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PubMed1993

Late cardiac toxicity of doxorubicin, epirubicin, and mitoxantrone therapy for Hodgkin's disease in adults.

Cardiotoxicity is a well recognized side effect of anthracyclines (doxorubicin and epirubicin) or antracenadiones (mitoxantrone) at cumulative or high doses. However the side effects have not been evaluated in adults with Hodgkin's disease who received therapeutic doses of these drugs. We analyzed the cardiac function studying the left ventricular ejection fraction (LVEF) at rest in 136 patients with Hodgkin's disease treated with doxorubicin, epirubicin or mitoxantrone used in combination with vinblastine, bleomycin and decarbazine. No other risk factors, such as radiation therapy to the mediastinum, were considered. The follow-up is 5 to 8 years for patients in complete remission. Forty-five patients received doxorubicin (from 325 to 685 mg/m2, median 475 mg/m2), 51 patients received epirubicin (from 310 to 610 mg/m2, median 510 mg/m2) and 40 patients were treated with mitoxantrone (from 70 to 165, median 125 mg/m2). The median time between the end of treatment and the evaluation was 6.7 years. Thirty seven percent of the patients (similar rates in the three groups) showed abnormalities in the LVEF with decreased rates independent of the drug dosage. These were compared with two control groups, 46 patients treated with the MOPP combination (mechlorethamine, vincristine, prednisone and procarbazine) or LOPP (chlorambucil, for mechlorethamine) and 35 healthy volunteers. We believe that the use of anthracyclines or antracenadione will produce late cardiac effects in a fraction of patients independently of the doses used and that the indications for these drugs be carefully monitoring so as to evaluate the development of late side effects.

Adult↗
PubMed2005

Evaluation of protective ointments used against dermal effects of nitrogen mustard, a vesicant warfare agent.

Mustard, a vesicant warfare agent, has cytotoxic, mutagenic, and cytostatic effects via alkylation of DNA and inhibition of DNA replication. Since symptoms appear following a latent period, it can cause some subacute and chronic effects to occur and delay in the treatment. Therefore, the main approach should be the use of protective preparation to reduce the skin toxicity. Thus, this study was conducted in guinea pigs (350-400 g) shaved in areas of 10 x 10 cm. Mechlorethamine HCl (100 mg), a nitrogen mustard derivative, in ethanol was applied by spraying on hairless regions where previously prepared pharmaceutical topical formulations were medicated before. The experimental regions of the animals were kept preserved from environmental factors. Forty-eight hours after the application of the protective ointments and mechlorethamine consecutively, skin-damaging effects were macroscopically evaluated in terms of erythema formation, ulceration, necrosis, and inflammation occurrences. Then, punch biopsy was performed from these damaged sites for histopathological evaluation. Although numerous topical formulations were prepared and tested for protection, according to microscopic examination of the pathologic sections, tissue specimen treated with the ointment containing the mixture of zinc oxide, zinc chloride, dimethylpolysiloxane in a base of petroleum jelly was determined as being the most effective protective against skin injury caused by the vesicant agent.

Animals↗
PubMed1990

Can MOPP be replaced in the treatment of advanced Hodgkin's disease?

MOPP (mechlorethamine, vincristine, procarbazine, prednisone) was the first successful regimen for the treatment of Hodgkin's disease. It has the longest period of follow-up and is best studied as to its benefits and acute and long-term side effects. The acute toxicity of the side effects, including nausea and/or vomiting, hair loss, and myelosuppression, may have been reason to modify doses of nitrogen mustard, an agent whose dose intensity may be critical in achieving long-term benefits. The substitution of chlorambucil and vinblastine in the ChlVPP (chlorambucil, vinblastine, procarbazine, prednisone) program has relieved all of these acute toxicities, except myelosuppression. The long-term toxicity of sterility, especially in males, and myelodysplasia is most likely due to alkylating-agent toxicity and would not be influenced by the various MOPP variants, such as MVPP (mechlorethamine, vinblastine, procarbazine, prednisone), ChlVPP, and COPP (chlorambucil-vincristine, procarbazine, prednisone). Doxorubicin-containing regimens, such as ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and ABDIC (doxorubicin, bleomycin, dacarbazine, lomustine, prednisone), have been second-line treatments that have significant antitumor effect and, as such, have resulted in few, if any, long-term cures in most series. ABVD has been incorporated into alternating MOPP/ABVD schemes or in hybrids that attempt to offer all active agents, such as MOPP/ABV. The initial experience has been encouraging with high and durable complete remissions (CRs). MOPP/ABVD x 12(1) and MOPP-2/ABVD-2(2) have been compared with MOPP alone with a significant superiority for the alternating regimens. Other randomized trials have not shown any superiority for the alternating program. The Cancer and Leukemia Group B (CALGB) has compared MOPP with MOPP/ABVD given with a third arm of ABVD alone. The complete response and time-to-treatment failure rates for MOPP/ABVD and ABVD alone were superior to those for MOPP. Significant modifications of MOPP doses may explain the differences, since only 20% of patients were receiving full doses of nitrogen mustard by the sixth dose. ABVD has unique toxicity, and myelodysplasia and sterility are not seen. Pulmonary fibrosis with radiation and bleomycin is unique to ABVD, as shown in the ABVD experience at the NCl (Milan). Can ABVD be improved? The demonstrated single-dose activity of etoposide in Hodgkin's disease has prompted its inclusion in second-line programs, such as EVA (etoposide, vincristine or vinblastine, doxorubicin). The second-line response rates in the St Bartholomew's (London, England) series (where vincristine was used) was 11 of 19 patients (58%);3 in the ongoing CALGB trial of EVA (vinblastine combination), the response rate is 67%. (ABSTRACT TRUNCATED AT 400 WORDS)

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

Salvage chemotherapy in Hodgkin's disease irradiation failures: superiority of doxorubicin-containing regimens over MOPP.

One hundred and twenty-two consecutive patients with Hodgkin's disease who relapsed after primary curative irradiation were treated with either MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) or a doxorubicin-containing regimen (ADM-Reg). The main pretreatment characteristics were comparable in the two groups. Complete remission was achieved in 74.6% of patients treated with MOPP (44 of 59) and in 90.5% of those given ADM-Reg (57 of 63). No difference was observed in the incidence of complete remission with regard to the type of ADM-Reg utilized [MABOP (mechlorethamine, doxorubicin, bleomycin, vincristine, and prednisone), 92.9%; ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), 95.6%; and MOPP alternated with ABVD, 84.6%]. The superiority of ADM-Reg versus MOPP was also confirmed in the 7-year analysis of freedom from disease progression (73.2% vs 42.2%), relapse-free survival (81.2% vs 54.3%), and overall survival (80.5% vs 44.4%). Thrombocytopenia was less frequently observed with ADM-Reg (30%), particularly following ABVD (13%), compared to MOPP (73%). The lowest incidence of alopecia occurred in patients given MOPP (15%) or MOPP/ABVD (19%). Acute nonlymphoblastic leukemia was observed in patients treated with MOPP (five of 59) and MABOP (one of 14). The observed findings indicate that in patients failing to respond to primary radiotherapy, salvage regimens containing doxorubicin are more effective than MOPP. Furthermore, combinations devoid of procarbazine and alkylating agents (ABVD) or with less intensive administration of these drugs (MOPP/ABVD) were not associated with secondary leukemia.

Adolescent↗
PubMed1968

Mycosis fungoides. Topical use of nitrogen mustard in recurrent cases.

The management of the patient with mycosis fungoides requires a variety of therapeutic modalities depending on the stage of the disease. Topically applied nitrogen mustard in the early stages of the disease has a beneficital palliative effect. The effects of nitrogen mustard paintings in the later course of the disease have not been previously reported. In the present study, topically applied nitrogen mustard solution was used to control recurrences of mycosis fungoides following electron beam therapy in 11 patients. Each patient received whole body applications of freshly prepared 10 mg per 50 ml solution of mechlorethamine hydrochloride (a nitrogen mustard) in water daily for seven days. In all patients pruritus disappeared within the first week and ulcers and plaques improved or disappeared in two to four weeks. The seven-day courses of mechlorethamine paintings were repeated as recurrences were noted. Mycosis fungoides was controlled by this therapy for periods ranging up to 15 months. Absence of systemic toxicity, a low incidence of cutaneous irritation and application of the treatments at home make topical nitrogen mustard a useful adjunct in the management of the late stages of mycosis fungoides.

Adult↗
PubMed1980

Skin infiltration in Hodgkin's disease.

Hodgkin's disease involving the skin is an unusual occurrence and often portends a poor prognosis. We present a case of Hodgkin's disease and extensive skin infiltration with a favorable outcome. A variety of therapeutic modalities, including a mixture of mechlorethamine hydrochloride, vincristine sulfate, prednisone, and procarbazine; electron-beam radiation; topical mechlorethamine hydrochloride; and intravenous vinblastine sulfate were employed with moderate success.

Adult↗
PubMed1977

Comparative trial of combination chemotherapy in extensive squamous carcinoma of the lung: a Southwest Oncology Group Study.

The Southwest Oncology Group carried out a comparative study of two combination chemotherapy regimens in 231 patients with extensive squamous carcinoma of the lung. One regimen consisted of bleomycin, adriamycin, CCNU, vincristine, and mechlorethamine (BACON). The other involved mechlorethamine, adriamycin, and CCNU (NAC) in the same dose and schedule but with the deletion of vincristine and bleomycin. The response rate was 21% for BACON and 16% for NAC. The median survival time (MST) was 16 weeks for all patients receiving each regimen. Pretreatment performance statues (PS) was significantly related to the response rates: these were 28% for BACON and 23% for NAC among fully ambulatory patients (PS, 8-10) versus 15% for BACON and 10% for NAC among those with a lesser PS (P less than 0.05). Survival was also influenced by PS; the MST was 28 weeks for PSs 8-10 with either regimen compared to an overall MST of 11.5 weeks for patients with PSs 5-7 and 2.8 weeks for PSs 1-4. The toxicity of the two regimens was comparable with a 4% incidence of treatment-related deaths. An additional 10% of the patients were hospitalized because of life-threatening but reversible toxic effects. The only patients for whom there may be an improvement in MST over that expected from supportive care alone are those with PSs 8-10. Patients who demonstrated response or improvement, regardless of PS, had a significantly longer MST: 39.5 versus 11.2 weeks for those who did not respond (P = 0.001).

Aged↗
PubMed1994

Retrovirus-mediated gene transfer of rat glutathione S-transferase Yc confers alkylating drug resistance in NIH 3T3 mouse fibroblasts.

A major limitation to successful cancer treatment is the existence of drug resistance. While several mechanisms of drug resistance have now been well characterized, mechanisms of resistance to alkylating drugs have remained less well defined. Several experimental models of alkylator resistance have implicated isoforms of glutathione S-transferase (GST) but transfection experiments using cloned isoforms of GST have yielded conflicting results. While there are several plausible explanations for these apparently contradictory findings, the issue that clonal variability might potentially confound the results of conventional transfection experiments has been raised. To address this issue properly, we have studied rat GST-Yc expression and drug sensitivity to alkylating drugs in populations of mouse NIH 3T3 fibroblasts following either transfection or transduction with an N2-based retrovirus vector. In comparison with cells treated with an antisense vector, Yc-transfected and Yc-transduced populations of NIH 3T3 cells expressed increased levels of GST-Yc mRNA (Northern blot), increased levels of immunodetectable GST-Yc (Western blot), and, respectively, 1.4- and 1.9-fold increases in total GST activity and 6.1- and 8.3-fold increases in glutathione peroxidase activity (associated with the Yc subunit). Yc-transfected and Yc-transduced cell populations were, respectively, 5.8- (P < 0.001) and 2.4-fold (P < 0.05) resistant to chlorambucil and 10.8- (P < 0.01) and 5.4-fold (P < 0.001) resistant to mechlorethamine. The range of resistance of clonal isolates from either population was 1.8-6.0-fold for chlorambucil and 4.6-6.1-fold for mechlorethamine (P < 0.05). In contrast, these cells showed unaltered sensitivity to the antimetabolite methotrexate, a nonalkylating drug. These results clearly demonstrate that the rat GTS-Yc is able to confer alkylating drug resistance in mouse fibroblasts. The ability to confer alkylating drug resistance following retrovirus-mediated gene transfer also raises the possibility of using GST-Yc somatic gene transfer to confer protection to the hematopoietic system in a gene therapy strategy applicable to cancer.

3T3 Cells↗
PubMed1993

Expression of a rat glutathione-S-transferase complementary DNA in rat mammary carcinoma cells: impact upon alkylator-induced toxicity.

The role of glutathione-S-transferase (GST) in alkylator drug resistance has been studied in MatB rat mammary carcinoma cells. A series of GST transfectant cell lines was established by using an expression vector containing the complementary DNA for the rat GST Yc gene under regulation of the SV40 early region promoter and the antibiotic resistance plasmid pSV2neo. Transfectant cell lines expressing up to 4-fold higher total GST activity than in the parental wild type cell line were identified. Southern blot analysis confirmed a DNA fragment corresponding in size to the transfected GST Yc complementary DNA. Wild type MatB cells contain very low levels of Yc protein, whereas the Yc+ clones showed greatly increased amounts of the Yc subunit. The effect of increased GST Yc activity on the sensitivity of the transfected clones to various cytotoxic agents was assessed by using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell survival assay. The clones expressing recombinant GST Yc were more resistant to melphalan (6- to 12-fold), mechlorethamine (10- to 16-fold), and chlorambucil (7- to 30-fold). In late passage populations of the GST Yc+ clones that had been grown over a period of 14 months under continuous selection in G418, GST activity was decreased and it was paralleled by a decrease in Yc protein. These late passage clones with diminished GST Yc content also demonstrate a partial reversion toward the wild type phenotype as determined by cytotoxicity assays using melphalan, mustargen, and chlorambucil. Interstrand DNA cross-links induced by mechlorethamine were significantly lower at 0, 2, and 20 h posttreatment in one of the GST Yc+ clones when compared to wild type MatB cells. These studies indicate that GST Yc overexpression can confer resistance to alkylating agents and that this correlates with inhibition of DNA cross-link formation.

Alkylating Agents↗
PubMed1998

The risk of acute leukemia in patients treated for Hodgkin's disease is significantly higher aft [see bined modality programs than after chemotherapy alone and is correlated with the extent of radiotherapy and type and duration of chemotherapy: a case-control study.

BACKGROUND AND OBJECTIVE: Patients treated for Hodgkin's disease have an increased risk of developing subsequent acute leukemia. This co-operative study was conducted to assess the relative risk associated with several candidate factors including age, splenectomy, combined modality therapy and cumulative drug dose including alkylating agents and nitrosurea derivatives. DESIGN AND METHODS: This study evaluated the risk of acute leukemia according to pretreatment variables and therapy modalities among 1659 patients treated for Hodgkin's disease and followed for a median time of 10 years. Both case-control and actuarial risk studies were performed. Median age was 34 years (range: 12-83); 53% of patients were splenectomized. As to the overall therapy, 348 patients (21%) were given radiotherapy (RT) alone, 375 (23%) chemotherapy (CT) alone (including MOPP, MOPP + ABVD or MOPP + ABVD + lomustine); 936 (56%) received both CT and RT, either as primary or salvage treatment. RESULTS: The overall 15-year actuarial risk of leukemia was 4.2%; the hazard function curve showed two peaks of risk at the 3th and the 8th year from the initiation of therapy and no leukemia beyond the 12th year of follow-up. Risk of leukemia was 0.3% after RT alone, 2.8% after CT alone (2.2% after MOPP; 4.4% after MOPP + ABVD + lomustine), and 5.4% in patients given combined modality therapy (10.2% for RT + MOPP; 15.6% for RT + MOPP + lomustine). No leukemia occurred after ABVD alone and the risk was low (0.6%) when neither mechlorethamine nor lomustine were utilized. Patients who had received extended radiotherapy including abdomen and pelvis in addition to MOPP showed a significantly higher risk of leukemia compared to those given limited RT + MOPP (P = 0.01). Case-control analysis indicated advanced stage, type and duration (> 8 months) of CT and extension of RT as significant risk factors for leukemia. Compared to RT alone, the odds ratio was 5.9 after MOPP + extended RT, and 8 when a lomustine-containing regimen was used, as well. Neither age nor splenectomy were independent risk factors for leukemia; splenectomy was influential only when patients had been given MOPP chemotherapy, as well. INTERPRETATIONS AND CONCLUSIONS: Both case-control and actuarial analyses indicated that: a) combined modality therapy with MOPP and extensive RT (including abdomen and pelvis), and the use of lomustine added to the leukemogenic risk of MOPP alone; b) programs without mechlorethamine, procarbazine and lomustine were almost devoid of leukemogenic risk.

Abdomen↗
PubMed1998

Risk of secondary myeloid leukemia and myelodysplastic syndrome following standard-dose chemotherapy or high-dose chemotherapy with stem cell support in patients with potentially curable malignancies.

Secondary acute myeloid leukemia (s-AML) and secondary myelodysplastic syndrome (s-MDS) probably represent the worst possible long-term complications of cancer therapy in patients originally cured of their primary malignancy. The frequency and type of s-AML and s-MDS are reviewed for patients treated with standard and/or high-dose chemotherapy for Hodgkin's disease, non-Hodgkin's lymphoma (NHL), and breast or testicular cancer. Patients treated for Hodgkin's disease, have a 20- to 40-fold increased risk of developing s-AML, this risk increasing with the number of mechlorethamine-containing cycles given as well as following splenectomy and in patients more than 40-50 years of age. Generally, patients with NHL, breast or testicular cancer experience a lower, 2- to 15-fold, risk of developing s-AML. Epipodophyllotoxins appear to be the most important factor for s-AML in patients treated for testicular cancer. Doses of 2g/m2 or more are associated with an increased risk of s-AML and, with these high doses, a cumulative incidence of 2% 3% at 5 years is observed. Adjuvant cyclophosphomide, methobrexate, 5-Fu therapy in breast cancer patients does not appear to increase risk significantly as compared to the general population. The extent of the leukemogenic potential of anthracyclines remains to be defined. NHL patients receiving mechlorethamine, prednimustine or long-term maintenance therapy are also at an increased risk of s-AML. A considerably increased risk of developing AML, with a cumulative incidence of approximately 9% at 5 years, has been observed following allogenic bone marrow transplantation (ABMT) or peripheral stem cell transplantation (PBSCT) in patients with NHL. It is likely that the increased risk of s-AML/s-MDS following high-dose chemotherapy with ABMT or PBSCT is related to prior treatment rather than to high-dose chemotherapy itself. However, this issue remains to be conclusively addressed. s-AML or s-MDS rarely develops after allogenic bone marrow transplantation. s-AML and s-MDS increasingly represent a problem in modern cancer therapy because of better treatment strategies, which result in improved cure rates. Patients who receive chemotherapy must be informed about the potential risk of developing s-AML or s-MDS. Future studies should include a follow-up long enough to record the occurrence of all s-AML/s-MDS and all potential influencing factors reliably. These data would enable risk factors to be defined and risk/benefit analyses to be carried out, allowing the correct assessment of current and future therapy strategies.

Acute Disease↗
PubMed1990

Antidotes to vesicant chemotherapy extravasations.

The foregoing sections have reviewed the experimental studies and clinical anecdotes describing potential pharmacologic antidotes to extravasations of vesicant anticancer agents. Numerous prior reviews have also suggested specific antidotes or very conservative, non-pharmacologic approaches. Many antidotal approaches to extravasation have not been experimentally validated and thus, few 'antidotes' share a rationale which is founded on positive experimental and clinical studies. However, using this criteria, a few active antidotes can be distilled from the literature. These are outlined in Table 6. These antidotes include isotonic (1/6 M) sodium thiosulfate for mechlorethamine (and optionally for cisplatin), hyaluronidase for the vinca alkaloids (and optionally for epipodophyllotoxins such as etoposide), and cooling with very topical DMSO and low dose hydrocortisone for the anthracyclines. For the alkylating agent mitomycin C, topical DMSO has been effective experimentally but has not yet received clinical validation, at least in published studies. Nonetheless, the severity of mitomycin C ulcerations and the documented safety of topical DMSO in the small series of doxorubicin extravasation patients argues for its use when mitomycin extravasates in the clinic. Furthermore, except for DMSO, all of these extravasation antidotes are listed in the official FDA-approved package inserts for each vesicant agent. Thus, the inserts for vincristine and vinblastine specify hyaluronidase, for doxorubicin, glucocorticosteroids, and for mechlorethamine, sodium thiosulfate. New studies are clearly needed to clarify the role of topical DMSO with anthracyclines and mitomycin C. In addition, efforts should be made to begin clinical development of radical dimers such as DHM3 which can directly inactivate quinone-containing vesicants like doxorubicin and mitomycin C. Although the incidence of chemotherapy extravasation may be lessened with vascular access devices, it nonetheless, continues to comprise a serious and highly litigious area of oncology practice. This commands continued extravasation intervention studies and diligent prevention when ever possible.

Animals↗
PubMed2002

Lung cancer following chemotherapy and radiotherapy for Hodgkin's disease.

BACKGROUND: Lung cancer is a frequent cause of death in patients cured of Hodgkin's disease, but the contributions of chemotherapy, radiotherapy, and smoking are not well described. We quantified the risk of treatment-associated lung cancer, taking into account tobacco use. METHODS: Within a population-based cohort of 19 046 Hodgkin's disease patients (diagnosed from 1965 through 1994), a case-control study of lung cancer was conducted. The cumulative amount of cytotoxic drugs, the radiation dose to the specific location in the lung where cancer developed, and tobacco use were compared for 222 patients who developed lung cancer and for 444 matched control patients. All statistical tests were two-sided. RESULTS: Treatment with alkylating agents without radiotherapy was associated with increased lung cancer risk (relative risk [RR] = 4.2; 95% confidence interval [CI] = 2.1 to 8.8), as was radiation dose of 5 Gy or more without alkylating agents (RR = 5.9; 95% CI = 2.7 to 13.5). Risk increased with both increasing number of cycles of alkylating agents and increasing radiation dose (P for trend <.001). Among patients treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), risk increased with cumulative amounts of mechlorethamine and procarbazine (P<.001) when evaluated separately. Statistically significantly elevated risks of lung cancer were apparent within 1-4 years after treatment with alkylating agents, whereas excess risk after radiotherapy began 5 years after treatment and persisted for more than 20 years. Risk after treatment with alkylating agents and radiotherapy together was as expected if individual excess risks were summed. Tobacco use increased lung cancer risk more than 20-fold; risks from smoking appeared to multiply risks from treatment. CONCLUSIONS: Past treatments with alkylating agents and radiation therapy for Hodgkin's disease were associated with an increased risk of lung cancer in a dose-dependent and additive fashion. The precise risk estimates, however, should be interpreted cautiously, given the possible residual and enhancing effects of tobacco.

Adolescent↗
PubMed1994

ChlVPP/PABlOE and radiotherapy in advanced Hodgkin's disease. The Central Lymphoma Group.

PURPOSE: The United Kingdom Central Lymphoma Group (CLG) has modified mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) by substituting mechlorethamine with chlorambucil and dacarbazine with etoposide in the treatment of patients with advanced Hodgkin's disease (HD). Prednisolone is included in the bleomycin-containing combination, and the vinca alkaloids have been switched to balance the myelotoxicity of the two component regimens. PATIENTS AND METHODS: The resulting ChlVPP/PABlOE regimen is as follows: on days 1 to 14, chlorambucil 6 mg/m2 orally, procarbazine 100 mg/m2 orally, and prednisolone 30 mg/m2 orally; on days 1 and 8, vinblastine 6 mg/m2 intravenously (i.v.); on day 29, doxorubicin 40 mg/m2 i.v.; on days 29 and 36, vincristine 1.4 mg/m2 (maximum, 2 mg) i.v., and bleomycin 10 mg/m2 i.v.; on days 30, 31, and 32, etoposide 200 mg/m2/d orally; on days 29 to 43, inclusive, prednisolone, 30 mg/m2 orally. The second full cycle restarts on day 50. Treatment continues to maximum response plus two full cycles, but with a minimum of three full cycles. Radiotherapy is administered, after chemotherapy, to sites of previously bulky disease. Since 1983, 216 patients with previously untreated, advanced Hodgkin's disease (HD) have entered this study. RESULTS: The complete remission (CR) rate after chemotherapy was 73% (95% confidence interval [CI], 67% to 79%), and after additional radiotherapy was 85% (95% CI, 80% to 90%). The failure-free survival (FFS) rate at 5 years was 68% (95% CI, 61% to 74%), and the overall actuarial survival at 5 years was 78% (95% CI, 72% to 84%). The CR rate in patients in the poorer prognostic categories was high: 81% in patients with albumin levels less than 37 g/L, 79% in patients older than 40 years of age, 84% in stages IIIB plus i.v. disease, and 79% in patients presenting with B symptoms. As expected, nausea and vomiting were not major problems, although infection, often in the context of myelosuppression, complicated almost half the cases, and 29% of patients required admission at some stage for treatment of infection. CONCLUSION: In this multicenter study, ChlVPP/PABlOE produced results comparable to those reported for MOPP/ABVD, but with less nausea and vomiting. Treatment duration was shorter than in the original MOPP/ABVD regimen, and than that used in the Cancer and Leukemia Group B (CALGB) trial. It will now be compared with PABlOE alone.

Adult↗
PubMed1999

Treatment of advanced Hodgkin's lymphoma: standard and experimental approaches.

The introduction of polychemotherapy and improved radiation techniques has transformed Hodgkin's lymphoma from an incurable disease to a malignancy with one of the highest cure rates. Milestones were the development of the MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) and ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) regimens. Radiotherapy is commonly used, although its precise role has not been defined for patients with advanced-stage disease. More recently, dose-intensified schedules such as Stanford V (doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone) were shown to be effective in this group of patients. In particular, the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), in both standard and escalated doses, has produced impressive results in a randomized three-arm study when compared with COPP (cyclophosphamide, vincristine, procarbazine, and prednisone)/ABVD. The significantly higher rates of complete remission (CR) and freedom from treatment failure (FFTF) suggest that the new BEACOPP regimen improves efficacy, but definitive conclusions require further years of follow-up evaluation. Interestingly, BEACOPP abrogates the impact of the newly described seven-factor prognostic scoring system that was reported for patients treated with MOPP/ABVD or similar regimens. The prognostic index includes factors such as serum albumin, hemoglobin, male sex, stage IV disease, age more than 45 years, white blood cell count, and lymphocyte count. Whereas patients with Hodgkin's lymphoma have a good prognosis on first diagnosis, those with relapsed or refractory disease face a poor outcome.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Advances in chemotherapy for large cell lymphoma.

Three generations of chemotherapy regimens for the treatment of aggressive lymphomas have evolved in the past decade. The first-generation combination regimen, CVP, also known as COP (cyclophosphamide, vincristine, prednisone), produced maximum long-term survivals in considerably less than 20% of patients. With the MOPP (mechlorethamine, vincristine, procarbazine, prednisone) regimen, 40% of patients achieved complete remission (CR). This signal study was paralleled by other first-generation studies including CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), HOP (doxorubicin, vincristine, prednisone), CHOP-Bleo/BACOP (CHOP plus bleomycin), and COMLA (cyclophosphamide, vincristine, methotrexate, leucovorin, cytarabine). None of the regimens was shown to be particularly superior to the others. Survival plateaus were seen in approximately 20% to 40% of patients. Second-generation therapies, COP-BLAM (cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, procarbazine), ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, prednisone), M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone), and m-BACOD (same as M-BACOD, but with a moderate dose of methotrexate and modified leucovorin given on days 8 and 15 instead of just day 10) were characterized by an increasing number of drugs, more frequent administration of myelosuppressive agents, and flexible dose schedules. This new treatment intensity resulted in CRs in excess of 70%. The third generation regimens have been characterized by innovative concepts of chemotherapy, including alternative modes of drug administration, greater use of marrow-sparing, cycle-active, and/or putatively non-cross-resistant agents, and more frequent and/or intense dose administration. These regimens, COP-BLAM III, MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin), ProMACE-CytaBOM (ProMACE plus cytarabine, bleomycin, vincristine, methotrexate), and high-dose doxorubicin with cytarabine, have produced over 80% CRs and survival plateaus in excess of 60%. In the COP-BLAM III regimen, 84% of patients achieved a pathologic CR. Overall, 65% of patients are alive, well, and free of disease, and potentially in the survival plateau. COD-BLAM IV (same as COP-BLAM, except dexamethasone is substituted for prednisone) is a new program that further intensifies treatment by using sequential, rather than alternate-cycle, infusions of bleomycin and vincristine. Results are still preliminary, with a short median follow-up of 19 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1983

[Effect of different cytostatic agents and antibiotics on the biology of Trichomonas in vitro].

The purpose of these examinations was an attempt to elucidate the influence of some cytostatic preparations (Fluorouracil, Triaziquone (Treminon), Mechlorethaminee Oxide Hydrochloride (Mitomen), Methotroxate, Mitomycins, Cyclophosphamide (Endoxan), Mechlorethamin (Nitrogranulogen) and antibiotics (Penicillin, Streptomycin, Aureomycin, Nystatin) on formation of the multinuclear forms of Trichomonas under the conditions of culture on artificial medium and to investigate the cidal and static effects of chosen cytostatics and antibiotics of different species of Trichomonas in vitro. It was found that Mechlorethamine (Nitrogranulogen) and Mitomycins have distinct influence on formation of the multinuclear forms of Trichomonas in culture. Similar effects were observed in the antibiotic group with aureomycin only if applied pure or combined with other antibiotic drugs. In addition, it was shown that Triaziquone (Treminon) exerts the strongest effects on the examined species of Trichomonas.

Anti-Bacterial Agents↗
PubMedDate not supplied

Examination of the correlation of first-week mortality with the gastrointestinal syndrome following chemotherapy.

The equation frequently made between mortality of mammals within the first week after treatment by cytotoxic drugs and the "gastrointestinal syndrome" has been critically examined. Six clinically used drugs were employed. Only for carmustine and 5-FU was a plateau in survival time observed, for increasing single doses. With cyclophosphamide or dactinomycin, mean survival time in the period of interest decreased sharply with dose, in marked contrast to the constancy observed over a large range of doses of radiation. The dynamics of expression of intestinal injury, as judged by mitotic activity in the crypts, was the same for all drugs and for radiation. However, the clonogenic response of the intestine (crypt microcolony assay) differed widely between agents. Cyclophosphamide and dactinomycin did not destroy any crypts at dose ranges containing the 50% lethality dose for mice. Of the remaining four drugs (carmustine, 5-FU, mechlorethamine hydrochloride, and doxorubicin), the surviving fraction of crypts corresponding to 50% lethality of mice varied 17-fold. Altering the route of administration of mechlorethamine hydrochloride from ip to iv increased the lethality dose and the dose for a given level of crypt survival, but not by the same factor. Survival of primitive, clonogenic cells of the bone marrow was also altered, but in the opposite direction. It is concluded that even where mean survival times are closely similar to radiation, the interpretation of the gastrointestinal syndrome following radiation cannot be applied quantitatively in a similar manner after many cytotoxic drugs.

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