|REAL WORLD DATA
|Year : 2020 | Volume
| Issue : 1 | Page : 64-68
Oral etoposide and cyclophosphamide: A low-cost palliative metronomic chemotherapy in advanced pediatric cancers
Kiran Kumar, Venkatraman Radhakrishnan, Manikandan Dhanushkodi, Jayachandran Perumal Kalaiyarasi, Nikita Mehra, Arun Rajan Kumar, Gangothri Selvarajan, Trivadi S Ganesan, Tenali Gnana Sagar
Department of Medical Oncology, Cancer Institute (WIA), Chennai, Tamil Nadu, India
|Date of Submission||27-Oct-2019|
|Date of Decision||04-Nov-2019|
|Date of Acceptance||14-Dec-2019|
|Date of Web Publication||24-Feb-2020|
Department of Medicalc Oncology, Cancer Institute (WIA), Adyar, Chennai, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Introduction: Oral metronomic chemotherapy (OMC) is a less intensive and cost-effective palliative treatment modality in children with relapsed/refractory cancers in low-middle income countries. We aimed to study the safety and efficacy of OMC with oral etoposide and cyclophosphamide in relapsed/refractory pediatric malignancies treated at our center.
Patients and Methods: This was a retrospective study from the case records of patients treated at our center from 2011 to 2018. Patients <18 years old and who received at least one cycle of OMC were included in the study. Cyclophosphamide and etoposide were given at a dose of 25 mg or 50 mg daily. Schedule of the drugs was variable; the most common schedule followed was 2 weeks on, followed by 2 weeks off. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method.
Results: A total of 49 patients were included in the study. The median age was 8 years (range, 1–18 years) and 23/49 (46%) were males. The most common malignancies were Ewing's sarcoma (n = 13, 26%) and neuroblastoma (n = 11, 22%). The median duration of OMC intake was 50 days (range, 9–570 days). The clinical benefit rate was 22.4% with 10.2% patients having partial response and 12.2% having stable disease. Thirty-two (65.3%) patients had progressive disease on OMC and six (12.2%) were lost to follow-up. The median PFS was 63 days (95% confidence interval [CI], 18–107 days) and median OS was 155 days (95% CI, 19–219 days). Lower age and longer duration of treatment were independent predictors of higher OS.
Conclusion: Oral cyclophosphamide and etoposide are a convenient and economical regimen with response rates and survival similar to those historically reported from other OMC regimes.
Keywords: Metronomic chemotherapy, pediatric cancer, survival, OMCT, metronomic, LMIC
|How to cite this article:|
Kumar K, Radhakrishnan V, Dhanushkodi M, Kalaiyarasi JP, Mehra N, Kumar AR, Selvarajan G, Ganesan TS, Sagar TG. Oral etoposide and cyclophosphamide: A low-cost palliative metronomic chemotherapy in advanced pediatric cancers. Cancer Res Stat Treat 2020;3:64-8
|How to cite this URL:|
Kumar K, Radhakrishnan V, Dhanushkodi M, Kalaiyarasi JP, Mehra N, Kumar AR, Selvarajan G, Ganesan TS, Sagar TG. Oral etoposide and cyclophosphamide: A low-cost palliative metronomic chemotherapy in advanced pediatric cancers. Cancer Res Stat Treat [serial online] 2020 [cited 2020 Apr 4];3:64-8. Available from: http://www.crstonline.com/text.asp?2020/3/1/64/279152
| Introduction|| |
Cure rates in children with cancer in low-middle income countries (LMIC) remain at 30%–50%; although, the survival in high-income countries has approached 80%. Therefore, children with relapsed/refractory cancers in LMIC constitute a large proportion of patients undergoing treatment at oncology centers. There are no standard chemotherapy options in the majority of pediatric cancers that progress after one or two lines of chemotherapy. Oral metronomic chemotherapy (OMC) has been used as a less intensive and cost-effective treatment modality to palliate symptoms in children with advanced cancer. OMC involves the administration of low dose chemotherapy continuously rather than once in 2–3 weeks. Multiple mechanisms of action of OMC have been proposed which include antiangiogenic action, activation of immunity, and induction of tumor dormancy and senescence., Many drugs have been tried in the pediatric population as OMC. These include etoposide, cyclophosphamide, celecoxib, temozolomide, thalidomide, retinoic acid, and vinblastine.,,, The aim of the present study was to assess the safety and efficacy of OMC with oral etoposide and cyclophosphamide in relapsed/refractory pediatric malignancies treated at our center.
| Patients and Methods|| |
Clinical data and treatment details were collected retrospectively from the case records of patients who underwent treatment in our center from 2011 to 2018. Pediatric patients aged <18 years who received at least one cycle of oral etoposide and cyclophosphamide were included in the study. Patients had been diagnosed with progressive disease (PD) after all available standard therapies, based on clinical and imaging findings before starting OMC. Written informed consent was obtained from the parents/guardians before starting OMC. Patients were followed up after each cycle, and response was assessed clinically and in a few patients, based on imaging studies.
Oral etoposide and cyclophosphamide combination were used as OMC. Doses and schedules of the drugs were variable and were based on the treating physician's decision, patient's performance status, age, and previous tolerance to chemotherapy. Patients' complete blood count was monitored once in 7–14 days, and biochemistry parameters once in 21–28 days and the dose adjustments for future cycles were made based on the white blood cell counts and platelet counts. For patients with grade 3–4 neutropenia and grade 3–4 mucositis, the modification of the dose and schedule was at the discretion of the treating physician; no specific protocol was followed. The duration of chemotherapy in each cycle was reduced, for example from 2 weeks on, 1 week off every 21 days to 10 days on, and 11 days off every 21 days. In other patients, the drugs were given on alternate days or 5 days on, 2 days off, and every 7 days. Dose was reduced to 25 mg in one patient. For an absolute neutrophil count more than 1000/mm3 and platelet count more than 50000/mm3, chemotherapy was continued at the same dose and schedule.
Response to treatment was captured as recorded in the patients' case records. Responses were classified as complete response (CR), partial response (PR), stable disease (SD), and PD. Assessment of response was made either clinically or by imaging; X-ray, ultrasound, or positron emission tomography with computed tomography (CT). The Response Evaluation Criteria in Solid Tumors criteria were used in patients in whom CT scan had been done. Clinical benefit rate (CBR) was defined as the proportion of patients achieving CR, PR, or SD. Progression-free survival (PFS) was calculated from the date of starting OMC till the date of progression. Progression was defined clinically with progressive symptoms or on examination and imaging. In patients who did not come for follow-up, date of last outpatient follow-up was taken as the date of progression for survival analysis. Overall survival (OS) was calculated from the date of starting OMC till date of death. Patients who did not follow-up after 3 months of the given follow-up date were contacted telephonically to assess their status; if the patient could not be contacted, he/she was considered lost to follow-up. PFS and OS were analyzed by the Kaplan–Meier method, and risk factors were compared by using the log-rank test for univariable analysis and a Cox-proportional hazards model, for multivariable analysis. Toxicity was graded as per Common Terminology Criteria for Adverse Events (CTCAE) v. 4. SPSS (Statistical Package for the Social Sciences) software version 16.0 (SPSS, Chicago, IL, USA) was used for statistical analysis. A value of P < 0.05 was considered statistically significant.
| Results|| |
The study included 49 patients with a median age of 8 years (range, 1–18 years); 23/49 (46%) were males. The most common malignancies were Ewing's sarcoma (n = 13, 26%) and neuroblastoma (n = 11, 22%). The other malignancies included rhabdomyosarcoma (n = 7, 14%), non-Hodgkin's lymphoma (NHL) (n = 7, 14%), osteosarcoma (n = 4, 8%), acute myeloid leukemia (AML) (n = 4, 8%), and Hodgkin's lymphoma (n = 3, 6%).
Different schedules of OMC were followed, and the common schedules were 2 weeks on followed by 2 weeks off (n = 22, 44.8%), and 2 weeks on and 1 week off (n = 16, 32.6%). The other schedules were 5 days/week, and alternate day continuously. Cyclophosphamide was given at 50 mg per dose except for seven patients (14%) who received 25 mg/dose. Etoposide was also given at 50 mg per dose except for 3 patients (6%) who received 25 mg.
Median duration of taking OMC was 50 days (range, 9–570 days). The mean duration of taking OMC in all patients ranged between 70 and 120 days, except in rhabdomyosarcoma and NHL where it was 191 days and 39 days, respectively [Table 1].
|Table 1: Duration and the number of cycles of oral metronomic chemotherapy taken in 49 patients with relapsed/refractory pediatric malignancies treated with oral metronomic chemotherapy consisting of the combination of etoposide with cyclophosphamide according to the diagnosis|
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The CBR was 22.4% with 10.2% having PR and 12.2% having SD. Thirty-two (65.3%) patients had PD and six (12.2%) were lost-to-follow up. No patient had a CR with OMC. The CBR was maximum for Hodgkin's lymphoma (33.3%) and Ewing's sarcoma (36.3%) and least for osteosarcoma (0%) [Table 2].
|Table 2: Mean survival and response rates 49 patients with relapsed/refractory pediatric malignancies treated with oral metronomic chemotherapy consisting of the combination of etoposide with cyclophosphamide according to diagnosis|
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The median duration of follow-up was 469 days (95% confidence interval [CI], 258–679 days). The median PFS was 63 days (95% CI, 18–107 days) [Figure 1] and median OS was 155 days (95% CI, 19–219 days) [Figure 2]. Median PFS was the longest for Hodgkin's lymphoma (227 days) and shortest for AML (21 days). Similarly, the median OS was longest for Hodgkin's lymphoma (463 days) and shortest for AML (26 days) [Table 2]. In univariate analysis, lower age and longer duration of treatment were significant predictors of longer OS. Using Cox regression analysis, age and duration of treatment were independent predictors of OS. Duration of treatment was the only factor predicting PFS.
|Figure 1: Kaplan–Meier analysis showing progression-free survival of 49 patients with relapsed/refractory pediatric malignancies treated with oral metronomic chemotherapy consisting of the combination of etoposide with cyclophosphamide. The median progression-free survival was 63 days (95% confidence interval, 18–107 days)|
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|Figure 2: Kaplan–Meier analysis showing overall survival of 49 patients with relapsed/refractory pediatric malignancies treated with oral metronomic chemotherapy consisting of the combination of etoposide with cyclophosphamide. The median overall survival was 155 days (95% confidence interval, 19–219 days)|
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Six patients (12%) had neutropenia and 4 patients (8%) developed fever. One patient had varicella infection and one patient had oral candidiasis. One death was attributed to severe sepsis with febrile neutropenia. No other toxicity was observed. Four patients (8.1%) required modification of the dosing schedule in view of intolerance.
| Discussion|| |
Our study adds to the limited literature on OMC in pediatric cancers. We found that OMC is a cheap and effective option in the palliative setting in patients who had exhausted standard lines of therapies; some patients achieved clinically meaningful PFS. Oral cyclophosphamide and etoposide with or without other drugs have been the most common OMC regimen used in the literature. Majority of the studies on OMC in pediatric cancers have included a heterogeneous mix of relapsed/refractory cancers similar to our study population.
The CBR observed with OMC in the literature has varied from 20% to 50% and this is because of the heterogeneity of the patient population treated.,, We observed a CBR of 22.4% in our study; whether the addition of other agents would have improved the CBR is not known. The only Phase III trial of OMC in relapsed/refractory pediatric solid tumors conducted by Pramanik et al. did not show a survival benefit with OMC. In this study, OMC with etoposide and cyclophosphamide alternating with celecoxib and thalidomide was compared with placebo. They reported a median PFS of 46 days (95% CI, 33–58 days) in the placebo group and 49 days (95% CI, 43–59 days) in the metronomic chemotherapy group; the median OS was 89 days (95% CI, 69–113 days) in both the groups. The median PFS was 56 days in our study and similar to the results by Pramanik et al., however, the median OS in our study appeared to be longer at 155 days in comparison to Pramanik et al.
Conventionlly, OMC has been prescribed in patients with solid tumors; however, 28% of patients in our study had hematolymphoid malignancies. We observed that OMC does have efficacy in patients with hematolymphoid malignancies, with differential results based on the type of malignancy; it was more effective in Hodgkin's lymphoma and NHL than in an aggressive disease like AML.
There is no accepted standard dose and schedule for OMC and treatment is often empirical. We used a dose of 50 mg cyclophosphamide and etoposide because this was the smallest strength, in which these tablets were available. The schedule was based on the child's weight, performance status and drop in white blood cell counts while on treatment. OMC was well tolerated in our study and grade 3–4 neutropenia was observed in 8% of patients. There was one death due to febrile neutropenia and this highlights the importance of regular follow-up and evaluation of the white blood cell counts in patients receiving OMC. Among the nonhematologic adverse effects, mucositis was the most common (grade 1–2, 8.8%; grade 3–4, 5.3%).
In our study, many patients received the convenient and easy regimen of oral cyclophosphamide and etoposide. The drugs were cheap with less burden on the healthcare system compared to regimens with weekly injections and other expensive drugs. The cost of 50 mg oral cyclophosphamide was Rs. 2.40 and 50 mg etoposide tablet was Rs. 33 at our hospital. The approximate cost of 10 days OMC at our hospital was Rs. 354, which made it affordable for most of the patients receiving treatment.
The major limitations of our study were its retrospective nature, heterogeneous treatment population, and treatment schedule.
| Conclusion|| |
We conclude that the combination of oral etoposide and cyclophosphamide is a promising approach with acceptable efficacy and tolerance. However, more research is needed to identify optimal dosing, schedule and combination of drugs. There is a need to identify biomarkers that can accurately predict which patients will benefit the most from metronomic chemotherapy. Given its mechanism of action, which is different from conventional cytotoxic chemotherapy, studies need to be done to evaluate whether combining metronomic chemotherapy with conventional chemotherapy improves outcomes in the curative setting.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Molyneux E, Scanlan T, Chagaluka G, Renner L. Haematological cancers in African children: Progress and challenges. Br J Haematol 2017;177:971-8.
Maiti R. Metronomic chemotherapy. J Pharmacol Pharmacother 2014;5:186-92.
] [Full text]
Scharovsky OG, Mainetti LE, Rozados VR. Metronomic chemotherapy: Changing the paradigm that more is better. Curr Oncol 2009;16:7-15.
Zapletalova D, André N, Deak L, Kyr M, Bajciova V, Mudry P, et al
. Metronomic chemotherapy with the COMBAT regimen in advanced pediatric malignancies: A multicenter experience. Oncology 2012;82:249-60.
Robison NJ, Campigotto F, Chi SN, Manley PE, Turner CD, Zimmerman MA, et al
. A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer. Pediatr Blood Cancer 2014;61:636-42.
Fousseyni T, Diawara M, Pasquier E, André N. Children treated with metronomic chemotherapy in a low-income country: METRO-MALI-01. J Pediatr Hematol Oncol 2011;33:31-4.
Klingebiel T, Boos J, Beske F, Hallmen E, Int-Veen C, Dantonello T, et al
. Treatment of children with metastatic soft tissue sarcoma with oral maintenance compared to high dose chemotherapy: Report of the HD CWS-96 trial. Pediatr Blood Cancer 2008;50:739-45.
Chakraborty S. A step-wise guide to performing survival analysis. Cancer Res Stat Treat 2018;1:41-5. [Full text]
Dessai S, Simha V, Patil V. Stepwise cox regression analysis in SPSS. Cancer Res Stat Treat 2018;1:167-70. [Full text]
Dessai S, Patil V. Testing and interpreting assumptions of COX regression analysis. Cancer Res Stat Treat 2019;2:108-11. [Full text]
Sterba J, Valik D, Mudry P, Kepak T, Pavelka Z, Bajciova V, et al
. Combined biodifferentiating and antiangiogenic oral metronomic therapy is feasible and effective in relapsed solid tumors in children: Single-center pilot study. Onkologie 2006;29:308-13.
Kieran MW, Turner CD, Rubin JB, Chi SN, Zimmerman MA, Chordas C, et al
. A feasibility trial of antiangiogenic (metronomic) chemotherapy in pediatric patients with recurrent or progressive cancer. J Pediatr Hematol Oncol 2005;27:573-81.
Stempak D, Gammon J, Halton J, Moghrabi A, Koren G, Baruchel S. A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors. J Pediatr Hematol Oncol 2006;28:720-8.
Pramanik R, Agarwala S, Gupta YK, Thulkar S, Vishnubhatla S, Batra A, et al
. Metronomic chemotherapy vs. best supportive care in progressive pediatric solid malignant tumors: A randomized clinical trial. JAMA Oncol 2017;3:1222-7.
Philip CC, Mathew A, John MJ. Cancer care: Challenges in the developing world. Cancer Res Stat Treat 2018;1:58-62. [Full text]
Noronha V. Making a case for cancer research in India. Cancer Res Stat Treat 2018;1:71-4. [Full text]
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