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© 2002 American Society for Clinical Oncology Brief Chemotherapy and Involved-Region Irradiation for Limited-Stage Diffuse Large-Cell Lymphoma: An 18-Year Experience From the British Columbia Cancer AgencyByFrom the Divisions of Medical Oncology, Radiation Oncology, and Pathology of the British Columbia Cancer Agency and the University of British Columbia, Vancouver, Canada. Address reprint requests to Tamara N. Shenkier, MD, British Columbia Cancer Agency, 600 W 10th Ave, Vancouver, BC, Canada V5Z 4E6; email: tshenkier{at}bccancer.bc.ca
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.
BEFORE 1980, THE standard treatment for patients with limited-stage large-cell lymphoma, usually after meticulous staging with laparotomy, was irradiation. With this approach, approximately 50% of those with stage I and 20% of those with stage II remained disease-free at 5 years.1,2 With the observation that chemotherapy could cure advanced disease,3 it became attractive to add chemotherapy to the treatment of limited-stage lymphoma. The advantages of the combined modality approach included decreasing the need for invasive staging by eliminating laparotomy, increasing local and systemic control, and decreasing the size of the irradiation field.4 Preliminary observations that chemotherapy alone could also cure patients with early-stage lymphoma5 led to a large randomized trial of combined modality treatment versus chemotherapy alone.6 At a median follow-up of 4.4 years, this trial demonstrated superior progression-free survival (PFS) and overall survival and less life-threatening toxicity in the combined modality arm. Furthermore, by applying a modified International Prognostic Index (IPI), it identified subgroups of patients with different prognoses. At the British Columbia Cancer Agency, we have been using brief chemotherapy and involved-region irradiation for patients with limited-stage diffuse large-cell lymphoma since 1980. This analysis was conducted to examine the long-term results of this approach and to identify additional prognostic subgroups. We also sought to verify Miller’s modification of the IPI in an independent cohort of patients.
Using the British Columbia Cancer Agency lymphoma database, we found 4,723 patients aged 16 years or more, who were diagnosed with lymphoma in British Columbia between July 1, 1980, and December 31, 1997. One thousand six hundred eight-two of them had diffuse large-cell lymphoma in its various forms (diffuse mixed, diffuse large-cell, and immunoblastic lymphoma in the Working Formulation7 or diffuse large B-cell lymphoma and its variants, or peripheral T-cell lymphoma and its variants in the World Health Organization [WHO] classification8). Patients with nodal or extranodal stage IA or IIA disease who were sufficiently well to stage and treat were included in this analysis. Patients were excluded if they were known to be HIV positive, if their tumor exceeded 10 cm in largest diameter or could not be encompassed safely in a radiation field, if they presented with primary CNS disease, or if they presented with concomitant other life-threatening malignancies. This report describes the remaining 308 patients identified who were treated uniformly with three cycles of anthracycline-containing chemotherapy, followed by involved-region irradiation.
Pathology
Staging Procedures
Treatment Plan Three to 4 weeks after the last dose of chemotherapy, involved-region irradiation was administered. Before July 1996, the irradiated volume encompassed the entire lymph node region or regions of the initially involved sites, with no attempt to include adjacent uninvolved regions. After this date, the volume was reduced to include the full width of the region at the site of initial lymph node involvement and a margin of 5 cm proximally and distally (but not extending beyond the borders of a conventional mantle or inverted Y field). For those presenting with stage IE disease, only the extranodal site or organ was encompassed, without including the regional nodes. For example, the whole of Waldeyer’s Ring or the whole scrotal contents or the stomach was included if any part was involved. Soft tissue lesions, such as skin, were treated with a 3-cm margin. Radiation doses prescribed depended on the volumes of the fields. For smaller volumes, such as unilateral neck, 30 Gy in 10 fractions (during 2 weeks) was used; for larger volumes, 35 Gy in 20 fractions (during 4 weeks) was used. In 4% of cases, protocol violations occurred and 45 Gy in 25 fractions (during 5 weeks) was prescribed. The majority of patients were treated on a 4-MV linear accelerator. Patients with superficial sites were treated with the appropriate radiation modality (electrons 250 KV). Patients with initial sinus or epidural involvement received prophylactic intrathecal chemotherapy (methotrexate 12 mg alternating with cytarabine 50 mg administered twice weekly for a total of 3 weeks) after radiation.
Evaluation of Response and Follow-Up
Statistical Analysis
The main patient characteristics are listed in Table 1. Sixty percent of patients were male. The median age was 64 years, with a range of 15 to 87 years. Thirty-two percent of patients were 70 years of age or older. There was a predominance of stage I (61%) over stage II disease. Overall, 203 (66%) patients presented with an extranodal site of disease. One hundred and sixty-two of these had only a single site of extranodal disease, and the remaining 41 had locally extensive disease that involved two or more adjacent extranodal sites (ie, sinus, soft tissue, and bone). The most common sites of extranodal disease are shown in Fig 1. Abnormally high lactate dehydrogenase (LDH) was documented in 57 patients, but the median increase in LDH was only 1.15 times the upper limit of normal (range, 1.01 to 4.4).
Pathology The original Working Formulation histopathologic classification for all 308 patients is shown at the bottom in Table 1. The majority of patients were diagnosed with diffuse large-cell lymphoma. The revised REAL/WHO classification for the 182 patients who were reviewed as part of other ongoing studies is listed in Table 2. This subsequent review confirms that the large majority of patients included in this series had diffuse large B-cell lymphoma.
Treatment Response Treatment was delivered as planned in the majority of patients, although 32 did not receive any irradiation for the following reasons: 17 patients had all their primary disease resected at initial diagnosis (eight with gastric lymphoma, nine with small or large bowel lymphoma) and 15 patients were not irradiated for other reasons (four because of patient refusal, two who were too frail after chemotherapy, two who experienced progressive disease while on chemotherapy, and seven because of unknown reasons reflecting the referring oncologist’s preference). Fourteen patients received intrathecal chemotherapy (12 for sinus lymphoma and two for epidural involvement). Two hundred and ninety-nine patients (97%) achieved complete remission. Of the nine patients who did not, three had no response or disease progression during initial treatment, but one of these patients responded to high-dose chemotherapy and allogeneic bone marrow transplant; two achieved a partial response only but went on to develop progressive disease and death from lymphoma; one refused all initial treatment but was successfully treated at disease progression later with a more prolonged chemotherapy course; one was too frail to complete treatment; and two died during chemotherapy, one of a myocardial infarction and the other of infection.
Outcome One hundred and four patients have died, 43 from lymphoma, three from toxicity, and 58 from other causes. Of these 58 patients, 18 died of cardiovascular disease (seven with congestive heart failure, six with myocardial infarction, and five with other cardiac problems); 18 patients died of other malignancies (one colorectal, one liver, one pancreas, two esophagus, four lung, two bladder, two head and neck, three primary unknown, one prostate, and one sarcoma,); seven died of neurologic problems (six of these with stroke or hemorrhage), and 15 died of other causes. The overall survival for the whole cohort is shown in Fig 2. The median survival time was 13.8 years, with 80% of patients alive at 5 years and 63% alive at 10 years. The PFS rate at 5 years was 81% and 74% at 10 years (Fig 3). The disease-specific survival rate was 87% at 5 years and 82% at 10 years. Age at diagnosis had a significant impact on PFS. Patients 60 years or younger had PFS rates of 90% and 85% at 5 and 10 years, respectively, compared with 75% and 66% for those older than age 60. Both the PFS and overall survival for the 182 patients whose pathology was reviewed as part of other ongoing studies were identical to those for the entire cohort. In addition, there was no difference in PFS or overall survival when the data were analyzed by chemotherapy regimen. However, there was a modest imbalance of prognostic variables across the three chemotherapy regimens (Table 3). Using Cox regression analysis, we simultaneously compared the effect of treatment and prognostic factors on PFS and found no difference between ACOP-6 and the other two treatment groups.
Because the original IPI had been derived for patients with advanced-stage lymphoma,13 Miller proposed a modification for patients with limited-stage disease.6 Adverse risk factors were identified as: age more than 60 years, stage II disease, increased serum LDH, and a performance status of  2. We applied these criteria to our cohort and found that they conferred prognostic discrimination, especially when combined in three distinct groupings. This is listed in Table 4 and Figs 4 and 5. Three groups with quite distinct outcomes emerged. A moderate number of patients (74 patients, 24%) had an excellent prognosis, with a 10-year disease-specific survival rate of 95%. The largest group (203 patients, 66%) also had a good but somewhat less favorable outcome with a 10-year disease-specific survival rate of 81%. A third, smaller group (31 patients, 10%) had an inferior 10-year disease-specific survival rate of 61%.
Review and updating of histopathology was performed in 182 cases (Table 2). There were only 21 patients with T-cell or natural killer–cell neoplasms. There were 158 patients with diffuse large B-cell lymphoma. When these two cohorts were compared, there was a trend to poorer outcome, with a difference in 10-year PFS rates (T v B, 65% v 72%; P = .12), but any firm conclusions are unreliable as a result of the small number in the T/natural killer immunophenotype group.
Toxicity We did not prospectively measure left ventricular ejection function. As reported above, seven patients died of congestive heart failure a median of 97 months (range, 15 to 192 months) after treatment for their lymphoma. The median age of these patients at diagnosis was 74 years (range, 60 to 78 years). Although the majority of these patients had ischemic cardiomyopathy, the independent additional contribution of doxorubicin cardiotoxicity cannot be ascertained. We recorded 119 other malignancies, including both those seen before and after the diagnosis of lymphoma, in 87 patients. Fifty-seven malignancies were diagnosed in 46 patients at a median of 60 months (range, 0 to 391 months) before their diagnosis of large-cell lymphoma. Twenty-eight of these cancers were nonmelanoma skin cancer. The median age of these patients was 72 years (range, 32 to 85 years) at the time of diagnosis of lymphoma. Sixty-two malignancies were diagnosed in 51 patients a median of 51 months (range, 1 to 186 months) after the diagnosis of large-cell lymphoma. Eighteen of these cancers were nonmelanoma skin cancers. The median age of these patients was 67 years (range, 26 to 85 years). The types of these malignancies are listed in Table 5. Excluding nonmelanomatous skin cancers, a total of 44 malignancies subsequently developed in 39 treated patients (28 male, 11 female). We were able to ascertain the site of second malignancy and correlate it with the irradiation field in 40 of the 44 tumours. Six of these cancers developed within the previous irradiation field. Using British Columbia incidence rates for 1997, we would have expected to see 16 cancers (excluding nonmelanomatous skin cancer) develop within 51 months for individuals of the same age and sex distribution as in our sample. It is unclear whether the noted excess was a result of the lymphoma treatment, heightened posttreatment surveillance, or a cancer-prone phenotype in these patients. The fact that there was also an excess of other neoplasms diagnosed before the lymphoma (expected, 19; observed, 29) is most consistent with the last of these hypotheses.
Three cycles of chemotherapy followed by involved-region irradiation is effective treatment for the majority of patients with localized large-cell lymphoma. The patients in our experience had stage I or II disease, nodal or extranodal sites of disease, and a median age typical of the spectrum of patients with this condition. Although the irradiation was delivered by a small number of radiation oncologists working at three tertiary referral centers in British Columbia, the chemotherapy was administered by 34 medical oncologists, hematologists, or internists either at the British Columbia Cancer Agency or in the community, with no difference in outcome across the various treatment settings (data not shown). Therefore, we feel these results are applicable to the general population of patients with limited-stage diffuse large-cell lymphoma. Overall, our program of brief chemotherapy and irradiation was effective, especially for younger patients without negative prognostic factors. However, 25% of patients with one or two risk factors and 50% of those with three or four risk factors experienced disease progression or died from non-Hodgkin’s lymphoma within 10 years of their original diagnosis. These results are comparable to other series in the literature with smaller numbers of patients and shorter follow-up times.6,14-16 Our results seem superior to those with irradiation alone.17,18 The randomized Southwest Oncology Group trial reported by Miller et al6 showed that the addition of irradiation to a short course of chemotherapy, instead of prolonging the chemotherapy, was not only valuable in reducing the number of chemotherapy courses but also produced superior PFS and overall survival results. Our data confirmed that local control with irradiation was excellent (only 18% of patients experienced relapse and only 14% of these relapses occurred exclusively in the previously irradiated field). Because the majority of patients experienced relapse outside the radiated field, it is clear that further improvements in treatment will require more effective systemic therapy. Possible approaches to this problem could include additional chemotherapy or other newer agents for systemic consolidation (monoclonal antibodies, radioimmunoconjugates, and so on). These are all areas for future clinical research. We did identify one exceptional extranodal site that required a change in management. Twelve of 27 patients with testicular lymphoma experienced relapse after brief chemotherapy and involved-region irradiation. We now recommend a more prolonged course of chemotherapy for these patients before the administration of involved-region irradiation. In addition, four of these patients experienced relapse in the CNS. Because all of these relapses were in the parenchyma and not the leptomeninges, effective prophylactic treatment would need to consist of either high-dose systemic chemotherapy or whole-brain irradiation. Whether the toxicity of such additional treatment would be acceptable to attempt to prevent an event that only affected four of 27 patients is unclear. As opposed to many reports in the literature, the data from our study are mature. The median follow-up for living patients was 7.3 years. These results allow observations on the long-term outcome for these patients. Half of the relapses occurred before 2 years, but relapses continued to occur up to 15 years after diagnosis, emphasizing the necessity for ongoing follow-up and the pitfalls of drawing conclusions from studies with short follow-up. As in the general population of older people, other malignancies and cardiovascular disease remain significant causes of subsequent death. Forty-four subsequent cancers (excluding nonmelanomatous skin cancer) developed in 39 patients after treatment. This number seems to be moderately higher than we would have expected on the basis of crude population statistics, but whether this increase was a result of the treatment, an inherent risk as a result of prior diagnosis with non-Hodgkin’s lymphoma, or a result of more intensive surveillance cannot be ascertained. Our observation that these patients also had an excess of cancer preceding their lymphoma suggested that at least part of the excess after lymphoma treatment was because of a cancer-prone phenotype. Because our data were assembled during an 18-year period, not all the cases were classified according to the WHO criteria.8 However, the PFS, overall survival, and disease-specific survival rates of the 182 patients who were reclassified as part of other ongoing studies were identical to those of the overall cohort of patients, which strongly suggested that the phenotypic and subtype mixture remained the same during our entire study period. Three different chemotherapeutic regimens were used during this 18-year period. These were CHOP or close variations. All contained cyclophosphamide, doxorubicin, vincristine, and prednisone. These modest variations were unlikely to have an overall impact on patient outcome. In fact, there was no difference in PFS or overall survival when these outcomes were analyzed according to chemotherapy treatment protocol. Nevertheless, there was a modest difference in distribution of prognostic variables across these three eras, with the group administered ACOP-6 having significantly fewer poor prognostic risk factors than the earlier two cohorts. Although all the patients were staged in a similar fashion, it is possible that stage migration may have occurred as a result of the availability of higher-resolution CT scanners in the last decade. This drift in distribution of prognostic variables highlights the dangers of historical comparisons, even in uniformly assembled cohorts. Given all the available data, including the Southwest Oncology Group randomized controlled trial,6 we would recommend three cycles of CHOP followed by involved-region irradiation as the regimen of choice. Our mature data demonstrate that a program of three cycles of doxorubicin-based chemotherapy and involved-region irradiation is a successful approach for the majority of patients with limited-stage diffuse large-cell lymphoma. Special groups of patients who have an inferior PFS and overall survival can be identified. Patients with testicular presentation or those with three or four adverse factors using the modified version of the IPI proposed by Miller should be given alternative treatments, preferably in the setting of clinical trials.
We thank J. Archer, MD, R. Beck, MD, W. Boldt, MD, C. Bryce, MD, B. Czerkawski, MD, N. Denegri, MD, K. Donaldson, MD, P. Galbraith, MD, K. Gelmon, MD, J. Holmes, MD, P. Malpass, MD, H. Manson, MD, T. McMurtry, MD, B. Melosky, MD, K. Murphy, MD, M. Noble, MD, L. Scotland, MD, T. Sparling, MD, D. Stuart, MD, A. Tolcher, MD, L. Vickars, MD, K. Wilson, MD, and J. Yun, MD, for referring their patients; D. Gibeault for secretarial support; and Yulia D’Yachkova for statistical support.
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Miller TP, Dahlberg S, Cassady JR, et al: Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin’s lymphoma. N Engl J Med 339: 21-26, 1998 7. National Cancer Institute–sponsored study of classifications of non-Hodgkin’s lymphomas: Summary and description of a working formulation for clinical usage—The Non-Hodgkin’s Lymphoma Pathologic Classification Project. Cancer 49: 2112-2135, 1982[CrossRef][Medline]
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Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84: 1361-1392, 1994
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Carbone PP, Kaplan HS, Musshoff K, et al: Report of the Committee on Hodgkin’s Disease Staging Classification. Cancer Res 31: 1860-1861, 1971 11. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 12. Peto R, Peto J: Asymptotically efficient rank invariant test procedures. J R Stat Soc 135: 185-207, 1972
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A predictive model for aggressive non-Hodgkin’s lymphoma: The International Non-Hodgkin’s Lymphoma Prognostic Factors Project. N Engl J Med 329: 987-994, 1993 14. van der Maazen RW, Noordijk EM, Thomas J, et al: Combined modality treatment is the treatment of choice for stage I/IE intermediate and high grade non-Hodgkin’s lymphomas. Radiother Oncol 49: 1-7, 1998[CrossRef][Medline]
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Velasquez WS, Fuller LM, Jagannath S, et al: Stages I and II diffuse large-cell lymphomas: Prognostic factors and long-term results with CHOP-bleo and radiotherapy. Blood 77: 942-947, 1991 16. Tondini C, Zanini M, Lombardi F, et al: Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I or II histologically aggressive non-Hodgkin’s lymphomas. J Clin Oncol 11: 720-725, 1993[Abstract] 17. Vaughan Hudson B, Vaughan Hudson G, MacLennan KA, et al: Clinical stage 1 non-Hodgkin’s lymphoma: Long-term follow-up of patients treated by the British National Lymphoma Investigation with radiotherapy alone as initial therapy. Br J Cancer 69: 1088-1093, 1994[Medline] 18. Jeffery GM, Mead GM, Whitehouse JM, et al: Involved field rad-iotherapy or chemotherapy in the management of stage I nodal intermediate grade non-Hodgkin’s lymphoma. Br J Cancer 64: 933-937, 1991[Medline] Submitted March 23, 2001; accepted July 25, 2001.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
