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The Journal of Clinical Investigation Dec 1995We have studied the effect of chemotherapy on the level of a particular kind of genetic instability in patients with Hodgkin's disease. The particular type of genetic...
We have studied the effect of chemotherapy on the level of a particular kind of genetic instability in patients with Hodgkin's disease. The particular type of genetic instability assayed is exemplified by trans-rearrangements between two (rather than within one) T cell antigen receptor. 16 patients were studied during their course of treatment. Presentation samples were available for 13 of these patients; 9 of them showed an increase in the level of trans-rearrangements during their exposure to chemotherapeutic agents (P < 0.043). All patients for whom posttherapy samples were available (10 out of 16) showed a return to baseline levels of trans-rearrangements 1-5 mo after completion of therapy (P < 0.03). Thus, this assay appears to be a marker for the "destabilizing" effects of certain chemotherapeutic agents.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Dacarbazine; Doxorubicin; Etoposide; Female; Gene Rearrangement, T-Lymphocyte; Hodgkin Disease; Humans; Male; Mechlorethamine; Middle Aged; Neoplasm Staging; Prednisone; Procarbazine; Recurrence; Time Factors; Vinblastine; Vincristine
PubMed: 8675643
DOI: 10.1172/JCI118343 -
Annals of Oncology : Official Journal... Nov 1995The optimal number of chemotherapy courses in responding patients with advanced-stage Hodgkin's disease (HD) is unknown. (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
The optimal number of chemotherapy courses in responding patients with advanced-stage Hodgkin's disease (HD) is unknown.
PATIENTS AND METHODS
With minimizing chemotherapy and thereby reducing late complications as the objective, patients with advanced HD were randomized to receive either 4 full MOPP/ABVD courses or treatment up to complete remission (CR). Forty-seven patients were given the fixed (FT) and 41 patients the individual treatment (IT). The two groups were balanced according to age, histopathology and sex, although stage IVB dominated in the IT group (20 vs. 8).
RESULTS
Sixty-six of 88 patients (75%) achieved CR. No difference between the two treatment groups in the proportion of stage IVB patients was seen when those achieving CR, i.e., the efficacy population were compared. The mean number of single chemotherapy courses given was 3.7 of MOPP and 3.5 of ABVD in the FT group, compared to 2.6 of MOPP and 2.5 of ABVD in the IT group (p < 0.001). The predicted progression-free survival at 10 years was 81% in the FT and 68% on the IT arm, respectively (p < 0.05). No statistically significant difference in cause-specific 10 year survival was observed (82% and 83%, respectively; p = 0.18). Long-standing CRs were achieved following minimal chemotherapy.
CONCLUSIONS
Since there are no available methods to identify long-term disease-free survivors among CR patients following a limited induction treatment, we suggest that the policy of giving 3-4 full MOPP/ABVD courses should continue. The price for such an approach is the overtreatment of a subset of already cured patients.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Disease-Free Survival; Doxorubicin; Drug Administration Schedule; Female; Hodgkin Disease; Humans; Male; Mechlorethamine; Middle Aged; Neoplasm Staging; Prednisone; Procarbazine; Prognosis; Prospective Studies; Survival Rate; Treatment Outcome; Vinblastine; Vincristine
PubMed: 8624292
DOI: 10.1093/oxfordjournals.annonc.a059356 -
Blood Nov 1995Posttransplant lymphoproliferative disorder (PTLD) is a frequently fatal complication of organ transplantation, occurring in 2% to 6% of cardiac recipients. Treatment...
Posttransplant lymphoproliferative disorder (PTLD) is a frequently fatal complication of organ transplantation, occurring in 2% to 6% of cardiac recipients. Treatment remains poorly defined. Reduction in immunosuppression is effective in a proportion of cases, but mortality on the order of 80% is reported for patients requiring chemotherapy. The reason for such poor outcomes is unclear, but may be partly caused by the concomitant use of immunosuppressives. Nineteen consecutive cardiac recipients with PTLD were studied retrospectively in terms of clinical features and outcome. Patients were managed according to a uniform treatment approach. Initial therapy was a trial of reduced immunosuppression with concomitant acyclovir followed, if unsuccessful, by aggressive combination chemotherapy. The regimen used was predominantly ProMACE-CytaBOM. Six patients with phenotypically polyclonal PTLD presented less than 6 months after transplantation (median 6 weeks). Only 1 of 4 (25%) treated patients responded to reduced immunosuppression; the remainder died of multiorgan failure. Thirteen patients presented with phenotypically monoclonal disease > or = 6 months after transplantation. In 8 of 12 (75%) treated patients initial therapy was reduction in immunosuppression. None achieved complete remission (CR) and 2 experienced fatal rejection. Two patients achieved durable surgical CR. The remaining 8 patients received chemotherapy; 2 of 8 (25%) died during treatment, 6 of 8 (75%) achieved CR. None have relapsed, at a median duration of follow-up of 38 months. Neutropenic sepsis and subclinical doxorubicin cardiotoxicity at a mean cumulative dose of 63 mg/m2 were the principal toxicities. Our data indicate that aggressive chemotherapy is both feasible and effective in phenotypically monoclonal PTLD refractory to reduced immunosuppression. ProMACE-CytaBOM is well suited to cardiac recipients, minimizing doxorubicin exposure and obviating the need for concurrent immunosuppressives.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Cyclophosphamide; Cytarabine; Disease-Free Survival; Doxorubicin; Etoposide; Female; Heart Transplantation; Humans; Immunocompromised Host; Immunosuppression Therapy; Life Tables; Lymphoproliferative Disorders; Male; Mechlorethamine; Methotrexate; Middle Aged; Multiple Organ Failure; Postoperative Complications; Prednisone; Procarbazine; Retrospective Studies; Survival Analysis; Treatment Outcome; Vincristine
PubMed: 7579436
DOI: No ID Found -
Blood Jul 1995Patients with Hodgkin's disease (HD) who fail to enter a complete remission after an initial course of combination chemotherapy are usually considered to have an... (Clinical Trial)
Clinical Trial
High-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) and autologous transplantation for patients with Hodgkin's disease who fail to enter a complete remission after combination chemotherapy.
Patients with Hodgkin's disease (HD) who fail to enter a complete remission after an initial course of combination chemotherapy are usually considered to have an induction failure (IF); this subset of patients has an extremely poor outcome with further conventional therapy. Since 1985, we have entered 30 IF patients into protocols using conditioning with high-dose cyclophosphamide, carmustine (BCNU), and etoposide (VP16-213) with or without cisplatin (CBV +/- P) followed by autologous stem cell transplantation (ASCT) with bone marrow (19 patients), peripheral blood stem cells (PBSCs; 8 patients), or both (3 patients). All except 2 patients had previously received chemotherapy regimens for HD that contained at least 7 drugs, and 9 had received prior radiotherapy (RT). After documentation of IF, the majority of patients received some cytoreductive therapy as specified by protocol (local RT in 9, two cycles of conventional chemotherapy in 2, both modalities in 2, or high-dose cyclophosphamide to enhance PBSC collection in 11) before CBV +/- P. Five treatment-related deaths occurred, all before day 150 posttransplant. Eleven patients have had progressive HD at a median of 6 months (range, 0.1 to 45 months) after ASCT. The actuarial progression-free survival (PFS) at a median follow-up of 3.6 years (range, 0.2 to 8.2 years) is 42% (95% confidence intervals, 21% to 61%). The statistical analysis identified only prior clinical bleomycin lung toxicity as an adverse risk factor for PFS, mainly because of the increased nonrelapse mortality seen in these patients. CBV +/- P and ASCT can produce durable remission in a substantial proportion of IF HD patients who otherwise have a poor survival, and we believed ASCT approaches represent the best therapy currently available for these patients. Additional measures are needed to reduce the primary problem of disease progression despite high-dose chemotherapy and stem cell transplantation.
Topics: Actuarial Analysis; Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Diseases; Bone Marrow Transplantation; Carmustine; Cisplatin; Cyclophosphamide; Dacarbazine; Disease-Free Survival; Doxorubicin; Etoposide; Female; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Leucovorin; Male; Mechlorethamine; Methotrexate; Prednisolone; Prednisone; Procarbazine; Remission Induction; Salvage Therapy; Survival Analysis; Treatment Outcome; Vinblastine; Vincristine
PubMed: 7541661
DOI: No ID Found -
Annals of Oncology : Official Journal... Feb 1995In patients with advanced Hodgkin's disease (HD), the alternation of MOPP with ABVD or hybrid MOPP/ABVD are associated with a high CR rate and a high probability of...
BACKGROUND
In patients with advanced Hodgkin's disease (HD), the alternation of MOPP with ABVD or hybrid MOPP/ABVD are associated with a high CR rate and a high probability of 5-year survival. However, even after effective chemotherapy the risk of nodal relapse is not negligible, and not only in initial bulky site(s) of disease. For this reason, in an attempt to prevent relapses after combination chemotherapy alone, we performed a prospective study to evaluate the efficacy and toxic effects of 6 courses of hybrid MOPP/ABVD followed by radiotherapy (RT) in stages II A bulky, II B, III and also in stage IV with bulky disease of residual after chemotherapy.
PATIENTS AND METHODS
From January 1985 to August 1993, 133 patients with HD (128 newly diagnosed, stage II A bulky-IV, 5 in first relapse after RT) were treated according to the following program: 6 courses of the hybrid MOPP/ABVD regimen followed by RT (STNI + spleen in stages II A, II B, III without pelvic lymph node involvement, TNI + spleen in stage III with pelvic lymph node involvement, involved field in stage IV with bulky disease or residual after chemotherapy). The total dose of RT was 4000 cGy to the sites of bulky or residual disease and 2000 cGy to the other sites.
RESULTS
After hybrid MOPP/ABVD, 107 of 130 (82.3%) fully evaluable patients were classified as in CR or CR(U). After completion of RT, 108 patients were in CR and 3 were in PR, for an overall response rate of 85%. With a median follow-up duration of 45 months, the actuarial 5-year survival is 76% and the progression-free survival 68.6%. So far, only 14 patients have relapsed (6 within the irradiation field) and the 5-year relapse-free survival is 82.5%.
CONCLUSION
Six courses of hybrid MOPP/ABVD followed by RT in stages II A bulky, II B, III and in stage IV with bulky disease or residual after chemotherapy produced a high CR rate with low risk of relapse. However, a longer follow-up is necessary to evaluate the late effects of combined therapy.
Topics: Actuarial Analysis; Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Bone Marrow Diseases; Combined Modality Therapy; Dacarbazine; Doxorubicin; Female; Hodgkin Disease; Humans; Lymphatic Irradiation; Male; Mechlorethamine; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Second Primary; Patient Compliance; Prednisone; Procarbazine; Prognosis; Prospective Studies; Survival Analysis; Treatment Outcome; Vinblastine; Vincristine
PubMed: 7540419
DOI: 10.1093/oxfordjournals.annonc.a059113 -
Blood Dec 1994
Comparative Study
Topics: Antineoplastic Combined Chemotherapy Protocols; Hematopoietic Stem Cell Transplantation; Hodgkin Disease; Humans; Life Tables; Lymphoma, Non-Hodgkin; Mechlorethamine; Myelodysplastic Syndromes; Neoplasms, Radiation-Induced; Prednisone; Procarbazine; Risk Factors; Transplantation, Autologous; Vincristine; Whole-Body Irradiation
PubMed: 7949159
DOI: No ID Found -
Annals of Oncology : Official Journal... Nov 1994This study evaluated the therapeutic effect of the weekly administration of vinorelbine (5'-nor-anhydrovinblastine), a semisynthetic vinca alkaloid, in heavily... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
This study evaluated the therapeutic effect of the weekly administration of vinorelbine (5'-nor-anhydrovinblastine), a semisynthetic vinca alkaloid, in heavily pretreated patients with Hodgkin's disease.
PATIENTS AND METHODS
Twenty-four patients with Hodgkin's disease refractory or resistant to at least two chemotherapy regimens were enrolled in this study. Vinorelbine was administered in a weekly dose of 30 mg/m2 i.v. bolus and patients were evaluated after four courses. All but two were considered evaluable for drug response. The reasons for their exclusion were early death due to pancytopenia and loss to follow-up after two courses. In complete responders, six additional courses were administered; in all other patients, treatment was continued until their diseases progressed. Toxicity was evaluated in 23 patients according to the Common Toxicity Criteria.
RESULTS
Eleven of 22 evaluable patients (50%) showed objective response (complete 14% and partial 36%). The median duration of response was six months for both complete and partial responders (range 2-10 months). Thirteen patients are still alive and five are still on therapy. Grade 3-4 granulocytopenia was documented in 53% of patients and grade 3 infections in 13%. Anemia and thrombocytopenia were negligible. Nausea and vomiting were not observed; grade 2 alopecia occurred in only one patient. There were grade 3 reactions at the injection site in the first five patients, so a venous central access was utilized in the subsequent patients. Two patients had grade 1 constipation and only one developed an adynamic ileum. Although all patients had previously been treated with vinca alkaloid analogs, peripheral neuropathy was mild.
CONCLUSIONS
Our data indicate that vinorelbine is active as a single agent in heavily pretreated patients with Hodgkin's disease. The efficacy in patients pretreated with at least two vinca alkaloids suggests a possible absence of cross-resistance between vinorelbine and other vinka analogs. Toxicity is mild and reversible. The inclusion of vinorelbine in secondline combination chemotherapy regimens for Hodgkin's disease is strongly recommended.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Combined Modality Therapy; Dacarbazine; Doxorubicin; Female; Follow-Up Studies; Hodgkin Disease; Humans; Male; Mechlorethamine; Prednisone; Procarbazine; Radiotherapy; Remission Induction; Salvage Therapy; Survival Rate; Vinblastine; Vincristine; Vinorelbine
PubMed: 7531487
DOI: 10.1093/oxfordjournals.annonc.a059010 -
Blood Aug 1994Second primary cancers are a serious late occurrence for patients surviving Hodgkin's disease (HD). In addition to previously described risk factors such as age, gender,... (Comparative Study)
Comparative Study
Second primary cancers are a serious late occurrence for patients surviving Hodgkin's disease (HD). In addition to previously described risk factors such as age, gender, clinical stage, and treatment modalities, splenectomy was found to correlate with an increase in risk for secondary acute leukemia. We assumed that splenic irradiation inducing functional hyposplenia and splenectomy could have similar consequences on second cancer risk. We studied a series of 892 continuously disease-free HD adult patients treated at a single institution between 1960 and 1984. The risk of second cancer was analyzed (1) relative to the general population and (2) between risk subgroups using the Cox proportional hazards model. Fifty-six patients developed a second cancer (8 acute leukemias, 3 myelodysplastic syndromes, 8 non-Hodgkin's lymphomas, and 37 solid tumors; basal cell and in situ cervix carcinomas were excluded). The 15-year cumulative incidence rate (with 95% confidence limits) was 13.2% (9.3% to 17.2%). Relative to the general population incidence data, the risk of second cancer was multiplied by 4.68 (3.51 to 6.12; P < .001); it was multiplied by 2.80 (1.63 to 4.48; P < .001) in patients whose spleen was not treated and multiplied by 6.87 (4.81 to 9.51; P < .001) in splenectomized patients or patients whose spleen was irradiated. Multivariate regression analysis that controlled for confounding variables (age, gender, clinical stage, extent of radiation therapy, and chemotherapy regimen) showed that, in addition to age above 40 years (relative risk [RR] = 3.72; P < .001), combination of MOPP chemotherapy and regional irradiation (RR = 4.99; P = .015) and combination of MOPP chemotherapy and extended irradiation (RR = 10.86; P < .001), splenic irradiation (RR = 3.67; P = .003), and splenectomy (RR = 2.54; P = .018) also significantly correlated with an increased risk. The results of this hospital-based registry study strongly suggest that splenic irradiation and splenectomy might increase the risk for treatment-related second cancer. These findings, if confirmed, have to be considered in future HD treatment policies.
Topics: Adolescent; Adult; Age Factors; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Follow-Up Studies; Hodgkin Disease; Humans; Incidence; Male; Mechlorethamine; Middle Aged; Neoplasm Staging; Neoplasms, Second Primary; Prednisone; Procarbazine; Risk Factors; Sex Factors; Spleen; Splenectomy; Vincristine
PubMed: 8049435
DOI: No ID Found -
Annals of Oncology : Official Journal... May 1994A prospective study was conducted to assess the efficacy and toxicity of a salvage regimen consisting of CCNU, Melphalan, and VP-16 (CAV) given at 28-day intervals in...
BACKGROUND
A prospective study was conducted to assess the efficacy and toxicity of a salvage regimen consisting of CCNU, Melphalan, and VP-16 (CAV) given at 28-day intervals in patients with Hodgkin's disease (HD) relapsing after primary therapy or refractory to the alternating MOPP/ABVD regimen.
PATIENTS AND METHODS
This study included 58 patients (median age: 34 years), with resistant or relapsing HD. Primary therapy had consisted of alternating MOPP/ABVD (81%) or MOPP alone (19%); 38% of patients were relapsing from prior complete remission (CR) while 62% had resistant disease. Extranodal disease was present in 55% and B-symptoms in 72% of patients; one-fifth had bulky disease and/or bone marrow involvement. The CAV was used as first salvage in half of the patients.
RESULTS
Complete remission was obtained in 17 patients (29%); unfavorable factors for CR in univariate analysis were the presence of bulky disease and the failure to achieve CR with prior therapy. Nine patients (53% of remitters) have subsequently relapsed with a 10-month median duration of CR. The 3-year overall survival after CAV was 25% with an 18-month median survival; significant differences in survival were found according to the extent of disease, the presence of B-symptoms and the HD status (prior sensitive or resistant disease, first or subsequent relapse). Seven patients are long-term remitters (12%), and one of them has been given high-dose chemotherapy and autologous bone marrow transplantation at relapse after CAV. The CAV toxicity was mostly hematological; severe pancytopenia occurred in six cases with two cases of fatal infections and one of fatal hemorrhage.
CONCLUSION
CAV therapy was moderately effective as third-line salvage in patients with HD resistant to alternating MOPP/ABVD or previously given two different regimens for relapse; the toxicity was mostly hematological and supportive therapy was needed in one-third of the patients.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Doxorubicin; Drug Resistance; Etoposide; Female; Hodgkin Disease; Humans; Lomustine; Male; Mechlorethamine; Melphalan; Middle Aged; Pancytopenia; Prednisone; Procarbazine; Prospective Studies; Recurrence; Remission Induction; Salvage Therapy; Survival Rate; Vinblastine; Vincristine
PubMed: 7521204
DOI: 10.1093/oxfordjournals.annonc.a058874 -
Annals of Oncology : Official Journal... Sep 1993Patients with Hodgkin's disease whose initial complete remissions (CR) after primary chemotherapy were longer than 1 year are thought to have better prognoses than...
BACKGROUND
Patients with Hodgkin's disease whose initial complete remissions (CR) after primary chemotherapy were longer than 1 year are thought to have better prognoses than patients whose initial remissions were shorter than 1 year. However, only a few studies have analyzed the long-term survival in addition to the results of retreatment in patients relapsing after CR lasting more than 1 year.
PATIENTS AND METHODS
We analyzed the data of 40 patients with Hodgkin's disease who were treated in a single institution and whose CR were > 1 year after primary chemotherapy. Therapy at relapse was not standardized: of 36 patients evaluable for response, 29 received second-line chemotherapy and 7 received radiotherapy alone.
RESULTS
Sixty-five percent of the patients obtained CR (median duration: 21 months). Sixty-eight percent of the complete responders relapsed again; however, long-lasting third and fourth remissions were observed. All of the 7 patients whose retreatment consisted of radiotherapy alone obtained CR, but only 1 is in continuous CR. The presence of nodular sclerosing histologic subtype, the absence of extranodal involvement and the use of hybrid MOPP/ABVD or ABVD alone as salvage treatment are independently associated with a higher CR rate and a higher probability of 5-year survival. The 5-year survival for all 40 patients is 49%. For the patients obtaining CR, the 5-year survival and the 5-year relapse-free survival are 76% and 25%, respectively. However, the survival curve continues to fall in the succeeding years because of third and fourth relapses and the occurrence of secondary acute leukemia and non-Hodgkin's lymphoma.
CONCLUSIONS
A high percentage of patients relapsing more than 12 months after primary chemotherapy can obtain second CR. Even if most of our patients eventually relapse, third and fourth CRs are not uncommon. However, the long-term survival is low and it is further diminished by secondary leukemia and non-Hodgkin's lymphoma.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Dacarbazine; Doxorubicin; Female; Hodgkin Disease; Humans; Male; Mechlorethamine; Middle Aged; Prednisone; Procarbazine; Prognosis; Recurrence; Remission Induction; Salvage Therapy; Survival Rate; Time Factors; Vinblastine; Vincristine
PubMed: 7694635
DOI: 10.1093/oxfordjournals.annonc.a058620