eMedicine Specialties > Hematology > Stem Cells and Disorders

Lymphoma, Diffuse Large Cell: Treatment & Medication

Author: Andre M Kallab, MD, Clinical Associate Professor of Oncology, Medical College of Georgia; Consulting Staff, Department of Oncology, Northeast Georgia Diagnostic Clinic
Contributor Information and Disclosures

Updated: Nov 4, 2009

Treatment

Medical Care

Therapy for aggressive NHL has evolved significantly in the last 30 years. The cyclophosphamide, Adriamycin, vincristine, prednisone (CHOP) regimen was among the first combinations to produce complete response (CR) rates and long-term survivors. New treatments to increase CRs have shown improvement in survival. For patients with advanced DLCL, a new standard therapy exists: the addition of a monoclonal antibody against CD20 (rituximab) to CHOP. In addition, high-dose chemotherapy in the setting of stem cell/bone marrow transplantation has become a useful treatment modality in the management of this disease.

In a study of 435 patients with DLCL, Villa et al compared the risk of CNS relapse in patients treated with CHOP (126 patients) with that of patients treated with rituximab and CHOP (R-CHOP; 309 patients).⁵ At follow-up (median 5.7 years), by which time 31 CNS relapses had occurred, the 3-year relapse risk for the CHOP patients was found to be 9.7%, while that for the R-CHOP patients was 6.4% (P = 0.085). The authors concluded, through multivariate analysis, that the risk of CNS relapse was significantly reduced in the R-CHOP group (hazard ratio [HR] 0.45, P = 0.034), with the reduction even more evident in patients who achieved a CR (HR 0.18, P = 0.005).

• Treatment of early stage DLCL (stage IA and IIA, nonbulky)
  • Current data suggest that either 6 cycles of CHOP or 3-4 cycles of CHOP followed by involved-field radiation therapy (IFRT) is reasonable treatment of early-stage nonbulky DLCL. The best approach to early-stage disease remains to be defined.
  • In patients treated with IFRT alone, relapses occur in nodal sites within and outside the irradiated field. In addition, relapses in the bone marrow and other parenchymal organs suggest the presence of microscopic disease in these organs at the time of diagnosis. As a result, radiation therapy as the sole treatment of early-stage disease has been abandoned. Treatment with either chemotherapy alone or a combination of chemotherapy and IFRT is considered the standard of care.
  • When the CHOP regimen was established as effective therapy for advanced-stage disease, some pursued the use of this regimen for early-stage disease. Connors and associates conducted a prospective study employing 3 cycles of CHOP followed by IFRT in 78 patients. Approximately 99% of these patients achieved a CR, and 86% remained free of disease with a median follow-up of 30 months. The actuarial survival rate for the entire group was 84%. Tordini and colleagues reported similar results in a large series of patients.
  • The Southwest Oncology Group (SWOG) conducted a randomized trial in patients with localized intermediate-grade or high-grade NHL, comparing 8 cycles of CHOP versus 3 cycles of CHOP followed by IFRT.⁶ The main objective was to compare 2 curative approaches with respect to differences in survival, time to treatment failure, and toxicity. Five-year estimated overall survival rates were 74% for CHOP (8 cycles) and 82% for CHOP (3 cycles) plus radiation. Progression-free survival also was significantly different in the 2 groups (67% for CHOP and 76% for the combination) (P = 0.03). This SWOG study concluded that 3 cycles of CHOP plus IFRT is more effective and less toxic than 8 cycles of CHOP alone for early-stage DLCL.
• A number of studies have analyzed factors predicting better or worse survival rates of subjects with limited-stage disease treated with combined modality programs:
  • In the SWOG study noted above, a subgroup analysis showed that the 5-year survival rate was better in patients who had a favorable International Prognostic Index (IPI) score (see Prognosis).
  • Similar results were found in a study of 308 patients with limited DLCL treated with 3 cycles of a doxorubicin-containing regimen followed by radiotherapy.
  • In an Eastern Cooperative Oncology Group (ECOG) study that compared 8 courses of CHOP with or without radiation in patients with previously untreated bulky or extranodal stage I or II DLCL, 10-year survival was similar in the two treatment arms (64 vs 60%). Patients with 3 or more disease sites or a poor performance status were more likely to fail CHOP with or without radiotherapy.
  • All these studies suggest that combined modality therapy is a successful approach for patients with limited stage I disease and a stage-modified IPI score of zero. This approach appears to be less successful in patients with bulky stage I or II disease, 3 or more involved disease sites, and/or a stage-modified IPI score of 1 or more.
• Treatment of advanced-stage DLCL (stages II bulky, III, and IV)
  • The CHOP regimen produced a CR rate of 45-62% in aggressive lymphomas. With up to 14 years of follow-up, CHOP was found to be curative to 32% of patients with advanced DLCL.
  • New and more complex regimens, such as M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone, leucovorin), PROMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, leucovorin), and PROMACE-CYTABOM (prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin), were developed in the 1970s and 1980s and are referred to as second-generation and third-generation regimens. Initial reports of single-institution pilot studies with third-generation regimens suggest 68-86% CR rates and 58-69% survival rates. The survival rates decreased with longer follow-ups.
  • Conclusions about the efficacy of the new regimens awaited results of prospective randomized trials. The SWOG conducted a randomized trial comparing standard CHOP to M-BACOD, PROMACE-CYTABOM, or MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin, prednisone). After 6 years, no difference in response rate, time to treatment failure, or overall survival was observed among the groups. However, the cost and toxicity of the new regimens were higher. Thus, CHOP remains the best available standard of care for most subtypes of DLCL. However, the newer-generation regimens have demonstrated benefit in selected subgroups of patients with DLCL.
  • Because CHOP cures less then 50% of patients with DLCL, new treatments are needed. Current investigations to improve treatment outcome include the following 3 goals:
    • Identification of new active therapies: Rituximab (Rituxan), a chimeric antibody that targets CD20⁺ B cells, produces a 48% response rate in patients with low-grade lymphomas.⁷ It also has activity in DLCL. A phase II pilot study of rituximab in combination with CHOP in patients with previously untreated DLCL or high-grade NHL was reported. The overall response rate was 97% (32 of 33 patients), with a 61% complete remission rate, a 36% partial remission rate, and a 3% progressive disease rate. Severe adverse events were similar to those observed with CHOP alone. These results are encouraging, and randomized studies currently are underway to determine if the addition of rituximab to standard chemotherapy should be considered the standard of care.
    • Intensification of current drugs with colony-stimulating factor support: The SWOG is undertaking a randomized phase II study of dose-intensified CHOP with growth factor support
    • Risk stratification: The use of prognostic factors can help identify patients with a high risk of relapse who will benefit from more aggressive therapy, such as high-dose chemotherapy with bone marrow or peripheral stem cell transplant.⁸
• Prognostic factors
  • The International Non-Hodgkin Lymphoma Prognostic Factors Project developed a predictive model of outcome for aggressive NHL.⁹ The project found 5 pretreatment characteristics that were independently statistically significant for higher-risk disease. They are (1) age older than 60 years, (2) tumor stage III or IV (advanced), (3) more than 1 extranodal site involved by disease, (4) patient performance status of 2 or more, and (5) LDH elevation above the reference range. Based on these 5 characteristics, patients were stratified into 4 categories, as follows:
    • Low-risk patients had 0 or 1 adverse factors.
    • Low-risk to intermediate-risk patients had 2 factors.
    • High-risk to intermediate-risk patients had 3 factors.
    • High-risk patients had 4 or 5 factors.
  • When patient outcomes were analyzed by risk stratification, they had different outcomes with regard to CR, disease-free survival, and overall survival. For example, patients with a low risk had a CR rate of 87% and a 5-year survival rate of 73%, as compared to a CR rate of 44% and a 5-year survival rate of 26% in the high-risk group.
  • Subsequent studies have confirmed the reproducibility of the International Prognostic Index for predicting clinical outcome for patients with DLCL. Currently, poor-risk patients (despite achieving CR) may be considered for aggressive therapy with high-dose chemotherapy and peripheral stem cell/bone marrow transplantation in first remission.
• Treatment of primary refractory disease
  • Up to 10% of patients with DLCL do not respond to induction chemotherapy (stable or progressive disease). These patients have a poor outcome.
  • Therapies that produce responses in 10% or fewer of these cases include (1) salvage chemotherapy with DHAP (dexamethasone, high-dose cytarabine, and cisplatin), (2) ESHAP (etoposide, methylprednisolone, high-dose cytarabine, and cisplatin), (3) MIME (mesna, ifosfamide, methotrexate, and etoposide), and (4) high-dose therapy with autologous bone marrow/stem cell support.
  • Patients who achieve only a partial response with standard conventional therapy but are considered to have chemosensitive disease should be evaluated for high-dose therapy and autologous stem cell support. These patients may have better outcomes than those with primary refractory disease.
• Treatment of relapse
  • Of patients with DLCLs who achieve an initial CR, 20-50% experience disease relapse. Numerous second-line salvage regimens have been used to induce a second remission. In general, 20-35% of patients who relapse achieve a second CR using a combination chemotherapy regimen, including DHAP, ESHAP, MIME, or IMVP-16 (ifosfamide, methotrexate, etoposide). However, the duration of the second CR frequently is less than 1 year, and patients treated with salvage chemotherapy at conventional doses are considered incurable unless treated with high-dose therapy and autologous transplantation.
  • A multicenter randomized trial evaluated patients with chemosensitive relapsed aggressive lymphomas treated with 2 cycles of DHAP. These patients were randomized to receive an additional 4 cycles of DHAP or high-dose chemotherapy followed by autologous bone marrow transplant. The patients in the transplant arm had a superior event-free survival rate (46% vs 12% at 5 y, P = 0.001) and overall survival rate (53% vs 32% at 5 y, P = 0.04) compared to those patients receiving conventional salvage therapy. Based on this study, transplantation for patients who experience relapse and have chemosensitive DLCL is considered the standard of care. Most series demonstrate that approximately 10-15% of patients with chemotherapy-resistant relapse also may benefit from this strategy.

Surgical Care

• The role of surgery in DLCLs usually is limited. Treatment of these tumors is primarily with cytotoxic agents, with or without radiation therapy.
• Surgery can be helpful in obtaining tissue for diagnosis or, rarely, to palliate a complication.

Consultations

• A surgical oncologist may be consulted if an open biopsy is needed for the diagnosis or to treat a complication such as perforated viscus.
• A radiation oncologist may be consulted if the primary therapy involves a combination of chemotherapy and radiotherapy. In addition, an initial large lymphoma mass or a large residual mass following completion of chemotherapy may be considered for IFRT.

Diet

• No specific diet is recommended, except a salt restriction when steroids are administered as part of the chemotherapy regimen.
• Patients undergoing cytotoxic chemotherapy may develop severe neutropenia, as defined by an absolute neutrophil count of less than 500/microliter. These patients should be advised to maintain a low microbial diet for the expected duration of neutropenia.

Activity

• No specific limitation of activity is necessary unless the patient is thrombocytopenic, in which case activity restriction may be necessary to avoid traumatic bleeding or bruising.

Medication

The CHOP regimen given for 6-8 cycles remains the standard treatment of DLCLs. More complicated regimens, as discussed in Medical Care, generally fail to improve overall survival.

Antineoplastic agents

Inhibit cell growth and proliferation

Cyclophosphamide (Cytoxan, Neosar)

This is a prototypical alkylator drug that is cell-cycle independent. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Doxorubicin (Adriamycin, Rubex)

Intercalates between DNA and inhibits topoisomerase I and II and produces free radicals, which may cause the destruction of DNA. The combination of these 2 events can, in turn, inhibit the growth of neoplastic cells.

Vincristine (Oncovin, Vincasar)

Binds to microtubular protein of the mitotic spindle, inhibiting key steps in the cell cycle.

Corticosteroids

These are used in combination with cytotoxic drugs to reduce inflammatory reactions.

Prednisone (Sterapred)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

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