Cyclophosphamide and Topotecan As First-Line Salvage Therapy in Patients with Relapsed Ewing Sarcoma at a Single Institution

ORIGINAL ARTICLE

Cyclophosphamide and Topotecan as First-line Salvage Therapy in Patients With Relapsed Ewing Sarcoma at a Single Institution

Rawad Farhat, MD,* Roy Raad, MD,w Nabil J. Khoury, MD,w Julien Feghaly, BS,* Touﬁc Eid, MD,z Samar Muwakkit, MD,* Miguel Abboud, MD,* Hassan El-Solh, MD,* and Raya Saab, MD*

stable disease (SD), with an overall objective response of Summary: The combination of cyclophosphamide and topotecan 35%.7 In a therapeutic window study conducted by the (cyclo/topo) has shown objective responses in relapsed Ewing sar- Children’s Oncology Group in the United States, treatment of coma, but the response duration is not well documented. We patients with Ewing sarcoma with cyclo/topo resulted in PR reviewed characteristics and outcome of 14 patients with Ewing in 21 of 37 patients, accounting for a response rate of 56%, sarcoma, treated uniformly at a single institution and offered cyclo/ 8 topo at first relapse. Six patients (43%) had relapse at distant and 15 more patients had SD. AreviewoftheGerman sites. All patients received first-line salvage therapy with cyclo- experience with this regimen, in patients with Ewing sarcoma phosphamide 250 mg/m2 and topotecan 0.75 mg/m2, daily for 5 days who received cyclo/topo at either first or second relapse, repeated every 21 days. The median number of cycles was 4 (range 1 showed a response rate of 32.6%.9 In that study, one third of to 10). All toxicities were manageable, the most common being the patients were alive at a median follow-up of 14.5 months transient cytopenias. There were also 4 episodes of febrile neu- (range, 2.1 to 59.8 mo), of whom a proportion had sub- tropenia, and 3 episodes of gross hematuria. Response was assess- sequently received other therapies. able in 13 patients and showed progressive disease in 6 (46%), stable Because of the promising early responses discussed disease in 4 (31%), and partial response in 3 (23%). Nine patients above, we decided to offer this combination as a first-line had local control, consisting of radical surgery in 2, radiation in 3, and a combination in 4 patients. Response, when it occurred, was salvage regimen for patients with first relapse or progres- maintained for a median of 8 months (range, 4 to 28 mo). Four sion of Ewing sarcoma, to identify the extent and duration patients (29%) are alive at 3, 7, 9, and 110 months after relapse; 1 is of response in this disease. We now report the results of receiving cyclo/topo, 1 is on third-line therapy, and 2 are in second treatment of Ewing sarcoma at first relapse with this com- and fourth remission. The low toxicity of this combination, and the bination, at a single institution and in a uniformly treated lack of sustained responses, warrant its investigation in combination patient population. with targeted or novel therapeutic agents in relapsed disease. Key Words: Ewing sarcoma, topotecan, cyclophosphamide, relapse, salvage therapy PATIENTS AND METHODS (J Pediatr Hematol Oncol 2013;35:356–360) All patients with first relapse or progression of Ewing sarcoma between January 2002 and December 2011, treated at the American University of Beirut Medical Center (AUBMC), were included. Clinical information was col- wing sarcoma is the third most common sarcoma in lected retrospectively from the medical records. This study childhood.1 With current multimodality therapy, approx- E was approved by the AUBMC Institutional Review Board. imately 40% of patients will experience disease recurrence or First-line treatment of all patients with Ewing Sar- progression.2 The outcome of patients with recurrent disease coma treated at the AUBMC after 2003 consisted of cycles is poor; especially those with disease not amenable to surgical of VDC (vincristine 2 mg/m2 IV push on day 1, doxorubicin resection or adequate local control.3–6 Over the past 10 years, 37.5 mg/m2/day as continuous infusion over 48 h, and a few new chemotherapeutic agents have been introduced, cyclophosphamide 1200 mg/m2/dose over 1 h on day 1), which have shown efficacy against Ewing sarcoma in phase II alternating every 21 days with IE (ifosfamide 1800 mg/m2/d clinical trials. The most effective such combination is that of IV over 1 h for 5 d and etoposide 100 mg/m2/day IV over 1 h cyclophosphamide and topotecan (cyclo/topo). In a phase II for 5 d), for a planned total of 14 cycles, as per the National study of patients with recurrent solid tumors, which included Cancer Institute protocol INT-0091.10 Before 2003, patients 17 patients with Ewing sarcoma, 2 achieved complete re- were treated with VDC alone, using the same doses as sponse (CR), 4 achieved partial response (PR), and 6 had described above. Upon documentation of disease relapse or progression, patients underwent staging of disease, and were then offered Received for publication February 27, 2012; accepted August 23, 2012. treatment with combination chemotherapy consisting of From the Departments of *Pediatric and Adolescent Medicine; 2 wDiagnostic Radiology; and zRadiation Oncology, American cyclophosphamide 250 mg/m /day as an infusion over University of Beirut, Beirut, Lebanon. 30 minutes, followed by topotecan 0.75 mg/m2/day over The authors declare no conflict of interest. 30 minutes, given daily for 5 days, and repeated every 21 Reprints: Raya Saab, MD, Department of Pediatrics, American Uni- versity of Beirut, Riad El Solh Street, Beirut 1107 2020, Lebanon days. Each cycle was followed by G-CSF support, and Mesna (e-mail: [email protected]). was used for uroprotection during and after the cyclo- Copyright r 2012 by Lippincott Williams & Wilkins phosphamide infusion.

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Response was evaluated by radiologic imaging (com- (5 pelvic, 3 chest wall, 1 scapula, 1 clavicle, 1 sinus), and in 1 puted tomography or magnetic resonance imaging) of all patient each was located in the axilla, extremity (femur), sites of disease after 2 cycles of chemotherapy then every 2 and multifocal bone. Three patients had initial metastatic to 3 cycles, or earlier if symptoms suggested disease pro- disease, and 2 patients with rib lesions had regional exten- gression. Response was defined as follows: CR was defined sive disease involving the pleural cavity. During their initial as resolution of all evidence of disease; PR as >25% reduc- treatment, all but 2 patients had received local control: tion in the sum of the maximum perpendicular diameters of 1 had undergone complete surgical resection of the tumor, all measurable lesions without appearance of any new 8 had undergone radiation alone, and 3 had undergone lesion or progression in any existing lesion; SD as <25% surgical resection as well as radiation therapy because of change in the sum of the maximum perpendicular diameters positive margins. For the 2 patients who did not receive of all measurable lesions without appearance of any new local control, the reasons were primary disease progression lesions; and progressive disease as >25% increase in the in 1 patient before timing of local control (patient #1), and sum of the maximum perpendicular diameters of any new-onset hepatitis C during therapy in the second patient, measurable lesion or appearance of any new lesion. so treatment had to be interrupted and local control was The incidence and pattern of toxicities were reviewed not pursued (patient #6). retrospectively, and were graded according to the CTCAE The patient characteristics at the time of first relapse version 4.0 criteria. Survival was defined as the time interval are detailed in Table 2. The median time to disease recur- from date of diagnosis of relapse/progression to either rence was 17.5 months (range, 6 to 36 mo). Eight patients death from any cause or last follow-up. Event-free survival had local or regional recurrences; the rest had recurrence at was defined as time to further disease progression, relapse, distant sites (2 presented with lung disease, 3 with bone or death from any cause. metastases, and 1 with bone marrow disease). Mean time of follow-up after start of salvage therapy was 35 months (median 32 mo; range, 2 to 110 mo). RESULTS Patient Characteristics Therapy Of a total of 41 patients with Ewing sarcoma treated at All 14 patients received combination chemotherapy our institution between January 2002 and December 2011, with cyclophosphamide and topotecan. As shown in recurrent disease occurred in 17 patients. Two patients Table 2, 2 patients also received oral Sirolimus during the refused further treatment upon relapse, and 1 patient was course of their treatment (3 mg/m2, maximum dose 5 mg, treated with a non–topotecan-containing regimen. There- orally once daily), and 1 patient (initially treated before fore these 3 patients were not included, and the study 2003 with VDC alone) received cyclo/topo alternating with included a total of 14 patients. ifosfamide/etoposide. The patient characteristics are detailed in Table 1. A total of 64 cycles of cyclo/topo chemotherapy were Median age was 11 years (range, 2 to 19 y). Three patients given, with a median number of 4 cycles per patient (range, had not completed the planned first-line therapy for initial 1 to 10 cycles per patient). Treatment-related toxicities were disease: 2 because of primary progression of disease while manageable, with the most frequently encountered tox- on first-line therapy (patients 1 and 2 in Table 1); and the icities being primarily limited to mild, transient cytopenia. third patient had interruption of his initial treatment after 8 Treatment was stopped because of either disease pro- cycles because of active hepatitis C infection, and subse- gression, or after at least 8 cycles in patients who achieved quently returned with disease progression (patient 6 in complete remission; no patient had treatment terminated Table 1). Primary tumor site was axial in 11 patients due to toxicity.

TABLE 1. Patient Characteristics at Initial Treatment Patient Age (y) Initial Site Initial Stage Local Control Used During Initial Therapy 1* 10 Scapula Metastatic None 2* 8 Pelvis Metastatic XRT 3 12 Clavicle Localized Surgery + XRT 4 11 Chest wall Regional extension (pleural deposits) Surgery + XRT 5 15 Pelvis Localized XRT 6w 5 Chest wall Regional extension (pleural deposits) None 7 15 Femur Localized Surgery 8 15 Bone (multifocal) Metastatic XRT to activez lesions 9 2 Pelvis Localized XRT 10 11 Pelvis Localized XRT 11 19 Sinus Localized XRT 12 4 Chest wall Localized Surgery + XRT 13 10 Pelvis Localized XRT 14 12 Axilla Localized XRT

*Treatment stopped early because of progressive disease. wTreatment stopped early because of active hepatitis C. zActive lesions deﬁned by continued avidity on technetium bone scan after chemotherapy. XRT indicates radiation. r 2012 Lippincott Williams & Wilkins www.jpho-online.com | 357 Farhat et al J Pediatr Hematol Oncol Volume 35, Number 5, July 2013

TABLE 2. Patient Characteristics at Relapse and Response to Cyclo/Topo Patient Time to Relapse (mo) Relapse Site No. Cycles Response Local Controlz Outcome (mo) 1 7 Lung 1 PD None DOD (2) 2 6 Bone 1 PD None DOD (3) 3 12 Lung 3 PD None DOD (12) 4 15 Local 2 PD XRT DOD (9) 5 24 Local 4 SD GTR DOD (10) 6 6 Local 8 PR GTR + XRT DOD (11) 7 14 Bone + Lung 9* SD XRT DOD (14) 8 15 Bone 10* SD XRT DOD (14) 9 21 Local 4 SD GTR DOD (17) 10 20 Local 3 PD None DOD (22) 11 33 Local 1 PD GTR + XRT NED on therapy in CR2 (7) 12 34 Local 8w PR GTR + XRT NED oﬀ therapy in CR4 (110) 13 36 Local + Bone 2 PR None AWD on therapy (3) 14 32 Local 8 NA GTR + XRT NED on therapy in CR2 (9)

*Patient received oral sirolimus during treatment with cyclo/topo. wPatient received only VDC initially. At relapse treated with cyclo/topo alternating with ifosfamide/etoposide, and received 8 cycles of each. zLocal control during or immediately after cyclo/topo salvage therapy. AWD indicates alive with disease; CR2, second remission; CR4, fourth remission; DOD, dead of disease; GTR, gross total resection; NA, not assessable; NED, no evidence of disease; PD, progressive disease; PR, partial response; SD, stable disease; XRT, radiation.

Toxicities: Hematologic toxicity was frequent. There a large retrospective study.12 Several chemotherapeutic were 20 episodes of grade 3-4 thrombocytopenia, which agents and regimens have shown efficacy in relapsed Ewing occurred in 5 of the 14 patients (range, 0 to 8 episodes per sarcoma, including cyclo/topo,7–9 irinotecan/temozolomide,13,14 patient). Grades 3 to 4 anemia occurred in 8 of the 14 and high-dose ifosfamide alone, or ifosfamide as part of ICE patients for a total of 23 episodes (range, 0 to 8 episodes per (ifosfamide, carboplatin, and etoposide).15,16 Other agents that patient); and grades 3 to 4 neutropenia in 11 of 14 patients, have shown promising activity include gemcitabine/docetaxel,17 with a total of 31 occurrences (range, 0 to 5 episodes per ecteinascidin-743,18,19 and recently developed targeted agents patient). Despite the frequent cytopenias, there were a total such as mTOR inhibitors, IGF1R-inhibitors, bevacizumab, of 4 episodes of febrile neutropenia (grade 3), which were and others.20,21 The emergence of new agents that have demo- managed by prompt inpatient intravenous antibiotics. Other nstrable efficacy against relapsed Ewing disease now neces- encountered toxicities were 3 episodes of hemorrhagic cys- sitates review of the available combination therapies to decide titis in 2 patients; of note, 1 patient had tumor invading the which are most suitable for further investigation, alone or in bladder wall (patient #2), which may have contributed to combination, to improve salvage rates after recurrence. The the hematuria, and he had disease progression after 1 cycle fact that patients are treated heterogenously after relapse makes of cyclo/topo. The other patient had 2 episodes of hemor- it difficult to draw conclusions about efficacy of a particular rhagic cystitis (grade 3), and was able to receive subsequent regimen, as prior exposure to different chemotherapeutic agents cycles of cyclo/topo. There were no toxic deaths. may modulate response to therapy. We therefore performed this study to better define the extent and duration of response Response and Outcome to cyclo/topo, at first relapse in a uniformly treated population One patient could not be assessed for response because of patients with Ewing sarcoma. he underwent upfront complete tumor resection. Thus he Our results show that response rates to cyclo/topo at was in CR postoperatively, and no measurable disease was first relapse of Ewing sarcoma are very similar to those present at commencement of adjuvant cyclo/topo chemo- reported in a mixed cohort of patients treated at either first 9 therapy. Of the assessable 13 patients, 6 (46%) had disease or second relapse, and similar to results seen in phase II progression after 1 to 3 cycles, whereas 3 (23%) showed a trials conducted on patients with relapsed or refractory 7 measurable PR, and 4 (31%) had SD. For the 7 patients solid tumors. In addition, as previously reported, we found who showed PR or SD, the response was maintained for a that this regimen was associated with a very tolerable tox- median of 8 months (range, 4 to 28 mo). icity profile, with manageable cytopenias as the most Four of the 14 patients are currently alive: 1 continues common complication. Despite stabilization of disease and to receive cyclo/topo therapy with residual active disease; 1 measurable response in up to 46% of patients (6 out of 13); underwent upfront resection followed by 8 cycles of therapy only 4 patients (28%) are currently alive. Only 1 patient is and is in sustained second CR; 1 experienced disease pro- in maintained remission after cyclo/topo alone; 2 of the gression, underwent aggressive resection and is currently remaining 3 survivors had further disease progression after on second-line salvage therapy with no active disease; and cyclo/topo and responded to third-line therapy, and 1 1 patient is in sustained fourth complete remission 110 patient is still on treatment with active disease. Thus, treat- months after initial relapse. ment with cyclo/topo seems to induce responses in a subset of patients, but rates of long-term remission remain low. Of note, 2 of our patients received daily oral sirolimus in DISCUSSION addition to cyclo/topo at first relapse; these 2 patients had The outcome after relapse of Ewing sarcoma continues disease stabilization for 8 and 12 months, and no significant to be quite poor,4,5,11 as has been recently confirmed in side effects were noted. Whether sirolimus contributed

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TABLE 3. Outcome by Local Control Modality GTR GTR + XRT XRT None No. patients 2 4 3 5 Disease site Local Local 2 Metastatic* 3 Metastatic Response to cyclo/topo (no. patients) SD (2) PR (2) SD (2) PR (1) PD (1) PD (1) PD (4) Not assessable (1) Outcome [follow-up (mo)] 2 DOD (10, 17) 1 DOD (11) 3 DOD (9, 14, 14) 1 AWD (3) 3 NED (7, 9, 110) 4 DOD (2, 3, 12, 22)

*Both patients who had metastatic disease also received sirolimus during treatment. AWD indicates alive with disease; DOD, dead of disease; GTR, gross total resection; NED, no evidence of disease; PD, progressive disease; PR, partial response; SD, stable disease; XRT, radiation.

to this prolonged disease stabilization is unclear, but this Interestingly, the longest survivor in our series had combination may warrant further study in high-risk sar- disease that continued to show chemosensitivity despite comas, based on preclinical reports of synergism between multiple disseminated recurrences, and who continued to cyclophosphamide and sirolimus in pediatric sarcomas.22 have durable responses to therapy after each recurrence. The majority of disease sites in our reported series This patient had a late relapse (34 mo from diagnosis), and were local/regional recurrences. Of a total of 41 patients has achieved chemotherapy-induced remissions after a local with Ewing sarcoma, recurrent disease occurred in 17, and recurrence (reported here), then a recurrence with brain 14 of those were included in this study. Of the 17 patients, metastases (treated with irinotecan/temodal and radiation 8 (47%) had local recurrences, and 1 (6%) had both local therapy), and then a recurrence with disseminated bone and metastatic disease. The rate of local versus distant re- marrow disease (treated with gemcitabine/docetaxel). He is currences differs among reported series. For example, in the now doing well with no evidence of disease, 9 years after review of 220 patients treated at St Jude Children’s initial salvage therapy and 12 years from initial diagnosis. Research Hospital, 43% of recurrences were local/regional, This points to inherent biological differences among Ewing and an additional 18% had both local and metastatic sarcoma tumors, and serves as an example that therapy relapse.23 In another series from Italy, local sites accounted may continue to be successful in some patients despite for only 27% of recurrences, most of which were also multiple recurrences. associated with synchronous metastatic progression.24 The Our results show that, in a homogenously treated small number of patients in our report precludes any patient population at a single institution, cyclo/topo could definitive comparisons, because of potential biases due to achieve measurable response and disease stabilization in a individual patient risk features. For example, 7 of the 8 subset of patients with Ewing sarcoma at first relapse. patients with local/regional recurrences in our series had However, the response was short-lived in the majority of tumor location at axial sites, 2 of the 3 patients with patients. The lack of durability of response and the low- recurrent chest wall tumors had initial multiple pleural toxicity profile, both warrant the future investigation of deposits, and the third had not undergone initial local regimen that add other active agents to this chemo- control because of acute hepatitis C infection. therapeutic backbone in relapsed disease. Such regimen In our series, aggressive surgical local control was may include irinotecan/temozolomide, which have shown pursued in patients in whom the tumor was deemed re- activity in relapsed Ewing sarcoma,13,14 especially because sectable, and radiation was performed for positive margins the mechanism of tumor resistance to irinotecan seems when possible. A recent study showed that local control to be different than that to topotecan25; other possibilities was associated with a better survival in relapsed Ewing could involve addition of targeted agents such as inhib- sarcoma,9 whereas a prior study showed that it had no itors of the mTOR and/or the insulin growth factor prognostic significance.11 Nine of our 14 patients had local pathways.21,26,27 control pursued. Patient outcome by local control is shown in Table 3. Six patients achieved complete surgical resec- REFERENCES tion, and 4 of those also received postoperative radiation 1. Crist WM, Kun LE. Common solid tumors of childhood. therapy. The remaining 3 patients had unresectable tumors, N Engl J Med. 1991;324:461–471. and received radiation therapy as the only local control 2. Bernstein M, Kovar H, Paulussen M, et al. Ewing’s sarcoma modality. Of the 6 patients who underwent complete tumor family of tumors: current management. 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