Pediatric Hematology and Oncology, 30:170–177, 2013 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2013.767868
SARCOMA
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A Modified Protocol with Vincristine, Topotecan, and Cyclophosphamide for Recurrent/Progressive Ewing Sarcoma Family Tumors Rejin Kebudi,1,2 Fatma Betul Cakir,3 Omer Gorgun,1,2 Fulya Yaman Agaoglu,2 and Emin Darendeliler2 1
Department of Pediatric Hematology-Oncology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey; 2 Institute of Oncology, Istanbul University, Istanbul, Turkey; 3 Department of Pediatric Hematology-Oncology, Bezmialem Vakif University, Istanbul, Turkey
Purpose: Topotecan has recently been used in the treatment of pediatric cancer. We evaluated our experience with the modified combination of vincristine, topotecan, and cyclophosphamide (VTC) given in 3 days, in children with recurrent Ewing sarcoma. Method: Children received vincristine (1.5 mg/m2 /1st day), cyclophosphamide (600 mg/m2 /day × 2 days) + mesna, and topotecan (1 mg/m2 /day × 3 days) every 21 days. Result: A total of 118 courses of VTC were given to 13 patients. One patient received VTC both at first and at second relapse. Thus, 14 relapse episodes in 13 patients were evaluated. After three courses of VTC chemotherapy (CT), two achieved complete response (CR), five achieved partial response, thus an objective response was attained in 7/14 (50%) episodes. Two patients had stable disease and two patients progressed. In three episodes, CR was achieved by surgery before CT. One of them had a second relapse and attained CR with VTC. Median time from diagnosis to relapse was 23 months (5–45 months). Site of relapse was local in four patients, and metastatic in 10 episodes of nine patients. Seven patients are alive, three with no evidence of disease and four alive with disease; six have died of disease. Local treatment was used in 11 episodes. The toxicity of the VTC combination was limited mainly to the hematopoietic system. Conclusion: In conclusion, the modified VTC protocol in 3 days every 3 weeks seems to be effective and tolerable in children and adolescents with recurrent/progressive Ewing sarcoma. Keywords chemotherapy, Ewings sarcoma, pediatric oncology, topotecan
INTRODUCTION Current treatments using multiagent chemotherapy (CT) combined with surgery and/or radiation can now cure the majority of patients with localized Ewing sarcoma. However, outcomes are much worse for patients who develop disease recurrence after initial therapy, or who have metastases at diagnosis [1]. Unfortunately, fewer than 20% of patients with relapsed Ewing sarcoma are likely to be long-term survivors [2]. Thus, novel therapeutic approaches are necessary to improve overall survival for these patients. Camptothecin agents have been evaluated in Ewing sarcoma patients for the Received 30 October 2012; accepted 15 January 2013; published online 2013. Address correspondence to Prof. Dr. Rejin Kebudi, Department of Pediatric Hematology-Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey. E-mail:
[email protected]
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Topotecan for Relapsed Ewing Sarcoma
last decade. They exert cytotoxicity by stabilizing the covalent complex between DNA and topoisomerase I, the enzyme which relieves torsional strain of DNA. This stabilization process prevents relegation of DNA, and the ensuing collision of the stabilized complex with the advancing replication fork results in double strand breaks and cell death [3]. Preclinical studies have shown synergistic antitumor activity of combinations of camptothecin agents and alkylating agents [4]. Responses of about 33–35% have been reported with cyclophosphamide 250 mg/m2 and topotecan 0.75 mg/m2 , both administered daily for 5 days [5, 6]. Thus, this schedule has been used in recurrent/progressive Ewing sarcoma and in other solid tumors. In this study, we evaluated our experience with a modified protocol with the combination of vincristine, topotecan, and cyclophosphamide (VTC) given in 3 days as a second-line treatment in children with recurrent/progressive Ewing sarcoma in our institute. We added vincristine to the 2-drug combination, and administered topotecan for 3 days and cyclophosphamide for 2 days. The main aim of this modified schedule was to improve the quality of life of the patients, most of them were adolescents, providing them a shorter duration in the hospital. METHODS All newly diagnosed Ewing sarcoma patients had received a first-line treatment consisting of ifosfamide–etoposide alternating with vincristine–doxorubicin and cyclophosphamide (IE/VAC) for 1 year; actinomycin being substituted for doxorubicin after a total dose of 375 mg/m2 , and local therapy with surgery and/or radiotherapy (RT). Until May 2009, multiple salvage CT regimens including oral etoposide [7], ifosfamide–carboplatin–etoposide, and cisplatin–etoposide were used in relapse Ewing sarcoma patients in our institution. Since then, recurrent/progressive Ewing sarcoma patients received vincristine (1.5 mg/m2 /1st day), cyclophosphamide (600 mg/m2 /day × 2 days) + mesna, and topotecan (1 mg/m2 /day × 3 days) every 21 days as the second-line treatment. Fourteen relapse episodes in 13 patients with Ewing sarcoma treated in the Oncology Institute of Istanbul University were prospectively assessed in this study. With this modified protocol, patients were hospitalized for 2 nights and discharged the third day after the topotecan administration. The main aim of this modified schedule was to improve the quality of life of the patients, most of them were adolescents, providing them a shorter duration in the hospital. The secondary aim was to measure the response of this modified protocol having almost the same doses of the original topotecan–cyclophosphamide treatment [5, 6]. Supportive care including antiemetics, hydration, and granulocyte colony-stimulating factors (GCSFs) (filgrastim or lenograstim) were used. This institutional protocol was approved by the local ethics committee and informed consent was obtained from parents of all patients. The protocol was designed for an initial accrual of 10 patients. Patients were evaluated clinically by physical examination after each cycle, and with imaging studies after three cycles if no overt progression was observed until then taking into account cost-effectiveness of imaging studies. Relapse patients having their tumor removed prior to VTC were enrolled in the study, however they were not assessed for tumor response, but for median survival duration. Subsequent relapses after termination of treatment were eligible if the prior episode was responsive to VTC. Response was assessed by computerized tomography, magnetic resonance imaging (MRI), bone scintigraphy, and/or fluorodeoxyglucose–positron emission tomography–computed tomography (FDG–PET–CT) depending on the localization of the recurrent tumor and/or metastasis. A complete response (CR) was defined as resolution of all evidence of disease for at least 4 weeks. Partial response (PR) was defined as 50% reduction in the sum of the maximum perpendicular diameters of all measurable lesions for at C Informa Healthcare USA, Inc. Copyright
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least 4 weeks without progression of any existing lesions or appearance of new lesions. Radiological PR of the patients having recurrence in a bone was determined as diminished contrast enhancement and increase in fibrosis in repeated MRI. Stable disease (SD) was defined as less than 25% decrease in the sum of the maximum perpendicular diameters of all measurable lesions without appearance of new lesions. Progressive disease (PD) was defined as 25% increase in the sum of the maximum perpendicular diameters of any measurable lesion and/or appearance of new lesions. Toxicity was graded using the National Cancer Institute Common Toxicity Criteria [8]. Toxicity was evaluated after each course of VTC by checking complete blood count and chemistry.
RESULTS Thirteen patients, seven boys and six girls, with a median age of 13 years (3–16 years) were evaluated. A total of 118 courses of VTC were given to 13 patients (Table1). Four patients were metastatic at diagnosis (one lung, three both lung and bone). One patient received VTC both at first and at second relapse. Thus, 14 relapse/progressive episodes in 13 patients were evaluated. After three courses of VTC, two patients achieved CR and five patients achieved PR, thus an objective response was attained in 7/14 (50%) episodes. Two patients had SD and two patients progressed after three courses of VTC. Three more patients who had attained CR by surgery at relapse had continued CR after three courses of VTC; one of the patients had a second relapse and attained CR with VTC. Median follow-up time from diagnosis to the last visit or death of the patients was 41 months (10–76 months). Median time from diagnosis to relapse/progression was 23 months (5–45 months). Site of relapse/progression was local in four patients, and metastatic in 10 episodes of nine patients (three lung only, bone ± lung in others). Seven patients are alive, three with no evidence of disease (NED) (25+, 26+, 31+ months from relapse) and four alive with disease (AWD) (8+, 15+, 15+, 19+ months from relapse/progression), six have died of disease (DOD) at a median of 11 months after relapse/progression. Median survival duration after relapse was 15 (5–31 months) (Table1). One of the patients who is AWD, responded to the VTC treatment only without any local therapy, had regression in the mass in MRI and there was no uptake at FDG–PET–CT for the last 9 months, whereas a hypermetabolic uptake in FDG–PET–CT at initial progression was detected (Patient 3). Another patient, who is AWD also, had regression in the volume of the mass in MRI and no uptake at FDG–PET–CT after concurrent CT and RT to the metastatic sites (Patient 4) (Table1). One of the three patients who relapsed before 1 year of initial diagnosis is AWD and the two are DOD. Three of four patients who relapsed after 1 but before 2 years of diagnosis died due to progression, the other is AWD. Three of six patients who relapsed after 2 years of diagnosis have NED, two are AWD and one is DOD. Local treatment (1 surgery only, 3 surgery + RT, and 7 RT) was used in 11 episodes in addition to VTC treatment. Zoledronic acid was not used before the first three courses of VTC treatment where the initial response evaluation was done. Zoledronic acid was added to five patients with widespread bone metastasis in every 28 days after the response evaluation was done after three courses VTC. The toxicity of the combination was limited mainly to the hematopoietic system with grade 2–4 toxicity, but was manageable. The patients experienced grade 3–4 neutropenia after 55% of the courses, despite the use of G-CSFs for prophylaxis. Ten (8%) febrile neutropenia episodes requiring hospitalization were observed in 118 courses, with no deaths due to infection. Grade 3–4 thrombocytopenia was observed in 44% of all courses; grade 3–4 anemia was detected in 24% of courses. Transfusions were given as outpatients as required. Pediatric Hematology and Oncology
14 years
9 years
13 years
14 years
16 years
8 years
13 years
6 years
2.2
3.
4.
5.
6.
7.
8.
Age
1.
F
M
F
M
F
F
M
F
Gender
Femur
Right fourth rib
C5–6 vertebra
Femur
Pelvis
Pelvis
L3–4 vertebra
Primary disease
Metastasis
Relapse
Nonmetastatic Relapse
Multiple bone Relapse and lung metastasis
Non metastatic
Nonmetastatic Relapse
Multiple bone Relapse and lung metastasis
Nonmetastatic PD
Relapse
Nonmetastatic Relapse
Relapse or PD
22 months
17 months
Multiple bone metastasis
Multiple bone metastasis
Local
Localization of relapse/ progression
Relapse therapy (in order of treatment)
1. 3 cycles VTC 2. ∗∗∗ RT
1. 12 cycles VTC 2. ∗∗∗ RT
1. 9 cycles VTC 2. RT 7 months from Lung 1. 18 more the end of metastasiscycles relapse two VTC 2. ∗∗ RT treatment nodules 9 months Local 13 cycles VTC 26 months Multiple RT and ∗∗∗ bone RT metastasis concurrent with 10 cycles VTC 40 months Bone 3 cycles metastasis VTC 41 months Bone 1. Subtotal metastasis surgery 2. RT 3. 7 cycles VTC
45 months
Time to relapse /PD after the initial diagnosis
Table 1 Demographic Characteristics and Outcome of the Relapse Ewing Sarcoma Patients
SD
PR
PR
PR
PR
PR
CR
CR
Initial response to 3 VTC
41 months
∗ PR
32 months
42 months
53 months
48 months
28 months
∗ PR
PR still under treatment SD after 7 VTC, Refused therapy after 7 VTC and received VP-16. PD after 13 months and received third-line CT for 12 months PD after 5 months and received oral VP-16
58 months
76 months
Follow-up time
CR
CR
Outcome at the end of relapse therapy
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10 months
25 months
12 months
8 months
15 months
19 months
26 months
31 months
Survival duration after relapse
DOD
DOD
DOD
AWD
AWD
AWD
NED
NED
Final outcome
14 years
14 years
9 years
7 years
12 years
10.
11.
2.1
12.
13.
M
M
M
M
M
F
Fibula
Talus
Pelvis
Tibia
Scapula
C5–D2 vertebra PD
Relapse
Nonmetastatic Relapse
Nonmetastatic Relapse
Nonmetastatic Relapse
Multiple bone PD and lung metastasis
Non metastatic
Lung metastasis
18 months
32 months
25 months
6 months
5 months
23 months
1. 3 cycles VTC 2. ∗∗∗ RT
3 cycles VTC
1. 3 cycles VTC 2. ∗ RT and ∗∗∗ RT Lung 1. Surgery metastasis(metastwo tasecnodules tomy) 2. 10 cycles VTC 3. ∗ RT Lung 1. Surgery metastasis(metassingle tasecnodule tomy) 2. 12 cycles VTC 3. ∗ RT Local 1. Surgery (amputation) 2. 8 cycles VTC
Multiple bone metastasis
Multiple bone metastasis
Local
N/A
15 months
33 months PD after 6 months (lung nodule); Metastasectomy (CCR) and received 3 courses of third-line CT
5 months
5 months
11 months
25 months
N/A
58 months
11 months
10 months
34 months
57 months
CCR
N/A
PD
PD
PD after 8 months under third-line CT and fourth-line CT PD (lung and bone metastasis) after 2 months and received oral VP-16 PD (bone metastasis) after 3 VTC and received oral VP-16 CCR
SD
AWD
NED
DOD
DOD
DOD
Note. 2.1 = first relapse of the patient; 2.2 = second relapse of the patient; AWD = alive with disease; CR = complete response; CCR = continued complete response; DOD = died of disease; N/A = not applicable; NED = no evidence of disease; PR = partial response; PD = progressive disease; RT = radiotherapy; SD = stable disease; VTC = vincristine–topotecan–cyclophosphamide; Third-line CT = irinotecan + temozolomide chemotherapy; Fourth-line CT = ifosfamide + etoposide + carboplatin chemotherapy. ∗ RT = whole lung radiotherapy; ∗∗ RT = boost RT to localized nodule site; ∗∗∗ RT = palliative RT to the metastatic bone; ∗ PR = regression of the mass with magnetic resonance imaging and hypermetabolic fluorodeoxyglucose positron emission tomography-computed tomography uptake at progression or relapse and no uptake for the last 9 months.
3 years
9.
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Topotecan for Relapsed Ewing Sarcoma
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DISCUSSION After Blaney et al. [9] demonstrated that the continuous infusion of topotecan is inactive for recurrent Ewing sarcoma and preclinical studies showed the efficacy of protracted schedule [10], trials on repeated administration of topotecan were undertaken [11, 12]. Besides, continuous infusion of topotecan might actually downregulate free topoisomerase I and lead to drug resistance [13]. In the last decade, clinical trials of topotecan as a single agent for recurrent Ewing sarcoma have been relatively disappointing. The response rates for relapsed Ewing sarcoma patients treated on Phase II studies using various doses and schedules were 8% and 10% [14, 15]. Preclinical studies have shown synergistic antitumor activity of combinations of topoisomeraseI inhibitors and alkylating agents [4]. A dose escalation Pediatric Oncology Group (POG) Phase I trial reached final doses of cyclophosphamide 250 mg/m2 and topotecan 0.75 mg/m2 , both administered daily for 5 days, followed by G-CSF and found responses in 6/17 (35%) Ewing sarcoma patients [5]. Thus, they suggested this combination may increase antitumor effect in pediatric Ewing sarcoma patients. Hunold et al. [6] obtained PR in 16 of 50 patients (33%) with the same schedule. As a result, the greatest activity for topotecan against Ewing sarcoma has been in combination with cyclophosphamide, in which both drugs are given daily for 5 days (i.e., d × 5 schedule) [5, 6]. As a modified protocol, we added vincristine to these two-drug combination because tumor response rates to single-known active agents, vincristine and cyclophosphamide, were well-known and also VTC was found to be feasible and safe in other types of solid tumors such as rhabdomyosarcoma [16]. We administered topotecan for 3 days and cyclophosphamide for 2 days. The main aim of this modified schedule, that is, 3 days duration versus 5 days duration in previous studies, was to improve the quality of life of the patients, most of them were adolescents, providing them a shorter duration of hospitalization. Adolescents are at a time period that they have challenges belonging to that period even without a cancer diagnosis. Second-time hospitalization for relapsed disease is too hard to cope with. They tolerate 3 days hospitalization easier than 5 days. They prefer to spend time out of hospital and generally ask for a possible oral CT. Our next second-line CT option in our institute might be oral irinotecan and temozolomide, which was recently published by the Children’s Oncology Group (COG) [17]. In our institute, the outpatient unit is active only for limited hours during the day, so CT schedules requiring post-CT hydration or mesna may not be given as outpatients. In addition to that, families have limited resources for transportation, to come as outpatients for several days, and as the duration of hospitalization increases, the burden of losing a working day’s income for the family is very high. Most patients have to be hospitalized for CT for socioeconomic reasons. Relapsed disease is an extra burden for the families both psychologically and economically. With this modified protocol, patients were hospitalized for 2 nights and discharged the third day after topotecan administration. Duration and dose changes did not seem to worsen the response rates in our series. Among 14 episodes, there were seven objective responses (two CR, five PR), two SD and three continued CRs, which is encouraging. We cannot make a reliable comparison in terms of survival outcome before 2009 and modified VTC CT in our institution, since heterogeneous CT regimens were used in relapse patients previously. Although Hunold et al. [6] reported a definitive advantage in terms of survival outcome for patients having both systemic and local therapy in their series (49%), Shankar et al. [1] obtained no different results among patients who received multimodal treatment for localized or systemic recurrence. We think the local treatment used in 11 episodes in addition to VTC treatment may have resulted in better tumor control and survival outcome. On the other hand, Hunold et al. [6], in their series including 50 patients, did not establish a superior outcome in localized versus C Informa Healthcare USA, Inc. Copyright
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R. Kebudi et al.
systemic relapses. However, Stahl et al. [18] reported a significantly superior outcome with a 5-year survival rate of 0.24 in patients following local relapse compared to systemic or combined recurrence. They stated that local relapse is an important prognostic factor associated with longer survival. Leavey et al. [19] also showed recurrence at combined local and distant sites were associated with significantly lower survival. We cannot make a suggestion on difference of survival duration according to the type of relapses; two of seven survivors had systemic relapses in our series. Both Stahl et al. [18] and Leavey et al. [19] established that the most important prognostic factor for outcome is the time to relapse. Both centers found out that patients having recurrence after 2 years had an estimated 5-year survival of 30% (European group 29%) versus 7% with an earlier recurrence. Likewise, in our series, patients having relapse after 2 years tend to live longer, but we do not have a large sample to draw a conclusion. Hence, we have some limitations in this study such as small sample size having heterogeneous population with different local treatment approaches. Besides, the patients have limited follow-up duration, with the median follow-up duration being 41 months (10–76 months) from the initial diagnosis. Saylors et al. [5] had a very limited response duration in their report of relapse Ewing sarcoma patients since these patients were referred to autologous stem cell transplantation after topotecan–cyclophosphamide CT. Hunold et al. [6] had a relatively short median follow-up of 14.5 (2.1–59.8) months after diagnosis of relapse under topotecan–cyclophosphamide treatment. The primary dose-limiting toxicity of topotecan is myelosuppression. Clinical studies using topotecan in combination with alkylating agents have demonstrated a degree of hematopoietic toxicity in excess of that expected from either agent delivered alone, indicating that there may be synergy within these combinations with regard to hematopoietic toxicity [11, 12]. In the largest Phase II experience, 53% of all courses resulted in grade 3–4 neutropenia, all patients had received filgrastim [5]. However, no infectious deaths were observed. The patients in our series experienced grade 3–4 neutropenia after 55% of the courses, despite the use of prophylactic G-CSFs, only 10 (8%) febrile neutropenia episodes requiring hospitalization were observed in 118 courses, and there were no deaths due to infection. Grade 3–4 thrombocytopenia was observed in 44% and grade 3–4 anemia was detected in 24% of all courses. Transfusions were given as outpatients as required. In conclusion, modified VTC protocol given in 3 days every 3 weeks seems to be effective and tolerable and improve quality of life of the patients mostly adolescents with recurrent Ewing Sarcoma.
Declaration of Interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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Topotecan for Relapsed Ewing Sarcoma
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