Journal of Medical Imaging and Radiation Oncology 58 (2014) 523–527 bs_bs_banner
R ADIATION O N C O LO GY —O R I G I N AL A RTICLE
Treatment outcomes for patients with chloroma receiving radiation therapy Matthew D. Hall,1 Yi-Jen Chen,1 Timothy E. Schultheiss,1 Richard D. Pezner,1 Anthony S. Stein2 and Jeffrey Y. C. Wong1 Departments of 1Radiation Oncology and 2 Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Cancer, Duarte, California, USA
MD Hall MD MBA; Y-J Chen MD PhD; TE Schultheiss PhD; RD Pezner MD; AS Stein MD; JYC Wong MD. Correspondence Dr Matthew D Hall, Department of Radiation Oncology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA. Email: [email protected] Conflict of interest: The authors declare no potential conflicts of interest. Submitted 22 January 2014; accepted 31 January 2014. doi:10.1111/1754-9485.12172
Abstract Introduction: This study aims to analyse treatment outcomes, disease control and toxicity in patients with chloromas referred for radiation therapy (RT). Methods: Medical records were retrospectively reviewed for 41 patients with chloromas treated with RT at our institution. Results: Twenty-five patients were treated with palliative intent, whereas sixteen received RT as a component of curative intent therapy in addition to systemic chemotherapy with or without haematopoietic stem cell transplant (HSCT). All patients received RT for chloroma (median dose 24 Gy). Median survival was 5.4 months after RT (95% confidence interval (CI) 3.5–12.6 months), and no significant difference in overall survival was identified based on prior treatment with systemic chemotherapy alone or HSCT. Patients treated with curative intent had a median survival of 26.2 months (95% CI 6.1–48.9 months) and a Kaplan–Meier estimate of 15% overall survival at 5 years. At the end of the study follow-up period, 38 patients were dead and three patients treated with curative intent remained alive. After palliative RT, 44% of patients experienced partial relief and 48% experienced complete symptomatic improvement without significant acute toxicities. Conclusions: RT provides timely symptom palliation for patients with chloromas with minimal morbidity, but the prognosis remains poor. Longterm remission can be achieved in selected patients with salvage chemotherapy and HSCT. Key words: acute myeloid leukaemia; granulocytic sarcoma; haematopoietic stem cell transplantation; myeloid sarcoma; total body irradiation.
Introduction Chloromas (granulocytic sarcomas) are extramedullary tumours of immature myeloid cells that develop in the setting of acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and accelerated phase myelodysplastic syndrome (MDS). First observed in 18111 and later characterised by King in 1853,2 the incidence of granulocytic sarcoma is estimated to range from 3.1% to 9.5% in AML but may be underestimated in certain groups, including patients with chromosome (8;21) translocation and children. Chloromas can present synchronously, after and rarely before the onset of leukaemia.3,4 The most commonly involved sites com© 2014 The Royal Australian and New Zealand College of Radiologists
prise the skin, soft tissue, bone, periosteum and lymph nodes, although any organ or tissue may be affected.5,6 Chemotherapy is the primary treatment modality for patients with chloroma. Radiation therapy (RT) is also utilised, although existing publications remain limited by small numbers of cases. Retrospective series have identified that RT provides safe and reliable local control and symptom palliation,7 but clear guidelines regarding the selection of patients who may benefit from RT are lacking. The purpose of this retrospective study is to analyse treatment outcomes, disease control and toxicity in patients referred for RT at our institution. As a major transplant centre, outcomes were also evaluated in patients treated with prior haematopoietic stem cell 523
MD Hall et al.
transplant (HSCT) with and without prior total body irradiation (TBI).
Table 1. Patient characteristics
Methods
Patients (n) Age (years) Median [range] Male [%] Haematologic diagnosis AML CML MDS RT dose (Gy) Median [range] RT to 2 + sites [%] Sites of chloroma Bone Soft tissue Other Prior treatment Chemotherapy only HSCT with TBI HSCT without TBI Treatment in addition to RT Chemotherapy HSCT Best supportive care
Forty-one patients were identified who received RT for chloroma at City of Hope National Medical Center in Duarte, California, between November 1999 and June 2011 by departmental database query. No patients had received prior RT for chloroma. A retrospective study was performed of patient characteristics and treatment outcomes with the approval of the institutional review board. Patient characteristics were entered into an electronic database, including age, gender, haematological diagnosis, site of chloroma, dose prescription, prior systemic therapy including HSCT, treatment intent, salvage therapy administered in addition to RT, recurrence of treated chloromas and new sites of relapse, timing of subsequent treatment courses, reported toxicities and disease status. Treatment intent was distinguished based on the purpose for RT either for symptom palliation or as a component of curative intent therapy. Treatment was considered curative in patients who were referred for RT with persistent disease or for local boost in addition to salvage systemic therapy and without palliative indications including pain, impending fracture and neurological deficit. Radiation treatment decisions and prescriptions were made at the discretion of the radiation oncologist. Survival curves were plotted by the Kaplan–Meier product limit method for the entire cohort and selected patient subgroups. Treatment-related toxicities were classified according to the Common Terminology Criteria for Adverse Events, version 3.0, scoring system. Patients were followed up to 01/05/2012, the study close-out date. Overall survival (OS) was measured from the start date of RT to the date of death from any cause. Progression free survival (PFS) was measured from the start date of RT to the date of progression on imaging, tissue biopsy or death from any cause. Survival times were censored at the close-out date for patients who remained alive (for OS) or alive without evidence of progression (for PFS). Local control was defined as the absence of clinical or radiographic evidence of disease progression within the irradiated volume or at the field margin.
Results Patient demographics, segregated by treatment intent, are presented in Table 1. The median age for patients treated with RT for chloromas was 37 years (range 12–77 years). The leukaemia diagnosis comprised 76% AML, 19% CML and 5% MDS. All patients had received prior systemic chemotherapy. Twelve patients were previously treated with systemic chemotherapy only, 15 patients had previously received HSCT with TBI and 14 patients had HSCT without TBI. The diagnosis of 524
Treatment intent
Curative
Palliative
16
25
29 [12–69] 7 [44]
42 [13–77] 19 [76]
13 2 1
18 6 1
24 [18–36] 3 [19]
24 [5–34] 5 [20]
9 7 3
15 9 7
2 5 9
10 10 5
9 7 0
20 0 5
AML, acute myeloid leukaemia; CML, chronic myeloid leukaemia; HSCT, haematopoietic stem cell transplant; MDS, myelodysplastic syndrome; RT, radiation therapy; TBI, total body irradiation.
chloroma was confirmed by biopsy in 82% of cases and by imaging and clinical features in the remainder. Ninety per cent of patients were confirmed to have concurrent bone marrow involvement in addition to extramedullary relapse. All patients in this series were treated with RT for chloroma. The chloroma-affected sites were extremity 34%, spine 20%, head and neck 15%, pelvis 12%, breast 9%, thorax 6% and central nervous system 4%. Eight patients were treated for two or more chloroma sites during the first course of RT. Median dose was 24 Gy (range 5–36 Gy) at 1.8–2.5 Gy per fraction. The prescription dose was ≥20 Gy in 87% of cases. Twenty-five patients were treated with palliative intent, whereas 16 received RT as a component of curative intent therapy. For the palliative care cases, 13 patients were treated for pain, 10 for neurological symptoms, one for airway obstruction and one for superior vena cava syndrome. Overall, 29 patients received salvage chemotherapy, 7 patients received chemotherapy followed by HSCT in addition to RT and 5 patients were treated with RT alone. In the subset of patients treated with curative intent, salvage therapy administered in addition to RT was systemic chemotherapy in nine patients and chemotherapy followed by HSCT in seven patients. Fourteen of the 16 patients in this subgroup had previously undergone HSCT and all received AML-like reinduction chemo© 2014 The Royal Australian and New Zealand College of Radiologists
Radiation therapy for chloroma
Fig. 1. Overall survival from the start date of radiation therapy (RT) for chloroma.
therapy. At the time of the study close-out date, 38 patients were dead and 3 patients treated with curative intent were alive and without evidence of disease 41 months, 105 months and 108 months after receiving RT for chloroma. The median OS for the entire cohort was 5.4 months (95% confidence interval (CI) 3.5–12.6 months). Patients treated with curative intent had a median OS of 26.2 months (95% CI 6.1–48.9 months) versus 3.2 months (95% CI 1.7–7.9 months) for patients treated with palliative RT. The Kaplan–Meier plot for OS of the entire cohort is displayed in Figure 1, and the OS curves stratified by treatment intent are shown in Figure 2. No significant difference in OS was identified based on prior treatment with HSCT versus chemotherapy alone or age (≥40 years versus 24 Gy). The median dose for retreatment was 24 Gy (range 15–30 Gy). Although local failure within the irradiated volume was relatively rare in the series, median PFS was only 3.6 months (95% CI 2.7–6.2 months) due to the competing effects of distant progression and death. In the subgroup treated with curative intent, median PFS was 12.6 months (95% CI 5.4–56.0 months), with no local failures recorded as the first site of failure. The Kaplan–Meier estimates of both 5-year OS and PFS in patients treated with curative intent were 15%. According to the radiation oncology treatment records, 44% of patients who received palliative RT experienced partial relief and 48% experienced complete symptomatic improvement after the completion of treatment. RT was generally well tolerated. One patient began palliative RT for a femoral lesion but suffered a pathological fracture during treatment after 5 Gy. This represented a single grade 4 musculoskeletal toxicity in this series, although not as a direct consequence of RT. The patient subsequently discontinued treatment in favour of hospice care. No grade 3 non-haematological treatmentrelated toxicities were reported. The most common reported acute toxicities were haematologic and gastrointestinal. The most common late toxicities were haematological and were likely multifactorial due to the combined effects of prior systemic therapies, underlying disease and RT.
Discussion Treatment strategies for chloromas remain highly individualised and are largely determined by performance status, response to systemic chemotherapy and guidance from retrospective studies. All patients in our series had previously been diagnosed with haematologic malignancy and were referred for radiation oncology consultation in the setting of disease relapse. Prior treatment with chemotherapy or HSCT had no significant effect on OS in our series. In general, patients were heavily pretreated with 71% having one or more prior HSCTs. The prognosis for patients with chloroma is poor; however, our results indicate that select patients may prove longterm survivors. The diagnosis of chloroma indicates systemic rather than localised disease, and chemotherapy with AML regimens is warranted.5,8 Lan et al. evaluated prognostic factors associated with survival in 24 patients with granulocytic sarcoma. Although RT and surgery provided rapid symptom improvement, patients receiving chemotherapy had superior 5-year OS compared with those who did not (24.3% versus 0%, P = 0.0009).9 Isolated chloroma arising in the absence of marrow involvement is rare, although most cases will develop AML with a median time ranging from 5 to 12 months.8,10,11 Antic et al. reported the outcomes for 12 patients treated for 526
isolated chloroma and found that disease-free survival was significantly longer for patients treated with systemic therapy in comparison with surgery alone in the absence of medullary involvement. In addition, patients who received chemotherapy plus HSCT had significantly longer event-free survival than those treated with chemotherapy alone.12 Two retrospective series reported favourable patient outcomes for myeloid sarcoma treated with HSCT. Pileri et al. assessed survival for 67 patients with chloroma, including 47 treated with chemotherapy and 10 treated with allogeneic or autologous HSCT. Patients treated with HSCT had longer 4-year OS (76% versus 0%, P < 0.0001) with a median follow-up of 150 months. Seven patients remained alive at time of analysis with six having received allogeneic HSCT.13 Chevallier et al. reported a 5-year OS estimate of 47% (95% CI 33%– 61%) in 51 patients with chloroma treated with allogeneic HSCT with a transplant-related mortality of 22% at 1 year. Thirty-nine per cent of patients relapsed at a median of 204 days after HSCT, with one-quarter successfully salvaged by a second allogeneic HSCT with complete response. Remission status at the time of HSCT was a significant predictor of improved OS (relative risk 0.22, 95% CI 0.08–0.57, P = 0.002).14 In our series, five of six patients surviving longer than 3 years were treated with HSCT plus localised RT for chloroma, and this combination was used in the only three patients surviving longer than 5 years. In patients treated with curative intent, salvage HSCT showed a non-significant trend towards improved OS versus salvage chemotherapy (P = 0.07), but this comparison was hampered by small sample size. Our results, however, are consistent with the findings of Pileri et al.13 and Chevallier et al.14 that treatment intensification with HSCT should be considered in patients with chloroma to achieve durable remission. In addition, patients in our series were all pretreated. Four of the six long-term survivors had previously been treated with HSCT. Our results suggest that select patients, even if previously treated with HSCT, can still achieve long-term remission with salvage HSCT plus local RT for chloroma. Few studies have addressed the role of RT in the management of patients who present with chloroma. RT provides effective symptom relief. In our cohort, 92% of patients with pain or other symptoms experienced partial or complete symptomatic relief following the completion of palliative RT. A regimen of 24 Gy in 12 fractions provided favourable rates of local control with safety and acceptable side effects, even in patients treated with prior TBI. This is consistent with the findings of Bakst et al.7 Tsimberidou et al. reported that treatment with RT in addition to chemotherapy was associated with better failure-free survival in non-leukaemic granulocytic sarcoma and that RT for consolidation in addition to chemotherapy may confer superior outcomes.11 Failure © 2014 The Royal Australian and New Zealand College of Radiologists
Radiation therapy for chloroma
to achieve complete response of chloroma also poses significant risk of early medullary relapse after systemic therapy.6 Bakst et al. suggest that RT be considered in patients with incomplete response to chemotherapy, recurrence after HSCT and for palliation.15 In our series, RT provided local control and palliation of symptoms in the majority of patients, but the overall poor prognosis indicates that better treatment options are still needed. Our study supports that long-term remission can be achieved with combined modality therapy and HSCT in selected patients. Retrospective design, small case numbers and subject heterogeneity are unavoidable limitations of this study on a rare clinical entity, which may contribute to selection bias. Despite the limitations inherent in this single institution series, our study is the largest to date for patients treated with RT for chloroma and verifies that RT should be considered in symptomatic patients and in the setting of disease relapse.
Conclusion RT provides timely symptom palliation for chloroma with modest doses and minimal morbidity, but the prognosis remains poor. Even in the setting of relapse after prior HSCT, long-term remission can still be achieved. In our series, selected patients treated with curative intent had long-term survival with salvage systemic therapy plus RT. Although not based on randomised data, several retrospective studies indicate that selected patients with chloroma may be cured with aggressive salvage chemotherapy and HSCT. Prospective clinical trials are unlikely given the rarity of chloroma, although collaboration by institutions and cooperative groups may help to formulate treatment guidelines. Further study of multimodality therapy is needed to better define the role of RT in patients with chloroma.
References 1. Burns A. Observations on the Surgical Anatomy of the Head and Neck. Thomas Royce, Edinburgh, 1811. 2. King A. A case of chloroma. Mon J Med 1853; 17: 97.
© 2014 The Royal Australian and New Zealand College of Radiologists
3. Muss HB, Moloney WC. Chloroma and other myeloblastic tumors. Blood 1973; 42: 721–8. 4. Byrd JC, Weiss RB, Arthur DC et al. Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. JCO 1997; 15: 466–75. 5. Paydas S, Zorludemir S, Ergin M. Granulocytic sarcoma: 32 cases and review of the literature. Leuk Lymphoma 2006; 47: 2527–41. 6. Byrd JC, Edenfield WJ, Shields DJ, Dawson NA. Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review. JCO 1995; 13: 1800–16. 7. Bakst R, Wolden S, Yahalom J. Radiation therapy for chloroma (granulocytic sarcoma). Int J Radiat Oncol Biol Phys 2012; 82: 1816–22. 8. Yamauchi K, Yasuda M. Comparison in treatments of nonleukemic granulocytic sarcoma: report of two cases and a review of 72 cases in the literature. Cancer 2002; 94: 1739–46. 9. Lan TY, Lin DT, Tien HF, Yang RS, Chen CY, Wu K. Prognostic factors of treatment outcomes in patients with granulocytic sarcoma. Acta Haematol 2009; 122: 238–46. 10. Neiman RS, Barcos M, Berard C et al. Granulocytic sarcoma: a clinicopathologic study of 61 biopsied cases. Cancer 1981; 48: 1426–37. 11. Tsimberidou AM, Kantarjian HM, Estey E et al. Outcome in patients with nonleukemic granulocytic sarcoma treated with chemotherapy with or without radiotherapy. Leukemia 2003; 17: 1100–3. 12. Antic D, Elezovic I, Milic N et al. Is there a ‘gold standard’ treatment for patients with isolated myeloid sarcoma? Biomed Pharmacother 2013; 67: 72–7. 13. Pileri SA, Ascani S, Cox MC et al. Myeloid sarcoma: clinico-pathologic, phenotypic and cytogenetic analysis of 92 adult patients. Leukemia 2007; 21: 340–50. 14. Chevallier P, Mohty M, Lioure B et al. Allogeneic hematopoietic stem-cell transplantation for myeloid sarcoma: a retrospective study from the SFGM-TC. JCO 2008; 26: 4940–3. 15. Bakst RL, Tallman MS, Douer D, Yahalom J. How I treat extramedullary acute myeloid leukemia. Blood 2011; 118: 3785–93.
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R ADIATION O N C O LO GY —O R I G I N AL A RTICLE
Treatment outcomes for patients with chloroma receiving radiation therapy Matthew D. Hall,1 Yi-Jen Chen,1 Timothy E. Schultheiss,1 Richard D. Pezner,1 Anthony S. Stein2 and Jeffrey Y. C. Wong1 Departments of 1Radiation Oncology and 2 Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Cancer, Duarte, California, USA
MD Hall MD MBA; Y-J Chen MD PhD; TE Schultheiss PhD; RD Pezner MD; AS Stein MD; JYC Wong MD. Correspondence Dr Matthew D Hall, Department of Radiation Oncology, City of Hope National Medical Center, 1500 East Duarte Road, Duarte, CA 91010, USA. Email: [email protected] Conflict of interest: The authors declare no potential conflicts of interest. Submitted 22 January 2014; accepted 31 January 2014. doi:10.1111/1754-9485.12172
Abstract Introduction: This study aims to analyse treatment outcomes, disease control and toxicity in patients with chloromas referred for radiation therapy (RT). Methods: Medical records were retrospectively reviewed for 41 patients with chloromas treated with RT at our institution. Results: Twenty-five patients were treated with palliative intent, whereas sixteen received RT as a component of curative intent therapy in addition to systemic chemotherapy with or without haematopoietic stem cell transplant (HSCT). All patients received RT for chloroma (median dose 24 Gy). Median survival was 5.4 months after RT (95% confidence interval (CI) 3.5–12.6 months), and no significant difference in overall survival was identified based on prior treatment with systemic chemotherapy alone or HSCT. Patients treated with curative intent had a median survival of 26.2 months (95% CI 6.1–48.9 months) and a Kaplan–Meier estimate of 15% overall survival at 5 years. At the end of the study follow-up period, 38 patients were dead and three patients treated with curative intent remained alive. After palliative RT, 44% of patients experienced partial relief and 48% experienced complete symptomatic improvement without significant acute toxicities. Conclusions: RT provides timely symptom palliation for patients with chloromas with minimal morbidity, but the prognosis remains poor. Longterm remission can be achieved in selected patients with salvage chemotherapy and HSCT. Key words: acute myeloid leukaemia; granulocytic sarcoma; haematopoietic stem cell transplantation; myeloid sarcoma; total body irradiation.
Introduction Chloromas (granulocytic sarcomas) are extramedullary tumours of immature myeloid cells that develop in the setting of acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML) and accelerated phase myelodysplastic syndrome (MDS). First observed in 18111 and later characterised by King in 1853,2 the incidence of granulocytic sarcoma is estimated to range from 3.1% to 9.5% in AML but may be underestimated in certain groups, including patients with chromosome (8;21) translocation and children. Chloromas can present synchronously, after and rarely before the onset of leukaemia.3,4 The most commonly involved sites com© 2014 The Royal Australian and New Zealand College of Radiologists
prise the skin, soft tissue, bone, periosteum and lymph nodes, although any organ or tissue may be affected.5,6 Chemotherapy is the primary treatment modality for patients with chloroma. Radiation therapy (RT) is also utilised, although existing publications remain limited by small numbers of cases. Retrospective series have identified that RT provides safe and reliable local control and symptom palliation,7 but clear guidelines regarding the selection of patients who may benefit from RT are lacking. The purpose of this retrospective study is to analyse treatment outcomes, disease control and toxicity in patients referred for RT at our institution. As a major transplant centre, outcomes were also evaluated in patients treated with prior haematopoietic stem cell 523
MD Hall et al.
transplant (HSCT) with and without prior total body irradiation (TBI).
Table 1. Patient characteristics
Methods
Patients (n) Age (years) Median [range] Male [%] Haematologic diagnosis AML CML MDS RT dose (Gy) Median [range] RT to 2 + sites [%] Sites of chloroma Bone Soft tissue Other Prior treatment Chemotherapy only HSCT with TBI HSCT without TBI Treatment in addition to RT Chemotherapy HSCT Best supportive care
Forty-one patients were identified who received RT for chloroma at City of Hope National Medical Center in Duarte, California, between November 1999 and June 2011 by departmental database query. No patients had received prior RT for chloroma. A retrospective study was performed of patient characteristics and treatment outcomes with the approval of the institutional review board. Patient characteristics were entered into an electronic database, including age, gender, haematological diagnosis, site of chloroma, dose prescription, prior systemic therapy including HSCT, treatment intent, salvage therapy administered in addition to RT, recurrence of treated chloromas and new sites of relapse, timing of subsequent treatment courses, reported toxicities and disease status. Treatment intent was distinguished based on the purpose for RT either for symptom palliation or as a component of curative intent therapy. Treatment was considered curative in patients who were referred for RT with persistent disease or for local boost in addition to salvage systemic therapy and without palliative indications including pain, impending fracture and neurological deficit. Radiation treatment decisions and prescriptions were made at the discretion of the radiation oncologist. Survival curves were plotted by the Kaplan–Meier product limit method for the entire cohort and selected patient subgroups. Treatment-related toxicities were classified according to the Common Terminology Criteria for Adverse Events, version 3.0, scoring system. Patients were followed up to 01/05/2012, the study close-out date. Overall survival (OS) was measured from the start date of RT to the date of death from any cause. Progression free survival (PFS) was measured from the start date of RT to the date of progression on imaging, tissue biopsy or death from any cause. Survival times were censored at the close-out date for patients who remained alive (for OS) or alive without evidence of progression (for PFS). Local control was defined as the absence of clinical or radiographic evidence of disease progression within the irradiated volume or at the field margin.
Results Patient demographics, segregated by treatment intent, are presented in Table 1. The median age for patients treated with RT for chloromas was 37 years (range 12–77 years). The leukaemia diagnosis comprised 76% AML, 19% CML and 5% MDS. All patients had received prior systemic chemotherapy. Twelve patients were previously treated with systemic chemotherapy only, 15 patients had previously received HSCT with TBI and 14 patients had HSCT without TBI. The diagnosis of 524
Treatment intent
Curative
Palliative
16
25
29 [12–69] 7 [44]
42 [13–77] 19 [76]
13 2 1
18 6 1
24 [18–36] 3 [19]
24 [5–34] 5 [20]
9 7 3
15 9 7
2 5 9
10 10 5
9 7 0
20 0 5
AML, acute myeloid leukaemia; CML, chronic myeloid leukaemia; HSCT, haematopoietic stem cell transplant; MDS, myelodysplastic syndrome; RT, radiation therapy; TBI, total body irradiation.
chloroma was confirmed by biopsy in 82% of cases and by imaging and clinical features in the remainder. Ninety per cent of patients were confirmed to have concurrent bone marrow involvement in addition to extramedullary relapse. All patients in this series were treated with RT for chloroma. The chloroma-affected sites were extremity 34%, spine 20%, head and neck 15%, pelvis 12%, breast 9%, thorax 6% and central nervous system 4%. Eight patients were treated for two or more chloroma sites during the first course of RT. Median dose was 24 Gy (range 5–36 Gy) at 1.8–2.5 Gy per fraction. The prescription dose was ≥20 Gy in 87% of cases. Twenty-five patients were treated with palliative intent, whereas 16 received RT as a component of curative intent therapy. For the palliative care cases, 13 patients were treated for pain, 10 for neurological symptoms, one for airway obstruction and one for superior vena cava syndrome. Overall, 29 patients received salvage chemotherapy, 7 patients received chemotherapy followed by HSCT in addition to RT and 5 patients were treated with RT alone. In the subset of patients treated with curative intent, salvage therapy administered in addition to RT was systemic chemotherapy in nine patients and chemotherapy followed by HSCT in seven patients. Fourteen of the 16 patients in this subgroup had previously undergone HSCT and all received AML-like reinduction chemo© 2014 The Royal Australian and New Zealand College of Radiologists
Radiation therapy for chloroma
Fig. 1. Overall survival from the start date of radiation therapy (RT) for chloroma.
therapy. At the time of the study close-out date, 38 patients were dead and 3 patients treated with curative intent were alive and without evidence of disease 41 months, 105 months and 108 months after receiving RT for chloroma. The median OS for the entire cohort was 5.4 months (95% confidence interval (CI) 3.5–12.6 months). Patients treated with curative intent had a median OS of 26.2 months (95% CI 6.1–48.9 months) versus 3.2 months (95% CI 1.7–7.9 months) for patients treated with palliative RT. The Kaplan–Meier plot for OS of the entire cohort is displayed in Figure 1, and the OS curves stratified by treatment intent are shown in Figure 2. No significant difference in OS was identified based on prior treatment with HSCT versus chemotherapy alone or age (≥40 years versus 24 Gy). The median dose for retreatment was 24 Gy (range 15–30 Gy). Although local failure within the irradiated volume was relatively rare in the series, median PFS was only 3.6 months (95% CI 2.7–6.2 months) due to the competing effects of distant progression and death. In the subgroup treated with curative intent, median PFS was 12.6 months (95% CI 5.4–56.0 months), with no local failures recorded as the first site of failure. The Kaplan–Meier estimates of both 5-year OS and PFS in patients treated with curative intent were 15%. According to the radiation oncology treatment records, 44% of patients who received palliative RT experienced partial relief and 48% experienced complete symptomatic improvement after the completion of treatment. RT was generally well tolerated. One patient began palliative RT for a femoral lesion but suffered a pathological fracture during treatment after 5 Gy. This represented a single grade 4 musculoskeletal toxicity in this series, although not as a direct consequence of RT. The patient subsequently discontinued treatment in favour of hospice care. No grade 3 non-haematological treatmentrelated toxicities were reported. The most common reported acute toxicities were haematologic and gastrointestinal. The most common late toxicities were haematological and were likely multifactorial due to the combined effects of prior systemic therapies, underlying disease and RT.
Discussion Treatment strategies for chloromas remain highly individualised and are largely determined by performance status, response to systemic chemotherapy and guidance from retrospective studies. All patients in our series had previously been diagnosed with haematologic malignancy and were referred for radiation oncology consultation in the setting of disease relapse. Prior treatment with chemotherapy or HSCT had no significant effect on OS in our series. In general, patients were heavily pretreated with 71% having one or more prior HSCTs. The prognosis for patients with chloroma is poor; however, our results indicate that select patients may prove longterm survivors. The diagnosis of chloroma indicates systemic rather than localised disease, and chemotherapy with AML regimens is warranted.5,8 Lan et al. evaluated prognostic factors associated with survival in 24 patients with granulocytic sarcoma. Although RT and surgery provided rapid symptom improvement, patients receiving chemotherapy had superior 5-year OS compared with those who did not (24.3% versus 0%, P = 0.0009).9 Isolated chloroma arising in the absence of marrow involvement is rare, although most cases will develop AML with a median time ranging from 5 to 12 months.8,10,11 Antic et al. reported the outcomes for 12 patients treated for 526
isolated chloroma and found that disease-free survival was significantly longer for patients treated with systemic therapy in comparison with surgery alone in the absence of medullary involvement. In addition, patients who received chemotherapy plus HSCT had significantly longer event-free survival than those treated with chemotherapy alone.12 Two retrospective series reported favourable patient outcomes for myeloid sarcoma treated with HSCT. Pileri et al. assessed survival for 67 patients with chloroma, including 47 treated with chemotherapy and 10 treated with allogeneic or autologous HSCT. Patients treated with HSCT had longer 4-year OS (76% versus 0%, P < 0.0001) with a median follow-up of 150 months. Seven patients remained alive at time of analysis with six having received allogeneic HSCT.13 Chevallier et al. reported a 5-year OS estimate of 47% (95% CI 33%– 61%) in 51 patients with chloroma treated with allogeneic HSCT with a transplant-related mortality of 22% at 1 year. Thirty-nine per cent of patients relapsed at a median of 204 days after HSCT, with one-quarter successfully salvaged by a second allogeneic HSCT with complete response. Remission status at the time of HSCT was a significant predictor of improved OS (relative risk 0.22, 95% CI 0.08–0.57, P = 0.002).14 In our series, five of six patients surviving longer than 3 years were treated with HSCT plus localised RT for chloroma, and this combination was used in the only three patients surviving longer than 5 years. In patients treated with curative intent, salvage HSCT showed a non-significant trend towards improved OS versus salvage chemotherapy (P = 0.07), but this comparison was hampered by small sample size. Our results, however, are consistent with the findings of Pileri et al.13 and Chevallier et al.14 that treatment intensification with HSCT should be considered in patients with chloroma to achieve durable remission. In addition, patients in our series were all pretreated. Four of the six long-term survivors had previously been treated with HSCT. Our results suggest that select patients, even if previously treated with HSCT, can still achieve long-term remission with salvage HSCT plus local RT for chloroma. Few studies have addressed the role of RT in the management of patients who present with chloroma. RT provides effective symptom relief. In our cohort, 92% of patients with pain or other symptoms experienced partial or complete symptomatic relief following the completion of palliative RT. A regimen of 24 Gy in 12 fractions provided favourable rates of local control with safety and acceptable side effects, even in patients treated with prior TBI. This is consistent with the findings of Bakst et al.7 Tsimberidou et al. reported that treatment with RT in addition to chemotherapy was associated with better failure-free survival in non-leukaemic granulocytic sarcoma and that RT for consolidation in addition to chemotherapy may confer superior outcomes.11 Failure © 2014 The Royal Australian and New Zealand College of Radiologists
Radiation therapy for chloroma
to achieve complete response of chloroma also poses significant risk of early medullary relapse after systemic therapy.6 Bakst et al. suggest that RT be considered in patients with incomplete response to chemotherapy, recurrence after HSCT and for palliation.15 In our series, RT provided local control and palliation of symptoms in the majority of patients, but the overall poor prognosis indicates that better treatment options are still needed. Our study supports that long-term remission can be achieved with combined modality therapy and HSCT in selected patients. Retrospective design, small case numbers and subject heterogeneity are unavoidable limitations of this study on a rare clinical entity, which may contribute to selection bias. Despite the limitations inherent in this single institution series, our study is the largest to date for patients treated with RT for chloroma and verifies that RT should be considered in symptomatic patients and in the setting of disease relapse.
Conclusion RT provides timely symptom palliation for chloroma with modest doses and minimal morbidity, but the prognosis remains poor. Even in the setting of relapse after prior HSCT, long-term remission can still be achieved. In our series, selected patients treated with curative intent had long-term survival with salvage systemic therapy plus RT. Although not based on randomised data, several retrospective studies indicate that selected patients with chloroma may be cured with aggressive salvage chemotherapy and HSCT. Prospective clinical trials are unlikely given the rarity of chloroma, although collaboration by institutions and cooperative groups may help to formulate treatment guidelines. Further study of multimodality therapy is needed to better define the role of RT in patients with chloroma.
References 1. Burns A. Observations on the Surgical Anatomy of the Head and Neck. Thomas Royce, Edinburgh, 1811. 2. King A. A case of chloroma. Mon J Med 1853; 17: 97.
© 2014 The Royal Australian and New Zealand College of Radiologists
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