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PubMed2003

Topical nitrogen mustard in the management of mycosis fungoides: update of the Stanford experience.

OBJECTIVE: To evaluate and update the response and survival outcomes and toxic effects in patients treated with topical nitrogen mustard (mechlorethamine hydrochloride) as primary therapy. DESIGN: A single-center, retrospective cohort analysis. SETTING: Academic referral center for cutaneous lymphoma. PATIENTS: A total of 203 patients with mycosis fungoides (clinical stages I-III) treated with topical nitrogen mustard as initial therapy. MAIN OUTCOME MEASURES: Long-term actuarial survival, freedom-from-relapse, and freedom-from-progression results as calculated by the Kaplan-Meier method. RESULTS: The overall response rate for the 203 patients was 83%, with a complete response rate of 50%. The median time to achieve complete response was 12 months (T1, 10 months; T2, 19 months), and the median time to relapse was 12 months. The duration of complete response increased with longer maintenance therapy; however, after completion of therapy, the response duration or relapse rate was similar regardless of maintenance regimen. Patients with T1 disease had better response and survival outcomes than those with T2 disease, with overall and complete response rates in T1 of 93% and 65%, respectively, and in T2, 72% and 34%, respectively. A similar clinical response was seen for patients with stage IIA vs IB. Sixty-eight percent of 203 patients received only topical nitrogen mustard therapy throughout their follow-up course, including most of the patients who achieved an initial complete response. The clinical response to topical nitrogen mustard as salvage therapy was similar to initial response rates. The efficacy results were similar in patients treated with aqueous vs ointment preparations. Freedom-from-progression rates in T1 disease (no progression to higher T classification or worse clinical stage) at 5 and 10 years were 92% and 85%, respectively, and in T2, 83% at 5 and 10 years. Fewer than 10% of patients experienced contact hypersensitivity reactions when topical nitrogen mustard was used as an ointment preparation. Only 8 patients (4%) developed secondary cutaneous malignancy, none attributable to topical nitrogen mustard monotherapy. Pediatric patients experienced no significant toxic effects with topical nitrogen mustard therapy. CONCLUSIONS: Topical nitrogen mustard remains an effective primary initial or salvage therapy in mycosis fungoides for patients with T1 and T2 disease. Long-term follow-up results confirm its safety.

Administration, Topical↗
PubMed1986

Second malignant neoplasm in treated Hodgkin's disease. Report of a patient and scope of the problem.

The condition of a 6-year-old boy was diagnosed as mixed-cellularity Hodgkin's disease that involved the right side of the neck. Five years after the completion of radiation therapy for the involved area, followed by six courses of chemotherapy with mechlorethamine hydrochloride (nitrogen mustard), vincristine sulfate, procarbazine hydrochloride, and prednisone, he developed cerebral gliosarcoma. Numerous second malignant neoplasms have been reported in adults following treatment for Hodgkin's disease; however, the sequence of events in our patient is a new finding that has not, to our knowledge, been reported previously. While the second malignant tumor may have been induced by prior treatment, direct evidence is lacking.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Advanced stage and unfavorable Hodgkin's disease in the Chinese-a 20-year experience.

We retrospectively analyzed 57 patients with advanced stage (stage III/IV) or unfavorable (presence of B symptoms or bulky disease) Hodgkin's disease from January 1977 to December 1997. There were 29 male and 28 female patients. The median age was 27 years old (range, 13-59). Lactate dehydrogenase levels ranged from 104 units/l to 2320 units/l (median, 433). Eighteen (31.6%), 13 (22.8%), and 26 (45.6%) patients had stage II bulky, stage III, and stage IV disease, respectively. Twenty-five (44%) patients had B symptoms. One (1.8%), 3 (5.3%), 36 (63.2%), and 17 (29.8%) had lymphocyte predominant, lymphocyte depleted, nodular sclerosis, and mixed cellularity histology, respectively. Chemotherapy regimens included mechlorethamine, vincristine, procarbazine, prednisone (MOPP) (n = 9), adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) (n = 23), MOPP alternating with ABVD (n = 13), and COPP-ABV hybrid (n = 12). Complete remission was achieved in 47 (82.4%) patients. Eleven patients (23%) relapsed after the first complete remission and four (36%) attained a second complete remission with salvage chemotherapy. Projected overall survival was 69.0% at 10 years and 20 years. Disease-free survival rates were 71% at 10 years and 20 years. Of the potential prognostic factors analyzed (age, sex, stage, lactate dehydrogenase, serum albumin level, regimen, B symptoms and bulky disease) by using the Cox regression model, only a low albumin level was found to adversely affect overall survival (P = 0.003). In conclusion, despite the relative low incidence of Hodgkin's disease in Hong Kong Chinese, the treatment outcomes in patients with advanced stage or unfavorable Hodgkin's disease is comparable to Caucasian patients.

Adolescent↗
PubMed1996

Irreversible gonadal damage in male survivors of pediatric Hodgkin's disease.

BACKGROUND: Gonadal damage in adult patients after chemotherapy for Hodgkin's disease is well documented, but data of patients treated before adulthood are scarce. METHODS: Gonadal and hormonal function were studied in 19 male long term survivors of Hodgkin's disease who were treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP chemotherapy) before (n = 15) or during puberty (n = 4). The studies were performed a median of 10 years after treatment and repeated in the majority of the patients at the time of yearly visits. RESULTS: Germ cell damage was present in all patients. Semen analysis revealed azoospermia in 12 patients and oligospermia in 6; no recovery of spermatogenesis was seen at follow-up. Testicular size was small in all but one patient. Follicle-stimulating hormone levels were elevated (mean, 14.4 +/- 7.8 U/l) and increased over time (mean, 21.1 +/- 10.5 U/l, P < 0.001). In seven patients, luteinizing hormone (LH) was elevated, indicating Leydig cell dysfunction; also in four of those patients, plasma testosterone was decreased. In three other patients, the response of LH to gonadotropin-releasing hormone was exaggerated with a normal basal LH and testosterone. Comparing testicular function of prepubescent versus pubescent state at time of treatment appears to show a trend for improved outcome in the younger patients. CONCLUSIONS: Gonadal function of long term survivors of pediatric Hodgkin's disease treated with MOPP chemotherapy is severely impaired permanently.

Adolescent↗
PubMed2000

Short term treatment with Escherichia coli recombinant human granulocyte-macrophage-colony stimulating factor prior to chemotherapy for Hodgkin disease.

BACKGROUND: Granulocyte-macrophage-colony stimulating factor (GM-CSF) administration stimulates the proliferation of hemopoietic progenitors. Shortly (48-96 hours) after its discontinuation, feedback phenomena occur and the progenitor proliferation rate drops below baseline levels. As the quiescence of hyperplastic bone marrow suggests that hemopoietic cells may be refractory to the toxic effects of cytostatic drugs, the decision was made to test the hypothesis that GM-CSF given before chemotherapy may be myeloprotective. METHODS: Fifty-six patients with newly diagnosed Stage II-IV Hodgkin disease, ages 18-77 years, were randomized to receive GM-CSF (5 microg/kg subcutaneously) or placebo from Day 7 to Day 4 before each chemotherapy administration (6 cycles of a hybrid of mechlorethamine, vincristine, procarbazine, and prednisone with doxorubicin, bleomycin, vinblastine, and dacarbazine). The treatment was considered a success if the delivery rate of chemotherapy was >90% after 3 cycles and >80% after 6 cycles. RESULTS: Thirty patients received GM-CSF and 26 placebo. The dose intensity (85.2% vs. 79.6%) and the overall success in terms of delivery rate (56.7% vs. 50%) were higher in the GM-CSF group, although these differences were not statistically significant. The neutrophil nadirs were higher in the GM-CSF group during the first three cycles and subsequently similar in both groups. CONCLUSIONS: No significant differences in terms of myelotoxicity or drug delivery were observed between the two treatment arms. Although the myeloprotective effect of the prechemotherapy administration of GM-CSF seems to be minimal, the data indicate a safe timing between GM-CSF discontinuation and further chemotherapy. Because cumulative myelotoxicity has been observed with other growth factors, given in the interval between the chemotherapy cycles, this may be relevant to the planning of rapid cycling.

Adolescent↗
PubMed1979

Long term follow-up of combination chemotherapy-radiotherapy of stage III Hodgkin's disease: a Cancer and Acute Leukemia Group B study.

The Cancer and Acute Leukemia Group B studied the effect of combination chemotherapy-radiotherapy on Stage III Hodgkin's disease. Chemotherapy consisting of 4 weekly doses of vinblastine and one dose of mechlorethamine hydrochloride was followed by no therapy (CT), radiation to involved fields (CTIF) or total nodal radiation (CTTN). Two other treatment arms included total nodal radiation alone (TN) or total nodal radiation followed by chemotherapy (TNCT). Maximum follow-up is ten years. Complete remission percentages were 36 (8/22) for CT, 71 (17/24) for CTIF, 100 (21/21) for CTTN, 86 (19/22) for TNCT and 89 (16/18) for TN. Disease-free survival in patients receiving radiation +/- chemotherapy is 23% (19/73) at 5 years, but even after 9 years relapses were observed in two patients. Forty-one percent of all patients are alive and 32% have survived for five years. Ability to administer adequate therapy was the main determined for response duration and survival. Factors influencing the outcome of the disease include histology, age, splenectomy, initial white blood cell count and performance status, whereas symptomatology, initial absolute lymphocyte count and sex played no role on survival.

Adult↗
PubMed1980

A new effective four-drug combination of CCNU (1-[2-chloroethyl]-3-cyclohexyl-1-nitrosourea) (NSC-79038), vinblastine, prednisone, and procarbazine for the treatment of advanced Hodgkin's disease.

Five hundred and sixty-six patients with either Stage III or IV Hodgkin's disease were prospectively randomized to test whether CCNU and/or vinblastine are more effective than mechlorethamine and/or vincristine with procarbazine and prednisone. The combination of CCNU, vinblastine, procarbazine, and prednisone (CVPP) was shown to be a highly effective program with a complete response frequency of 69%. The use of CCNU as part of the induction program was also shown to be the most significant determinant of prolonged remissions (P = .025). Reduced vomiting and neurotoxicity, as well as the oral administration, were the chief advantages of the CVPP as compared with MOPP. These factors resulted in improved patient and physician compliance. The MVPP regimen was also shown to be a highly effective regimen with a complete response frequency of 73% in patients without prior exposure to chemotherapy. However, the induction regimens containing vinblastine were associated with a significantly higher frequency of fatal hematopoietic toxicities than the induction regimens containing vincristine (P = .05). This higher frequency was almost exclusively seen in the elderly or in patients previously treated with both chemotherapy and radiotherapy. At this time, the remission durations maintained by vinblastine with periodic reinforcement are longer when compared with vinblastine maintenance alone (P = .06), but there is no corresponding increase in survival.

Adult↗
PubMed1983

Diagnosis and management of Hodgkin's disease in the adult.

Appropriate management of Hodgkin's disease is based on both the stage of disease and the specific anatomic sites of involvement within each stage. As a result of the combination of sequential staging and effective treatment, histopathologic subclassification has become less important. Although not generally appreciated, this is also true for constitutional symptoms. During the past 15 years, differences in survival between early and advanced stages have diminished progressively with refinements both in management of newly diagnosed patients, and in management of relapsing disease. Currently, our five-year survival figure for laparotomy-Staged I and II patients is 95%. The corresponding result for Stages IIIA and IIIB patients is 85%; and 67% of our Stage IV patients, who were treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) are projected to be surviving at five years. With the anticipation of a high probability for cure, quality of life including the possibility for parenthood has become increasingly important. In the past, the trend has been to increase treatment for patients with poor prognostic factors. However, very little attention has been paid to the possibility of administering less treatment for very precisely staged patients with good prognostic factors. In this review, management is discussed by stage. Emphasis is placed on the indications for less treatment as well as for more intensive therapy in adult patients with Hodgkin's disease.

Antineoplastic Agents↗
PubMed1984

Combined modality in Hodgkin's disease. Comparison of six versus three courses of MOPP with clinical and surgical restaging.

Between 1972 and 1979, 121 patients with Hodgkin's disease (clinical Stages IInA, IB, IIB, and III) were treated by two different, successive, therapeutic protocols. The first group received six MOPP (mechlorethamine, vincristine, procarbazine, prednisone) cycles before radiotherapy, whereas the second group received only three MOPP cycles before irradiation. A total of 118 patients underwent surgical restaging with splenectomy before irradiation. Clinical criteria used in defining complete remission were verified by surgical restaging. Three MOPPs were just as effective as six MOPPs when combined with radiotherapy in achieving complete remission and in treating occult splenic disease. Following extended-field irradiation, complete remission rates were 96% for three MOPPs versus 94% for six MOPPs. The actuarial survival rates, 4 years after therapy completion, were 89% for three MOPPs and 94% for six MOPPs, with a relapse-free survival rate of 88% and 96.6%, respectively.

Adolescent↗
PubMed1985

Prognostic factors for Stage IV Hodgkin's disease treated with MOPP, with or without bleomycin.

Prognostic factors for 53 previously untreated patients with Stage IV Hodgkin's disease were analyzed for their effects upon complete remission rate, survival, and disease-free survival following treatment with mechlorethamine, Oncovin (vincristine), procarbazine, and prednisone (MOPP) or MOPP plus bleomycin (MOPP-Bleo). Although 75% of those patients with only one site of extranodal disease achieved complete remission, only 25% of those with more than one site of involvement entered complete remission. Seven of the eight patients with more than one extranodal site were dead of disease at 4 years, compared with a 5-year survival of 75% for those with only one site of involvement. Disease-free survival from complete remission was dependent upon the percentage of planned doses of nitrogen mustard actually administered. Patients who received higher doses of nitrogen mustard had significantly longer freedom from relapse and survival after attaining complete remission than those who received reduced doses. Age, symptoms, pathologic features, and presence or size of mediastinal disease did not affect the couple remission rate, survival, or disease-free survival. Patients with Stage IV disease treated with MOPP alone should receive the highest tolerable dose of nitrogen mustard early in their treatment, since those receiving lower doses have a higher risk of relapse.

Adolescent↗
PubMed1985

Evaluation of drug efficacy in vitro using human small cell carcinoma of the lung spheroids.

Five human small cell carcinoma of the lung (SCCL) cell lines selected from 25 established cultures were grown as three-dimensional spheroid tumor models in either spinner culture or in static, agar-coated multiwells. Volume doubling times for the cell lines were approximately 4.5 days. Decreases in spheroid volumes after exposure to a variety of chemotherapeutic agents were used as indicators of drug activity. To further quantify cell killing in SCCL spheroids by chemotherapeutic agents 24 hours after exposure to drugs, a technique was employed that measured maximum levels of incorporation of 125IUdR after continuous labeling for 48 hours. The results of the use of this assay report for SCCL spheroid responses to various concentrations of doxorubicin hydrochloride, cytosine arabinoside, mechlorethamine hydrochloride, cisplatin, or etoposide. Some evidence for an intertumor heterogeneous response to chemotherapy is presented for some of the drugs tested. This assay was also used to characterize a potentiated cell kill when etoposide is combined with cisplatin and to identify activity by a new compound, diazoacetylcholine iodide (DACI), which was synthesized as an agent targeted for SCCL cells.

Animals↗
PubMed1987

Erythrocyte mean corpuscular volume during cytotoxic therapy is a predictive parameter of secondary leukemia in Hodgkin's disease.

Mean corpuscular volume (MCV) evolution during cytotoxic therapy was studied in 32 patients with Hodgkin's disease (HD) who developed therapy-related acute nonlymphocytic leukemia (t-ANLL) and in 64 HD controls matched for age, therapy duration, and MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) administration. Maximum MCV during therapy reached 108.3 +/- 8.2 fl in t-ANLL patients and 103.4 +/- 9.1 fl in the controls (P = 0.001). Maximum MCV increase was 26.7 +/- 8.3 fl in t-ANLL patients and 16.6 +/- 8.3 fl in the controls (P = 10(-9). The greatest 3-month increase observed during therapy was 14.8 +/- 6 fl in the t-ANLL patients and 10.1 +/- 4.8 fl in the controls (P = 0.0001). During initial MOPP therapy, the greatest 3-month increase reached 14.1 +/- 5.3 fl in t-ANLL patients and 9.8 +/- 4.5 fl in the controls (P = 0.01). The relative risk of developing t-ANLL was 9 for a MCV maximum increase over 24 fl during therapy, which was observed in 71% of the patients with t-ANLL and in only 22% of the controls. For the greatest 3-month MCV increase over 15 fl observed in 57% of the t-ANLL patients and in 17% of the controls, the relative risk reached 15. This suggests that there is at least one factor, independent from therapy, which predisposes to t-ANLL. MCV evolution during therapy appears useful in determining which HD patients have a high risk of developing t-ANLL.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Treatment of Hodgkin's disease in children with or without radiotherapy.

From 1975 until 1984 37 children with newly diagnosed Hodgkin's disease were treated with six mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) courses with or without involved field radiotherapy (25 Gy) independent of the stage of their disease. Patients with small lymph node tumors (less than 4 cm) received only six MOPP-courses. Patients with large lymph node tumors (greater than 4 cm) received involved field radiotherapy, 25 Gy to the large tumor masses, between the third and fourth MOPP-course. For the 21 patients with "small" tumors, the disease-free survival (DFS) rate is 90%. In this group two patients with clinical stage (CS) III disease have relapsed but both are alive after successful salvage treatment. The median follow-up time is 69.7+ months. For the 16 patients with larger tumor masses (greater than 4 cm) the DFS rate is 87.5%. In this group one patient with CS II relapsed and died of Hodgkin's disease, and one with CS III relapsed after 37 months, but is now without evidence of disease, 61 months from diagnosis. The median follow-up time is 62+ months. Most of the children with Hodgkin's disease diagnosed before or during puberty can be cured with chemotherapy alone, and thus will not suffer from the damaging late effects of radiotherapy.

Adolescent↗
PubMed1987

Predictive value of the early response to chemotherapy in high-risk stages II and III Hodgkin's disease.

A series of 60 patients with "high risk" Stage II and III Hodgkin's disease (B symptoms, or large mediastinal mass, or E lung disease) were staged without laparotomy and treated with combined modality treatment: mechlorethamine, vincristine, procarbazine, and prednisone (6 MOPP) plus radiotherapy. Patients were restaged after the first three courses of MOPP and the status of response to therapy at that time was called early response to chemotherapy (ERC). The rate of nitrogen mustard and procarbazine delivery (MRD) during the first three cycles of chemotherapy also was assessed. At the completion of the therapy patients were restaged and the final response was assessed. Fifty-two (86.7%) patients entered complete remission (CR). Forty-eight percent of the complete responders achieved CR in the first three courses of MOPP. Eight-year survival and disease-free survival (DFS) rates of the patients achieving CR were 71% and 73%, respectively. Survival and DFS were significantly better for the patients who achieved CR in the first three cycles of chemotherapy than for patients who entered CR at a later stage of therapy: 8-year survival 90% versus 55% (P = 0.00); 8-year DFS 87% versus 59% (P = 0.01). The attainment of a complete ERC was adversely affected by lymphocyte depletion (LD) histologic type (P = 0.01) and MRD less than 65% (P = 0.04). However, when a multivariate regression analysis was used, ERC was the only significant prognostic variable for survival and DFS and its predictive value was confirmed even after correction by MRD. These data suggest that the rapidity of response to chemotherapy could be an important prognostic factor in high-risk Stage II and III Hodgkin's disease.

Adult↗
PubMed1990

The intergroup Hodgkin's disease in children. A study of stages I and II.

A total of 228 previously untreated and eligible children with pathologic Stage I or II Hodgkin's disease were registered in the Intergroup Study of Hodgkin's Disease in Children between February 1977 and April 1981. Patients were randomized in the Southwest Oncology Group (later the Pediatric Oncology Group [POG] to involved-field (IF) radiotherapy alone or IF radiotherapy followed by six courses of mechlorethamine, vincristine, prednisone, and procarbazine (MOPP) chemotherapy; patients in the Children's Cancer Study Group (CCSG) and Cancer and Leukemia Group B (CALGB) were randomized to receive extended-field (EF) radiotherapy or IF radiotherapy followed by six courses of MOPP. An estimated 97% of patients receiving IF + MOPP were relapse-free and surviving (RFS) at 5 years, which was significantly better than 41% for patients receiving IF alone; however there was essentially no overall difference in survival experience between groups. Patients in CCSG and CALGB receiving IF + MOPP had significantly superior RFS at 5 years than patients receiving EF. Survival rate was not different between these two groups, an estimated 93% of patients surviving 5 years or longer. Although patients were not randomized between IF or EF radiotherapy, they were similar with respect to patient characteristics. There was some statistical evidence that RFS was superior at 5 years for patients receiving EF than for IF; however, there was no evidence of a difference in survival experience. The percentages of patients with late effects of therapy were not significantly different by treatment. The most common types of late effects were endocrine dysfunction and impaired resistance to infection. Overall, the response rate to therapy for relapse patients was good, being 83% among all patients who relapsed. Patient characteristics related to poor prognosis were the presence of constitutional (B) symptoms (fever, night sweats, and weight loss) and poor performance status.

Adolescent↗
PubMed1992

Four cycles of chemotherapy and regional radiation therapy for clinical early-stage and intermediate-stage Hodgkin's disease.

To achieve a high percentage of durable complete remissions (CR) and prolonged survivals and reduce toxicity in patients with early-stage and intermediate-stage Hodgkin's disease, a randomized trial of four cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) versus four cycles of thiotepa, bleomycin, and vinblastine (TBV) combined with regional radiation therapy (RT) was conducted. For MOPP and RT, the CR percentage was 98% (60 of 61), and at 5 years, the percentage of patients in CR was 90%, with freedom from progression of 89% and overall survival of 91%. For TBV and RT, the CR percentage was 93% (55 of 59), with a 5-year duration of CR of 83%, freedom from progression of 81%, and overall survival of 91% (P greater than 0.15). The median follow-up was 65 months (range, 7 to 96 months). For 27 patients with clinical Stage IIIA, the CR percentage for MOPP and RT was 75% (12 of 16), with 1 relapse and 4 deaths. For TBV and RT, the CR percentage for clinical Stage IIIA was 73% (8 of 11) with 2 relapses and 2 deaths. Short-term toxicity except for transient leukopenia was less for TBV and RT than for MOPP and RT. Good results are achievable with combined treatment without excessive toxicity.

Adolescent↗
PubMed1992

Comparison of psychosocial adaptation and sexual function of survivors of advanced Hodgkin disease treated by MOPP, ABVD, or MOPP alternating with ABVD.

BACKGROUND: Survivors of advanced Hodgkin disease, who were assigned randomly to treatment by mechlorethamine, vincristine, procarbazine, and prednisone (MOPP); doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); or MOPP alternating with ABVD in a clinical trial of the Cancer and Leukemia Group B (protocol 8251), were compared in terms of their psychosocial adaptation and psychosexual function an average of 2.2 years after completion of treatment (range, 1-5 years). The study was undertaken to determine if there were differences among treatments in these functional areas as a consequence of differential long-term gonadal damage in the three regimens. METHODS: Ninety-three disease-free survivors of advanced Hodgkin disease (56 men and 37 women) were studied (a minimum of 1 year after completion of treatment) by an interview conducted over the telephone. Standardized measures were used to assess their psychologic, sexual, family, and vocational functioning, including the following tests: the Psychosocial Adjustment to Illness Scale--Self Report, the Brief Symptom Inventory, the Profile of Mood States, and the Impact of Event Scale. RESULTS: Contrary to expectation, no statistically significant differences in survivors' psychosocial adaptation or psychosexual function were found by treatment arm. Infertility (based on survivors' reports of medical test results and perceptions) and lower income 1 year before the diagnosis of cancer were significant predictors of poorer adjustment. Most survivors reported a range of problems that they attributed to having had cancer: 35%, proven or perceived infertility; 24%, sexual problems; 31%, health and life insurance problems; 26%, a negative socioeconomic effect; and 51%, conditioned nausea, associated with visual or olfactory reminders of chemotherapy. CONCLUSIONS: No significant long-term advantage in psychosocial adaptation or psychosexual function was found for survivors of Hodgkin disease treated by the less gonadally toxic ABVD regimen 1 to 5 years after completion of treatment.

Adaptation, Psychological↗