Interpretation of clinical trials in diffuse large-cell lymphoma

Diffuse large-cell lymphoma is one of the neoplasms curable with chemotherapy in an appreciable percentage of patients. However, all patients are not cured and the best combination of agents is not certain. This reflects the lack of completed comparative trials using the regimens that appear most effective. Despite this uncertainty, several principles for the therapy of diffuse large-cell lymphoma can be identified that allow an analysis of the results reported in the literature. These principles include the following: (1) for a regimen to be curative in a substantial number of patients it must achieve a high rate of complete remissions; (2) cure must be accomplished with frontline therapy; (3) drugs must be delivered at curative doses; (4) rapidity of achieving a complete response might be related to chance for cure; (5) prolonged treatment for diffuse large-cell lymphoma is unnecessary; and (6) aggressive therapy is toxic. In analyzing the results with any regimen it is important to have long follow-up since late relapses do occur and initial very positive results tend to decay with greater numbers of patients treated. Applying these principles to the reported chemotherapy studies in patients with diffuse large-cell lymphoma suggest that no one of the new regimens is clearly superior to the others. Also, it is not clear that cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) delivered at full doses to comparable patients is inferior to the newer regimens. The results of ongoing studies comparing these regimens might help resolve these questions.     

Prognostic indicators in diffuse large-cell (histiocytic) lymphoma

Identification of prognostic groups among patients with diffuse large-cell (histiocytic) lymphoma (DHL) would help to select specific therapy for individual patients and allow comparisons among combination chemotherapy clinical trials. The Ann Arbor staging system is of limited value in predicting outcome in diffuse histiocytic lymphoma. Prognostic factors have been examined by various groups without a consensus of reliable prognostic indicators. This study was undertaken to examine the validity of a predictive model for response to treatment and survival in DHL. Eighty-six patients with the diagnosis of DHL treated with combination chemotherapy between the years 1976 and 1982 were examined for prognostic variables influencing response to treatment and survival. The variables examined included: age, sex, presence or absence of systemic symptoms, serum lactic dehydrogenase (LDH), sites of disease involvement, bulk of disease, prior therapy, stage of disease, according to the Ann Arbor classification, and pathological criteria, according to the Lukes Collins classification. Factors achieving a p-value in the 0 to 0.05 range with univariate analysis for predicting response were age and systemic symptoms. Factors significant for overall survival were age and bone marrow involvement. These factors have been found to influence survival in previous studies, but there has not been a consistency regarding the importance of these factors. Large numbers of patients must be examined for various factors in order to allow identification of prognostic groups among patients with DHL.     

Immunobiologic factors predictive of clinical outcome in diffuse large-cell lymphoma

The prognostic importance of immunobiologic factors in diffuse large-cell lymphoma (DLCL) is studied in 105 consecutive DLCL patients. Multivariate results using the Cox proportional hazards model clearly indicate that the Ki-67 index (P = .002), a marker of cell proliferation activity, and the presence or absence of human leukocyte antigen-DR (HLA-DR) (P = .007) are strong predictors of survival even in the presence of established clinical factors of stage (P = .015) and symptoms (P = .050). Using these four variables, prognostic groups were formed identifying patient groups with varying degrees of risk. The group of patients with three or four risk factors present at the time of diagnosis had a median survival of 4 months compared with a median survival of 59 months for the group with no risk factors. Similarly, prognostic groups for disease-free survival (DFS) were constructed based on the proportional hazards model that involved B versus T phenotype (P = .035) and HLA-DR (P = .054). Median DFS for the patient group with one or two risk factors present was 11 months compared with 43 months with no risk factors present. This study suggests immunobiologic parameters are important predictors of clinical outcome in DLCL patients and are of value in identifying subgroups of patients who have not responded to currently available therapy. The practical significance of this study is to identify parameters that may suggest specific changes in therapy of patient subgroups.     

Stage IV diffuse large-cell lymphoma: a long-term analysis

A long-term analysis of the clinical outcome of previously untreated adult patients who presented with stage IV diffuse large-cell lymphoma at diagnosis was performed to identify possible prognostic factors. Sixty-one patients were seen between 1974 and 1981; all were treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin followed by cyclophosphamide, vincristine, prednisone, and bleomycin for a total of one year. Overall five-year survival was 48.5%, with a median follow-up of 53 months. Of the 56 patients evaluable for remission status, 41 achieved a complete remission, and 27 are alive and disease free. Clinical factors of prognostic importance for survival included age, constitutional symptoms, lactate dehydrogenase (LDH) level, presence of mediastinal disease, large-cell infiltration of bone marrow, and number of extranodal sites of disease. The proportional hazards model then identified age, number of extranodal sites, and, to a lesser extent, serum LDH level as independent risk factors for survival. Four distinct patient risk groups were identified using these three factors. Younger patients with only one extranodal site of disease and normal LDH levels responded well on this therapy, with 100% alive at five years. In contrast, survival was less than 30% at five years for patients in the lowest risk group. There were 11 relapses; LDH level, constitutional symptoms, and mediastinal disease predicted for relapse. Knowledge of these risk factors permits individualization of treatment planning and allows more meaningful comparisons with the results of treatment studies using other intensive regimens.     

Somatic rearrangement of the c-myc oncogene in primary human diffuse large-cell lymphoma

Chromosome translocations involving 8q24, the band to which c-myc has been mapped (Dalla-Favera et al., 1982), are a uniform finding in Burkitt's lymphoma (Bernheim et al., 1981). However, in only a minority of the tumors is the rearrangement of the c-myc locus sufficiently close to the gene to be detected with currently available probes (Dalla-Favera et al., 1983). Approximately 25% of diffuse large-cell lymphomas have also been reported to have translocations involving 8q24 (Mitelman, 1985), but there have been no reports of c-myc rearrangements in this form of non-Hodgkin's lymphoma. We have examined the structure of the c-myc locus in primary tumor tissue of 10 cases of diffuse large-cell lymphoma. In one patient, Southern blot analysis revealed additional c-myc fragments in the tumor DNA but not in the germ-line DNA. Southern blot analysis using probes from both the heavy- and light-chain immunoglobin loci showed that the myc rearrangement was unlikely to involve the immunoglobulin loci in this patient.     

Influence of differing radiotherapy strategies on treatment results in diffuse large-cell lymphoma: a review

In the absence of evidence from randomised trials, radiation treatment of diffuse large-cell lymphoma of B-cell type represents an area of controversy with considerable differences in patterns of practice. The present literature survey aims at clarification of the role of radiotherapy in combined modality settings by identification of dose-response relationships, predictive factors for local control, and potential pitfalls in the interpretation of retrospective studies. Radiotherapy might increase local control in initially involved areas and is usually delivered to these sites (involved-field treatment). Combined modality treatment is currently recommended for patients in stage I or II if they are not treated in the context of prospective studies. Whether involved-field consolidation radiotherapy after systemic treatment in patients with bulky, stage III-IV lymphomas should be routinely recommended is presently unclear. Definition of bulky disease is arbitrary and varied between 6 and 10cm, reflecting a considerable difference in the number of clonogenic tumour cells.Several retrospective and one prospective randomised study suggest improved disease-free and overall survival by radiotherapy in advanced stages. The 5-year local control by radiotherapy was 93-98%. Currently, we recommend the following minimum doses for involved-field radiotherapy derived from this literature survey. Lymphomas with initial size <3.5 cm (possibly <6 cm) can be treated with 30 or 30.6Gy when a complete remission (CR) has been achieved by chemotherapy. The next group might be sufficiently controlled by 36Gy, but it remains unclear whether the cut-off should be 6cm or higher. Forty Gy appears to control tumours in the range of 7-10cm. Most likely, 45Gy does not have to be exceeded for larger lesions. Data on those with less than CR are contradictory. Judging the amount of viable tumour in these patients is problematic, but crucial to determine the intensity of further treatment. The value of positron emission tomography is still under investigation. Because the difference between doses of 30 and 40Gy might actually make a difference for the long-term toxicity of radiotherapy in some of the normal tissues and organs at risk (salivary glands, orbital structures, lung, heart, etc.), it appears prudent to resolve the open questions in prospective trials with careful documentation of side effects.     

COPBLAM III: infusional combination chemotherapy for diffuse large-cell lymphoma

COPBLAM III, a polychemotherapy regimen consisting of cyclophosphamide, infusional vincristine, prednisone, infusional bleomycin, doxorubicin, and procarbazine, was administered to 51 patients with diffuse large-cell lymphoma. Ninety-six percent of patients age 60 or younger achieved a complete response (CR); none have relapsed. Overall, 88% of patients are alive and well and potentially in the survival plateau. For patients greater than 60 years, CR was obtained in 73%, with 42% potentially in the survival plateau, the difference resulting in part from four relapses, three toxic deaths, and one presumed unrelated death. These results in the elderly were paralleled by a relatively reduced ability to tolerate therapy. Toxicity was primarily pulmonary, occurring in 39% of patients, two of whom died. With an overall CR rate of 84%, of which 92% are sustained at a median follow-up of 40 months, COPBLAM III represents a highly effective treatment in a sizeable cohort of patients.     

MACOP-B treatment in diffuse large-cell lymphoma: identification of prognostic groups in an Italian multicenter study.

PURPOSE: The prognosis of advanced-stage diffuse large-cell lymphoma (DLCL) has improved with the use of the third-generation regimens such as methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B). However, different results have been reported. Therefore, we started a cooperative study to confirm the efficacy of MACOP-B. An analysis of prognostic factors was also performed to identify poor-prognosis patients. PATIENTS AND METHODS: Between June 1986 and March 1989, 180 patients with advanced-stage DLCL were treated with MACOP-B. MACOP-B was given according to the original scheme. Numerous clinical features possibly predictive for complete response (CR), disease-free survival (DFS), and survival were analyzed in univariate and multivariate analyses. RESULTS: One hundred twenty-seven patients (71%) achieved a complete remission, 20 (11%) achieved a partial remission, 24 (13%) had unchanged or progressive disease, and nine (5%) died due to toxicity. With a median follow-up of 28 months, 71% of 127 CRs remain in first remission. Predicted 3-year survival for all 180 patients is 60%, and 3-year DFS for the 127 CRs is 67%. Overall toxicity was acceptable, with mucositis being the most frequent severe side effect. A multivariate regression analysis identified lactate dehydrogenase (LDH) level, bone marrow involvement, and tumor burden as independent risk factors for survival. These factors were also important for achievement of remission and DFS and allowed us to identify three distinct risk groups of patients with good, intermediate, and poor prognosis, with 3-year survival rates of 80%, 59%, and %29, respectively. CONCLUSIONS: These results confirm the effectiveness of MACOP-B in advanced-stage DLCL at low or intermediate risk; however, high-risk patients are in urgent need of new therapeutic approaches. A better definition of prognostic features would allow a more reliable comparison of different treatment regimens, as well as an effective tailoring of therapy by prognostic groups.     

Prognostic variables in patients with diffuse large-cell lymphoma treated with MACOP-B.

One hundred twenty-six patients with diffuse large-cell lymphoma were treated with methotrexate with leucovorin, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B) between April 1981 and June 1986. Univariate and multivariate analyses were performed using overall survival as of September 1989 as the end point. Four independent negative predictors of survival were identified: presence of B symptoms; more than two involved lymph node sites; more than one extranodal site (variables related to tumor burden), and age older than 60, a variable related to the patient's ability to tolerate treatment. Each variable contributed the same relative risk of dying and, accordingly, this simple predictive formula was developed empirically: (4-N) x 30 = the approximate percentage of chance of survival at 5 years. "N" is the number of predictive variables present. The same four predictors were also found to be significant by multivariate analysis when only those patients achieving a complete response were analyzed.     

Brief chemotherapy and involved-region irradiation for limited-stage diffuse large-cell lymphoma: an 18-year experience from the British Columbia Cancer Agency.

PURPOSE: To evaluate clinical outcome of patients with limited-stage diffuse large-cell lymphoma (DLCL) treated with three cycles of chemotherapy followed by involved-region irradiation (IRRT). PATIENTS AND METHODS: Adults with limited-stage DLCL were treated with brief doxorubicin-containing chemotherapy regimens between 1980 and 1998. IRRT was administered 3 to 4 weeks after the third chemotherapy treatment in a dose equivalent to 30 Gy in 10 fractions. RESULTS: Three hundred and eight patients (median age, 64 years) were included, and 299 experienced complete remission. After a median follow-up of 86 months, 64 patients developed progressive disease, and 104 patients died (43 from lymphoma, three from toxicity, and 58 from other causes). Actuarial overall and progression-free survival (PFS) rates were, respectively, 80% and 81% at 5 years and 63% and 74% at 10 years. For subgroups identified using the Miller modification of the International Prognostic Index (IPI), the overall survival rates at 5 and 10 years were, respectively, 97% and 89% (no factors), 77% and 56% (one or two factors), and 58% and 48% (three or four factors), and the 5-year and 10-year PFS rates were, respectively, 94% and 89% (no factors), 79% and 73% (one or two factors), and 60% and 50% (three or four factors). Men with testicular presentation, had a definitely inferior outcome. CONCLUSION: Long-term outcome with three cycles of doxorubicin-based chemotherapy and IRRT confirms that this is a successful approach for the majority of patients with limited-stage DLCL. Subgroups with worse prognoses can be identified, and these patients should be offered alternative treatment approaches.     

Combination chemotherapy (modified CHOP-Bleo) in non-Hodgkin's lymphoma]

Twenty-six adults with advanced non-Hodgkin's lymphoma (73% in clinical stage IV) were treated with a combination of cyclophosphamide, hydroxyldaunorubicin, vincristine, prednisolone and bleomycin (modified CHOP-Bleo), from May 1978 to July 1987. Complete remission (CR) was obtained in 12 of 26 patients (46%). The median survival time was 19.5 months (2-77 + months), Median duration of CR was 30.5 months (2-76 + months). The survival of patients with diffuse lymphoma large cell type (DL) was better than those with other diffuse lymphomas. The 50% of patients with DL are projected to be free of disease. The survival of patients with clinical stage III was significantly better than those with clinical stage IV. Major complications during chemotherapy with modified CHOP-Bleo were myelosuppression, constipation and peripheral neuropathy. These toxicities were generally mild and well tolerated.     

Tumor burden assessment and its implication for a prognostic model in advanced diffuse large-cell lymphoma

Previously untreated adult patients who presented with advanced diffuse large-cell lymphoma (DLCL) at diagnosis were studied to identify possible prognostic factors. One hundred five patients were seen between 1974 and 1981; 45 patients were stage III and 60 patients were stage IV. All patients received cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo). Stage III patients also received radiation therapy alternated with chemotherapy. Overall survival was 50% at 5 years and 43% at 8 years. Seventy-four patients achieved a complete remission (CR) and 37 are alive and disease-free with a median follow-up of 72 months. There was no difference in clinical outcome between stage III and stage IV. However, a proportional hazards model identified lactic dehydrogenase (LDH) level and tumor burden, among all clinical factors studied, as independent risk factors for survival. These two factors were also important for achievement of remission and relapse-free survival. Three distinct patient risk groups were identified with 5-year survival rates of 87%, 48%, and 20%, respectively. The measure of tumor burden proposed herein, along with LDH level, can be used for developing treatment programs, and for meaningful comparison of different treatment regimens, as well as assessment of prognosis.     

The role of maintenance therapy in the treatment of large-cell non-Hodgkin's lymphoma.

Eighty-one patients with large-cell non-Hodgkin's lymphoma achieving complete restaging verified remission after induction chemotherapy (CHOP-Bleo or m-BACOD) were randomized to the following 3 arms: 1. No further treatment (observation). 2. Early consolidation therapy with 6 courses of CVP (cyclophosphamide, vincristine, prednisone) given monthly. 3. Maintenance therapy with cyclophosphamide and prednisone given every 6 weeks for 2 years. The relapse-free survival was better in the maintenance and consolidation arms than in the observation arm. The additional therapy given after the initial complete remission produced lasting disease control in a considerable number of patients and with acceptable toxicity. The authors feel that patients with large-cell lymphoma do not need more aggressive and toxic initial management because the use of maintenance therapy can increase the number of patients remaining in complete remission by more conventional, less toxic chemotherapy.     

Diffuse large-cell lymphoma of the testis.

PURPOSE: To evaluate clinical outcome of patients with testicular diffuse large-cell lymphoma treated with conventional-dose systemic chemotherapy. PATIENTS AND METHODS: This study is a retrospective analysis of adult patients with testicular diffuse large-cell lymphoma who were treated with a doxorubicin-based chemotherapy regimen at our institution, the Istituto Nazionale Tumori of Milan. Twenty-nine assessable patients, with a median age of 61 years, were identified. Sixteen patients had limited stage (Ann Arbor stage I/II) disease, whereas 13 patients had a testicular mass and distant organ involvement (Ann Arbor stage IV). Patients were retrospectively classified according to the International Prognostic Index. RESULTS: After a median follow-up of 82 months, 22 patients presented disease progression and 22 patients had died. Actuarial median time to treatment failure and overall survival were 44 and 41 months for patients with limited stage and 9 and 16 months for patients with advanced stage, respectively. Eight patients failed initial treatment, and 14 patients relapsed from clinical remission after a median disease-free time of 17 months (range, 6 to 98 months). Median survival time after progression of lymphoma was 5 months (range, 0 to 22 months). In nine (41%) of the 22 failing patients, the initial site of relapse was either the CNS or the contralateral testis; the remaining patients experienced relapse in multiple extranodal sites. CONCLUSION: Poor prognosis of patients with diffuse large-cell lymphoma calls for more effective treatment strategies, such as high-dose chemotherapy programs for younger patients or specifically designed chemotherapy regimens for patients not suitable for high-dose treatment, with the purpose to provide control of both systemic disease and disease of the CNS and contralateral testis. The potential benefit of contralateral testicular irradiation has to be taken into account in the treatment planning.