Low-dose Involved-field Radiotherapy Research Articles

[A single-center retrospective analysis of 85 children and adolescents with limited-stage Hodgkin lymphoma].

目的总结ABVD方案治疗儿童和青少年局限期（Ⅰ/Ⅱ期）霍奇金淋巴瘤（HL）的治疗效果和预后，探讨低危组患者化疗达完全缓解（CR）后可否不放疗。方法回顾性分析2004–2016年在中山大学肿瘤防治中心接受ABVD方案单纯化疗或联合低剂量侵犯野放疗治疗的85例儿童和青少年局限期HL患者的临床资料。结果85例儿童和青少年局限期HL患者的中位年龄12（3~18）岁，男66例，女19例，Ⅰ期5例，Ⅱ期80例，低危组56例，中危组29例。中位随访72（8~196）个月，复发12例，发生第二肿瘤2例，死亡2例。全组5年无事件生存（EFS）率为（85.6±3.8）%，5年总生存（OS）率100%。低危组5年EFS率和OS率分别为（89.1±4.2）%和100%，中危组5年EFS率和OS率分别为（79.3±7.5）%和100%。低危组化疗后达CR者共39例，其中15例化疗后接受放疗，单纯化疗组和化疗联合放疗组5年EFS率分别为（87.0±7.0）%和100%（P=0.506），OS率均为100%。结论ABVD方案治疗儿童和青少年局限期HL患者OS率较高，与发达国家相当，低危组化疗后达CR者放疗无获益，鉴于放疗远期不良反应，应根据危险度分层和治疗反应调整治疗强度。

Children and Adolescent Hodgkin Lymphoma in Argentina: Long-term Results After Combined ABVD and Restricted Radiotherapy.

Prospective analysis of clinical characteristics and long-term treatment results of a pediatric cohort with Hodgkin lymphoma (HL) treated in a single institution with ABVD and restricted radiotherapy (RT). Between September 2000 and December 2015, 165 new consecutive assessable patients with HL were registered at our institution. Lymphocyte predominant nodular HL was excluded. Low risk (LR) patients were stage I and IIA (no bulky disease, <4 involved ganglionar areas and no lung hilar nodes), high risk (HR) was assigned to stage IV and any other stage with bulky mediastinum. The rest of the cohort was treated as intermediate risk (IR). Chemotherapy for LR and IR patients was 4 and 6 courses of ABVD regimen, respectively. These subsets received Low-dose involved field radiotherapy only in case of partial remission at the end of chemotherapy (21 Gy in initially involved areas, plus 14 Gy boost on residual disease). The HR group was treated with 6 courses of ABVD followed always with 21 Gy involved field radiotherapy if complete remission (CR) was achieved. A boost of 14 Gy was added to residual disease in case of partial remission. Median age was 10.6 years (range, 2.7 to 17 y). Males: 117 (71%); females: 48 (29%). Eighteen (11%) patients were stage I, 76 (46%) stage II, 35 (21%) stage III, and 35 (21%) stage IV. Forty-nine (30%) patients were assigned to LR, 49 (30%) to IR, and 67 (40%) to HR. Forty-three patients (26%) had "bulky" mediastinum involvement. One hundred thirty (79%) patients achieved CR after chemotherapy and 161 (98%) after RT. Four patients (all HR), did not respond to initial therapy and died of disease. One patient died in first CR due to adenovirus infection on previously therapy-related damaged lungs. Seventeen (10%) patients relapsed and 13 of them remained in second CR after further therapy. Seventy-six (46%) patients could be spared from RT and cured of disease (88% of LR patients and 67% of IR patients). With a median follow-up of 5 years, event free and overall survival were 0.84 (SE: 0.03) and 0.95 (SE: 0.02), respectively. Overall survival according to risk group was 1 for LR, 0.93 for IR, and 0.85 for HR. Acute toxicity and late effects due to therapy were not significant. The strategy of avoiding RT for LR and IR patients that responded completely to ABVD chemotherapy achieved very good results. For the HR group, the combination of 6 cycles of ABVD and Low-dose involved field radiotherapy was efficacious with similar good results. Nearly half of the patients could be cured without RT.

Clinical study of 83 cases of pediatric Hodgkin lymphoma

Objective To explore the clinical and pathological features of children with Hodgkin lymphoma (HL) and EBV status, and to summarize the efficacy and toxicity of risk-adapted combination of chemotherapy and low-dose involved-field radiation therapy (IFRT) according to the risk stratification. Methods 83 children with HL from January 2003 to April 2013 were enrolled, who received the detection of biopsy pathological morphology and immunohistochemistry. Pathology samples were reviewed and classified based on the World Health Organization (WHO) guidelines. Staging was based on clinical evaluation and was defined by the Ann Arbor staging system. According to the different risk factors, 83 patients were divided into three groups: low-risk group, intermediate-risk group and high-risk group. Results 83 HL children included 69 males and 14 females. 59 cases(71.1 %) were in stage Ⅲ-Ⅳ. Among 83 patients, one case suffered nodular lymphocyte predominant subtype, other 82 patients had classical HL including 64 cases (77.1 %) of mixed cellularity. Tumor invasion was extensive, 34 cases (41.0 %) had bulky lymph nodes, 26 cases (31.3 %) had more than 4 node regions involved, and 35 ceses (42.2 %) had B symptoms at presentation. 70 cases of pathology samples were detected by EBV encoded RNA (EBER) and/or latent membrane protein (LMP) staining, and 65 cases (92.9 %) were positive. There were 3 cases in low-risk group, 27 cases in intermediate-risk group and 53 cases in high-risk group. The overall survival (OS) rate was 97.5 % and the 5-year event free survival (EFS) rate was 92.8 % with a median follow-up of (72±32) months. Conclusions Pediatric HL occurs more frequent in male than in female, which is correlated with EBV and is consist mostly of mixed cellularity. Combined-modality therapy using risk-adapted chemotherapy with radiation is effective and well tolerated, with good prognosis, however, the adverse reaction needs to be observed further. Key words: Hodgkin disease; Children; Diagnosis; Therapies, investigational

Clinical Profile and Chemotherapy Response in Children with Hodgkin Lymphoma at a Tertiary Care Centre.

Optimal treatment strategy in children with advance stage Hodgkin Lymphoma (HL) still remains controversial. To evaluate the clinical profile and the efficacy of chemotherapy (CT) as a treatment modality in paediatric HL. Retrospective case record evaluation of paediatric HL cases over 5 years (October 2005 to October 2010) period. Thirty five cases (31 boys) with a median age of eight years were studied. 24 cases were <10-year-old, and 23 had late stage disease (stage III to IV). B-symptoms were present in 60%, bulky mediastinal disease in 25.7%, and spleen involvement in 60% cases. None had bone marrow involvement. Most common histological type was nodular sclerosis (28.6%). Most cases received ABVD/COPP or ABVD regimen. Two cases needed BEACOPP due to progressive disease, and 4 needed low-dose involved field radiotherapy (RT). At a mean (SD) extended event-free follow-up of 42.7(±17.1) months, four cases relapsed (one was lost to follow-up, and three were treated with chemotherapy and low-dose involved field RT). None died due to the disease. Present study found systemic CT alone to be an effective therapy in childhood Hodgkin lymphoma. However, a small sample in present study limits the generalisability of these findings. The findings needs to be replicated in larger population, preferably randomized clinical trials, before any firm conclusion can be made.

Low-Dose Involved-Field Radiotherapy in Relapsed Low-Grade Non-Hodgkin's Lymphoma in Elderly Patients (Mansoura University Experience)

Purpose: To assess the response rate, duration of response and prognostic factors affecting response after low-dose involved-field radiotherapy in patients with relapsed low-grade B-cell non-Hodgkin lymphoma. Patients and Methods: Forty-four patients were included. Patients were treated with a total dose of 4 Gy (2 × 2 Gy) using 6 - 15 Mv photon or electron beam. Results: most patients were above age of 60 years (59%) with male predominance. Follicular lymphoma was the most common pathological type; bulky disease (>5 cm) was presented in 61.4%. Patients who received only 2 regimens were 63.7% and 31.8% had >2 involved sites. No treatment related toxicity was observed. The overall response rate was 88.7%; complete response was reached in 59.1% and stable disease in 6.8%, progressive disease in 4.5%. Median time to local progression was 33 months (95% CI 23.70 - 42.29); 2-year local progression free survival was 78%. Response rate was found to be dependent on age, number of involved sites and lymph node size but independent on sex, pathological type, number of prior regimens, LDH level and time since diagnosis. Conclusion: Short-course-low dose palliative radiotherapy (2 × 2 Gy) affords an attractive option for treatment of relapsed low-grade non-Hodgkin’s lymphoma due to high response rates. However, these results had to be confirmed in a larger number of patients.

Combining Low-Dose External Beam With Radioimmunotherapy for Patients With Relapsed/Refractory B-Cell Lymphoma

Purpose/Objective(s)Radioimmunotherapy (RIT) is an effective and increasingly utilized therapy for patient with B-cell non-Hodgkin lymphomas (NHL). In the relapsed/refractory setting, patients may have measurable disease in only one or a couple of sites. Many relapsed patients have been heavily pretreated with rituximab and exhibit down-regulation of CD20. Evidence suggests that oxidative stress (such as low-dose radiation therapy) may up-regulate CD20 expression on B-cell NHL and stimulate intrinsic cell death pathways. Such low-dose radiation could sensitize bulkier sites of NHL prior to RIT.Materials/MethodsBetween July 1, 2009 and June 30, 2012, we treated 21 patients with a combination of low-dose, involved-field radiation therapy (IFRT) and RIT for relapsed/refractory B-cell NHL: 9 transformed, 7 follicular, 2 marginal zone, 2 CLL/SLL, and 1 lymphoplasmacytic NHL. All patients received 4 Gy in 2 fractions IFRT to sites of active disease greater than 2.5 cm. 131I-tositumomab was used for 9 patients and 90Y-ibritumomab tiuxetan in 12. In all cases, IFRT was delivered just prior to RIT injection. The median age of patients was 61 (38-82). The median number of prior therapies was 2 (1-4). The median size of IFRT targets was 5.2 cm (2.5-19.5).ResultsWith a median follow-up of 40 months (15-51), 19 of 21 (90.5%) patients obtained a complete response (CR), and 18 of those (94.7%) remain in CR today. No patients failed within IFRT fields. Both patients failing to obtain a CR progressed outside the IFRT fields, went on to bone marrow transplant, and died of transplant-related complications. All patients tolerated IFRT + RIT very well without unexpected complications, with only the typical Grade 2/3 myelosuppression from RIT noted.ConclusionsThe addition of low-dose IFRT to sites of active disease ≥ 2.5 cm just prior to RIT in patients with relapsed/refractory B-cell NHL is very well-tolerated, adds no toxicity to that of RIT alone, and results in excellent progression-free survival, particularly in those patients obtaining a CR. As the only failures seen were outside IFRT fields, the addition of IFRT to larger sites of active disease may play an important adjunctive role to RIT. Prospective studies are necessary to further evaluate this novel combined therapeutic approach. Correlative studies should be pursued to determine the mechanism for this improved tumor control. Purpose/Objective(s)Radioimmunotherapy (RIT) is an effective and increasingly utilized therapy for patient with B-cell non-Hodgkin lymphomas (NHL). In the relapsed/refractory setting, patients may have measurable disease in only one or a couple of sites. Many relapsed patients have been heavily pretreated with rituximab and exhibit down-regulation of CD20. Evidence suggests that oxidative stress (such as low-dose radiation therapy) may up-regulate CD20 expression on B-cell NHL and stimulate intrinsic cell death pathways. Such low-dose radiation could sensitize bulkier sites of NHL prior to RIT. Radioimmunotherapy (RIT) is an effective and increasingly utilized therapy for patient with B-cell non-Hodgkin lymphomas (NHL). In the relapsed/refractory setting, patients may have measurable disease in only one or a couple of sites. Many relapsed patients have been heavily pretreated with rituximab and exhibit down-regulation of CD20. Evidence suggests that oxidative stress (such as low-dose radiation therapy) may up-regulate CD20 expression on B-cell NHL and stimulate intrinsic cell death pathways. Such low-dose radiation could sensitize bulkier sites of NHL prior to RIT. Materials/MethodsBetween July 1, 2009 and June 30, 2012, we treated 21 patients with a combination of low-dose, involved-field radiation therapy (IFRT) and RIT for relapsed/refractory B-cell NHL: 9 transformed, 7 follicular, 2 marginal zone, 2 CLL/SLL, and 1 lymphoplasmacytic NHL. All patients received 4 Gy in 2 fractions IFRT to sites of active disease greater than 2.5 cm. 131I-tositumomab was used for 9 patients and 90Y-ibritumomab tiuxetan in 12. In all cases, IFRT was delivered just prior to RIT injection. The median age of patients was 61 (38-82). The median number of prior therapies was 2 (1-4). The median size of IFRT targets was 5.2 cm (2.5-19.5). Between July 1, 2009 and June 30, 2012, we treated 21 patients with a combination of low-dose, involved-field radiation therapy (IFRT) and RIT for relapsed/refractory B-cell NHL: 9 transformed, 7 follicular, 2 marginal zone, 2 CLL/SLL, and 1 lymphoplasmacytic NHL. All patients received 4 Gy in 2 fractions IFRT to sites of active disease greater than 2.5 cm. 131I-tositumomab was used for 9 patients and 90Y-ibritumomab tiuxetan in 12. In all cases, IFRT was delivered just prior to RIT injection. The median age of patients was 61 (38-82). The median number of prior therapies was 2 (1-4). The median size of IFRT targets was 5.2 cm (2.5-19.5). ResultsWith a median follow-up of 40 months (15-51), 19 of 21 (90.5%) patients obtained a complete response (CR), and 18 of those (94.7%) remain in CR today. No patients failed within IFRT fields. Both patients failing to obtain a CR progressed outside the IFRT fields, went on to bone marrow transplant, and died of transplant-related complications. All patients tolerated IFRT + RIT very well without unexpected complications, with only the typical Grade 2/3 myelosuppression from RIT noted. With a median follow-up of 40 months (15-51), 19 of 21 (90.5%) patients obtained a complete response (CR), and 18 of those (94.7%) remain in CR today. No patients failed within IFRT fields. Both patients failing to obtain a CR progressed outside the IFRT fields, went on to bone marrow transplant, and died of transplant-related complications. All patients tolerated IFRT + RIT very well without unexpected complications, with only the typical Grade 2/3 myelosuppression from RIT noted. ConclusionsThe addition of low-dose IFRT to sites of active disease ≥ 2.5 cm just prior to RIT in patients with relapsed/refractory B-cell NHL is very well-tolerated, adds no toxicity to that of RIT alone, and results in excellent progression-free survival, particularly in those patients obtaining a CR. As the only failures seen were outside IFRT fields, the addition of IFRT to larger sites of active disease may play an important adjunctive role to RIT. Prospective studies are necessary to further evaluate this novel combined therapeutic approach. Correlative studies should be pursued to determine the mechanism for this improved tumor control. The addition of low-dose IFRT to sites of active disease ≥ 2.5 cm just prior to RIT in patients with relapsed/refractory B-cell NHL is very well-tolerated, adds no toxicity to that of RIT alone, and results in excellent progression-free survival, particularly in those patients obtaining a CR. As the only failures seen were outside IFRT fields, the addition of IFRT to larger sites of active disease may play an important adjunctive role to RIT. Prospective studies are necessary to further evaluate this novel combined therapeutic approach. Correlative studies should be pursued to determine the mechanism for this improved tumor control.

Low-Dose Involved-Field Radiation in the Treatment of Non-Hodgkin Lymphoma: Predictors of Response and Treatment Failure

To investigate clinical and pathologic factors significant in predicting local response and time to further treatment after low-dose involved-field radiation therapy (LD-IFRT) for non-Hodgkin lymphoma (NHL). Records of NHL patients treated at a single institution between April 2004 and September 2011 were retrospectively reviewed. Low-dose involved-field radiation therapy was given as 4 Gy in 2 fractions over 2 consecutive days. Treatment response and disease control were determined by radiographic studies and/or physical examination. A generalized estimating equation model was used to assess the effect of tumor and patient characteristics on disease response. A Cox proportional hazards regression model was used to assess time to further treatment. We treated a total of 187 sites in 127 patients with LD-IFRT. Histologies included 66% follicular, 9% chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma, 10% marginal zone, 6% mantle cell lymphoma (MCL), and 8% other. Median follow-up time was 23.4 months (range, 0.03-92.2 months). The complete response, partial response, and overall response rates were 57%, 25%, and 82%, respectively. A CLL histology was associated with a lower response rate (odds ratio 0.2, 95% confidence interval 0.1-0.5, P=.02). Tumor size, site, age at diagnosis, and prior systemic therapy were not associated with response. The median time to first recurrence was 13.6 months. Those with CLL and age ≤ 50 years at diagnosis had a shorter time to further treatment for local failures (hazard ratio [HR] 3.63, P=.01 and HR 5.50, P=.02, respectively). Those with CLL and MCL had a shorter time to further treatment for distant failures (HR 11.1 and 16.3, respectively, P<.0001). High local response rates were achieved with LD-IFRT across most histologies. Chronic lymphocytic leukemia and MCL histologies and age ≤ 50 years at diagnosis had a shorter time to further treatment after LD-IFRT.

Low-dose Involved-field Radiation in the Palliation Of Non-Hodgkin Lymphoma: Predictors of Response and Treatment Failure

Purpose/Objective(s)Low-dose involved-field radiation therapy (LD-IFRT) is successful in palliating local sites in patients with advanced indolent non-Hodgkin lymphoma (NHL). We investigated clinical and pathologic factors significant in predicting local response and freedom from further treatment (FFFT) following LD-IFRT for NHL.Materials/MethodsThis was an IRB-approved retrospective review of records. The study cohort consisted of advanced-stage NHL patients treated at a single institution between April, 2004 and September, 2011. LD-IFRT was given as 4 Gy in 2 fractions over two consecutive days. Treatment response and disease control were determined by radiographic studies and/or physical examination.ResultsA total of 187 sites in 127 patients received LD-IFRT. The median age at diagnosis was 54 years. Fifty-four percent of patients were male. Histology of NHL included 66% follicular, 9% CLL, 10%, MALT/marginal zone (MZ), 6% mantle cell, and 8% other. Sites treated included head and neck (HandN) (36%), cutaneous (19%), supradiaphragmatic (non-HandN) (15%), infradiaphragmatic (12%) and pelvic (19%). The median tumor size was 4.0 cm (range, 0.6-35.0 cm). Median follow-up time was 19.1 months (range, 0.03-77.8 months). The complete response (CR), partial response (PR) and overall response rates were 50%, 32%, and 82%, respectively. Median time to CR or PR was 2.3 months. Histology was the only significant predictor of response (CR or PR), with all histologies having a response rate ≥84% except CLL, which had a 52% response rate (p = 0.01). Tumor size, site, age at diagnosis and the use of prior systemic therapy were not associated with response. The median time to local failure leading to re-irradiation or initiation of systemic therapy was not reached. The median time to distant failure requiring irradiation or systemic therapy was 39.1 months. Significantly higher 2-year rates of FFFT (local and/or systemic therapy) were associated with histologies other than CLL/MCL (p = 0.01), no prior systemic therapy (p = 0.01), cutaneous sites (p = 0.03) and having achieved an initial CR or PR (p = 0.03).ConclusionsHigh local response rates were achieved with LD-IFRT across most histologies. Histologies other than CLL/MCL, cutaneous sites, initial response to LD-IFRT and lack of prior systemic therapy were associated with significantly longer freedom from further therapy after LD-IFRT. Purpose/Objective(s)Low-dose involved-field radiation therapy (LD-IFRT) is successful in palliating local sites in patients with advanced indolent non-Hodgkin lymphoma (NHL). We investigated clinical and pathologic factors significant in predicting local response and freedom from further treatment (FFFT) following LD-IFRT for NHL. Low-dose involved-field radiation therapy (LD-IFRT) is successful in palliating local sites in patients with advanced indolent non-Hodgkin lymphoma (NHL). We investigated clinical and pathologic factors significant in predicting local response and freedom from further treatment (FFFT) following LD-IFRT for NHL. Materials/MethodsThis was an IRB-approved retrospective review of records. The study cohort consisted of advanced-stage NHL patients treated at a single institution between April, 2004 and September, 2011. LD-IFRT was given as 4 Gy in 2 fractions over two consecutive days. Treatment response and disease control were determined by radiographic studies and/or physical examination. This was an IRB-approved retrospective review of records. The study cohort consisted of advanced-stage NHL patients treated at a single institution between April, 2004 and September, 2011. LD-IFRT was given as 4 Gy in 2 fractions over two consecutive days. Treatment response and disease control were determined by radiographic studies and/or physical examination. ResultsA total of 187 sites in 127 patients received LD-IFRT. The median age at diagnosis was 54 years. Fifty-four percent of patients were male. Histology of NHL included 66% follicular, 9% CLL, 10%, MALT/marginal zone (MZ), 6% mantle cell, and 8% other. Sites treated included head and neck (HandN) (36%), cutaneous (19%), supradiaphragmatic (non-HandN) (15%), infradiaphragmatic (12%) and pelvic (19%). The median tumor size was 4.0 cm (range, 0.6-35.0 cm). Median follow-up time was 19.1 months (range, 0.03-77.8 months). The complete response (CR), partial response (PR) and overall response rates were 50%, 32%, and 82%, respectively. Median time to CR or PR was 2.3 months. Histology was the only significant predictor of response (CR or PR), with all histologies having a response rate ≥84% except CLL, which had a 52% response rate (p = 0.01). Tumor size, site, age at diagnosis and the use of prior systemic therapy were not associated with response. The median time to local failure leading to re-irradiation or initiation of systemic therapy was not reached. The median time to distant failure requiring irradiation or systemic therapy was 39.1 months. Significantly higher 2-year rates of FFFT (local and/or systemic therapy) were associated with histologies other than CLL/MCL (p = 0.01), no prior systemic therapy (p = 0.01), cutaneous sites (p = 0.03) and having achieved an initial CR or PR (p = 0.03). A total of 187 sites in 127 patients received LD-IFRT. The median age at diagnosis was 54 years. Fifty-four percent of patients were male. Histology of NHL included 66% follicular, 9% CLL, 10%, MALT/marginal zone (MZ), 6% mantle cell, and 8% other. Sites treated included head and neck (HandN) (36%), cutaneous (19%), supradiaphragmatic (non-HandN) (15%), infradiaphragmatic (12%) and pelvic (19%). The median tumor size was 4.0 cm (range, 0.6-35.0 cm). Median follow-up time was 19.1 months (range, 0.03-77.8 months). The complete response (CR), partial response (PR) and overall response rates were 50%, 32%, and 82%, respectively. Median time to CR or PR was 2.3 months. Histology was the only significant predictor of response (CR or PR), with all histologies having a response rate ≥84% except CLL, which had a 52% response rate (p = 0.01). Tumor size, site, age at diagnosis and the use of prior systemic therapy were not associated with response. The median time to local failure leading to re-irradiation or initiation of systemic therapy was not reached. The median time to distant failure requiring irradiation or systemic therapy was 39.1 months. Significantly higher 2-year rates of FFFT (local and/or systemic therapy) were associated with histologies other than CLL/MCL (p = 0.01), no prior systemic therapy (p = 0.01), cutaneous sites (p = 0.03) and having achieved an initial CR or PR (p = 0.03). ConclusionsHigh local response rates were achieved with LD-IFRT across most histologies. Histologies other than CLL/MCL, cutaneous sites, initial response to LD-IFRT and lack of prior systemic therapy were associated with significantly longer freedom from further therapy after LD-IFRT. High local response rates were achieved with LD-IFRT across most histologies. Histologies other than CLL/MCL, cutaneous sites, initial response to LD-IFRT and lack of prior systemic therapy were associated with significantly longer freedom from further therapy after LD-IFRT.

Successful Treatment in Children with Hodgkin Lymphoma in Greece; A 20-Year Experience in a Single Institution

During the last 30 years, combined chemotherapy regimens with radiotherapy or not significantly improved the prognosis for patients with Hodgkin lymphoma. We retrospectively studied 58 children (35 boys and 23 girls) with Hodgkin lymphoma who were treated at our institution during the period 1987–2006 and we correlated age, sex, stage, histology, and therapy with the outcome of patients. Of our patients, 9 children were 8 years old or younger. Nodular sclerosis was the predominant histology subtype (69%), whereas 26 patients (45%) had advanced disease (stage III or IV). Chemotherapy (CT) with various drug combinations, according to the period of treatment plus low-dose involved field radiation therapy (IFRT), was used in all patients. Five children experienced relapse and in 3 other patients second or third malignancies were documented. The overall survival was found to be 98%. No factors related to the outcome could be detected. The prognosis of children with Hodgkin lymphoma is excellent with CT combined with low dose IFRT but in long-time survivors late effects of the combined modality treatment are still issues of major concern. Longer followup of a greater number of patients is necessary to detect prognostic factors related to the outcome of children with Hodgkin lymphoma and to identify some patients who would be treated without radiation.

1081P - Low-Dose Involved-Field Radiotherapy in Relapsed Low-Grade Non-Hodgkin's Lymphoma in Elderly Patients (MANSOURA UNIVERSITY EXPERIENCE)

ABSTRACT Purpose To assess the response rate, duration of response and prognostic factors affecting response after low-dose involved field radiotherapy in patients with relapsed low-grade B-cell non-Hodgkin lymphoma. Patients and methods Forty-four patients of relapsed low grade B-cell non-hodgkin lymphoma were included. Patients were treated with, involved field radiotherapy of a total dose of 4 Gy (2 x 2 Gy) using 6-15 Mv photon or electron beam. Results Most patients were above age of 60 years (59%) with male predominance. Follicular lymphoma was the most common pathological type, bulky disease (>5 cm) was presented in 61.4%. Patients received only 2 regimens were 63.7% and 31.8% had > 2 involved sites. No treatment related toxicity was observed. The overall response rate was 88.7%; complete response was reached in 59.1% and stable disease in 6.8%, progressive disease in 4.5% .Median time to local progression was 33 months (95% CI 23.70-42.29), 2 –year local progression free survival was 78%. Response rate was found to be dependent on age, number of involved sites and lymph node size but independent on sex, pathological type, number of prior regimens, LDH level and time since diagnosis. Conclusion Short-course-low dose palliative radiotherapy (2 x 2 Gy) affords an attractive option for treatment of relapsed low-grade non-Hodgkin's lymphoma due to high response rates. However, these results had to be confirmed in a larger number of patients. Disclosure All authors have declared no conflicts of interest.

Impact of low‐dose involved‐field radiation therapy on pediatric patients with lymphocyte‐predominant Hodgkin lymphoma treated with chemotherapy: A report from the Children's Oncology Group

Treatment of pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) is controversial but has typically consisted of both chemotherapy and radiation. Radiation therapy is associated with potential late effects in children and adolescents. We examined the impact of radiation therapy on long-term outcome of patients with LPHL treated on CCG-5942, a large pediatric cooperative group study of Hodgkin lymphoma (HL). Eighty-two patients with LPHL were registered on CCG-5942. Fifty-two patients (63%) received chemotherapy alone; 29 patients (35%) received chemotherapy followed by involved-field radiation therapy (IFRT). The median follow-up of the LPHL patients is 7.7 years; 63 patients (77%) have >5 years of follow-up. The 5-year event-free survival (EFS) and overall survival (OS) were 97% and 100%. Two relapses occurred, both in patients who did not receive IFRT. There were no significant differences in EFS or OS between patients who received or did not receive IFRT. This subset analysis demonstrates the chemosensitivity of pediatric LPHL. Patients who had a complete response to chemotherapy had an excellent EFS and OS without the addition of radiotherapy.

Refining the Role of Radiation Therapy in Pediatric Hodgkin Lymphoma

The role of radiation therapy in the treatment of pediatric Hodgkin lymphoma has continued to be refined, motivated by the desire to avoid disruption to normal tissue development and function and secondary carcinogenesis. Such progress has occurred in tandem with modifications of the multiagent chemotherapy regimens that have been used in place of or in combination with low-dose involved-field radiation that are also associated with dose-related risks of cardiopulmonary and gonadal dysfunction and leukemogenesis. Consequently, treatment strategies for young patients, who have an excellent prognosis of long-term survival, utilizes a risk-adapted approach that provides optimal efficacy for disease control whereas limiting toxicity associated with both radiation and chemotherapy. Because of the differences in age-related developmental status and gender-related sensitivity to chemotherapy and radiation toxicity, no single treatment approach is ideal for all pediatric patients. This manuscript summarizes results from published clinical trials with the goal of defining optimal treatment strategies for children and adolescents with Hodgkin lymphoma in regards to the use of radiation therapy.

Long-term results of CCG 5942: a randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin's lymphoma--a report from the Children's Oncology Group.

In 1995, the Children's Cancer Group (CCG) opened a trial for patients with Hodgkin's lymphoma evaluating whether low-dose involved-field radiation therapy (IFRT) improved event-free survival (EFS) for patients achieving a complete response after chemotherapy. We present the long-term study outcome using final data through March 2007. Between January 1995 and December 1998, 826 eligible patients were enrolled onto CCG 5942. Four hundred ninety-eight patients achieving an initial complete response to chemotherapy were randomly assigned to receive IFRT or no further therapy. EFS and overall survival (OS) were assessed from the date of study entry or random assignment, as appropriate. Ten-year EFS and OS rates for the entire cohort were 83.5% and 92.5%, respectively. In an as-treated analysis for randomly assigned patients, the 10-year EFS and OS rates were 91.2% and 97.1%, respectively, for IFRT and 82.9% and 95.9%, respectively, for no further therapy. For EFS and OS comparisons, P = .004 and P = .50, respectively. Bulk disease, "B" symptoms, and nodular sclerosis histology were risk factors for inferior EFS. With a median follow-up of 7.7 years, IFRT produced a statistically significant improvement in EFS but no improvement in OS. For individual patients, the relative risks of relapse versus late effects of IFRT must be considered. Patient and disease characteristics and early response assessment will aid in deciding which patients are most likely to benefit from IFRT.

Stanford V chemotherapy and involved field radiotherapy for children and adolescents with unfavorable risk Hodgkin lymphoma: Results of a multi-institutional prospective clinical trial.

9502 Background: To evaluate the efficacy of 12 weeks of Stanford V chemotherapy (prednisone, vinblastine, doxorubicine, nitrogen mustard, etoposide, vincristine, and bleomycin) without routine growth factor support plus response-adapted low-dose, involved-field radiotherapy (IFRT) in children and adolescents with unfavorable risk Hodgkin lymphoma (HL). Methods: Multi-institutional (St. Jude Children’s Research Hospital, Stanford University, Children’s Hospital Boston, Massachusetts General Hospital and Maine Children’s Hospital) clinical trial. One hundred forty-one patients with clinical stages IIB (n=43), IIIB (n=19), IVA (n=27), and IVB (n=52) HL were treated with 12 weeks of Stanford V chemotherapy and low dose IFRT between June 2002 and May 2011. Involved nodal sites in complete remission (CR, defined as &gt; 75% shrinkage of the original tumor and PET negative) after 8 weeks of Stanford V received 15 Gy IFRT; those sites that achieved only partial response received 25.5 Gy IFRT after completion of all 12 weeks of chemotherapy. Results: With a median follow-up of 4.6 years, the 3-year overall and event-free survival (EFS) are 97% (SE=2%) and 79% (SE=4%) respectively. There was no significant difference in EFS by stage (IIB vs. IIIB vs. IV; P=0.84). Ten patients developed progessive disease and 18 relapsed, while 5 have died (1 after relapse in an accident and 4 of refractory disease). Most common toxicities were grade 3 hematologic with 234 episodes of neutropenia in 101 patients (72%) and 85 episodes of anemia in 52 patients (37%); Fever and neutropenia occurred 13 times in 12 patients (9%). Conclusions: Risk-adapted, combined-modality therapy using 12 weeks of Stanford V chemotherapy plus IFRT is well tolerated in this population with manageable acute toxicities. Overall survival is comparable to other more intense chemotherapy regimens. Future high-risk front line therapies may consider a Stanford V backbone with targeted intensification and further tailoring of radiation therapy.

Low-Dose Radiotherapy in Indolent Lymphoma

To assess the response rate, duration of response, and overall survival after low-dose involved-field radiotherapy in patients with recurrent low-grade lymphoma or chronic lymphocytic leukemia (CLL). Forty-three (24 women, 19 men) consecutive patients with indolent lymphoma or CLL were treated with a total dose of 4 Gy (2 × 2 Gy) using 6- 18-MV photons. The median age was 73 years (range, 39-88). Radiotherapy was given either after (n = 32; 75%) or before (n = 11; 25%) chemotherapy. The median time from diagnosis was 48 months (range, 1-249). The median follow-up period was 20 months (range, 1-56). The overall response rate was 90%. Twelve patients (28%) had a complete response, 15 (35%) had a partial response, 11 (26%) had stable disease, and 5 (11%) had progressive disease. The median overall survival for patients with a positive response (complete response/partial response/stable disease) was 41 months; for patients with progressive disease it was 6 months (p = 0.001). The median time to in-field progression was 21 months (range, 0-24), and the median time to out-field progression was 8 months (range, 0-40). The 3-year in-field control was 92% in patients with complete response (median was not reached). The median time to in-field progression was 9 months (range, 0.5-24) in patients with partial response and 6 months (range, 0.6-6) in those with stable disease (p < 0.05). Younger age, positive response to radiotherapy, and no previous chemotherapy were the best factors influencing the outcome. Low-dose involved-field radiotherapy is an effective treatment in the management of patients with recurrent low-grade lymphoma or CLL.

A Phase III Study for the Treatment of Children and Adolescents with Newly Diagnosed Low Risk Hodgkin Lymphoma (HL)

AbstractAbstract 767 Introduction:Optimal therapy for favorable risk HL in children and adolescents continues to evolve. Although the great majority of children will be cured, the potential for long-term adverse sequelae of treatment remains significant. Current regimens seek to define less toxic approaches that effectively treat low risk HL patients. The Children's Oncology Group (COG) HL studies have focused on the use of a response based paradigm for reduction of therapy. Methods:COG protocol AHOD0431 was a single arm study designed to investigate: 1) the rate at which three cycles of doxorubicin, vincristine, prednisone and cyclophosphamide (AVPC) induces complete response (CR), 2) whether achieving CR after 3 cycles of chemotherapy alone allows elimination of involved-field radiation therapy (IFRT), while maintaining excellent disease control and 3) whether very early response as measured by [18F]–fluorodeoxyglucose-positron emission tomography (FDG-PET) after the first course of chemotherapy is predictive of outcome. Eligibility requirements were: ages 0–21 years with newly diagnosed Stages IA and IIA HL without bulk and without lymphocyte predominance (LP) histology. All subject received chemotherapy. Patients who achieved a CR after 3 cycles of AVPC received no further therapy. Those with a partial response (PR) received 21 Gy IFRT. CR was defined as at least 80% reduction in the size of each of the nodal masses, or return to normal size, and negative findings on FDG-PET or Gallium scanning. Imaging studies were centrally reviewed. Results:287 subjects were enrolled between February, 2006 and December, 2008. 9 subjects were subsequently found to be ineligible, and an additional 3 were inevaluable for 3-cycle response. The CR rate after 3-cycles of AVPC was 63.6%, lower than the goal rate of 80%. However, event free survival (EFS) for the entire cohort at 2 years was 84%, and overall survival (OS) was 100%. Analysis by CR vs. PR status after 3 cycles of chemotherapy showed a 2 yr EFS of 80% for those achieving CR after 3 cycles of AVPC (no IFRT) vs. 88% for those achieving PR and therefore receiving IFRT (p=0.11). 227 subjects had evaluable FDG-PET results after one cycle of chemotherapy (PET1). Among subjects who achieved a CR (no IFRT) the 2 year EFS for PET1 positive/equivocal vs. negative was 65% vs. 87% (p=0.005). Among subjects who achieved a PR after 3 cycles of chemotherapy and received IFRT per protocol, 2 year EFS for PET1 positive/equivocal vs. negative was 82% vs. 96% (p=0.047). In December, 2008 the Study Committee recommended IFRT for all CR patients who were PET1 positive or PET1 status unknown, and were within one year of completing chemotherapy. 12 subjects received IFRT based on this recommendation, and all remain in CR. At a median f/u of 25 months, 46% of the entire cohort remain in CR without receiving any radiation therapy. Conclusions:Low risk HL in pediatric and adolescents is well recognized to be a highly curable malignancy, however late toxicities of therapy are frequent and may be life threatening or substantially affect quality of life. Nearly half of our patients have not received radiation therapy on this protocol. These outcomes are similar to other published pediatric regimens for low risk HL (excluding LP histology), even those that incorporated radiation therapy for all or most patients. The OS of 100% suggests that those who did recur after limited therapy were quite salvageable, many without aggressive salvage regimens or stem cell transplant. CR status after 9 weeks of chemotherapy may not optimally identify patients in whom IFRT can be avoided. Very early response, as measured by FDG-PET after 3 weeks of therapy, had significant prognostic implications in both CR and PR subjects, suggesting that this assessment may have a role in identifying a cohort of patients for whom limited volume/low dose RT remains an important component of therapy. Alternatively, AVPC may require intensification to optimize EFS while limiting need for IFRT. The role of a limited intensity chemotherapy regimen with low-dose IFRT for those subjects that experience localized recurrence after chemotherapy alone is the subject of an ongoing investigation. Disclosures:No relevant conflicts of interest to declare.

Autologous Peripheral Blood Stem Cell Transplantation in Children with Refractory or Relapsed Lymphoma: Results of Children’s Oncology Group Study A5962

This prospective study was designed to determine the safety and efficacy of cyclophosphamide, BCNU, and etoposide (CBV) conditioning and autologous peripheral blood stem cell transplant (PBSCT) in children with relapsed or refractory Hodgkin and non-Hodgkin lymphoma (HL and NHL). Patients achieving complete remission (CR) or partial remission (PR) after 2 to 4 courses of reinduction underwent a granulocyte-colony stimulating factor (G-CSF) mobilized PBSC apheresis with a target collection dose of 5 × 10⁶ CD34(+)/kg. Those eligible to proceed received autologous PBSCT after CBV (7200 mg/m², 450-300 mg/m², 2400 mg/m²). Forty-three of 69 patients (30/39 HL, 13/30 NHL) achieved a CR/PR after reinduction. Thirty-eight patients (28 HL, 10 NHL) underwent PBSCT. All initial 6 patients who received BCNU at 450 mg/m² experienced grade III or IV pulmonary toxicity compared to none of the subsequent 32 receiving 300 mg/m² (P < .0001). The probability of overall survival (OS) at 3 years for all patients is 51% and for transplanted patients is 64%. The 3-year event-free survival (EFS) is 38% (45% for HL; 30% NHL). The 3-year EFS in transplanted patients is 66% (65% HL; 70% NHL). Initial duration of remission of ≥12 versus <12 months was associated with a significant increase in OS (3 years OS 70% versus 34%) (P = .003). BCNU at 300 mg/m(2) in a CBV regimen prior to PBSCT is well tolerated in relapsed or refractory pediatric lymphoma patients. A short duration (<12 months) of initial remission is associated with a poorer prognosis. Last, a high percentage of patients achieving a CR/PR after reinduction therapy can be salvaged with CBV and autologlous PBSCT.

Advanced-Stage III/IV Follicular Lymphoma

In patients with advanced-stage III/IV follicular lymphoma (FL), there are many treatment options available. The current challenge is to choose the optimal strategy for the individual patient. The literature was reviewed with respect to treatment strategies in patients with advanced FL by screening the PubMed databank. In advanced-stage III/IV FL, median survival may approach 8-10 years. Treatment strategies include a watch-and-wait strategy, chemoimmunotherapy, monotherapy with rituximab, and - as an experimental approach so far - radioimmunotherapy. The use of autologous hematopoietic stem cell transplantation (HSCT) for patients in first remission or chemosensitive relapse prolongs progression-free survival while the effect on overall survival remains unclear compared to standard chemotherapy. However, long-term results are flawed by high relapse rates and risk of secondary malignancies. In patients with relapsed/chemoresistant disease, allogeneic HSCT constitutes the only curative approach but is associated with high treatment-related mortality. In the palliative setting, low-dose involved-field irradiation constitutes an effective treatment option in order to control local symptoms with potential long-lasting response. In case of advanced-disease FL, asymptomatic patients can be managed expectantly. In symptomatic patients, chemoimmunotherapy is regarded as standard therapy. In symptomatic elderly patients with relevant comorbidities, rituximab +/- single-agent chemotherapy, or low-dose involved-field radiotherapy might be appropriate. For younger patients with chemoresistant/relapsed disease, allogeneic HSCT might be considered, since advances in supportive care and better patient selection have resulted in improved outcomes.

Balancing Efficacy and Safety in the Treatment of Adolescents With Hodgkin's Lymphoma

Most children with Hodgkin’s lymphoma can expect to be cured with contemporary therapy. However, the improved survival in childhood cancer over the past decades has not been uniformly translated across older age groups, so that adolescents and young adults have not enjoyed the same progress in survival. Although variations in tumor biology may be responsible for some of these differences, access to care may play a more important and modifiable role. The success in pediatric oncology in Europe and the United States has largely been attributed to the almost uniform participation of children in clinical trials and the delivery of pediatric cancer care in specialized centers. In contrast, only 10% of adolescents and 1% to 2% of young adults are enrolled onto clinical trials. Historically, treatment approaches for Hodgkin’s lymphoma did not differ between children and adults, using similar extended radiation fields and doses (35 to 44 Gy) and chemotherapy regimens. However, severe musculoskeletal and soft tissue growth impairment in children and late-occurring second malignancies and cardiovascular complications motivated the development of treatment protocols prescribing lower doses of radiation (15 to 25 Gy) in combination with non–cross-resistant chemotherapy. To avoid radiation complications altogether, some pediatric investigators administered chemotherapy-alone regimens consisting of nitrogen mustard, vincristine, procarbazine, and prednisone (MOPP) or derivatives of the combination for up to 12 months. This approach proved to be quite effective in producing long-term disease-free survival in children with Hodgkin’s lymphoma and offered advantages for children treated at centers where radiation and precise clinical staging were difficult to perform. However, chemotherapy-alone protocols typically prescribe higher cumulative doses of alkylating agents compared with those used in combined-modality therapy regimens. Increased morbidity from myelosuppression, gonadal toxicity, and secondary leukemia eventually led to efforts to limit the use of MOPP. In pediatric protocols, cyclophosphamide, vincristine, procarbazine, and prednisone (COPP; the MOPP derivative that substitutes cyclophosphamide for nitrogen mustard) proved to have less leukemogenic potential and is still favored by many investigators today. The next generation of protocols was based on the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen, which did not by itself carry a significant risk of sterility or secondary malignancy. However, the ABVD combination is associated with anthracyclineinduced cardiotoxicity and bleomycin-induced pulmonary toxicity. ABVD, in combination with MOPP or COPP or as a hybrid, followed by low-dose involved-field radiotherapy achieved excellent results in pediatric trials. The hypothetical advantage of these hybrid and alternating regimens is lower cumulative doses of each agent and, possibly, enhanced antitumor effect; however, long-term effects of these regimens have not yet been systematically evaluated. The desire to further limit therapy-related long-term complications led to the development of ABVD derivatives like vinblastine, doxorubicin, methotrexate, and prednisone (VAMP); doxorubicin, bleomycin, vincristine, and etoposide (DBVE); and vincristine, procarbazine, prednisone, and doxorubicin (OPPA) or vincristine, etoposide, prednisone, and doxorubicin (OEPA; in which the procarbazine is substituted by etoposide in boys to reduce the dose of alkylators and the risk of infertility). Contemporary pediatric therapy largely using derivatives of the original MOPP and ABVD regimens in combination with or without low-dose (15 to 25 Gy), involved-field radiotherapy has led to event-free survival rates that exceed 80% for intermediateand high-risk patients and 90% for favorable-risk patients. Improvements in diagnostic imaging modalities have led to better characterization of the extent of disease involvement and have refined the concept of risk-adapted therapy. The routine use of functional imaging, initially performed with gallium scintigraphy and now largely replaced by [F]fluorodeoxyglucose positron emission tomography, has further enhanced the ability to differentiate active disease from sterile residual nodal masses. This modality continues to play an important role in modern response-based protocols in which especially low-risk patients achieving a complete response early on can be spared further radiotherapy. In the treatment of adults with Hodgkin’s lymphoma, medical oncologists have used a different paradigm than pediatric oncologists. The search for a regimen that would achieve higher cure rates has primarily been the driving force, and refinement of prognostic factors has helped characterize patients who would benefit from intensification of therapy, rather than reduction. More than 95% of patients with early-stage disease and 85% of patients with advanced-stage disease have been reported to achieve long-term survival on adult trials. For early-stage/favorable Hodgkin’s lymphoma presenting in adults, treatment with two to four cycles of ABVD followed by 30 Gy of involved-field radiotherapy is considered the standard of care. For patients with advanced-stage or unfavorable presentations of disease, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 36 DECEMBER 2

Local Progression after Low-dose Involved-field Radiation for Non-Hodgkin Lymphoma

Local Progression after Low-dose Involved-field Radiation for Non-Hodgkin Lymphoma