Sterility and testicular atrophy related to cyclophosphamide therapy.

We conducted a controlled trial to investigate the long-term effects of treatment with methylprednisolone and chlorambucil in patients with idiopathic membranous nephropathy. We have previously reported that after a mean of 31 months, treated patients did better. We now report the results of a longer follow-up. Eighty-one patients with proteinuria (greater than or equal to 3.5 g per day) and biopsy-proved membranous nephropathy were randomly assigned to receive either supportive therapy alone or a six-month course of corticosteroids alternated with chlorambucil (0.2 mg per kilogram of body weight per day) every other month. Methylprednisolone was first given intravenously in three pulses (1 g per day) and was then given orally (0.4 mg per kilogram per day) for 27 days. The patients were followed for 2 to 11 years (median, 5). Two patients in the control group and one in the treatment group died. At the last follow-up visit, 9 of 39 patients assigned to the control group (23 percent) and 28 of 42 patients assigned to the treatment group (67 percent) did not have the nephrotic syndrome. At five years there were more remissions of the nephrotic syndrome in treated patients than in controls (22 of 30 vs. 10 of 25; P = 0.026). Compared with base-line values, the mean reciprocal of the plasma creatinine level declined significantly in the control group (33 percent; P = 0.0002) but not in the treatment group (6 percent; P not significant). Plasma creatinine increased by 50 percent or more in 19 controls (49 percent) and in 4 treated patients (10 percent). We conclude that a six-month course of methylprednisolone and chlorambucil can bring about sustained remission of the nephrotic syndrome and help to preserve renal function in patients with idiopathic membranous nephropathy.

https://www.nejm.org/doi/pdf/10.1056/NEJM198404123101503?listPDF=true

A Randomized Trial of Methylprednisolone and Chlorambucil in Idiopathic Membranous Nephropathy

BACKGROUND
Estimation of the risk of adverse long-term outcomes such as second malignant neoplasms and infertility often requires reproducible quantification of exposures. The method for quantification should be easily utilized and valid across different study populations. The widely used Alkylating Agent Dose (AAD) score is derived from the drug dose distribution of the study population and thus cannot be used for comparisons across populations as each will have a unique distribution of drug doses.

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The Cyclophosphamide Equivalent Dose as an Approach for Quantifying Alkylating Agent Exposure. A Report from the Childhood Cancer Survivor Study

Since the introduction of antineoplastic chemotherapy, lasting clinical remissions have been obtained for many patients with acute lymphoblastic leukemia, Hodgkin's disease, gestational trophoblastic tumors, and other malignancies. With this therapeutic success there have been concerns about persistent or delayed toxicities of cancer chemotherapy that may become clinically significant for long-term survivors. Gonadal toxicity and infertility occur in many men, women, and children treated with antineoplastic drugs. In this paper we review the clinical syndromes of chemotherapy-related gonadal toxicity and discuss how particular drug classes, doses, or combinations correlate with the degree of gonadal injury and with the potential for recovery of function. Further, we examine how drug effects on germ cell production and endocrine function vary with the age of the patient at the time of treatment. Finally, we comment on the need for long-term prospective studies of fertility, teratogenesis, and mutagenesis in patients receiving cancer chemotherapy.

Gonadal dysfunction in patients receiving chemotherapy for cancer.

Publisher Summary This chapter consolidates and quantitates some deleterious effects of cancer chemotherapeutic agents in humans—namely, their ability to induce chromosomal aberrations, their antifertility effects, their ability to produce congenital malformations under certain conditions, and their carcinogenic potential when used to treat neoplastic and nonneoplastic diseases. It discusses the three classes of antitumor compounds: alkylating agents, antimetabolites, and antitumor antibiotics. These compounds have been extensively studied in vitro and in vivo and they induce chromosomal aberrations; these abnormalities vary according to the agent and the test system used. Combinations of agents or agents plus irradiation also produce cytogenetic damage in human cells. It also provides information on the possible adverse effects of the antimetabolites, antitumor antibiotics, and miscellaneous synthetic agents on spermatogenesis. The current evidence indicates that these effects are related to the dose and duration of chemotherapy, both for single alkylating agents and for combination chemotherapy in which the alkylating agent is one of the components. Anticancer drugs other than the alkylating agents should be more thoroughly studied for possible effects on the fertility in the human female.

Toxicity of antineoplastic agents in man, chromosomal aberrations antifertility effects, congenital malformations, and carcinogenic potential.

This report is concerned with the action of chlorambucil in males. A group of 8 patients with malignant lymphoma were studied. Diagnoses of Hodgkins disease lymphosarcoma and reticulosarcoma had been established by biopsy. Ages were 18 to 38. As the sole medication chlorambucil was given in doses of .1 mg to .4 mg/Kg/day. Hormonal studies were done based on the determination of 17-ketosteroids in the urine and urinary excretion of gonadotropins. Testicular biopsies were performed by open surgery or at autopsy. After treatment 6 patients became azoospermic 1 developed sever oligospermia and 1 showed no change. With total doses up to 400 mg a progressive oligospermia developed from which the patient could recover slowly if the drug was stopped. 4 patients had elevated values of neutral 17-ketosteroids 3 had slightly low values. Gonadotropins were all within normal limits. Micropic studies showed that the germinal like disappears only Sertoli cells remain and peritubular fibrosis develops. The interstitial cells and blood vessels appeared normal. The condition of azoosperma is considered to be permanent.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%28197005%2925%3A5%3C1026%3A%3AAID-CNCR2820250506%3E3.0.CO%3B2-C

Effect of chlorambucil on spermatogenesis in the human with malignant lymphoma.

Several publications have pointed out the deleterious action exerted by cytostatic drugs on human spermatogenesis (Heller, Flegeolli & Watson, 1963; Richter, Calamera, Morgenfeld, Kierszenbaum, Lavieri & Mancini, 1970; Fairley, Barri\\l=e'\\& Johnson, 1972). As many of the patients who receive cytostatic drugs often have a normal life expectancy, it was considered of interest to study the reappearance of spermatogenesis during variable periods of time after withdrawal of treatment. Van Thiel, Sherins, Myers & De Vita (1972) pointed out that in a group of such men in remission for 1 to 5 years after treatment with different drugs, persistent azoospermia was present in five out of seven of the treated individuals. This report concerns observations on a group of five patients with lymphoma who recovered spermatogenesis either partially or totally after treatment with Chlorambucil was suspended. The average age of the patients was 26 years. The daily dose of Chlorambucil was 2 to 10 mg, and the total accumulated dose is shown in Table 1. The effect of treatment was assessed by examination of ejaculates which were provided by masturbation following a period of 4 to 6 days abstinence. Macroand microscopic studies were performed within 1 hr of the specimen being obtained. The volume, turbidity, viscosity, pH, sperm concentration (\\m=x\\ l06/ml), motility and percentage of abnormal cells were recorded in each case. It can be seen from Table 1 that the five patients received a total dose of Chlorambucil which varied from 410 to 2600 mg. After withdrawal of treat¬ ment, all patients except Patient 5 developed azoospermia. In this patient, only

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Recovery of spermatogenesis in patients with lymphoma after treatment with chlorambucil.

One hundred ninety patients who had advanced active Hodgkin's disease, lymphosarcoma, or reticulum cell sarcoma were treated with a combination of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) given in a cyclical fashion every month. Complete remission was produced in 91 of 138 (66%) patients with Hodgkin's disease and in 39 of 52 (75%) patients with non-Hodgkin's lymphoma (lymphosarcoma and reticulum cell sarcoma). The response rate was higher in patients who completed six cycles of therapy compared to those who completed only three to five cycles: 77% vs. 45%, respectively, in Hodgkin's disease, and 85% vs. 46%, respectively, in non-Hodgkin's lymphoma. The median duration of remission was longer for Hodgkin's disease patients who completed six cycles (30 months vs. 10 months). The median duration of complete remission of non-Hodgkin's lymphoma was 14 months. The response to treatment correlated positively with survival. The median survival time start of COPP treatment for patients with Hodgkin's disease was 7 months for nonresponders, 14 months for those who attained partial remission, and more than 48 months for those who attained complete remission. For patients with non-Hodgkin's lymphoma, the median survival time from start of COPP treatment was 24 months for nonresponders and those who had partial remission, and more than 32 months for those who attained complete remission. Of complete remission responders with Hodgkin's disease, 70% are still alive 84 months after diagnosis, and 63% of the patients witn non-Hodgkin's lymphoma are still alive 48 months after diagnosis.

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Combined cyclophosphamide vincristine, procarbazine, and prednisone (COPP) therapy of malignant lymphoma. Evaluation of 190 patients.

With the purpose of exploring new combinations less toxic and easier to manage, the Argentine Group for the Treatment of Acute Leukemia (GATLA) started a randomized controlled study to compare differences in efficacy of treatment in Hodgkin's disease using six courses of cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) versus the same drugs plus CCNU (CCVPP). A total of 298 patients entered this study; 157 with CVPP and 141 with CCVPP. No statistically significant difference was observed between both groups in each of the following features: prior therapy, sex, age, class, stage and histology. The doses in every monthly cycle are: cyclophosphamide 600 mg/m2 iv on day 1, vinblastine 6 mg/m2 iv on day 1, procarbazine 100 mg/m2/day 1 orally on day 1 to 14 and prednisone 40 mg/m2/day orally on day 1 to 14 in all the courses. The CCVPP group received also CCNU 75 mg/m2 day 1 orally on alternate cycles. Patients with stage I or II A received radiotherapy (4,000 rads) to involved areas as induction and were subsequently randomized to receive maintenance therapy. Patients in all other stages received only combination chemotherapy at random. Maintenance therapy consisted of one cycle every 2 months during the first year, every 4 months the second year and every 6 months the third year. Complete remission was obtained in 111 out of 157 patients (71%) of those receiving CVPP and in 110 out of 141 patients (78%) receiving CCVPP. There was no statistically significant difference between both regimens. The percentages of complete remission according to clinical stage and symptoms were: I-IIA 88%. III-IVA 84%, I-IIB 76%, IIIB 76% and IVB 58%. After 42 months of remaining in complete remission 53% and 64% of those patients were treated with CVPP or CCVPP, respectively. The survival percent as a function of therapeutic response at 48 months for patients who achieved complete remission was 80%, 63% for partial remission, and 14% for those who failed to respond or died within the first six courses, with a median duration of survival of 6 months.

Combined chemotherapy cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) V.S. CVPP PLUS CCNU (CCVPP) in Hodgkin's disease

The Rye classification was applied to 144 cases of Hodgkin's disease in Buenos Aires, Argentina. The distribution of the histologic types was determined and correlated with the sex, age, and survival of the patients. The most common histologic types were mixed cellularity and nodular sclerosis. In agreement with observations by others, the nodular sclerosis type affected predominantly young females and carried a significantly better prognosis than the mixed cellularity type. The frequency of the histologic groups was compared with other series from various regions of the world. Similarities and discrepancies were found, the latter due to differences in patient populations, in histologic interpretation, or true geographical variations. To test the reproducibility of the Rye classification, two pathologists undertook a blind study, and independently reached an overall agreement in 84% of the cases. Certain morphological features not sufficiently emphasized in the past were frequent in the nodular sclerosis type: the presence of numerous plasma cells, abundance of neutrophils, and deposits of iron pigment. The significance of these findings is not clear. The predominantly affected paracortical (thymus related) areas in partially involved lymph nodes may account for the impaired cellular immunity observed initially in patients with Hodgkin's disease.

Marcos C. Morgenfeld

Papers

Effect of chlorambucil on spermatogenesis in the human with malignant lymphoma.

Recovery of spermatogenesis in patients with lymphoma after treatment with chlorambucil.

Combined cyclophosphamide vincristine, procarbazine, and prednisone (COPP) therapy of malignant lymphoma. Evaluation of 190 patients.

Combined chemotherapy cyclophosphamide, vinblastine, procarbazine and prednisone (CVPP) V.S. CVPP PLUS CCNU (CCVPP) in Hodgkin's disease

Hodgkin's disease--a report from Buenos Aires, Argentina.