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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 1  |  Page : 1-6

Combined modality treatment: Outcome in patients with Hodgkin's lymphoma


1 Department of Radiation Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Radiation Oncology, MMIMSR, MMU, Ambala, Haryana, India
3 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission31-May-2017
Date of Acceptance25-Feb-2018
Date of Web Publication26-Oct-2018

Correspondence Address:
Budhi Singh Yadav
Department of Radiation Oncology, Regional Cancer Centre, Post Graduate Institute of Medical Education and Research, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_465_17

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 > Abstract 


Background: Hodgkin's lymphoma (HL) can be treated with combined modality treatment (CMT) to limit long-term toxicities in the early favorable stage. Early unfavorable and advanced stage HL is mainly treated with chemotherapy followed by radiation to the bulky site. This study examines the impact of CMT in early as well as advanced stage HL.
Materials and Methods: From 2001 to 2011, 125 patients with Stage I to IV HL were analyzed. Median age of the patients was 25 years (range 12–68 years). CMT, chemotherapy, and radiation alone were given to 51, 64, and 10 patients, respectively. Chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was given to 100 patients, 6 patients received ABVD-like regimen, and 9 patients received cyclophosphamide, vincristine, procarbazine, and prednisone regimen. Radiotherapy (RT) was given to 61 (49%) patients, involved field RT to 55 (90%), and extended-field RT to 6 (10%) patients, respectively. Median radiation dose was 30 Gy (18–40 Gy).
Results: All 25 patients with early-stage achieved complete response (CR) with CMT. At a median follow-up of 70 months (range 12–230 months), relapse was seen in two patients (1 local and 1 distant). Of 26 patients with advanced stage, 25 achieved a CR and 1 had stable disease with CMT. Relapse occurred in one patient (distant). In patients with early-stage treated with chemotherapy only ( n = 30, 24%), 9 patients had relapse (4 local and 5 distant) while in those with RT only ( n = 10, 8%), 4 developed distant relapse. In patients with advanced stage treated with chemotherapy only ( n = 34, 27%), 8 relapsed (5 local and distant, 3 distant only). Patients with relapse were salvaged with CMT ( n = 6), chemotherapy ( n = 15), or RT ( n = 3). Two patients have died. Five years' disease-free survival (DFS) in patients with early favorable stage, early unfavorable stage, and advanced stage was 91%, 82%, and 73%, respectively ( P = 0.026). DFS was significantly better with CMT than chemotherapy or radiation alone. Five years' overall survival (OS) was 93%, 92%, and 84%, respectively ( P = 0.139). Second malignancy occurred in 3 (2.4%) patients; carcinoma of the tongue, pseudomyxoma peritonei, and non-HL each, respectively. None of these patients had received prior radiation.
Conclusion: CMT improved DFS in patients with HL. OS was similar in all patients irrespective of treatment combinations. The incidence of second malignancy was 2.4%.

Keywords: Chemotherapy, combined modality, Hodgkin's lymphoma, radiotherapy


How to cite this article:
Yadav BS, Sharma SC, Malhotra P, Prakash G. Combined modality treatment: Outcome in patients with Hodgkin's lymphoma. J Can Res Ther 2020;16:1-6

How to cite this URL:
Yadav BS, Sharma SC, Malhotra P, Prakash G. Combined modality treatment: Outcome in patients with Hodgkin's lymphoma. J Can Res Ther [serial online] 2020 [cited 2020 Jul 8];16:1-6. Available from: http://www.cancerjournal.net/text.asp?2020/16/1/1/244217




 > Introduction Top


The management of Hodgkin's lymphoma (HL) has changed over the past 3 decades.[1] Combined modality treatment (CMT) has been shown to improve outcome in patients with HL. Early favorable stage HL patients are managed by chemotherapy alone 6 cycles or CMT with 2–4 cycles of chemotherapy and radiotherapy (RT) to the bulky site.[2],[3] In these patients, 2 cycles of chemotherapy with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 20 Gy of RT has been proven to be as effective as 4 cycles ABVD followed by 30 Gy RT (HD10).[4] Rationale behind such tailoring treatment is to reduce number of cycles of chemotherapy and RT dose to decrease long-term treatment-related toxicity of both the modalities and maintaining disease control rates, quality of life, and survival. In early-stage unfavorable HL, 4 cycles of baseline bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) does not significantly improve outcomes compared to 4 cycles of ABVD and 30 Gy of RT (HD11).[5] However, 2 cycles of BEACOPP and 2 cycles of ABVD followed by 30 Gy of RT was reported to improve freedom from treatment failure (FFTF) but not overall survival (OS) as compared to 4 cycles of ABVD followed by the same RT schedule (HD14).[6] BEACOPP cannot be administered in every setup because of its acute and late complications, so ABVD is still the standard regimen. Advanced stage HL is mainly treated with chemotherapy followed by radiation to the bulky site to consolidate the response. This study examines the impact of CMT in early as well as advanced stage HL.


 > Materials and Methods Top


From January 2001 to June 2011, 125 patients with HL with Ann Arbor Stage I to IV were analyzed. Pathologic specimens were reviewed by the hematologic pathologists of the institute according to the World Health Organization classification.[7] The stage was determined by clinical history, physical examination, and by computerized tomogram (CT) in all patients. Bulk was defined as mass >one-third of the maximal intrathoracic diameter by plain chest radiography or >10 cm by CT. Patients underwent standard staging studies to assess original extent of disease, including radiographic imaging (CT in conjunction with a positron emission tomography (PET) and routine blood tests including erythrocyte sedimentation rate, with or without a bone marrow biopsy. Staging was based on Ann Arbor classification.[8]

CMT was given to 51 patients, chemotherapy alone in 64 patients and radiation alone in 10 patients, respectively. Chemotherapy with ABVD regimen was given to 100 (80%) patients, 6 (5%) received ABVD-like modification, 5 (4%) received COPDAC-like regimen, and 4 (3%) received COPP regimen with a median number of 6 cycles. RT was delivered in 61 patients, as CMT in 51 (41%) and RT alone in 10 (8%) patients, respectively. RT was usually delivered after 3–6 weeks of completion of chemotherapy. Involved field RT (IFRT) was delivered in 57 (93%) and extended-field RT in 4 (7%) patients, respectively. Treatment techniques were two-dimensional or three-dimensional conformal treatment planning. Median RT dose was 30 Gy (range 18–40 Gy) with daily fraction of 1.8–2 Gy. Event-free survival (EFS) and OS were calculated from initiation of therapy until lymphoma relapse or death as a result of any cause and were plotted by the Kaplan and Meier method.


 > Results Top


Out of 125 patients, 87 (70%) were male and 38 (30%) were female. The median age was 25 years (range 6–68 years). B-symptoms were present in 52 (42%) patients. Supradiaphragmatic and infradiaphragmatic presentation was seen in 72 (58%) and 53 (42%) patients, respectively. Clinical Stage IA, IB, IIA, IIB, IIIA, IIIB, and IV disease was seen in 42 (34%), 3 (2%), 18 (14%), 11 (9%), 15 (12%), 15 (12%), and 21 (15%) patients, respectively. Classical HL was seen in 88 (60%) patients, the most common histology was nodular sclerosis 50 (40%) followed by mixed cellularity in 38 (30%) patients; 26 (21%) patients had HL not otherwise specified; nodular lymphocytic predominant histology was seen in 11 (9%) patients.

The clinical characteristics of patients with CMT and chemotherapy alone are outlined in [Table 1]. All 25 (100%) patients with early-stage achieved complete response (CR) with CMT. At a median follow-up of 70 months (range 12–236 months), relapse was seen in 2 (8%) patients (1 local and 1 distant). Out of 26 patients with advanced stage, 25 (96%) achieved a CR and 1 (4%) had stable disease with CMT. Relapse occurred in 1 (4%) patient at a distant site. In 30 patients with early-stage disease treated with chemotherapy alone, 9 (30%) patients had relapse (4 local and 5 distant) while out of 10 patients treated with RT alone, 4 (40%) developed distant relapse. In 34 patients with advanced stage treated with chemotherapy alone, 8 (23.5%) relapsed (5 local and distant, 3 distant only). None of the patients with CMT had local relapse as compared to 11 (17%) patients with chemotherapy alone. Distant relapse was also higher in patients treated with chemotherapy alone 6 (9%) as compared to 3 (6%) with CMT [Table 2].
Table 1: Patient characteristics

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Table 2: Pattern of relapse

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Out of 125 patients, two patients have died because of the disease. The other patients with relapse were salvaged with CMT in 6, chemotherapy in 13, and RT in 3, respectively. Five-year EFS and OS was 87% and 91%, respectively. In early favorable stage patients, EFS [Figure 1] was significantly better with CMT (100%) than chemotherapy (93%), or radiation alone (71%). In early unfavorable stage, patients EFS [Figure 2] was 83%, 61%, and 50% with CMT, chemotherapy, and RT alone, respectively ( P = 0.021). Similarly, in patients with advanced stage disease, 5-year EFS [Figure 3] was significantly better with CMT (96%) than chemotherapy alone (70%) P = 0.026. OS was not significantly different in all patients irrespective of treatment combinations. Survival and freedom from second treatment failure was better in patients who had relapse after RT as compared to chemotherapy alone or CMT. It was worse in patients who were treated with CMT at initial presentation. Median FFTF and OS were 72 and 79 months; 50 and 54 months; and 12 and 15 months, respectively, after salvage therapy in patients who were treated with RT alone, chemotherapy alone, and CMT, respectively. Leukocytopenia was most common acute toxicity with chemotherapy 50 (44%) followed by anemia in 7 (6%) patients [Table 3]. Acute radiation toxicity in the form of Grade 2 skin reaction and mucositis was seen in 11 (18%) patients [Table 4].
Figure 1: Event-free survival early favorable stage

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Figure 2: Event-free survival early unfavorable stage

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Figure 3: Event free survival advanced stage

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Table 3: Chemotherapy toxicity (n=115)

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Table 4: Radiotherapy toxicity (n=61)

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Two patients developed second malignancy; both were females. One developed carcinoma of the tongue and the other one pseudomyxoma peritonei. Both had not received any radiation in the respective sites. One male patient developed conversion to non-HL. He had also not received any radiation.


 > Discussion Top


In the present study, it was seen that CMT gives better EFS in patients with HL and this benefit was seen in all stages irrespective of risk stratification; however, there was no difference in OS. The late-term toxicity was minimal. HL is a curable disease, and patients achieve long-term survival, especially in an early stage. The aim of the treatment in these patients is to minimize long-term toxicities by tailoring treatment at the same time maintaining the survival advantage. Many trials have proved the benefit of CMT.[1],[2] In a study by Engert et al . in patients with early-stage HL and a favorable prognosis in German Hodgkin Study Group (GHSG) HD10 study, treatment with two cycles of ABVD followed by 20 Gy of IFRT was as effective as, and less toxic than, 4 cycles of ABVD followed by 30 Gy of IFRT. At 5 years, the rates of FFTF were 93.0% (95% confidence interval [CI], 90.5–94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3–93.2) with the two-cycle regimen. However, long-term effects of these treatments were not fully assessed because of a limited median follow-up of 79 months only. In the present study also, the EFS at 5 years was 94% with CMT which is comparable to that reported by GHLG HD10 study. In many studies, the omission of RT has been tried in patients with early favorable stage HL. In a study by Canellos et al . they concluded that 6 cycles of ABVD is an effective and safe treatment for limited-stage, nonbulky HL and would spare young patients from radiation toxicity. Salvage therapy was successful with second-line chemotherapy/radiation and autologous stem-cell transplantation in all patients who relapsed.[9] In the present study, CMT was used in patients with bulky disease or in those where treatment was tailored. The outcomes reported were better with CMT in all risk groups. However, many studies have also reported that RT is associated with the development of second malignancy 5–25 years after initial treatment,[10],[11],[12] so some studies have advocated the use of chemotherapy alone for patients with early-stage HL. In such patients, usually 6 cycles of ABVD is given, but this is not the standard treatment for patients with early favorable stage HL and the current literature also support this evidence.[13],[14],[15],[16],[17] For patients with early-stage HL, CMT approach has given better disease-free survival (DFS) when compared directly with chemotherapy alone in some studies[18],[19],[20],[21],[22] but not in others.[13],[17] However, at present, CMT approach is widely used as the treatment of choice in such group of patients with HL.

In the present study in early unfavorable stage patients, EFS was 81%, 63%, and 50% with CMT, chemotherapy, and RT alone, respectively, ( P = 0.021) which is comparable to the studies reported in the literature. In early unfavorable HL, GHLG HD 11 study found that moderate dose escalation using BEACOPP baseline did not significantly improve outcome but enhances toxicity, so they concluded that 4 cycles of ABVD should be followed by 30 Gy of IFRT as standard in these patients.[5] A similar study conducted by the European Organisation for Research and Treatment of Cancer–Groupe d'Etude des Lymphomes de l'Adulte (EORTC-GELA), the standard arm of 6 cycles of ABVD followed by 30 Gy of IFRT was compared with four cycles of ABVD or four cycles of BEACOPP baseline and IFRT of 30 Gy. The interim analysis of this H9U study concluded that there was no difference in response, EFS, or OS among the three treatment arms.[23] Recently, the GHSG HD14 trial demonstrated that 2 cycles of escalated BEACOPP and 2 cycles of ABVD, followed by 30 Gy of RT, was associated with better FFTF but not OS compared to 4 cycles of ABVD and the 30 Gy RT regimen.[6] Most recently a study by Torok et al . reported that lower doses of RT may be sufficient when combined with more than 4 cycles of ABVD for early stage, unfavorable HL and may result in a more favorable toxicity profile than 4 cycles of ABVD and 30 Gy of RT.[24] In a similar study published from India, the authors reported that with RT dose reduction in early stage unfavorable HL excellent disease control was seen in patients receiving 4–6 cycles of ABVD and 25 Gy following a CR to chemotherapy.[25] However, functional imaging was not used in this study.

Patients with early-stage HL survive longer, so there is always risk of second malignancy. In the present study, the incidence of second malignancy was only 2.4%. In GHLG HD10 study, the incidence of second malignancy was 4.6%, but there was no difference among different treatment groups.[4] None of our patients had second malignancy in the RT field, and only one patient developed mild late cardiac toxicity. She was treated with extended mantle field with a dose of 30 Gy at initial presentation, mechlorethamine, vincristine, procarbazine, and prednisolone regimen at first relapse and ABVD for the second relapse. Lower toxicity rate in the present study could be due to limited follow-up and small number of patients. Although it has been seen that more events occur with long follow-up, at this time, there is no excess risk of second malignancy. In GHLG HD11 study also, no differences in secondary neoplasia were observed between treatment arms or modalities.[5] Torok et al . in their study reported 7.7% incidence of second malignancy, 1% within the RT field.[24]

Survival and freedom from second treatment failure was better in patients who had relapsed after RT as compared to chemotherapy alone or CMT. It was worse in patients who were treated with CMT at initial presentation. Median FFTF and OS were 72 and 79 months; 50 and 54 months; and 12 and 15 months respectively after salvage therapy in patients who were treated with RT alone, chemotherapy alone and CMT, respectively. Similar findings were reported by Engert et al . in HD7 trial where survival in 68 patients who experienced relapse after EF-RT alone was significantly better than for those 10 patients who experienced relapse after CMT ( P = 0.003). Similarly, freedom from second treatment failure was better after EF-RT alone than after CMT ( P = 0.017).[26] There is a possibility that patients who receive fewer cycles of ABVD may become resistant to conventional chemotherapy.

PET has changed the management strategy in HL. Interim PET has been shown to have prognostic value in early-stage HL.[27] The potential effect of PET in patients with HL was suggested in a number of retrospective, nonrandomized studies.[28],[29] In both early favorable and early unfavorable HL, at present many ongoing trials are evaluating the role of PET in identifying patients who might not need additional RT or dose reduction after two to four cycles of initial chemotherapy. However, studies have shown that even with a negative interim[30] or end of treatment PET,[31] omission of RT is associated with a higher risk of relapse in early-stage HL. Another alternative to decrease radiation-induced late toxicity is the reduction of field size beyond IFRT. The EORTC-GELA group introduced the new involved-node RT (INRT) concept into the CMT of early HL. Here, RT is confined only to initially involved lymph nodes with an additional small isotropic margin.[32],[33] As seen in the present study, two-third of the patient treated with chemotherapy only relapsed locally in the nodes, so the concept of INRT was also developed in part based on the findings that recurrences in patients treated with chemotherapy alone typically occur in sites of initial nodal involvement. This technique should result in better DFS and less acute as well as late normal tissue toxicity.[34] Recently International Lymphoma Radiation Oncology Group, an international group of radiation oncologists expert in the treatment of lymphoma has published guidelines for “involved-site RT” in HL.[35]

Several ongoing trials are evaluating the role of PET in identifying patients with early HL and a favourable prognosis who might not need additional RT after two cycles of ABVD (the GHSG Hodgkin Disease 16 [the current GHSG HD16] trial [ClinicalTrials.gov number, NCT00736320]) or after three cycles of ABVD (the EORTC H10F trial [ClinicalTrials. gov number, NCT00433433] and others). INRT is also being evaluated in the ongoing EORTC-GELA and GHSG randomized trials H10U and HD17 for patients with early unfavorable HL.

The limitations of the study are its retrospective nature from a single institute with the limited patient number and follow-up with functional imaging done in only 27 (22%) patients for staging and response assessment.

Our experience further supports the fact that CMT is a reasonable approach with excellent disease control and minimal long-term toxicity in all stages in patients with HL. It is important for the Indian context with limited studies from our country. Our focus in the future would be the incorporation of modern RT techniques and use functional imaging for staging and therapy response assessment, RT field and dose reduction in patients with HL.


 > Conclusion Top


Our limited experience showed that CMT gives better EFS in patients with HL and this benefit was seen in all stages; however, there was no difference in OS. The late-term toxicity was minimal. Further follow -up and use of prospective functional imaging can strengthen these findings. Future studies should aim at reducing RT dose with effective and less toxic chemotherapy; avoid less effective and toxic drugs in ABVD regimen in CMT and adaptive RT with the incorporation of PET-CT.



Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

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