Combined modality therapy in previously untreated patients with advanced Hodgkin's disease: A 24-year follow-up study

PURPOSE: To describe the long-term results of treatment with chemotherapy plus adjuvant low-dose, involved-field radiation therapy (CMT) in patients with advanced Hodgkin's disease. Data on disease-free and failure-free survival, second malignancies, and the results of salvage therapy are presented. PATIENTS AND METHODS: From 1969 to 1989, CMT was administered to 186 patients with previously untreated stage IIB, III, and IV Hodgkin's disease. Chemotherapy included MVVPP (47%), MOPP (25%), MOPP/ABVD (26%) and ABVD (2%). After 6 months of chemotherapy, patients received radiation to all involved sites with the exception of the bone marrow. RESULTS: The failure-free survival for all patients was 63% at 5 years, 56% at 10 years, and 40% at 23.5 years, respectively. Significantly worse results were observed in patients older than 40 years and those with stage IV disease. The overall survival of 45 patients after recurrence was 39% at 10 years, but was only 21% if the initial complete remission lasted less than 1 year. Thus far, 21 of 165 patients (12.7%) who achieved complete remission have developed a second malignancy, and 16 have died. CONCLUSIONS: In comparison with comparable chemotherapy programs, chemotherapy plus radiation therapy may improve disease-free survival; however, the results of treatment in patients older than age 40 or with stage IV disease are still poor. Although patients with initial remissions lasting longer than 1 year can have durable second remissions, the long-term disease-free survival is poor and in the current series the majority of failures were due to recurrent Hodgkin's disease.     

The management of Hodgkin's disease with chemotherapy or combined modality treatment

Systemic polychemotherapy and local radiation are two well-established treatments for Hodgkin's disease. With the use of modern techniques, the great majority of patients with pathologic stage I-II Hodgkin's disease can be cured with irradiation alone. Since the invention of the MOPP and ABVD schemes, polychemotherapy has become indispensable for the treatment of advanced-stage Hodgkin's disease. The role of radiotherapy in combination with chemotherapy is limited to specific indications. ABVD therapy is as effective as MOPP alternating with ABVD, and both are superior to MOPP alone in the treatment of advanced Hodgkin's disease. MOPP/ABVD hybrid chemotherapy was significantly more effective than sequential MOPP-ABVD in 8-year failure-free survival and overall survival. The patients with advanced-stage Hodgkin's disease who did not achieve a complete remission from their initial treatment with combination chemotherapy have a dismal prognosis. Those whose initial remissions had lasted longer than 12 months had a very high probability of obtaining a second complete remission when re-treated with MOPP or ABVD, but those whose remission lasted less than 12 months fared less well with any conventional-dose chemotherapy. High-dose chemotherapy and radiotherapy with autologous hemopoietic stem cell transfusion are superior in the treatment of those whose disease is refractory or resistant to the initial therapy.     

Long term remissions with combined modality therapy for advanced Hodgkin's disease

A new treatment program for advanced Hodgkin's disease employing five-drug combination chemotherapy and low dose radiation to the sites of bulk disease (nodal or parenchymal) was designed in 1969. Eighty patients have now been treated, 60 of whom have achieved a complete remission. More significantly, only 5 of the 60 completed responders have relapsed with follow-up from 1-6 years. The cumulative survival at 5 years of patients entering complete remission is 92%. For those patients not sustaining a complete remission, it is 19% at 2 years. This program has resulted in substantially lower relapse rates than previously reported by other investigators, probably because of the administration of radiotherapy in the manner described. Hopefully, a significant number of these patients may be cured of their disease.     

Clinical analysis of elderly patients with malignant lymphoma

An epidemiological study on 173 consecutive elderly malignant lymphoma patients age 65 years or over was performed and the clinical outcome of chemotherapy is reported. Of there, 131 patients (75.7%) had non-Hodgkin's lymphoma (NHL) and 21 patients had Hodgkin's disease (HD). As for clinical staging, 58.9% of patients were in stage 3 or 4. The initial sites were nodal in 61.8% of the patients the most common sites of involvement in superficial lymph nodes being cervical, inguinal and axillar. The most frequent site of extranodal involvement was the gastrointestinal tract. The cases were treated with CHOP/COPP, BACOP or COP-BLAM combination chemotherapy. The clinical efficacy of these modalities was similar, with complete remission rates being about 50%. However, the total response rate (CR+partial remission) by the COP-BLAM regimen were 88.1%. The median survival time of cases achieving CR, was longer than 47 months. The most frequent cause of death was infection, especially pneumonia and septicemia. Many elderly ML patients were found and diagnosed when the disease developed to an advanced stage. Therefore it is necessary to make efforts to find early ML patients by screening apparently healthy elderly people. Improvement of the complete remission rate should be obtained if vigorous and intensive chemotherapy is carried out with careful supportive therapy concerning the general condition and complications in patients.     

A fearsome enemy (1); A history of sanitation in the British Army 1899-1914

This study presents the results of a prospective study of methyl-gag, ifosfamide, methotrexate and etoposide (MIME) as salvage regimen for Hodgkin's disease (HD) in Sweden. Sixty-four patients with recurrent or refractory HD were treated with MIME between July 1988 and December 1993. All patients except one had, earlier, been treated with and failed consecutive or alternating MOPP and ABVD. Median age was 37 yr (range 14-73). Twenty patients (31%) achieved a complete remission (CR) and 17 (27%) a partial remission (PR), giving an overall response rate of 58%. The 5-yr survival for all patients was 43%. In a multivariate analysis, the most important factors predicting a poor survival were the presence of extranodal disease at relapse, male gender and high age. Twenty-nine patients were treated with high-dose chemotherapy with stem-cell rescue after MIME. Those patients had a similar survival compared to the patients responding to MIME but not treated with high-dose chemotherapy. We conclude that MIME induces remissions in a high proportion of patients with recurrent and refractory HD with acceptable toxicity. The remissions probably need consolidation, but the nature of this consolidation is still controversial.     

Use of adjuvant ICE chemotherapy in the treatment of anaplastic ependymomas

Despite the improved outcome for patients with ependymoma treated by surgery and radiotherapy, their prognosis remains relatively poor. To assess the impact of adjuvant chemotherapy, we reviewed the overall survival of consecutive patients with anaplastic ependymoma treated over a 10-year period with surgery and ICE (ifosfamide+ VP 16+carboplatin) chemotherapy with or without radiation at our institution. There were 11 patients (6 male, 5 female), with a median age of 3.4 years (range 1.2-1 1.1): 4 under 2 years and 7 were over 2 years old. Overall, 5 had gross total resections: 4 are alive, 2 in continuous complete remission and 2 in second complete remission. One patient who was less than 2 years old died. Among the 6 with subtotal resection, 2 achieved a complete remission after chemotherapy. However, 5 of the 6 patients have since died of progressive disease, with a median overall survival of 75 months. Overall survival was 24% and progression-free survival was 39%. In 2 of 6 patients with residual postoperative disease a temporary objective response was noted with adjuvant ICE chemotherapy. This regimen did not confer an overall survival advantage.     

Safety and efficacy of ECT in patients with head injury: a case series

BACKGROUND: The role of postoperative radiotherapy and adjuvant chemotherapy in the treatment of synovial sarcoma remains to be determined. PROCEDURE: Twenty-five children were treated during a 23-year period with a multimodality approach. All of them had resection of the primary tumor (three amputations), followed by surgical retreatment in eight. Postoperative radiotherapy was delivered to 16 patients and adjuvant chemotherapy was given to 22. RESULTS: At the time of the report, 19 patients were alive and without evidence of disease. Six developed distant metastases (one associated with local recurrence); five of them died of their disease and one was alive in complete remission at 4 years from relapse. With a median follow-up of 9 years (range 2-23), the survival and the event-free survival at 5 years were 80% (SE 8.2) and 74% (SE 9.2), respectively. All relapsing patients had been classified as T2B. CONCLUSIONS: Multimodality treatment yielded satisfying survival results using limb-preserving surgery in most cases. Tumor size > 5 cm and invasiveness, which defined stage T2B, were the most important predictors of poor outcome. Evaluation of the role of adjuvant chemotherapy and radiotherapy awaits prospective studies, even if T2B patients, as well as children having nonradical surgery, seem worth managing by adjuvant treatments.     

Burkitt's lymphoma-leukemia in patients treated for Hodgkin's disease

We reviewed all reported cases of Burkitt's lymphoma and/or Burkitt's leukemia (BLL) occurring following therapy for Hodgkin's disease. In addition to the case described in this report, a total of 19 patients have been previously reported. The male/female ratio was 3.75. Treatment for Hodgkin's disease included chemotherapy combined with radiation therapy in 15 patients, chemotherapy in 3 patients, and radiation therapy alone in 1 patient. Median interval between Hodgkin's disease and the diagnosis of BLL was 97 months. Patient characteristics are similar to those with de novo BLL. Bone marrow, abdomen, central nervous system, as well as extranodal organs were commonly involved. Typical cytogenetic translocations seen in patients with primary BLL were found in 6 patients, but 5 of these patients had additional cytogenetic abnormalities. Only 2 patients achieved complete remission after chemotherapy. The mechanism for the development of BLL after treatment for Hodgkin's disease is unknown. Although the majority of cases have been seen in patients treated with combined-modality therapy, the role of previous therapy in causing this complication cannot be assessed in this study.     

Laminin-6 and laminin-5 are recognized by autoantibodies in a subset of cicatricial pemphigoid

To aid treatment choice in early stage of Hodgkin's disease, we analysed patients registered in the IDHD Database with clinical stages I or II Hodgkin's disease who were not staged with laparotomy and whose initial treatment was with radiotherapy alone. The factors analysed for outcome after first relapse included initial stage, age, sex, histology, number of involved areas, mediastinal involvement, E-lesions, B-symptoms, erythrocyte sedimentation rate, alkaline phosphatase, serum albumin and haemoglobin. As well as presentation variables, we analysed the disease-free interval after initial radiotherapy and the extent of disease at relapse. A total of 1364 patients with clinical stage I or II Hodgkin's disease were treated with initial radiotherapy, of whom 473 relapsed. The probability of survival 10 years after relapse was 63%. For cause-specific survival (CSS), both multivariate and univariate analysis identified the importance of age at presentation and histological subtypes. When all causes of death were considered, the multivariate analysis identified age as the only significant factor. The length of initial disease-free interval had no influence on prognosis after relapse, but the 169 patients with nodal relapse had a higher cause-specific survival than those with an extranodal component of relapse (74% versus 51% at 10 years, P < 0.005). Thus, the important factors for outcome after initial treatment with radiotherapy are those factors predicting the risk of relapse after initial treatment together with those predicting outcome after relapse, namely age, histologic subtype and extent of disease at relapse.     

The value of gallium imaging after therapy for Hodgkin's disease

BACKGROUND: Although it is used widely, the value of gallium imaging in managing Hodgkin's disease remains unclear. METHODS: A retrospective review of gallium imaging and treatment outcome in 60 patients with Hodgkin's disease treated between January 1990 and July 1995 was conducted. The minimum follow-up was 1 year. RESULTS: Based on gallium imaging, 46 patients were in complete remission (CR) after initial treatment, 10 were in partial remission (PR), and 4 had persistent or progressive disease (NR). Ten of 29 patients (34%) with gallium CR after chemotherapy subsequently recurred, compared with no recurrences in 17 patients receiving initial radiotherapy or combined chemoradiation. Eight of ten patients received further therapy after gallium PR, and nine patients remained disease free at last follow-up. Survival did not differ in patients achieving a gallium CR or PR. CONCLUSIONS: Gallium-67 imaging may help confirm the presence of active Hodgkin's disease, but was unreliable in defining disease remission after chemotherapy in this study population. Patients with a gallium PR may still have a good prognosis after additional therapy.     

Combination chemotherapy of Hodgkin's disease in children

Forty-five children with advanced Hodgkin's disease (stages III and IV) received combination chemotherapy in three schedules: MOPP (mustargen, Oncovin, procarbazine, prednisolone); COPP (cyclophosphamide was substituted for mustargen); and CVPP (cyclophosphamide, vinblastine, procarbazine, prednisone). The results showed the efficacy of all drug combinations (93% complete and partial remissions). However, the superiority of the MOPP program in prolonging the duration of the complete remission rate was demonstrated. Of 29 patients who showed complete response, 24 continued in complete remission from 8 to 53 months (median duration, 21 months). The other five patients relapsed within 2 to 6 months. Thirty-six of the 45 treated patients are still alive after an average period of follow-up of 19 months. The nine patients who died were followed for an average of seven months. The histologic type, prior chemotherapy, and the age of the patients influenced the results of treatment. The role of maintenance therapy is not discussed in this series     

Successful treatment of non-Hodgkin's lymphoma of the central nervous system with BMPD chemotherapy followed by radiotherapy

The treatment of patients with primary non-Hodgkin's lymphoma of the central nervous system (PCNSL) is still of limited success, as compared with other extranodal sites. The poor results obtained with radiotherapy alone can be improved by adding chemotherapy reaching a median survival up to over 30 months and 5-years-survival rate up to 35%. The optimal management for patients with CNS relapse of systemic lymphoma remains uncertain and their prognosis is even worse. Here, we describe our preliminary data on the treatment of patients with CNS lymphoma with a new regimen composed of CNS-penetrating drugs, namely: carmustine (BCNU) 80 mg/m2 i.v. dl, methotrexate 1500 mg/m2 over 24h i.v. d2, procarbacine 100 mg/m2 p.o. d1-8, and dexamethasone 3 x 8 mg p.o. d1-14. An average of 3 treatment courses were given under response control seen using CT-scan or NMR. Patients with positive CSF cytology received additionally intrathecal therapy with methotrexate. Until now between March 1994 and September 1997, 7 patients with PCNSL and 4 patients with CNS relapse of systemic lymphoma have been treated. The median age of the patients was 56 (range, 39-74); 5 patients were > or =60 years old. Three patients had multifocal disease. Whole brain radiotherapy with 4000 to 5000 cGy was given in 7 patients (cerebrospinal in 1 patient). Complete response at the end of chemotherapy was achieved in 6 patients, and a partial response in two. Most remarkably, 2 elderly patients (70 and 57 years), 1 patient with multifocal disease and 1 with simultaneous CNS and systemic relapse after chemotherapy had a complete remission lasting for 40 months, and a partial remission lasting for 37 months, respectively.     

Prognosis of hematological patients with relapse following high-dose chemotherapy and autologous stem cell transplantation

A retrospective analysis of the outcome for 283 haematological patients who relapsed after high dose chemotherapy and autologous stem cell transplantation during a five year period from 1989 to 1994 is presented. The patients were treated in accordance with local regimes at 20 Nordic transplantation centers and included patients with acute leukemia (157 patients), multiple myeloma (16 patients) and lymphoma (110 patients). Two hundred and twenty-nine patients with relapse or progressive disease were given chemo- and/or radiotherapy and the response was evaluated after 90 days. Fifty-four patients (24%) obtained a complete remission and 44 patients (19%) partial remission. The overall median survival after relapse was five months. In the group who received salvage treatment the median survival was seven months, and for the 54 patients in complete remission the median survival was 15 months. We found that survival after relapse depends upon primary disease, the time from transplantation to relapse and whether salvage therapy was initiated.     

ProMECE-CytaBOM vs MACOP-B in advanced aggressive non-Hodgkin's lymphoma: long term results of a multicenter study of the Italian Lymphoma Study Group (GISL)

A randomized trial was designed in order to compare the efficacy and feasibility of ProMECE-CytaBOM (P-C) and MACOP-B (M-B) in patients with advanced, aggressive non Hodgkin's lymphoma (NHL). P-C and M-B were chosen due to their association with a very high complete remission rate when compared to other published protocols. The study was conducted on 210 patients with intermediate or high-grade NHL in stage I bulky, or stages II-IV, randomized to receive either 6 courses of P-C delivered every 28 days (106 patients), or 12 weeks of M-B chemotherapy (104 patients). In both regimens doxorubicin was replaced by a 20% higher dose of epidoxorubicin (i.e. 30 mg/m2 of the analog). At the end of induction therapy patients could receive additional radiotherapy to residual masses or to sites of previous bulky disease. The two groups of patients were compared for response rates, number and severity of therapy related side effects, overall survival, disease-free survival, and time to treatment failure. Sixty-five patients (62%) treated with P-C and 69 patients (67%) treated with M-B achieved a complete remission, with no significant differences between the two treatment arms (P = 0.13). The overall objective response rate (complete + partial remission) was 74% for patients treated with P-C, and 81% for patients treated with M-B, respectively. The 4-year relapse-free survival rate was 59% for P-C and 69% for M-B, respectively (P = 0.11).(ABSTRACT TRUNCATED AT 250 WORDS)     

Long-term results from MOPPEBVCAD chemotherapy with optional limited radiotherapy in advanced Hodgkin's disease

The purpose was to verify the 5-year results of the MOPPEBVCAD chemotherapy regimen with limited radiotherapy in relation to the promising preliminary data. Mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, melphalan, and vindesine were delivered according to a schedule derived through hybridization, intensification, and shortening of the corresponding alternating CAD/MOPP/ABV regimen. Radiotherapy was restricted to sites of bulky involvement or to areas that responded incompletely to chemotherapy. This multicenter, controlled, nonrandomized trial involved 145 eligible patients. Radiotherapy was administered to 47 patients, 46 of whom were in complete remission after chemotherapy. Remissions were complete in 137 patients (94%), partial in 4 (3%), and null in the remaining 4. Tumor-specific, overall, relapse-free, and failure-free survival at 5 years were 0.89, 0.86, 0.82, and 0.78, respectively. Hematologic toxicity was considerable, whereas nonhematologic side effects were fully acceptable. Most of the unfavorable prognostic factors lost their clinical weight. Only age and lymphocyte depletion histologic type were statistically correlated with major follow-up endpoints; performance status and bone marrow involvement were subordinate to age. Seven patients developed a second cancer (including 3 myelodysplasias). MOPPEBVCAD with selected radiotherapy is a highly effective regimen in advanced Hodgkin's disease. Early and late toxicity are no more severe than what would be expected with other alternating or hybrid regimens. A comparison with ABVD, which is currently considered the standard regimen for advanced Hodgkin's disease, is needed.     

Index of pretreatment intensity predicts outcome of high-dose chemotherapy and autologous progenitor cell transplantation in chemosensitive relapse of Hodgkin's disease

PURPOSE: To identify prognostic factors in patients with chemosensitive relapsed Hodgkin's disease treated by high-dose chemotherapy with autologous progenitor cell transplantation (HDC) and to compare the duration of treatment-free remission prior to HDC with the progression-free survival after HDC in individual patients. PATIENTS AND METHODS: Forty-five consecutive patients were analyzed retrospectively. We devised an index of pretreatment intensity (IPTI) based number of different chemo- and radiotherapy regimens given between diagnosis and HDC and on the duration of disease. RESULTS: With a median follow-up of 47 months the post-transplant event-free survival (EFS) was 44% and the overall survival (OAS) was 62% at four years. The IPTI allowed to discriminate between a low and a high-risk group with a four-year post-transplant EFS of 66% and 11% and a OAS of 87% and 28%, respectively (P = 0.0001). Of the 39 patients with sufficient follow-up after HDC, post-transplant EFS lasted on average > or = 18.5 months longer than the pretransplant treatment-free remission. CONCLUSIONS: HDC with the CBV regimen confers significant benefit to patients with chemosensitive relapsed Hodgkin's disease. The IPTI may help to select patients with a good response to HDC and to identify poor prognosis patients suitable for experimental protocols or palliative care only.     

Chemotherapy of advanced malignant lymphomas comparative evaluation of results with single agent and combination therapy

86 patients with advanced malignant lymphomas (stage III and IV) were treated either with Vinblastine given as a single agent (49 cases) or with combination chemotherapy MOPP or COP (37 cases). In both, Hodgkin's disease and non-Hodgkin's lymphomas, induction of remission, relaps-free survival and prognostic significance of initial clinical stage were evaluated, in relation to the therapeutic modality. In patients with Hodgkin's disease, combination chemotherapy was found to produce significantly more durable remissions, when compared with single agent therapy. However, difference in the response rate, which was found to be more effective following the combination chemotherapy, was not statistically significant. In patients with non-Hodgkin's lymphomas overall lower response was recorded, regardless of the therapy applied. In all patients, better response rate and longer lasting remissions correlated with initial stage III.     

Stanford-Kaiser Permanente G1 study for clinical stage I to IIA Hodgkin's disease: subtotal lymphoid irradiation versus vinblastine, methotrexate, and bleomycin chemotherapy and regional irradiation

PURPOSE: We have demonstrated that a relatively mild chemotherapy regimen, vinblastine, methotrexate, and bleomycin (VBM), and involved-field radiotherapy (IFRT) could substitute for extended-field radiotherapy in patients with favorable Hodgkin's disease (HD) who have been laparotomy-staged. The purpose of this study is to determine if VBM and regional radiotherapy can substitute for extended-field radiotherapy in favorable clinical stage (CS) I and II HD. PATIENTS AND METHODS: Seventy-eight patients with favorable CS I to II HD were randomly assigned to subtotal lymphoid irradiation (STLI) or VBM chemotherapy and regional radiotherapy. Randomization was stratified on the basis of age, sex, number of Ann Arbor sites, histology, and institution. Patients were evaluated for freedom from progressive HD, survival, and toxicity. Results were compared with the predecessor trial in pathologically staged patients. RESULTS: With a median follow-up period of 4 years, the rate of freedom from progressive HD was 92% (95% confidence interval [CI], 88% to 96%) for patients treated with STLI and 87% (95% CI, 81% to 93%) for patients treated with VBM and regional radiotherapy. Six of seven patients who relapsed are alive and in remission following successful second-line therapy. CONCLUSION: Given the caveat of a small number of patients, the results of extended-field radiotherapy and VBM and regional radiotherapy are comparable with a median follow-up period of 4 years. VBM serves as a paradigm to reduce late effects in favorable early-stage HD. We do not advocate its routine use in clinical practice, but instead encourage participation in clinical trials with the objective of maintaining efficacy while reducing toxicity in CS I and II HD.     

Twice-daily compared with once-daily thoracic radiotherapy in limited small-cell lung cancer treated concurrently with cisplatin and etoposide

BACKGROUND: For small-cell lung cancer confined to one hemithorax (limited small-cell lung cancer), thoracic radiotherapy improves survival, but the best ways of integrating chemotherapy and thoracic radiotherapy remain unsettled. Twice-daily accelerated thoracic radiotherapy has potential advantages over once-daily radiotherapy. METHODS: We studied 417 patients with limited small-cell lung cancer. All the patients received four 21-day cycles of cisplatin plus etoposide. We randomly assigned these patients to receive a total of 45 Gy of concurrent thoracic radiotherapy, given either twice daily over a three-week period or once daily over a period of five weeks. RESULTS: Twice-daily treatment beginning with the first cycle of chemotherapy significantly improved survival as compared with concurrent once-daily radiotherapy (P=0.04 by the log-rank test). After a median follow-up of almost 8 years, the median survival was 19 months for the once-daily group and 23 months for the twice-daily group. The survival rates for patients receiving once-daily radiotherapy were 41 percent at two years and 16 percent at five years. For patients receiving twice-daily radiotherapy, the survival rates were 47 percent at two years and 26 percent at five years. Grade 3 esophagitis was significantly more frequent with twice-daily thoracic radiotherapy, occurring in 27 percent of patients, as compared with 11 percent in the once-daily group (P<0.001). CONCLUSIONS: Four cycles of cisplatin plus etoposide and a course of radiotherapy (45 Gy, given either once or twice daily) beginning with cycle 1 of the chemotherapy resulted in overall two- and five-year survival rates of 44 percent and 23 percent, a considerable improvement in survival rates over previous results in patients with limited small-cell lung cancer.     

Initial relapses in previously treated Hodgkin's disease. I. Results of second treatment

Two hundred forty-three consecutive patients with Hodgkin's disease who relapsed after an initial course of treatment at the Stanford University Division of Radiation Therapy underwent subsequent systematic evaluation and retreatment. An analysis of the influence of numerous parameters, including sex, histopathology, original stage, relapse site, and original and second therapy, on actuarial survival and on relapse-free survival was undertaken. Most relapses (87%) occurred within 3 years of the initial treatment course. The 5-year relapse-free survival measured from the time of second treatment increased from 14% before to 39% after the introduction of multiple agent chemotherapy (MOPP) for relapsing disease. Patients treated with MOPP chemotherapy for nodal relapses showed increased subsequent relapse-free survival (61%) when compared with patients treated only with radiotherapy for nodal relapses. Based on the combined findings of this analysis, recommendations are made regarding the management of patients with Hodgkin's disease who have suffered a relapse.