Cyclophosphamide and Etoposide as a Salvage Treatment in Metastatic Osteosarcoma Patients

Background and Objective: Osteosarcoma is a rare bone cancer with approximately 30% 35% of patients who will relapse either systemically or locally, with the lung being the commonest site of relapse. The objective of this trial was to evaluate the efficacy of cyclophosphamide and etoposide, in treatment of metastatic osteosarcoma patients progressed after one or more chemotherapy lines, with the progression free survival and treatment response as the primary endpoints, while the secondary endpoints were overall survival and treatment toxicity. Patients and Methods: Twenty seven metastatic osteosarcoma patients were enrolled into this trial and received cyclophosphamide and etoposide chemotherapy. Cyclophosphamide was given at a dose of 500 mg/m per day, I.V for 5 days and etoposide (100 mg/m per day I.V for 5 days). Response was assessed after 3 cycles according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Chemotherapy Toxicity was graded according to the Common Terminology Criteria for Adverse Events (CTCAE). Results: The median overall survival time and progression-free survival were 12 months and 8 months, respectively. Four patients (14.8%) achieved partial response; 14 patients (51.9%) had stationary disease (SD); and 9 (33.3%) expressed tumor progression. Hematologic toxicity was the main toxicity. None of the patients had G4 or life threatening toxicities. Conclusion: The combination of cyclophosphamide and etoposide represents an efficient and tolerable treatment option for patients with metastatic osteosarcoma.


Introduction
Osteosarcoma is a rare bone cancer affecting mainly adolescents and young How to cite this paper: Akl, F.M. and Akl, M.F.(2018) Cyclophosphamide and Etoposide as a Salvage Treatment in Metastatic adults.Most are high-grade malignancies with a high probability for lung metastases [1].
However, approximately 30% -35% of osteosarcoma patients will relapse either systemically or locally, with the lung being the commonest site of relapse [2].
Multi-agent chemotherapy together with surgery has improved the treatment results of patients with localized osteosarcoma [1] [2].Treatment options for relapsed patients are limited with short survival, specifically for those with extra lung metastasis.The 4 years overall survival for patients with bone metastasis is 0% [3].
Patients with unresectable, recurrent or metastatic osteosarcoma experience poor progression-free survival.Different treatment strategies like surgery, palliative chemotherapy, radiotherapy, proton and heavy ion therapy, samarium, embolization and thermal ablation (radiofrequency and cryotherapy), were applied to control disease and prolong survival [4].
Several second-line and further line chemotherapy, like ifosfamide, etoposide, high-dose carboplatin and etoposide, topotecan, irinotecan, gemcitabine, docetaxel, imatinib mesylate, and temozolamide, have been tried, but with low response rate ranged from 3% to 29% and, more importantly, short survival time where, the median (PFS) was from 1.4 to 4 months [3] [5].Second-line chemotherapy options are still limited and not standardized.At present, there is still no consensus on the best second-line chemotherapy [6].
Therefore, we designed this non randomized prospective phase II trial to evaluate the activity of cyclophosphamide and etoposide combination in metastatic osteosarcoma patients, progressed after one or more chemotherapy lines, with the progression free survival and treatment response were the primary endpoints, while the secondary endpoints were overall survival and treatment toxicity.

Patients and Methods
After acceptance of the Mansoura Faculty of Medicine, institutional research board MFM IRB (code R.18.03.68), twenty-seven patients were included into this trial between July 2015 and July 2017 at the department of clinical oncology and nuclear medicine, Mansoura University Hospital, Egypt.All patients or their parents had signed the informed consent forms before enrollment.
Eligibility criteria: 1) high-grade metastatic osteosarcoma, 2) more than or equal to 18 years, 3) Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2, 4) unresectable metastatic disease, 5) progressed disease after at least one line of chemotherapy, 6) availability of demographic, clinical and follow-up data, 7) normal bone marrow, renal and liver functions.Qualitative data were expressed as count and percent.
Quantitative data were initially tested for normality using Kolmogorov-Smirnov and Shapiro-Wilk's test with data being normally distributed if p > 0.050.Quantitative data were expressed as mean ± standard deviation (SD) or median.Progression-Free Survival (PFS) and Overall Survival (OS) were analyzed by Kaplan Meier curves from the first day of treatment until disease progression (PFS) or death or last follow up (OS).

Results
This study involved 27 patients diagnosed with high grade metastatic osteosarcoma.There were 22 males (81.5%) and 5 females (18.5%).The median age was 20 years (range 18 -40).ECOG performance status of grade 1 was the commonest.The femur was the commonest primary tumor site found in 22 (81.5%)patients, followed by tibia in 3 (11.1%)patients and chest wall in 2 (7.4%) patients.
Six months and 1 year OS were 75% and 39% respectively, while the six months and 1-year PFS were 50% and 18% respectively (Figure 1 and Figure 2).
Alopecia was the commonest non hematologic toxicity where 4 (14.8%)patients had GI and 23 (85.2%) patients were of GII.Six (22.2%) patients experienced GI nausea and only 2 (7.4%) patients had GI cystitis (Table 3).The effect of different factors (age, sex, PS, primary tumor site, metastatic sites and number of chemotherapy cycles) on OS and PFS was studied and revealed that the only significant factor which affected survival was performance status (OS p = 0.04, PFS p = 0.006).

Discussion
Despite multimodality treatments, about one third of localized osteosarcoma patients, as well as nearly 75% of metastatic patients at diagnosis relapse [10].
No accepted standard second-line chemotherapy for recurrent osteosarcoma is established.Choice of chemotherapy depends on the length of previous progression free survival, and mostly, it includes ifosfamide, etoposide, carboplatin and other active agents [6].
In this phase II non randomized study, we evaluated the efficacy of cyclophosphamide and etoposide in metastatic osteosarcoma patients progressed after one or more lines of chemotherapy.
Our reported results are comparable with those of a phase II trial carried out by Massimo et al., who treated 26 metastatic osteosarcoma patients (lung metastasis) with cyclophosphamide at dose of 4 g/m 2 on Day 1 and etoposide at 200 mg/m 2 on Days 2, 3, and 4. Four months progression-free survivals were 42%.Fever was the only grade 4 non-hematological toxicity (5%), bronchospasm (4%) and oral mucositis (18%).Nineteen percent of patients expressed response, 9 had stationary disease (35%), and 12 showed progressive disease (46%).The one year OS was 50% [3].
In a study by Mantadakis, it involved osteosarcoma patients, treated by combination of cyclophosphamide and etoposide (cyclophosphamide at a dose of 500 mg/m 2 daily, d1-5 and etoposide 100 mg/m 2 /day, d1-5).The median overall survival time was 11 months, approximately similar to this study [11].
In a study that assessed the efficacy of gemcitabine, docetaxel in 51 relapsed high-grade osteosarcoma patients, they received gemcitabine at a dose of 900 mg/m higher incidence and grades of toxicity in comparison to the present study [13].
These results were also in agreement with those reported in a phase II non-randomized trial that evaluated sorafenib and everolimus in progressed osteosarcoma patients.Median PFS was 5 months and 6 months PFS was 45%.
Median OS time was 11 months with 14 out of 38 (37%) patients were alive at 1 year and the 2-year OS was 5%.The commonest G3 -4 adverse events were lymphopenia and hypophosphataemia each in 6 (16%) patients, hand and foot syndrome in 5 (13%), thrombocytopenia in 4 (11%), and oral mucositis, diarrhoea, and anaemia each in 2 (5%).One patient (3%) had G3 pneumothorax that required intervention.This was reported as a serious toxicity related to the used drugs, denoting serious and more advanced grades of toxicity in comparison to the current study [14].
Song et al. retrospectively reviewed the data of 28 patients (20 male, 8 female) diagnosed with recurrent or refractory osteosarcoma, treated with gemcitabine (675 or 900 mg/m 2 on days 1 and 8) and docetaxel (100 mg/m 2 on day 8) at Korea Cancer Center Hospital.Eleven patients received adjuvant gemcitabine, docetaxel after surgery.Seventeen patients received gemcitabine, docetaxel as palliative treatment.They detected 24% response rate and median OS of 9 months, slightly lower than that of the current study (12 months).The 1 year OS for the adjuvant group in contrast to the palliative group was (72.7% ± 13.4% vs. 35.3%± 11.6%, p = 0.006) [5].
Compared to other expensive chemotherapeutic agents used in this setting, cyclophosphamide, etoposide combination represents comparable results with lesser toxicity profile, which is an important issue in with low income countries.

Conclusion
In conclusion, the combination of cyclophosphamide and etoposide is an efficient and tolerable protocol in addition to its low cost, representing a suitable treatment option for patients with metastatic osteosarcoma, but further large efforts are needed to improve chemotherapeutic and surgical treatments that can be offered to these patients.

Limitations of the Study
Non randomized, small cohort.

F
. M. Akl, M. F. Akl DOI: 10.4236/jct.2018.97044531 Journal of Cancer Therapy Before study inclusion, all patients had physical examination, computerized tomography, or magnetic resonance imaging of the primary tumor and metastatic sites, and a bone scan.Chemotherapy consisted of cyclophosphamide and etoposide, cyclophosphamide at a dose of 500 mg/m 2 per day I.V for 5 days and etoposide 100 mg/m 2 per day I.V for 5 days, given with granulocyte colony-stimulating factor (G-CSF) on the 7th day for 3 days.Response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [8].Response assessment was done after the first 3 cycles and then every 3 -4 cycles or as clinically indicated by computerized tomography, or magnetic resonance imaging.Chemotherapy Toxicity data were assessed during the clinical follow up visits and graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4 [9].Statistical analysis: Data were entered and analyzed using SPSS software (version 21) and Medcalc software (version 15.8).