- Email: [email protected]
Efficacy of Palliative Low-Dose Involved-Field Radiation Therapy in Advanced Lymphoma: A Phase II Study
Original Contribution Efficacy of Palliative Low-Dose Involved-Field Radiation Therapy in Advanced Lymphoma: A Phase II Study Vedang Murthy,1,2* Karen Thomas,3 Kerwyn Foo,1 David Cunningham,4 Bernadette Johnson,1,2 Andrew Norman,3 Alan Horwich1,2
Abstract Purpose: To confirm the efficacy of low-dose involved-field radiation therapy (LD-IFRT) as palliative treatment in patients symptomatic from advanced lymphoma. Patients and Methods: A total of 36 patients (47 sites), received 4 Gy in 2 fractions to the lymphoma with a 1.5-2–cm margin. Pathology subtypes included 29 (62%) sites with indolent lymphoma and 18 (36%) sites with aggressive lymphoma histology. Bulky disease was seen in 22 (48%) sites and, of these, 6 sites had disease > 10 cm. A median of 3 previous chemotherapy regimens (range, 0 to 9 regimens) preceded LD-IFRT. The primary endpoint of the study was in-field lymphoma control. Patients completed the European Organization for the Research and Treatment of Cancer QLQ-C30 quality of life (QOL) questionnaire before RT and at 3-4 weeks after treatment. Results: The overall response rate (RR) at 1-3 months after the RT was 75%. A complete remission (CR) was observed in 13 patients (36%) lasting up to a maximum of 31.3 months and ongoing at analysis. A partial remission (PR) was achieved in 14 patients (39%) lasting up to 10 months. The response rate for non–diffuse large B-cell lymphoma (DLBCL) sites was 86%, while it was 50% for sites with DLBCL histology. Median time to local progression for the entire group was 15 months. There was no statistical difference between the QOL before and after LD-IFRT. Conclusion: LD-IFRT is an effective and easy treatment for patients with advanced lymphoma that can be repeated at previously irradiated sites, a particularly useful attribute because of the relapsing nature, especially of advanced follicular subtypes.
Clinical Lymphoma & Myeloma, Vol. 8, No. 4, 241-245, 2008; DOI: 10.3816/CLM.2008.n.032 Keywords: Diffuse large B-cell lymphoma, Non-Hodgkin lymphoma, Quality of life
Introduction The majority of patients with low-grade lymphomas present with advanced disease and have a long survival; the median survival for patients with advanced follicular lymphoma (FL) is about 9 years.1 The natural history is characterized by multiple relapses after treatment, with the disease-free interval between subsequent relapses tending to shorten over time. Although FL is both chemotherapy and radiation sensitive, patients with advanced indolent lymphomas are considered incurable. Radiation has been used effectively as a method of palliation in these patients in the form of wide-field irradiation (total body, hemi-body), when low radiation doses have been used, or 1Academic
Unit of Radiotherapy and Oncology, The Royal Marsden NHS Foundation Trust, Surrey, UK 2The Institute of Cancer Research, Surrey, UK 3Department of Computing and Information 4Department of Medical Oncology The Royal Marsden NHS Foundation Trust, Surrey, UK *Currently at Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India Submitted: Feb 29, 2008 Revised: Apr 23, 2008; Accepted: May 6, 2008 Address for correspondence: Alan Horwich, The Academic Unit of Radiotherapy and Oncology, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, Surrey, SM2 5PT, United Kingdom Fax: 44-208-643-8809; e-mail: [email protected]
in the form of localized radiation therapy (RT), when conventional doses of 20-40 Gy have produced excellent local control.2 There is recent indication that low-dose, involved-field RT (LDIFRT) might be valuable in FL and achieve overall response rates (ORRs) in the region of 85%.3-5 In the largest study of 109 patients from The Netherlands, the ORR was 92%, with complete remission (CR) in 61% of the patients. The median time to local progression (TLP) was 25 months.3 Another study in nonfollicular indolent lymphomas and aggressive histologies showed that the ORR was 87%, with CR in 34 patients (48%) and a partial remission (PR) in 28 (39%) of the 71 patients. The median TLP was 22 months.6 To further assess these findings, we initiated a prospective phase II study of palliative LD-IFRT for patients with disseminated lymphoma to evaluate its efficacy and toxicity and to assess if it improved quality of life (QOL). The Royal Marsden Hospital Ethics Committee approved the trial.
Patients and Methods Eligibility From July 2003 to June 2006, we enrolled 37 patients with advanced, histologically proven lymphoma. Patients were eligible if they had symptomatic, recurrent disease at any site and were referred for palliative RT. Patients on concurrent corticosteroids or
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Lymphoma & Myeloma August 2008
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241
Low-Dose Involved-Field Radiation Therapy for Advanced Lymphoma Table 1 Patient and Tumor Characteristics Characteristic
Value
Total Number of Analyzable Patients
36
Total Number of Analyzable Sites
47
Median Age at Treatment, Years (Range) Sex (Male:Female)
65.1 (33.8-84.5) 17:19
Histologic Type by Site (Patient) Indolent Follicular lymphoma Small lymphocytic lymphoma Marginal-zone NHL/ MALT Aggressive
29 Sites (62%) 19 (16%) 5 (5%) 5 (2%) 18 Sites (36%)
Diffuse large B-cell lymphoma
8 (7%)
Mantle cell lymphoma
4 (2%)
Cutaneous T-cell lymphoma
6 (4%)
Median Number of Previous Systemic Treatment Regimen Median Size of Lymph Node Mass at Index Site (cm)
4.4 (Range, 2-15)
<5
24
5.1-10
16
> 10
6
Unknown
1
chemotherapy were excluded. They were also excluded if there was clinical or radiologic suspicion of impending vital organ compromise, eg, spinal cord compression. Eligible patients did not have the index site treated with RT previously. All patients were aged > 18 years and consented for the trial in writing.
Staging Before treatment, the patients underwent detailed physical examination to assess the extent of disease. Patients with disease in accessible sites were evaluated clinically, and the lesion was measured in 3 dimensions and recorded. The rest of the patients underwent cross-sectional imaging before radiation therapy and during subsequent follow-up. A total of 36 patients and 47 sites were assessable for analysis. Pathology subtypes are shown in Table 1. Follicular lymphoma, small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL)/ mucosa-associated lymphoid tissue were classified for study purpose as indolent lymphoma, whereas diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and cutaneous T-cell lymphoma were classified as aggressive lymphoma histology. Data were available on all except 1 site regarding the size of the treated mass. Bulky disease was defined as > 5 cm in maximum diameter. Bulky disease was observed in 22 (48%) sites, and of these, 6 sites had disease > 10 cm.
Radiation Therapy Technique All patients received a dose of 4 Gy in 2 fractions with a 48-hour gap between the 2 treatments with 6-15 MV photons.
•
Follow-up and Assessment Patients were seen at 3-4 weeks after the end of RT to assess response and toxicity. They also underwent imaging at this point if they had imaging at baseline for disease assessment. They were then seen 3 times monthly on follow-up until an endpoint of failure or a censoring event occurred. Response assessment was based on the standard definitions of the World Health Organization using CR, PR, stable disease (SD), and progressive disease (PD) as response assessment criteria.7
3 (Range, 0-9)
Abbreviations: MALT = mucosa-associated lymphoid tissue; NHL = non-Hodgkin lymphoma
242
The target volume consisted of the involved nodal mass lesion with a 1.5-2.0 cm margin. Adjacent nodal regions were not treated prophylactically. Only 1 (index) site was treated at any given point in a particular patient. Patients were prescribed antiemetics (non corticosteroid) and antimotility agents prophylactically for large abdominal and pelvic fields. Sites treated with electrons were prescribed to the 90% isodose, and the total dose prescribed was 4.2 Gy in 2 fractions. Tissue-equivalent bolus was used for superficial lesions as appropriate.
Clinical Lymphoma & Myeloma August 2008
Quality of Life The European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire is a cancer-specific, self-administered, structured questionnaire designed for use in clinical trials8,9 that contains 30 questions, 24 of which form 9 multi-item scales representing various aspects—or dimensions—of health-related QOL: 1 global scale, 5 functional scales (physical, role, emotional, cognitive, and social), and 3 symptom scales (fatigue, pain, and nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Questions are combined in scales according to predefined rules. All patients were asked to complete the EORTC QLQ-C30 QOL questionnaire at baseline, ie, before RT and again at 3-4 weeks after the second fraction of RT. This time interval was chosen because administering the second QOL later would increase the chance of its being influenced by other treatment that the patient receives.
Preradiation Therapy Treatment As expected from the natural history of advanced lymphoma, most patients were pretreated with multiple lines of chemotherapy. The median number of previous chemotherapy regimens was 3 (range, 0-9 regimens). None of the patients received concurrent chemotherapy with RT.
Statistical Methods A Simon’s 2-stage design was planned. The study, with 44 patients, would have a 90% power with a 0.05 level of significance to detect a minimum 65% response rate and an expected response of 85% with the LD-IFRT treatment. The first 15 patients had to have an adequate response in ≥ 11 patients to proceed to the completion of the study. The primary endpoint of the study was in-field lymphoma control. Patients with SD or PD at the index site were designated to have treatment failures. Also, patients with recurrence
Vedang Murthy et al Figure 1 Pre– and Post–Radiation Therapy Comparison of Periorbital Cutaneous T-Cell Lymphoma
Figure 2 Time to Local Progression by Histologic Grade
A
Locally Controlled (%)
100
Low Grade (n = 23) High Grade (n = 13) All Patients (N = 36)
80 60 40 20
0
12
24
36
Time (Months) At Risk (N = 36)
15
7
3
2
Local Progression 6
2
1
0
Censored
5
3
1
13
Results Response Rates
B
(A) Pre–radiation therapy; (B) Post–radiation therapy. This 75-year-old man was treated with LD-IFRT (4 Gy in 2 fractions) with 300 kV x-rays. He was chemotherapy naive.
of the mass at the index site, additional RT at the index site, or chemotherapy for inadequate local response were considered to have local failures. Patients who died or had systemic treatment including chemotherapy, corticosteroids, or experimental agents for disease progression at a nonindex site or were unavailable for follow-up were censored. Time to local progression was calculated by the Kaplan-Meier method. Time to local progression was calculated from the date of the second fraction of RT. Four patients did not have their response assessable at 1-3 months but were still included in the intent-to-treat analysis. The study was closed after a competing multicenter, randomized trial opened.
The overall response rate (RR; ORR) at 1-3 months after the RT was 75%. A CR was observed in 13 patients (36%) lasting up to a maximum of 134 weeks and ongoing at the time of analysis. A PR was achieved in 14 patients (39%) lasting up to a maximum of 43 weeks. Stable disease was maintained in 3 patients (8%). Progressive disease was observed after LD-IFRT in 2 patients. Among the patients with indolent histology, CR was achieved in 44%, and PR was observed in 39% at 1-3 months after treatment (ORR, 83%; 95% CI, 67%-98%). The figures for aggressive histology were 23% and 39%, respectively (ORR, 62%; 95% CI, 35%-88%). The difference was not statistically significant (P = .178). For the 36 patients analyzed, the median follow-up duration was 5 months. Figure 1 shows a patient with cutaneous T-cell lymphoma of the orbital region, before and after treatment. The median TLP for the entire group was 15 months. The TLP curves are shown in Figure 2 along with the numbers of patients at risk at 6-month intervals. Analysis by site rather than by patient revealed that of the 47 sites treated, CR was observed in 20 sites (43%), PR was achieved in 16 patients (34%), with an ORR of 77% (95% CI, 65%-89%). Analysis was also carried out looking at the responses in histologic sites with and without DLBCL. Of the 39 sites with non-DLBCL histology, the CR was observed in 48%, and PR was observed in 38% of the sites, with overall response in non-DLBCL lesions being 86%. In the 8 DLBCL sites, there were no CRs and 4 sites with a PR. Retreatment was given to 4 of the 7 patients who had local progression during the course of follow-up after a median interval of 176 days (range, 30-282 days). These patients are presented here even if they had chemotherapy for systemic progression but were censored from the analysis of response.
Quality of Life Analysis Valid data from complete EORTC QLQ 30 questionnaire was available for 35 of the 36 patients at baseline and 28 of the 36
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Low-Dose Involved-Field Radiation Therapy for Advanced Lymphoma Table 2 EORTC QLQ-C30 Scores Before and After Treatment Scores
Median Baseline
Median Follow-up
Paired Wilcoxon P Value
Global Quality of Life
53.8
59.3
.377
Physical function
67.7
74.6
.306
Role function
60.4
66.7
.547
Emotional function
73.3
75.1
.773
Cognitive function
71.9
74.6
.371
Social function
68.7
69.8
.981
46
36.2
.135
Functional Scale
Symptom Scale Fatigue Nausea/vomiting
5.3
5.4
.985
Pain
31.4
22.4
.238
Dyspnea
25.6
23.7
.878
39
29.6
.231
Appetite loss
19
13.1
.273
Constipation
18.1
8.9
.255
Diarrhea
5.7
11.5
.134
Financial difficulties
20.9
16.6
.972
Sleep disturbance
patients at 4 weeks after treatment. The forms were completed at a median of 8 days before RT (range, 0-22 days) and 23 days after RT (range, 9-58 days). The global QOL scale showed a small improvement, as did most of the specific functional and symptom scales (Table 2). None of the results were statistically significant.
Radiation Therapy Protocol Compliance All 47 treatment episodes fulfilled the protocol RT prescriptions. None of the patients received elective irradiation of uninvolved adjacent regions. One patient was excluded from the analysis because of corticosteroid medication after irradiation but before response assessment.
Toxicity None of the patients had any significant (> grade 2, Common Toxicity Criteria) toxicity after the primary LD-IFRT. Mild erythema was observed after LD-IFRT in 3 patients that was transient and had resolved at 4 weeks. One patient had mild transient alopecia in the treated site.
Discussion We studied the in-field lymphoma control in patients with advanced, often multiply chemotherapy-refractory lymphoma using LD-IFRT. Both indolent and aggressive histologies were studied, and we found an ORR of 75%. The RR at 4 weeks after treatment for indolent lymphomas was 83%, and RR for aggressive histology was 62%. The DLBCL histology showed a RR of 50% (no CR), whereas the non-DLBCL histologies showed an impressive ORR of 86% (48% CR). We also investigated age, sex, lymphoma grade, size of the index lesion, and number of previous chemotherapy regimens as prognostic
244
•
Clinical Lymphoma & Myeloma August 2008
parameters, but none significantly predicted response, possibly because of the small sample size. This is the only study to prospectively assess the QOL in patients receiving LD-IFRT. Although none of the scores was statistically significant, the mean global and the functional scores showed improvement after RT at 3 weeks. The median symptom scores generally showed a decrease after RT. Low-dose RT has been studied mostly in FL and other indolent lymphoma types. An early report from the Institute Gustave Roussy suggested this approach, based on the response to low-dose total body irradiation and some anecdotal responses in patients completing fractionated courses prematurely.10 In the largest study, Haas et al reported a RR of 92% in patients with FL, and the CR rate was 61%, with the median TLP being 14 months.3 Girinsky et al reported a 2-year actuarial freedom from local progression rate of 56% (95% CI, 46%-66%) in 135 sites in 48 patients with indolent lymphomas retrospectively.5 In another smaller study, Jóhansson et al reported 22 patients with indolent non-Hodgkin lymphoma (NHL), of whom 18 responded to the treatment, corresponding to an ORR of 82%; 12 patients (55%) had a CR, and 5 patients had (22%) a PR.4 Apart from FL, a further study by Haas et al investigated the role of low-dose, localized RT in advanced nonfollicular lymphoma, including indolent histologic subtypes such as SLL/ chronic lymphocytic leukemia and MZL, and the more aggressive DLBCL and MCL.6 The objective was to evaluate the rate and duration of response, pattern of relapse, and toxicity of LD-IFRT to explore its value in a palliative setting to reduce symptoms in advanced recurrent disease. The results showed that ORR was 87%; CR was reached in 48% of the patients, and a PR was reached in 39% of the patients. The median TLP was 22 months. The low number of patients in our study limits conclusions regarding the subgroups by grade or extent of disease. Although the response rates at 4 weeks for indolent (83%) and aggressive (62%) histology were not statistically significant in the present study, it is quite possible that, because of the large difference, it would be both statistically significant and clinically relevant in a larger study. The result of the primary endpoint of in-field lymphoma control, however, seems valid, especially for short-term palliation. The median follow-up of 5 months is relatively short, reflecting clinical practice in these patients with advanced lymphoma with a high rate of censoring of data on receiving any chemotherapy for progression at other sites after LD-IFRT. The molecular mechanisms responsible for the efficacy of lowdose radiation in lymphoid malignancy are unknown. The probable explanation is the occurrence of radiation-induced early and late apoptosis in lymphoid cells.11,12 The apoptotic mechanism has been linked to the suppression of the bcl-2 gene, often overexpressed in FL and mitochondrial membrane permeability.13,14 Currently, at least 2 randomized trials are further evaluating the role of LD-IFRT. An ongoing randomized phase III trial (the HOVON 47/EORTC 20013 Intergroup study) is comparing chlorambucil versus LD-IFRT in patients with advanced-stage previously untreated FL, with the main endpoints being progressionfree survival and QOL.15 Another trial, Follicular Radiotherapy Trial (FORT), launched recently in the United Kingdom is randomizing patients with FL needing RT to 24 Gy in 12 fractions versus 4 Gy in 2 fractions.16 These will hopefully provide further long-term data on the efficacy and durability of LD-IFRT.
Vedang Murthy et al Conclusion Low-dose RT is an effective and easy treatment for patients with both low-grade and high-grade NHL. Because of its low toxicity, it can be applied to all sites, including extranodal regions and previously irradiated sites, a particularly useful benefit because of the relapsing nature of advanced NHL.
Acknowledgements This work was undertaken in The Royal Marsden National Health Service (NHS) Trust who received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by the Institute of Cancer Research, the Bob Champion Cancer Trust, and Cancer Research UK Section of Radiotherapy (CUK) grant number C46/A2131. Permission for publishing the patient’s clinical photograph was taken on the condition that he would remain completely anonymous.
References 1. Johnson PW, Rohatiner AZ, Whelan JS, et al. Patterns of survival in patients with recurrent follicular lymphoma: a 20-year study. J Clin Oncol 1995; 13:140-7. 2. Glatstein E, Wasserman TH. Non-Hodgkins Lymphoma. In: Perez C, Brady L, eds. Principles and Practice of Radiation Oncology. Philadelphia: JB Lippincott Co, 1987. 3. Haas RL, Poortmans P, de Jong D, et al. High response rates and lasting remissions after low-dose involved field radiotherapy in indolent lymphomas. J Clin Oncol 2003; 21:2474-80. 4. Jóhannsson J, Specht L, Mejer J, et al. Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin’s
5.
6. 7. 8.
9. 10. 11. 12. 13. 14. 15. 16.
lymphoma and chronic lymphocytic leukemia. Int J Radiat Oncol Biol Phys 2002; 54:1466-70. Girinsky T, Guillot-Vals D, Koscielny S, et al. A high and sustained response rate in refractory or relapsing low-grade lymphoma masses after low-dose radiation: analysis of predictive parameters of response to treatment. Int J Radiat Oncol Biol Phys 2001; 51:148-55. Haas RL, Poortmans P, de Jong D, et al. Effective palliation by low dose local radiotherapy for recurrent and/or chemotherapy refractory non-follicular lymphoma patients. Eur J Cancer 2005; 41:1724-30. Miller AB, Hoogstraten B, Staquet M. Reporting results of cancer treatment. Cancer 1981; 47:207-14. Kaasa S, Bjordal K, Aaronson N, et al. The EORTC Core Quality of Life of Questionnaire (QLQ-30): Validity and reliability when analysed with patients treated with palliative radiotherapy. Eur J Cancer 1995; 31A:2260-3. Hjermstad MJ, Fossa SD, Bjordal K, et al. Test/retest study of the European Organisation for research and treatment of cancer core quality of life questionnaire. J Clin Oncol 1995; 13:1249-54. Ganem G, Lambin P, Socié G, et al. Potential role for low dose limitedfield radiation therapy (2 x 2 grays) in advanced low-grade non-Hodgkin’s lymphomas. Hematol Oncol 1994; 12:1-8. Radford IR, Murphy TK, Radley JM, et al. Radiation response of mouse lymphoid and myeloid cell lines. Part II. Apoptotic death is shown by all lines examined. Int J Radiat Biol 1994; 65:217-27. Palayoor ST, Macklis RM, Bump EA, et al. Modulation of radiationinduced apoptosis and G2/M block in murine T-lymphoma cells. Radiat Res 1995; 141:235-43. Chen M, Quintans J, Fuks Z, et al. Suppression of Bcl-2 messenger RNA production may mediate apoptosis after ionizing radiation, tumor necrosis factor, and ceramide. Cancer Res 1995; 55:991-4. Kroemer G, Reed JC. Mitochondrial control of cell death. Nature Med 2000; 6:513-9. Hovon study Web site. Available at: http://www.hovon.nl. Accessed: June 30, 2008. National Cancer Research Network Web site. Available at: http://www. public.ukcrn.org.uk/Search/StudyDetail.aspx?StudyID=1721. Accessed: June 30, 3008.
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Abstract Purpose: To confirm the efficacy of low-dose involved-field radiation therapy (LD-IFRT) as palliative treatment in patients symptomatic from advanced lymphoma. Patients and Methods: A total of 36 patients (47 sites), received 4 Gy in 2 fractions to the lymphoma with a 1.5-2–cm margin. Pathology subtypes included 29 (62%) sites with indolent lymphoma and 18 (36%) sites with aggressive lymphoma histology. Bulky disease was seen in 22 (48%) sites and, of these, 6 sites had disease > 10 cm. A median of 3 previous chemotherapy regimens (range, 0 to 9 regimens) preceded LD-IFRT. The primary endpoint of the study was in-field lymphoma control. Patients completed the European Organization for the Research and Treatment of Cancer QLQ-C30 quality of life (QOL) questionnaire before RT and at 3-4 weeks after treatment. Results: The overall response rate (RR) at 1-3 months after the RT was 75%. A complete remission (CR) was observed in 13 patients (36%) lasting up to a maximum of 31.3 months and ongoing at analysis. A partial remission (PR) was achieved in 14 patients (39%) lasting up to 10 months. The response rate for non–diffuse large B-cell lymphoma (DLBCL) sites was 86%, while it was 50% for sites with DLBCL histology. Median time to local progression for the entire group was 15 months. There was no statistical difference between the QOL before and after LD-IFRT. Conclusion: LD-IFRT is an effective and easy treatment for patients with advanced lymphoma that can be repeated at previously irradiated sites, a particularly useful attribute because of the relapsing nature, especially of advanced follicular subtypes.
Clinical Lymphoma & Myeloma, Vol. 8, No. 4, 241-245, 2008; DOI: 10.3816/CLM.2008.n.032 Keywords: Diffuse large B-cell lymphoma, Non-Hodgkin lymphoma, Quality of life
Introduction The majority of patients with low-grade lymphomas present with advanced disease and have a long survival; the median survival for patients with advanced follicular lymphoma (FL) is about 9 years.1 The natural history is characterized by multiple relapses after treatment, with the disease-free interval between subsequent relapses tending to shorten over time. Although FL is both chemotherapy and radiation sensitive, patients with advanced indolent lymphomas are considered incurable. Radiation has been used effectively as a method of palliation in these patients in the form of wide-field irradiation (total body, hemi-body), when low radiation doses have been used, or 1Academic
Unit of Radiotherapy and Oncology, The Royal Marsden NHS Foundation Trust, Surrey, UK 2The Institute of Cancer Research, Surrey, UK 3Department of Computing and Information 4Department of Medical Oncology The Royal Marsden NHS Foundation Trust, Surrey, UK *Currently at Department of Radiation Oncology, Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Centre, Navi Mumbai, India Submitted: Feb 29, 2008 Revised: Apr 23, 2008; Accepted: May 6, 2008 Address for correspondence: Alan Horwich, The Academic Unit of Radiotherapy and Oncology, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, Surrey, SM2 5PT, United Kingdom Fax: 44-208-643-8809; e-mail: [email protected]
in the form of localized radiation therapy (RT), when conventional doses of 20-40 Gy have produced excellent local control.2 There is recent indication that low-dose, involved-field RT (LDIFRT) might be valuable in FL and achieve overall response rates (ORRs) in the region of 85%.3-5 In the largest study of 109 patients from The Netherlands, the ORR was 92%, with complete remission (CR) in 61% of the patients. The median time to local progression (TLP) was 25 months.3 Another study in nonfollicular indolent lymphomas and aggressive histologies showed that the ORR was 87%, with CR in 34 patients (48%) and a partial remission (PR) in 28 (39%) of the 71 patients. The median TLP was 22 months.6 To further assess these findings, we initiated a prospective phase II study of palliative LD-IFRT for patients with disseminated lymphoma to evaluate its efficacy and toxicity and to assess if it improved quality of life (QOL). The Royal Marsden Hospital Ethics Committee approved the trial.
Patients and Methods Eligibility From July 2003 to June 2006, we enrolled 37 patients with advanced, histologically proven lymphoma. Patients were eligible if they had symptomatic, recurrent disease at any site and were referred for palliative RT. Patients on concurrent corticosteroids or
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
Clinical Lymphoma & Myeloma August 2008
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241
Low-Dose Involved-Field Radiation Therapy for Advanced Lymphoma Table 1 Patient and Tumor Characteristics Characteristic
Value
Total Number of Analyzable Patients
36
Total Number of Analyzable Sites
47
Median Age at Treatment, Years (Range) Sex (Male:Female)
65.1 (33.8-84.5) 17:19
Histologic Type by Site (Patient) Indolent Follicular lymphoma Small lymphocytic lymphoma Marginal-zone NHL/ MALT Aggressive
29 Sites (62%) 19 (16%) 5 (5%) 5 (2%) 18 Sites (36%)
Diffuse large B-cell lymphoma
8 (7%)
Mantle cell lymphoma
4 (2%)
Cutaneous T-cell lymphoma
6 (4%)
Median Number of Previous Systemic Treatment Regimen Median Size of Lymph Node Mass at Index Site (cm)
4.4 (Range, 2-15)
<5
24
5.1-10
16
> 10
6
Unknown
1
chemotherapy were excluded. They were also excluded if there was clinical or radiologic suspicion of impending vital organ compromise, eg, spinal cord compression. Eligible patients did not have the index site treated with RT previously. All patients were aged > 18 years and consented for the trial in writing.
Staging Before treatment, the patients underwent detailed physical examination to assess the extent of disease. Patients with disease in accessible sites were evaluated clinically, and the lesion was measured in 3 dimensions and recorded. The rest of the patients underwent cross-sectional imaging before radiation therapy and during subsequent follow-up. A total of 36 patients and 47 sites were assessable for analysis. Pathology subtypes are shown in Table 1. Follicular lymphoma, small lymphocytic lymphoma (SLL), and marginal zone lymphoma (MZL)/ mucosa-associated lymphoid tissue were classified for study purpose as indolent lymphoma, whereas diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and cutaneous T-cell lymphoma were classified as aggressive lymphoma histology. Data were available on all except 1 site regarding the size of the treated mass. Bulky disease was defined as > 5 cm in maximum diameter. Bulky disease was observed in 22 (48%) sites, and of these, 6 sites had disease > 10 cm.
Radiation Therapy Technique All patients received a dose of 4 Gy in 2 fractions with a 48-hour gap between the 2 treatments with 6-15 MV photons.
•
Follow-up and Assessment Patients were seen at 3-4 weeks after the end of RT to assess response and toxicity. They also underwent imaging at this point if they had imaging at baseline for disease assessment. They were then seen 3 times monthly on follow-up until an endpoint of failure or a censoring event occurred. Response assessment was based on the standard definitions of the World Health Organization using CR, PR, stable disease (SD), and progressive disease (PD) as response assessment criteria.7
3 (Range, 0-9)
Abbreviations: MALT = mucosa-associated lymphoid tissue; NHL = non-Hodgkin lymphoma
242
The target volume consisted of the involved nodal mass lesion with a 1.5-2.0 cm margin. Adjacent nodal regions were not treated prophylactically. Only 1 (index) site was treated at any given point in a particular patient. Patients were prescribed antiemetics (non corticosteroid) and antimotility agents prophylactically for large abdominal and pelvic fields. Sites treated with electrons were prescribed to the 90% isodose, and the total dose prescribed was 4.2 Gy in 2 fractions. Tissue-equivalent bolus was used for superficial lesions as appropriate.
Clinical Lymphoma & Myeloma August 2008
Quality of Life The European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire is a cancer-specific, self-administered, structured questionnaire designed for use in clinical trials8,9 that contains 30 questions, 24 of which form 9 multi-item scales representing various aspects—or dimensions—of health-related QOL: 1 global scale, 5 functional scales (physical, role, emotional, cognitive, and social), and 3 symptom scales (fatigue, pain, and nausea). The remaining 6 items are intended to be mono-item scales describing relevant cancer-oriented symptoms (dyspnea, insomnia, appetite, constipation, diarrhea, financial difficulties). Questions are combined in scales according to predefined rules. All patients were asked to complete the EORTC QLQ-C30 QOL questionnaire at baseline, ie, before RT and again at 3-4 weeks after the second fraction of RT. This time interval was chosen because administering the second QOL later would increase the chance of its being influenced by other treatment that the patient receives.
Preradiation Therapy Treatment As expected from the natural history of advanced lymphoma, most patients were pretreated with multiple lines of chemotherapy. The median number of previous chemotherapy regimens was 3 (range, 0-9 regimens). None of the patients received concurrent chemotherapy with RT.
Statistical Methods A Simon’s 2-stage design was planned. The study, with 44 patients, would have a 90% power with a 0.05 level of significance to detect a minimum 65% response rate and an expected response of 85% with the LD-IFRT treatment. The first 15 patients had to have an adequate response in ≥ 11 patients to proceed to the completion of the study. The primary endpoint of the study was in-field lymphoma control. Patients with SD or PD at the index site were designated to have treatment failures. Also, patients with recurrence
Vedang Murthy et al Figure 1 Pre– and Post–Radiation Therapy Comparison of Periorbital Cutaneous T-Cell Lymphoma
Figure 2 Time to Local Progression by Histologic Grade
A
Locally Controlled (%)
100
Low Grade (n = 23) High Grade (n = 13) All Patients (N = 36)
80 60 40 20
0
12
24
36
Time (Months) At Risk (N = 36)
15
7
3
2
Local Progression 6
2
1
0
Censored
5
3
1
13
Results Response Rates
B
(A) Pre–radiation therapy; (B) Post–radiation therapy. This 75-year-old man was treated with LD-IFRT (4 Gy in 2 fractions) with 300 kV x-rays. He was chemotherapy naive.
of the mass at the index site, additional RT at the index site, or chemotherapy for inadequate local response were considered to have local failures. Patients who died or had systemic treatment including chemotherapy, corticosteroids, or experimental agents for disease progression at a nonindex site or were unavailable for follow-up were censored. Time to local progression was calculated by the Kaplan-Meier method. Time to local progression was calculated from the date of the second fraction of RT. Four patients did not have their response assessable at 1-3 months but were still included in the intent-to-treat analysis. The study was closed after a competing multicenter, randomized trial opened.
The overall response rate (RR; ORR) at 1-3 months after the RT was 75%. A CR was observed in 13 patients (36%) lasting up to a maximum of 134 weeks and ongoing at the time of analysis. A PR was achieved in 14 patients (39%) lasting up to a maximum of 43 weeks. Stable disease was maintained in 3 patients (8%). Progressive disease was observed after LD-IFRT in 2 patients. Among the patients with indolent histology, CR was achieved in 44%, and PR was observed in 39% at 1-3 months after treatment (ORR, 83%; 95% CI, 67%-98%). The figures for aggressive histology were 23% and 39%, respectively (ORR, 62%; 95% CI, 35%-88%). The difference was not statistically significant (P = .178). For the 36 patients analyzed, the median follow-up duration was 5 months. Figure 1 shows a patient with cutaneous T-cell lymphoma of the orbital region, before and after treatment. The median TLP for the entire group was 15 months. The TLP curves are shown in Figure 2 along with the numbers of patients at risk at 6-month intervals. Analysis by site rather than by patient revealed that of the 47 sites treated, CR was observed in 20 sites (43%), PR was achieved in 16 patients (34%), with an ORR of 77% (95% CI, 65%-89%). Analysis was also carried out looking at the responses in histologic sites with and without DLBCL. Of the 39 sites with non-DLBCL histology, the CR was observed in 48%, and PR was observed in 38% of the sites, with overall response in non-DLBCL lesions being 86%. In the 8 DLBCL sites, there were no CRs and 4 sites with a PR. Retreatment was given to 4 of the 7 patients who had local progression during the course of follow-up after a median interval of 176 days (range, 30-282 days). These patients are presented here even if they had chemotherapy for systemic progression but were censored from the analysis of response.
Quality of Life Analysis Valid data from complete EORTC QLQ 30 questionnaire was available for 35 of the 36 patients at baseline and 28 of the 36
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Low-Dose Involved-Field Radiation Therapy for Advanced Lymphoma Table 2 EORTC QLQ-C30 Scores Before and After Treatment Scores
Median Baseline
Median Follow-up
Paired Wilcoxon P Value
Global Quality of Life
53.8
59.3
.377
Physical function
67.7
74.6
.306
Role function
60.4
66.7
.547
Emotional function
73.3
75.1
.773
Cognitive function
71.9
74.6
.371
Social function
68.7
69.8
.981
46
36.2
.135
Functional Scale
Symptom Scale Fatigue Nausea/vomiting
5.3
5.4
.985
Pain
31.4
22.4
.238
Dyspnea
25.6
23.7
.878
39
29.6
.231
Appetite loss
19
13.1
.273
Constipation
18.1
8.9
.255
Diarrhea
5.7
11.5
.134
Financial difficulties
20.9
16.6
.972
Sleep disturbance
patients at 4 weeks after treatment. The forms were completed at a median of 8 days before RT (range, 0-22 days) and 23 days after RT (range, 9-58 days). The global QOL scale showed a small improvement, as did most of the specific functional and symptom scales (Table 2). None of the results were statistically significant.
Radiation Therapy Protocol Compliance All 47 treatment episodes fulfilled the protocol RT prescriptions. None of the patients received elective irradiation of uninvolved adjacent regions. One patient was excluded from the analysis because of corticosteroid medication after irradiation but before response assessment.
Toxicity None of the patients had any significant (> grade 2, Common Toxicity Criteria) toxicity after the primary LD-IFRT. Mild erythema was observed after LD-IFRT in 3 patients that was transient and had resolved at 4 weeks. One patient had mild transient alopecia in the treated site.
Discussion We studied the in-field lymphoma control in patients with advanced, often multiply chemotherapy-refractory lymphoma using LD-IFRT. Both indolent and aggressive histologies were studied, and we found an ORR of 75%. The RR at 4 weeks after treatment for indolent lymphomas was 83%, and RR for aggressive histology was 62%. The DLBCL histology showed a RR of 50% (no CR), whereas the non-DLBCL histologies showed an impressive ORR of 86% (48% CR). We also investigated age, sex, lymphoma grade, size of the index lesion, and number of previous chemotherapy regimens as prognostic
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parameters, but none significantly predicted response, possibly because of the small sample size. This is the only study to prospectively assess the QOL in patients receiving LD-IFRT. Although none of the scores was statistically significant, the mean global and the functional scores showed improvement after RT at 3 weeks. The median symptom scores generally showed a decrease after RT. Low-dose RT has been studied mostly in FL and other indolent lymphoma types. An early report from the Institute Gustave Roussy suggested this approach, based on the response to low-dose total body irradiation and some anecdotal responses in patients completing fractionated courses prematurely.10 In the largest study, Haas et al reported a RR of 92% in patients with FL, and the CR rate was 61%, with the median TLP being 14 months.3 Girinsky et al reported a 2-year actuarial freedom from local progression rate of 56% (95% CI, 46%-66%) in 135 sites in 48 patients with indolent lymphomas retrospectively.5 In another smaller study, Jóhansson et al reported 22 patients with indolent non-Hodgkin lymphoma (NHL), of whom 18 responded to the treatment, corresponding to an ORR of 82%; 12 patients (55%) had a CR, and 5 patients had (22%) a PR.4 Apart from FL, a further study by Haas et al investigated the role of low-dose, localized RT in advanced nonfollicular lymphoma, including indolent histologic subtypes such as SLL/ chronic lymphocytic leukemia and MZL, and the more aggressive DLBCL and MCL.6 The objective was to evaluate the rate and duration of response, pattern of relapse, and toxicity of LD-IFRT to explore its value in a palliative setting to reduce symptoms in advanced recurrent disease. The results showed that ORR was 87%; CR was reached in 48% of the patients, and a PR was reached in 39% of the patients. The median TLP was 22 months. The low number of patients in our study limits conclusions regarding the subgroups by grade or extent of disease. Although the response rates at 4 weeks for indolent (83%) and aggressive (62%) histology were not statistically significant in the present study, it is quite possible that, because of the large difference, it would be both statistically significant and clinically relevant in a larger study. The result of the primary endpoint of in-field lymphoma control, however, seems valid, especially for short-term palliation. The median follow-up of 5 months is relatively short, reflecting clinical practice in these patients with advanced lymphoma with a high rate of censoring of data on receiving any chemotherapy for progression at other sites after LD-IFRT. The molecular mechanisms responsible for the efficacy of lowdose radiation in lymphoid malignancy are unknown. The probable explanation is the occurrence of radiation-induced early and late apoptosis in lymphoid cells.11,12 The apoptotic mechanism has been linked to the suppression of the bcl-2 gene, often overexpressed in FL and mitochondrial membrane permeability.13,14 Currently, at least 2 randomized trials are further evaluating the role of LD-IFRT. An ongoing randomized phase III trial (the HOVON 47/EORTC 20013 Intergroup study) is comparing chlorambucil versus LD-IFRT in patients with advanced-stage previously untreated FL, with the main endpoints being progressionfree survival and QOL.15 Another trial, Follicular Radiotherapy Trial (FORT), launched recently in the United Kingdom is randomizing patients with FL needing RT to 24 Gy in 12 fractions versus 4 Gy in 2 fractions.16 These will hopefully provide further long-term data on the efficacy and durability of LD-IFRT.
Vedang Murthy et al Conclusion Low-dose RT is an effective and easy treatment for patients with both low-grade and high-grade NHL. Because of its low toxicity, it can be applied to all sites, including extranodal regions and previously irradiated sites, a particularly useful benefit because of the relapsing nature of advanced NHL.
Acknowledgements This work was undertaken in The Royal Marsden National Health Service (NHS) Trust who received a proportion of its funding from the NHS Executive; the views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by the Institute of Cancer Research, the Bob Champion Cancer Trust, and Cancer Research UK Section of Radiotherapy (CUK) grant number C46/A2131. Permission for publishing the patient’s clinical photograph was taken on the condition that he would remain completely anonymous.
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