Dose-response analysis for radiotherapy delivered to patients with intermediate-grade and large-cell immunoblastic lymphomas that have completely responded to CHOP-based induction chemotherapy

Int. J. Radiation Oncology Biol. Phys., Vol. 49, No. 1, pp. 17–22, 2001 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved 0360-3016/01/$–see front matter

PII S0360-3016(00)01383-3

CLINICAL INVESTIGATION

Lymphoma

DOSE-RESPONSE ANALYSIS FOR RADIOTHERAPY DELIVERED TO PATIENTS WITH INTERMEDIATE-GRADE AND LARGE-CELL IMMUNOBLASTIC LYMPHOMAS THAT HAVE COMPLETELY RESPONDED TO CHOP-BASED INDUCTION CHEMOTHERAPY RICHARD B. WILDER,* M.D., SUSAN L. TUCKER, PH.D.,† CHUL S. HA, M.D.,* MARIA A. RODRIGUEZ, M.D.,‡ MARK A. HESS, B.B.A.,‡ FERNANDO F. CABANILLAS, M.D.,‡ AND JAMES D. COX, M.D.* Departments of *Radiation Oncology, †Biomathematics, and ‡Lymphoma/Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, TX Purpose: To test the hypothesis that prechemotherapy tumor size affects the dose of radiation that should be delivered to intermediate-grade and large-cell immunoblastic lymphomas that have completely responded to cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP)-based induction chemotherapy. Methods and Materials: From September 1988 through December 1996, 294 patients with newly diagnosed, Stage I–IV, intermediate-grade or large-cell immunoblastic lymphomas were enrolled on 2 prospective protocols at the M. D. Anderson Cancer Center. Treatment consisted of CHOP-based chemotherapy with or without involved field radiotherapy. One hundred seventy-two patients, with 178 nodal sites and 87 nonbony, extranodal sites of disease achieved a complete response to 2– 6 cycles of chemotherapy and underwent involved field radiotherapy. Total radiation doses ranged from 30.0 to 50.4 Gy (mean ⴞ standard deviation: 39.7 ⴞ 2.5 Gy) over 22– 49 days using a daily fraction size of 1.3–2.3 Gy. Because various fraction sizes were delivered, the linear-quadratic model was used to convert total radiation doses to biologically equivalent doses given at 1.8 Gy per fraction (D1.8). An ␣/␤ ratio of 10 Gy was used for the lymphomas, resulting in D1.8 ranging from 29.1 to 50.8 Gy. Regression tree analysis was performed on nodal sites of disease to determine which of the following factors were predictive of local control: age, tumor size, D1.8, total radiation dose, and duration of radiotherapy. Based on the results of the regression tree analysis, Kaplan-Meier analysis was used to determine the probability of local control per site as a function of tumor size and D1.8. Regression tree analysis was also performed on patients with nonbony disease who received D1.8 ⴝ 29.1–39.1 Gy to determine if small lymphomas could be locally controlled with relatively low doses of radiation. The log-rank test was used to compare local control curves. Results: The median length of follow-up among survivors was 63 months. Regression tree analysis of nodal sites identified 3 distinct groups: (a) lymphomas < 10 cm and D1.8 ⴝ 29.1–39.1 Gy; (b) lymphomas < 10 cm and D1.8 ⴝ 39.2–50.8 Gy; and (c) lymphomas > 10 cm. For nonbony lymphomas that measured < 3.5 cm, low doses of radiation resulted in excellent local control (5-year rates: 96% vs. 97% for D1.8 ⴝ 29.1–39.1 Gy vs. D1.8 ⴝ 39.2–50.8 Gy; p ⴝ 0.610). For 3.5–10.0 cm lymphomas, higher doses of radiation resulted in better local control (5-year rates: 40% versus 98% for D1.8 ⴝ 29.1–39.1 Gy versus D1.8 ⴝ 39.2–50.8 Gy, p < 0.0001). A narrow dose range (D1.8 ⴝ 39.2– 40.7 Gy) was delivered to the 8 lymphomas measuring > 10 cm that completely responded to 6 cycles of chemotherapy, resulting in a 5-year local control rate of only 70%. There was no difference in local control for nodal versus nonbony, extranodal sites of disease. Conclusion: D1.8 ranging from 29.1 to 39.1 Gy yielded excellent local control for nonbony lymphomas measuring < 3.5 cm that had completely responded to a median of 3 cycles of CHOP-based chemotherapy. D1.8 ranging from 39.2 to 50.8 Gy yielded excellent local control for nonbony lymphomas measuring 3.5–10.0 cm that completely responded to either 3 or 6 cycles of chemotherapy. For nonbony lymphomas measuring > 10 cm that completely responded to 6 cycles of chemotherapy, D1.8 ranging from 39.2 to 40.7 Gy yielded suboptimal local control, suggesting that higher doses of radiation are indicated. © 2001 Elsevier Science Inc. Lymphoma, Radiotherapy, Dose-response analysis.

Reprint requests to: Richard B. Wilder, M.D., Department of Radiation Oncology, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 97, Houston, TX 77030-4095. Tel: (713) 792-3400; Fax: (713) 792-3642; E-mail: [email protected]

This work was supported by National Cancer Institute Grant CA 6294. Accepted for publication 9 August 2000. 17

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INTRODUCTION Before the 1980s, Stage I–II, Working Formulation (1) intermediate-grade (follicular large cell, diffuse small cleaved cell, diffuse mixed small and large cell, and diffuse large cell) and large-cell immunoblastic lymphomas were mainly treated with radiotherapy alone. Between 1979 and 1987, 4 randomized trials (2–5) demonstrated an improvement in 5-year, disease-free survival with the addition of cyclophosphamide, vincristine, and prednisone chemotherapy. Doxorubicin was later found to be an active agent (6, 7), giving rise to the current practice of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy followed by involved field radiotherapy (8, 9). Most of the dose-response analyses of lymphoma in the literature were performed in the era when patients were treated with radiotherapy alone (10 –16). In 2 of these analyses (11, 15), no dose-response relationship was detected, most likely because tumor size was not taken into consideration. The Princess Margaret group found that patients aged ⱖ 60 years benefited from higher doses of radiation (14, 16), whereas other groups did not observe an association between age and local control (10, 12, 13). Lymphomas arising in the brain or bones are more radioresistant (10, 12). In the above articles, total doses ranging from 30 to 55 Gy were typically recommended for gross disease. However, after a complete response to chemotherapy has been achieved, lower doses may be adequate (17). Stryker et al. (18) reported that the mean dose that produces local control in patients treated with radiotherapy alone is 48 Gy versus 37 Gy in patients treated with chemotherapy and radiotherapy. Kamath et al. (19) at the University of Florida have reported that 30 Gy is sufficient for lymphomas ⱕ 6 cm that completely respond to induction chemotherapy. For lymphomas that measure ⱖ 10 cm or only partially respond to induction chemotherapy, radiotherapy doses ⱖ 40 Gy appear to be necessary (20, 21). Based on the literature cited above (17–20), the authors wished to test the hypothesis that the prechemotherapy size of intermediate-grade and large-cell immunoblastic lymphomas affects the dose of radiation that should be delivered after a complete response has been achieved to 2– 6 cycles of CHOP-based chemotherapy. METHODS AND MATERIALS From September 1988 through December 1996, 294 patients with newly diagnosed, clinical Stage I–IV, intermediate-grade and large-cell immunoblastic lymphomas were enrolled on 2 prospective protocols (DM 88-087 and DM 93-003) at The University of Texas M. D. Anderson Cancer Center (UTMDACC). Patients on protocol DM 88-087 had no mediastinal adenopathy on chest X-ray, ⬍ 3 extranodal sites of disease, a normal serum lactic dehydrogenase level and a ␤-2 microglobulin level ⬍ 1.5 times normal, and patients on protocol DM 99-003 had a UTMDACC tumor

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Table 1. Patient characteristics No. of patients Total no. of patients No. of irradiated sites of disease Nodal Non-bony, extranodal Age, years Median Range Male Ann Arbor clinical stage I II III IV B symptoms Elevated lactate dehydrogenase level Zubrod performance score ⱖ 2 Pre-chemotherapy tumor size ⬎ 10 cm Waldeyer’s ring involvement Mediastinal involvement Age-adjusted international prognostic index 0 1 2 ⬎2 Cycles of chemotherapy 2 3 4–5 6

172 265 178 87 55 16–87 83 (48%) 99 54 11 8 14 19 1 8 25 14

(58%) (31%) (6%) (5%) (8%) (11%) (⬍ 1%) (5%) (15%) (8%)

92 64 13 3

(53%) (37%) (8%) (2%)

1 74 6 91

(⬍ 1%) (43%) (34%) (53%)

score ⬍ 3 (22). The slightly different eligibility criteria for these 2 protocols represent an evolution of the prognostic system in use at M. D. Anderson. Patients with primary central nervous system lymphomas were not eligible. None of the patients had previously undergone treatment for lymphoma. Tissue biopsies were reviewed in every case by pathologists at M. D. Anderson, and diagnoses were reported in terms of the Working Formulation (1). Informed consent was obtained from all patients in accordance with institutional review board guidelines. Patient characteristics are summarized in Table 1. All of the hospital charts and radiotherapy records were reviewed by a radiation oncologist. Waldeyer’s ring was coded as an extranodal site (23) and the spleen was coded as a nodal site (24). Tumor sizes were measured after biopsy. Maximum prechemotherapy tumor sizes based on computed tomography (CT) scans and physical examination ranged from 0 to 17 cm (median 2.5). Because an excisional biopsy was performed in a number of cases to make the diagnosis, the size of a lymphoma was sometimes 0 cm at the start of chemotherapy. Treatment consisted of CHOP-based chemotherapy with or without involved field radiotherapy. CHOP-based chemotherapy doses for each 3-week cycle were 750 mg/m2 cyclophosphamide i.v. on day 1, 50 mg/m2 doxorubicin i.v. by continuous infusion on days 1 and 2, 1.4 mg/m2 vincristine i.v. on day 1, and 100 mg prednisone orally on days 1–5. Two to 6 cycles of chemotherapy were delivered

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Table 2. Local control as a function of pre-chemotherapy tumor size and chemoradiation delivered No. of chemotherapy cycles (%) Pre-chemotherapy tumor size

2

3

4

5

6

Biologically effective dose of radiation in Gy (D1.8)

5-Year local control rate (%) per site

No. of involved sites

⬍ 3.5 cm ⬍ 3.5 cm 3.5–10.0 cm 3.5–10.0 cm ⬎ 10.0 cm ⬎ 10.0 cm

8 0 0 0 0 0

46 59 33 17 0 0

0 4 0 0 0 0

8 1 0 0 0 0

38 36 67 83 0 100

29.1–39.1 39.2–50.8 29.1–39.1 39.2–50.8 29.1–39.1 39.2–40.7

96 97 40 98 Not applicable 70

30 158 6 63 0 8

before radiotherapy (Table 2). The number of cycles of chemotherapy depended on the stage of disease, size of the lymphoma, and response to chemotherapy. The decision regarding whether to irradiate a particular site was left to the discretion of the treating physician. Because the main endpoint of this study was local control, all stages of disease were analyzed, as in other studies (18, 20). One hundred seventy-two patients, with 178 nodal sites and 87 nonbony, extranodal sites of disease, achieved a complete response to chemotherapy and underwent involved field radiotherapy beginning 3– 4 weeks later, i.e., 265 sites of disease were treated with chemotherapy and involved field radiotherapy. A complete response was defined as no evidence of lymphoma based on physical examination, blood work, and CT scans in accordance with international working group guidelines (25). Because earlier studies had indicated that bony lymphomas are more radioresistant (10, 12), these sites were treated to higher radiotherapy doses, have already been reported (26) and are consequently excluded from this analysis. The minimum dose delivered to the region of interest was recorded whenever this information was available. Otherwise, the dose prescribed to isocenter was recorded. Total radiation doses ranged from 30.0 to 50.4 Gy (mean ⫾ standard deviation: 39.7 ⫾ 2.5 Gy) over 22– 49 days using a daily fraction size of 1.3–2.3 Gy. Because various fraction sizes were delivered, the following linearquadratic model (27) was used to convert total radiation doses to biologically equivalent doses given at 1.8 Gy per fraction (D1.8): D1.8 (Gy) ⫽ nd(1 ⫹ d/(␣/␤))/(1 ⫹ 1.8/(␣/␤))

(Eq. 1)

where n represents the number of fractions administered and d represents the dose (Gy) delivered per fraction. An ␣/␤ ratio of 10 Gy was used for the lymphomas (27), resulting in D1.8 ranging from 29.1 to 50.8 Gy. In this study, local control was defined as the absence of disease in one irradiated site rather than in all of the presenting sites of a particular patient, i.e., local control was analyzed by site rather than by patient. This approach was taken because not all sites of disease in a given patient were treated with the same dose of radiotherapy. If a patient developed recurrent lymphoma locally and distantly as the first event, the local recurrence was coded as a radiotherapy failure. Two patients died shortly after they were diagnosed

with recurrent lymphoma. Nine patients failed in one irradiated site and three patients failed in two irradiated sites. In the ten cases where salvage chemotherapy was administered, patients continued to be followed with regard to local control. Nonparametric regression tree analysis (28) was performed on nodal sites of disease to determine which of the following factors predicted for local control: age, tumor size, D1.8, total radiation dose, and duration of radiotherapy. Regression tree analysis was carried out on the null martingale residuals from the data concerning time to local failure. Based on the results of the regression tree analysis, Kaplan-Meier analysis (29) was used to determine the probability of local control per site as a function of tumor size and D1.8. Regression tree analysis was also performed on patients with nodal and nonbony, extranodal sites of disease who received D1.8 ⫽ 29.1–39.1 Gy to determine if small lymphomas could be locally controlled with low doses of radiation. Local control curves were compared using the log-rank test (30). The log-rank test was also used to compare local control for: (a) nodal versus nonbony, extranodal sites of disease; and (b) intermediate-grade versus large-cell immunoblastic lymphomas. RESULTS The median length of follow-up for the 154 surviving patients was 63 months. All 15 local recurrences were in-field as opposed to marginal. The time to local recurrence ranged from 8 to 77 months (median, 23 months). Local control was similar for intermediate-grade and large-cell immunoblastic lymphomas (5-year rates: 88% and 92%, respectively, p ⫽ 0.667). In general, radiotherapy was tolerated reasonably well, with the main toxicity being moderate myelosuppression in accordance with a previous report from M. D. Anderson (31). There were no treatment-related deaths. Nodal sites Regression tree analysis of nodal sites identified the following three groups: (a) lymphomas ⱕ 10 cm and D1.8 ⫽ 29.1–39.1 Gy; (b) lymphomas ⱕ 10 cm and D1.8 ⫽ 39.2– 50.8 Gy; and (c) lymphomas ⬎ 10 cm. Patients’ ages, total radiation dose without regard to fraction size, and duration of radiotherapy were not selected by regression tree analysis.

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Nonbony, extranodal sites There was no significant difference in local control for nodal versus nonbony, extranodal sites, taking tumor size and D1.8 into consideration. Nodal and nonbony, extranodal sites combined Five-year local control rates as a function of prechemotherapy tumor size, number of cycles of chemotherapy delivered, and D1.8 are summarized in Table 2. For ⬍ 3.5-cm lymphomas, relatively low doses of radiation resulted in excellent local control following the delivery of a median of 3 cycles of chemotherapy. Consequently, local control was similar for D1.8 ⫽ 29.1–39.1 Gy versus D1.8 ⫽ 39.2–50.8 Gy (5-year rates: 96% vs. 97%, respectively; p ⫽ 0.610). Among the ⬍ 3.5-cm lymphomas that received D1.8 ⫽ 29.1–39.1 Gy, there were 6 sites of disease that measured 0 cm and 24 sites that measured 0.1–3.4 cm. The 5-year local control rates for these 2 subgroups were 100% and 95%, respectively (p ⫽ 0.507). For sites of disease that received D1.8 ⫽ 29.1–39.1 Gy, local control was better for ⬍ 3.5-cm lymphomas than for 3.5–10.0-cm lymphomas (5-year rates: 96% vs. 40%, respectively; p ⫽ 0.0008). For 3.5–10.0 cm lymphomas, higher doses of radiation significantly improved local control (p ⬍ 0.0001). The 5-year local control rates for D1.8 ⫽ 29.1–39.1 Gy and D1.8 ⫽ 39.2–50.8 Gy were 40% and 98%, respectively. Because only eight lymphomas measured ⬎ 10 cm at the start of chemoradiation, and the range of radiotherapy doses delivered was narrow (D1.8 ⫽ 39.2– 40.7 Gy), we could not identify a dose-response relationship in this subgroup. DISCUSSION For ⬍ 3.5-cm nodal and nonbony, extranodal lymphomas that completely responded to a median of 3 cycles of CHOP-based induction chemotherapy, D1.8 ⫽ 29.1–39.1 Gy produced a 5-year local control of 96% (Table 2). D1.8 ⫽ 39.2–50.8 Gy resulted in a similar 5-year local control rate of 97% in ⬍ 3.5-cm nodal and nonbony, extranodal lymphomas. Similarly, Kamath et al. (19) at the University of Florida reported that 30 Gy is adequate for ⱕ 6 cm intermediate- and high-grade lymphomas that have completely responded to induction chemotherapy (72% of the patients at the University of Florida received ⱖ 4 cycles of chemotherapy). Mirza et al. (17) also recommend 30 Gy for lymphomas that completely respond to induction chemotherapy, which was the dose used in the ECOG study (9). Both the SWOG (8) and ECOG (9) randomized trials demonstrated that combined modality therapy is superior to chemotherapy alone. Consequently, current practice at M. D. Anderson consists of the delivery of 3 cycles of CHOP chemotherapy followed by radiotherapy to 30.0 – 30.6 Gy in 15–17 fractions over 3–3.5 weeks in patients with nonbony, Ann Arbor clinical Stage I–II intermediategrade or large-cell immunoblastic lymphomas that measure ⬍ 3.5 cm at the start of chemotherapy.

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For 3.5–10.0-cm lymphomas that completely responded to 3 or 6 cycles of CHOP-based chemotherapy, higher doses of radiation significantly improved local control (p ⬍ 0.0001; Table 2). D1.8 ⫽ 39.2–50.8 Gy produced a 5-year local control rate of 98%. In contrast, D1.8 ⫽ 29.1–39.1 Gy resulted in a 5-year local control rate of only 40%. Hence, current practice at M. D. Anderson consists of the delivery of either 3 or 6 cycles of CHOP chemotherapy followed by radiotherapy to a total dose of 39.6 Gy in 22 fractions over 4.4 weeks in patients with lymphomas measuring 3.5–10.0 cm at the start of chemotherapy. If patients have Stage III–IV disease, ⱖ 7 cm lymphomas or lymphomas that are still responding after 3 cycles of CHOP chemotherapy, 6 rather than 3 cycles of induction chemotherapy are administered. Stryker et al. (18) recommended 37 Gy for patients treated with chemotherapy and radiotherapy. In addition, most radiation oncologists who are regarded as experts in the management of lymphoma recommend comparable radiotherapy doses (32). For the 8 lymphomas measuring ⬎ 10 cm that completely responded to 6 cycles of CHOP-based chemotherapy, D1.8 ⫽ 39.2– 40.7 Gy resulted in a 5-year local control rate of only 70%. Consequently, for ⬎ 10 cm lymphomas, we now recommend 45 Gy in 25 fractions over 5 weeks, as opposed to lower radiotherapy doses following the delivery of 6 cycles of CHOP chemotherapy. A previous study at M. D. Anderson involving different patients found that, after a complete response to chemotherapy had been achieved, doses ⱖ 40 Gy resulted in better local control than lower doses for ⱖ 10-cm lymphomas (20). Similarly, Kamath et al. (19) recommend 40 – 45 Gy for ⬎ 6-cm intermediate- and high-grade lymphomas that completely respond to induction chemotherapy. Ferreri et al. (33) recommend 36 – 45 Gy for ⱖ 6-cm diffuse large B-cell lymphomas that completely respond to induction chemotherapy. Because a complete response to chemotherapy represents 5– 8.5 logs of tumor cell killing (34), there may be greater residual, subclinical tumor cell burden at the start of radiotherapy in patients with bulky disease that completely responds to chemotherapy (35). In support of the hypothesis that ⬎ 10-cm lymphomas need more aggressive treatment than 6 cycles of CHOP chemotherapy followed by involved field radiotherapy to D1.8 ⫽ 39.2– 40.7 Gy, some groups have suggested that surgical debulking before chemoradiation may be beneficial (36, 37). In accordance with other studies (18 –20), nodal and nonbony, extranodal sites of disease exhibited similar radiosensitivities. Patients with intermediate-grade and largecell immunoblastic lymphomas had similar outcomes (38 – 40). Also in accordance with other studies (12, 19), the age of patients and duration of radiotherapy were not predictive of local control. Weaknesses of this study include that it is retrospective, the minimum dose delivered to lymphomas was not always specified in the treatment records, there is a degree of subjectivity to the assessment of tumor sizes,

Dose-response analysis for lymphoma

there was a small sample size in certain subgroups, there were a small number of events, and results with regression tree analysis may vary with small changes in the data. Nevertheless, this is the largest dose-response analysis in the literature in the era of chemoradiation for

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intermediate-grade and large-cell immunoblastic lymphomas. We hope that future clinical trials of intermediate- and large-cell immunoblastic lymphomas will prospectively address radiotherapy doses in terms of tumor size at the start of chemoradiation.

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