Originally published as JCO Early Release 10.1200/JCO.2005.09.137 on June 13 2005
Journal of Clinical Oncology, Vol 23, No 22 (August 1), 2005: pp. 5027-5033
© 2005 American Society of Clinical Oncology.
Introduction of Combined CHOP Plus Rituximab Therapy Dramatically Improved Outcome of Diffuse Large B-Cell Lymphoma in British Columbia
Laurie H. Sehn,
Jane Donaldson,
Mukesh Chhanabhai,
Catherine Fitzgerald,
Karamjit Gill,
Richard Klasa,
Nicol MacPherson,
Susan O'Reilly,
John J. Spinelli,
Judy Sutherland,
Kenneth S. Wilson,
Randy D. Gascoyne,
Joseph M. Connors
From the Divisions of Medical Oncology and Pathology, and the Program for Disease Control of the British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada
Address reprint requests to Laurie H. Sehn, MD, MPH, BC Cancer Agency, Vancouver Clinic, 600 W 10th Ave, Vancouver, BC, Canada V5Z 4E6; e-mail: lsehn@bccancer.bc.ca
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ABSTRACT
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PURPOSE: For more than two decades, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard therapy for diffuse large B-cell lymphoma (DLBCL). The addition of rituximab to CHOP has been shown to improve outcome in elderly patients with DLBCL. We conducted a population-based analysis to assess the impact of this combination therapy on adult patients with DLBCL in the province of British Columbia (BC).
METHODS: We compared outcomes during a 3-year period; 18 months before (prerituximab) and 18 months after (postrituximab) institution of a policy recommending the combination of CHOP and rituximab for all patients with newly diagnosed advanced-stage (stage III or IV or stage I or II with "B" symptoms or bulky [> 10 cm] disease) DLBCL.
RESULTS: A total of 292 patients were evaluated; 140 in the prerituximab group (median follow-up, 42 months) and 152 in the postrituximab group (median follow-up, 24 months). Both progression-free survival (risk ratio, 0.56; 95% CI, 0.39 to 0.81; P = .002) and overall survival (risk ratio, 0.40; 95% CI, 0.27 to 0.61, P < .0001) were significantly improved in the postrituximab group. After controlling for age and International Prognostic Index score, era of treatment remained a strong independent predictor of progression-free survival (risk ratio, 0.59; 95% CI, 0.41 to 0.85; P = .005) and overall survival (risk ratio, 0.43; 95% CI, 0.29 to 0.66; P < .001). The benefit of treatment in the postrituximab era was present regardless of age.
CONCLUSION: The addition of rituximab to CHOP chemotherapy has resulted in a dramatic improvement in outcome for DLBCL patients of all ages in the province of BC.
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INTRODUCTION
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Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, accounting for approximately 30% of all new diagnoses.1 The median age at presentation is in the mid-60s, and most patients present with advanced-stage disease. The cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy regimen has been the mainstay of therapy since its development in the 1970s.2 Attempts to improve outcomes with more intensive chemotherapy regimens failed to demonstrate additional benefit, and therefore CHOP has remained the standard of care.3 Although some patients are cured, the 3-year progression-free survival (PFS) and overall survival (OS) remain disappointing at 44% and 52%, respectively.3
Rituximab, a chimeric anti-CD20 immunoglobulin G1 monoclonal antibody, was approved by the US Food and Drug Administration in 1997 for treatment of relapsed and refractory follicular lymphoma.4 Early studies also indicated activity in DLBCL, with a single-agent response rate of 37%.5 The feasibility and safety of combining CHOP with rituximab was demonstrated in a phase II trial, which reported a higher than expected complete remission rate of 61%.6 In December 2000, the Groupe d'Etude des Lymphomes de l'Adulte (GELA) reported preliminary results of a randomized, controlled trial comparing CHOP plus rituximab with CHOP alone for elderly patients (age  60 years) with advanced-stage DLBCL.7 The addition of rituximab to CHOP resulted in both an improved event-free survival and OS, representing an apparent major breakthrough in the management of DLBCL. This was confirmed in the 2-year analysis, which reported a 19% absolute improvement in event-free survival and a 13% improvement in OS with the CHOP plus rituximab combination.8
On the basis of these encouraging results, on March 1, 2001, the British Columbia (BC) Cancer Agency implemented a new policy recommending the combination of CHOP and rituximab for all newly diagnosed patients with advanced-stage DLBCL, regardless of age, in the province of BC. We present a population-based retrospective analysis designed to assess the impact of introducing this new treatment strategy on outcomes for DLBCL in the province of BC.
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METHODS
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Background
The BC Cancer Agency coordinates cancer care for the entire province of BC, population 4.2 million. Most patients receive treatment directly under the guidance of a Cancer Agency medical oncologist at one of four major cancer treatment facilities or at one of a network of cancer clinics throughout the province. The remaining patients are treated by local physicians. All physicians are expected to use BC Cancer Agency treatment guidelines, which are explicit documents outlining recommended therapy with drug dosages, as well as guidelines for managing treatment complications and follow-up recommendations. The aim of these guidelines is to promote a uniform standard of care according to current evidence-based medicine. Changes in treatment policy are communicated directly to all physicians treating patients with lymphoproliferative disorders via immediate e-mail notification and by updating the Web-based Cancer Management Guidelines of the BC Cancer Agency (http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/default.htm).
In addition to providing specific treatment guidelines, the BC Cancer Agency is responsible for the provision of all cancer drugs throughout the province. All antineoplastic agents, including chemotherapy and monoclonal antibodies, are dispensed through the centralized Cancer Agency pharmacy, which operates on a single provincial budget and maintains an electronic record of all medications dispensed. The province of BC also maintains an independent cancer registry (the BC Cancer Registry), which records all new cases of cancer diagnosed in the province. Pathologists are legally required to report all new cancer diagnoses to the registry. This registry allows independent verification of all cancers seen in the province, including all cases of DLBCL. Finally, the therapeutic records, independent pharmacy, and Cancer Registry records can be linked electronically to match patient diagnostic, treatment, and outcome data.
Study Design
This is a population-based retrospective analysis examining outcomes for all patients with advanced-stage DLBCL in a single Canadian province during a 3-year interval, September 1, 1999, through August 31, 2002. This represents an 18-month period before (prerituximab) and after (postrituximab) institution of a new policy recommending the combination of CHOP and rituximab for all patients with newly diagnosed advanced-stage DLBCL, regardless of age. Outcomes were compared based on the policy institution date of March 1, 2001.
Patient Identification
Patients were identified using three main sources of information: the BC Cancer Registry, the BC Cancer Agency Pharmacy Database, and the Lymphoma Clinical Database. The BC Cancer Registry was searched for all new diagnoses of DLBCL reported during the study interval. To ensure that all diagnoses of DLBCL were captured, an initial search was performed including a broad list of diagnostic categories within which occurrences of DLBCL might be listed. The BC Cancer Agency Pharmacy Database was searched for all patients who received CHOP-like chemotherapy or rituximab during the study interval. The Lymphoma Clinical Database is a computerized research database that contains clinical and pathologic information on more than 10,000 patients with lymphoma treated in BC since 1981. This database was searched for all occurrences of advanced-stage DLBCL diagnosed within the study interval.
All patients identified in the initial search of these three independent databases were cross correlated and flagged for possible inclusion. These records were then closely examined using information available in the Lymphoma Clinical Database, Cancer Agency clinical records, hospital records, and local physicians' records to establish the final cohort. Clinical information was retrievable on more than 99% of patients identified by the initial search.
Inclusion and Exclusion Criteria
The patients included in the final analysis were older than 15 years of age and had biopsy-proven, newly diagnosed DLBCL within the study interval. In addition, all patients had advanced-stage disease: stage III or IV; stage I or II with "B" symptoms or bulky disease (> 10 cm), or a contraindication to radiation; or testicular DLBCL of any stage. All patients received a CHOP-like chemotherapy regimen with curative intent. Patients were excluded if they were HIV positive, had CNS involvement at presentation, or had evidence of transformation from an indolent lymphoma. Patients who were never treated because of frailty or refusal, or who were treated with only palliative intent, were excluded.
Statistical Analysis
Clinical characteristics and outcome variables were compared between patients treated in the prerituximab and postrituximab eras, based on the policy institution date of March 1, 2001. This analysis is based on follow-up through March 15, 2004. This was an intention-to-treat analysis, including all patients treated with curative intent who received at least one cycle of CHOP-like chemotherapy. Prognostic variables were compared between the groups, using the independent-samples t test for continuous variables and the  2 test for categoric variables. Time to disease progression was calculated as the time from date of diagnosis to documented disease progression, relapse, or date the patient was last known to be alive; patients dying as a result of causes unrelated to lymphoma or treatment were censored at the time of death. OS was calculated as the time from date of diagnosis until death as a result of any cause or date last known alive. PFS and OS were assessed using the Kaplan-Meier method and compared between groups using the log-rank test.9,10 A multivariate analysis was performed using a Cox proportional hazards model to assess the independent effect of treatment in the postrituximab era on PFS and OS, after controlling for relevant clinical prognostic factors.11 The relative benefit of treatment in the postrituximab era between age groups was compared using the test for interaction from the Cox proportional hazards model. Data were analyzed using the Statistical Software Package for the Social Sciences (SPSS version 10.1 for Windows; SPSS Inc, Chicago, IL).
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RESULTS
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Patients
A total of 292 patients were identified: 140 in the prerituximab group and 152 in the postrituximab group. Central pathology review (M.C., R.D.G.) was available on 97% of patients. The distribution of pathologic subtypes was similar between the cohorts and is listed in Table 1. All patients were CD20 positive. The median age for all patients was 64 years (range, 19 to 86 years). Clinical characteristics at diagnosis are listed in Table 1. All relevant clinical prognostic factors were compared and revealed only minor differences, with no statistical differences found between the groups. The distribution of the International Prognostic Index scores12 was similar between the prerituximab and postrituximab groups (P = .48).
Treatment
All patients received a CHOP-like chemotherapy regimen. Patients were treated with curative intent, and it was planned for patients to receive six to eight cycles of therapy (two cycles beyond maximum response). In the prerituximab group, 50% received CHOP, 32% received doxorubicin, cyclophosphamide, vincristine, and prednisone (ACOP-12)13; 15% received cyclophosphamide, vincristine, prednisone, and doxorubicin (COPA)14; and 3% received CHOP followed by ECV.15 All of these regimens have been described previously and demonstrated to be equivalent to CHOP. There was no difference in PFS between patients receiving these different induction regimens in the prerituximab group (data not shown). In the postrituximab group, 98% of patients received CHOP and 2% received another CHOP-like regimen.
Rituximab was administered at the standard dose of 375 mg/m2 with each cycle of CHOP, between 24 to 72 hours after the CHOP infusion. Although it was intended that the rituximab policy be implemented on March 1, 2001, rituximab was available in the province for other indications before that date and was received by 10% of the prerituximab group. In addition, because of the lag time before the new policy could be embraced universally, rituximab was received by only 86% of the postrituximab group. More patients in the prerituximab group received postchemotherapy radiation therapy compared with the postrituximab group (24% v 14%; P = .04).
After completion of therapy, patients were seen in follow-up every 3 months for the first 2 years, every 6 months in the 2- to 5-year interval, then yearly after 5 years. Routine monitoring included physical examination and laboratory investigations, with radiologic investigations performed as indicated to investigate new symptomatic findings. No change in this standard monitoring was made during the 36-month study period. Standard diagnostic imaging included computed tomography scans and did not change; newer imaging techniques such as positron emission tomography scanning have not yet become available in BC. Patients whose lymphoma recurred despite first-line therapy were treated with a variety of salvage regimens at the discretion of the treating physician. Patients who were  65 years of age with chemotherapy-responsive disease were eligible to undergo high-dose chemotherapy and stem-cell transplantation. Nine percent of patients in the prerituximab era and 7% in the postrituximab era underwent stem-cell transplantation.
Outcome
Median follow-up time for living patients is 42 months for the prerituximab group (range, 5 to 52 months) and 24 months for the postrituximab group (range, 9 to 35 months). Outcome according to treatment era is listed in Table 2. PFS was markedly improved in the postrituximab group compared with the prerituximab group (risk ratio, 0.56; 95% CI, 0.39 to 0.81; P = .002; Fig 1). The 2-year PFS estimate increased from 51% to 69% in the postrituximab era. Similarly, OS was significantly improved in the postrituximab compared with the prerituximab group (risk ratio, 0.40; 95% CI, 0.27 to 0.61; P < .0001; Fig 2). The 2-year OS estimate increased from 52% to 78% in the postrituximab era. Of note, an analysis restricted to only patients who had received CHOP chemotherapy confirmed the significant benefit after the addition of rituximab (data not shown).
A multivariate analysis was performed to assess the impact of treatment era (postrituximab v prerituximab) on outcome after controlling for relevant clinical prognostic factors. After controlling for age and International Prognostic Index score, era of treatment remained a strong independent predictor of both PFS (risk ratio, 0.59; 95% CI, 0.41 to 0.85; P = .005) and OS (risk ratio, 0.43; 95% CI, 0.29 to 0.66; P < .001).
A subgroup analysis was performed based on age at diagnosis: younger than 60 v 60 years (Table 2). In the elderly patient group, there was a significant improvement in PFS in the postrituximab group (risk ratio, 0.53; 95% CI, 0.33 to 0.85; P = .007). In the younger age group, PFS was higher in the postrituximab group, although this did not meet statistical significance (risk ratio, 0.63; 95% CI, 0.35 to 1.16; P = .13). However, a significant improvement in OS was demonstrated postrituximab in both the elderly (risk ratio, 0.41; 95% CI, 0.25 to 0.68; P = .0003) and the younger patients (risk ratio, 0.41; 95% CI, 0.19 to 0.90; P = .02; Table 2; Fig 3). A test for interaction was performed to examine whether the impact of treatment in the postrituximab era differed between age groups. No significant difference in the relative benefit of treatment in the postrituximab era was demonstrated between age groups (PFS, P = .68; OS, P = .99).
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Fig 3. (A) Overall survival by treatment era. Elderly patients, n = 170. (B) Overall survival by treatment era. Younger patients, n = 122.
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DISCUSSION
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The treatment of aggressive non-Hodgkin's lymphoma has been one of the major success stories in cancer therapy. However, despite the development of newer chemotherapeutic agents and more intensive chemotherapy regimens, no improvement in outcome has been demonstrated during the last three decades.3 Advances in molecular biology have allowed the development of newer targeted therapies. In 1997, rituximab became the first monoclonal antibody approved by the US Food and Drug Administration for cancer therapy.4 Rituximab targets the CD20 cell surface protein, present on mature B cells and most B-cell malignancies. Its effects are likely multifactorial and include complement-dependent cell lysis, cell-mediated cytotoxicity, and induction of apoptosis.16,17 Preclinical models suggested a synergistic effect when rituximab was combined with chemotherapy,18,19 and early clinical trials demonstrated minimal increase in toxicity.6,20
The GELA trial demonstrated that the addition of rituximab to CHOP chemotherapy improved outcome in elderly patients with advanced-stage DLBCL.8 The current study is a population-based analysis designed to evaluate the impact of the introduction of this combination therapy across the general population of patients with advanced-stage DLBCL. Our results confirm a dramatic improvement in outcome after the adoption of a treatment policy combining CHOP and rituximab for all patients with advanced-stage DLBCL, regardless of age. Patients treated in the postrituximab era had an 18% absolute improvement in 2-year PFS and a 25% improvement in 2-year OS compared with those treated in the prerituximab era. The addition of rituximab resulted in an approximately 50% decrease in the risk of dying within the first 2 years after diagnosis.
The BC Cancer Agency offers a coordinated network of cancer care for the province of BC. By searching the BC Cancer Registry, the BC Cancer Pharmacy Database, and the Lymphoma Clinical Database, we were able to generate an inclusive list of all patients diagnosed with advanced-stage DLBCL during the study interval. Clinical information was retrievable on more than 99% of patients identified by the initial search. Because these include all patients with newly diagnosed DLBCL in a well-defined geographic area, their outcome should be representative of what can be achieved in other similar general populations. The population of BC is relatively stable over time, which allowed us to track clinical outcome reliably. Only three patients were lost to follow-up.
Although this study is not a concurrent comparison, it is unlikely that the improvement in outcome seen could be attributed to factors other than the change in treatment policy. Despite the serial testing of various multiagent chemotherapy protocols dating back to 1981 (including methotrexate, ACOP, and bleomycin;21 etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin;22 ACOP-12;13 and CHOP), we had observed no change in outcome for patients with DLBCL during a period of two decades. The treatment policy guidelines generated by the BC Cancer Agency before and after March 1, 2001, were similar with the exception of the addition of rituximab. These treatment guidelines explicitly outline an approach to curative therapy, recommending the timely provision of treatment cycles, with use of growth factors to ensure adherence to the schedule. Although a variety of CHOP-like regimens were received by the prerituximab group, outcomes were the same regardless of which chemotherapy regimen was used. In addition, an analysis restricted to only patients who had received CHOP chemotherapy confirmed the significant benefit after the addition of rituximab (data not shown). The study interval of 3 years was relatively short, and there were no changes in supportive care or follow-up surveillance techniques over that time. Lymphoma patients are managed by a small group of medical oncologists and internists who are accustomed to treating patients with curative intent, according to these guidelines. The fact that 86% of patients in the postrituximab era received rituximab attests to the high level of compliance with these policies.
The patient selection process in this study depended on diagnosis, not treatment, and captured all newly diagnosed patients. Thus, the availability of a new treatment should not have biased patient inclusion. This is supported by several observations. We identified comparable numbers of patients in the two treatment eras. The distribution of pathologic subtypes and clinical factors was remarkably similar between the two groups. Finally, similar small numbers of patients (nine patients from each group) were excluded because of treatment with palliative intent. Importantly, the outcome observed in the prerituximab group was similar to that observed during the last several decades at the BC Cancer Agency, and was in keeping with the expected outcome for this patient population.
Although the GELA trial was the first study to demonstrate a benefit of combining chemotherapy and rituximab for DLBCL, additional supportive data have emerged. Recently, the Eastern Cooperative Oncology Group has presented results of a randomized trial comparing CHOP versus CHOP and rituximab for elderly patients with advanced-stage DLBCL, followed by maintenance rituximab versus observation.23 This trial demonstrated a significant improvement in time to treatment failure for patients who received CHOP and rituximab as induction therapy. However, because of an interaction between induction and maintenance therapies, no improvement in overall survival has yet been observed.
Our study is the first to report a benefit of combined chemotherapy and rituximab for younger patients with DLBCL. The MabThera International Trial evaluating CHOP-like chemotherapy with or without rituximab in younger patients with a favorable prognostic profile was closed to accrual early and recently reported preliminary results demonstrating a benefit in both time to treatment failure and OS in this patient population.24
Our study complements these randomized prospective comparisons by demonstrating that the addition of rituximab to CHOP altered the outcome in an entire adult population. This is an important confirmation that the observations from carefully controlled trials with selected patients can be extended to a general population composed of a wide mixture of patients, including many who could not or would not participate in randomized comparisons. As costly new therapies emerge, it will become increasingly important to demonstrate their generalizability to justify societal costs. This study demonstrates the profound impact of the addition of rituximab to CHOP when administered to an unselected population of patients with DLBCL in routine clinical practice.
In conclusion, the addition of rituximab to CHOP chemotherapy has resulted in a dramatic improvement in outcome for DLBCL in the province of BC in adult patients of all ages. This study confirms the advantage of a combined chemotherapy-immunotherapy approach for the general population of patients with DLBCL, and provides corroboration of the benefit predicted from randomized trials.
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Authors' Disclosures of Potential Conflicts of Interest
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Although all authors have completed the disclosure declaration, the following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
| Authors |
Employment |
Leadership |
Consultant |
Stock |
Honoraria |
Research Funds |
Testimony |
Other |
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| Laurie H. Sehn |
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Roche Canada (A) |
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Roche Canada (A) |
Roche Canada (B) |
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| Jane Donaldson |
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Roche Canada (B) |
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| Mukesh Chhanabhai |
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Roche Canada (B) |
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| Catherine Fitzgerald |
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Roche Canada (A) |
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Roche Canada (A) |
Roche Canada (B) |
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Roche Canada (A) |
| Karamjit Gill |
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Roche Canada (B) |
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Roche Canada (A) |
| Richard Klasa |
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Roche Canada (A) |
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Roche Canada (A) |
Roche Canada (B) |
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| Nicol MacPherson |
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Roche Canada (B) |
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Roche Canada (A) |
| John J. Spinelli |
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Roche Canada (B) |
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| Judy Sutherland |
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Roche Canada (B) |
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| Kenneth S. Wilson |
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Roche Canada (B) |
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| Randy D. Gascoyne |
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Roche Canada (A); Biogen IDEC (A) |
Roche Canada (B); Berlex/AG Schering (B) |
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| Joseph M. Connors |
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Roche Canada (A) |
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Roche Canada (A) |
Roche Canada (B) |
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Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required
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Acknowledgment
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We thank all of the contributing physicians throughout the province of British Columbia, without whom a study of this magnitude would not be possible. In particular, we acknowledge the efforts of Dr James Archer, Dr Barrett Benny, Dr Winston Bishop, Dr Malcolm Brigden, Dr Noel Buskard, Dr Donna Cuthbert, Dr Michael Delorme, Dr Jorge Denegri, Dr Keith Donaldson, Dr Donna Forrest, Dr Paul Galbraith, Dr Ed Hardy, Dr Paul Hoskins, Dr Kong Khoo, Dr Paul Klimo, Dr Wendy Lam, Dr Charles Li, Dr Phillip Malpass, Dr Kevin Murphy, Dr Stephen Nantel, Dr Tom Nevil, Dr Michael Noble, Dr Willie Pewarchuk, Dr Len Scotland, Dr Tamara Shenkier, Dr Kevin Song, Dr Sheila Souliere, Dr David Stuart, Dr Simon Sutcliffe, Dr Marianne Taylor, Dr Cindy Toze, Dr Peter Tsang, Dr Linda Vickars, Dr Hilary Wass, Dr Christopher Williams, and Dr John Yun.
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NOTES
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Supported by the Turner Family Lymphoma Outcome Unit Fund, the Yvette Porte Lymphoma Research Endowment, and an unrestricted grant from Roche Canada Inc.
Presented at the annual meeting of the American Society of Hematology (preliminary results), San Diego, CA, December 2003.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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REFERENCES
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Submitted September 30, 2004;
accepted March 30, 2005.
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TOP
ABSTRACT
INTRODUCTION
