system. No abnormalities were detected but toxicity occurred within narrow concentration ranges; 125 μg/ml affected growth and differentiation slightly, and 150 μg/ml suppressed the embryonic development severely. Exposure to 125 μg/ml P without the liver enzymatic activating system had no effect on embryonic growth and differentiation, suggesting that the metablites responsible for the toxic effect were generated by the liver enzymatic preparation.Our results indicate that stable metabolites of P, responsible for its teratogenic action, are formed only within body compartments, whereas the formation of these metabolites does not take place in vitro in the presence of hepatic enzyme preparations.     

The role of chemotherapy in anaplastic astrocytoma patients

Objective

This retrospective study was performed to evaluate the role of chemotherapy in the management of patients with anaplastic astrocytoma (AA).

Methods

We compared the survival outcome among the 3 different treatment protocol groups in a single institution. A total of 86 patients (39 men and 47 women) with newly diagnosed AA after surgery were analyzed. Among them, 31 patients (36.0%) were treated with radiotherapy only (RT Group), 30 patients (34.9%) were treated with nimustine-cisplatin chemotherapy before RT (ACNU-CDDP group), and 25 patients (29.1%) were treated with procarbazine, lomustine and vincristine (PCV) chemotherapy after radiotherapy (PCV group).

Results

The median survival was 14.0, 30.0 and 72.0 months in RT, ACNU-CDDP, and PCV group, respectively and showed significant differences (RT vs. ACNU-CDDP; p=0.039, RT vs. PCV; 0.002, ACNU-CDDP vs. PCV; 0.045). PCV group showed less toxicity rate (5 patients; 20%) than ACNU-CDDP group (12 patients; 40%), while only 3 patients (9.6%) in RT group experienced grade 3 or 4 toxicities.

Conclusion

An application of chemotherapy before or after radiotherapy is beneficial in prolonging the survival of patients with AA. Adjuvant PCV chemotherapy after radiotherapy is recommendable.