Discussion:
In this study, we analyzed a retrospective cohort of AYA with osteosarcoma treated at our center using a uniform non-HDMTX-based protocol “OGS-12”, and Ewing’s sarcoma treated with our institutional standard “EFT-2001” protocol. We formulated and validated prognostic scores separately for metastatic and non-metastatic osteosarcoma and Ewing’s sarcoma based on baseline clinical factors and tailored to a unique population of patients treated in a resource constrained setting with our in-house, low-cost, institutional standard protocols which have previously demonstrated survival outcomes are comparable to those published from Western countries [12-15].
For non-metastatic AYA sarcomas, features of high tumor burden including higher baseline SAP, neurovascular bundle involvement and joint involvement predicted poor EFS. This is consistent with published literature - serum alkaline phosphatase and lactate dehydrogenase are surrogates of osteoblastic activity and thus, elevated levels may indicate increased disease aggressiveness [16]. Additionally, vascular involvement noted radiologically in pretreatment MRI has been found independently to be an risk factor for OS and EFS in patients with Enneking IIB primary osteosarcoma involving extremities. [17] Poor histological necrosis also predicted inferior EFS, which is well described in existing literature.
Importantly, failure to complete treatment and prior treatment independently predicted inferior EFS. This is particularly significant in LMIC, with high treatment abandonment rates as well as failure to complete treatment protocol due to various issues including financial challenges, lack of education and motivation for treatment and logistic issues relating to the need to travel long distances and stay far from the patient’s hometown for the duration of treatment due to unavailability of cancer care near the place of residences. Thus, prompt referral to dedicated centres specializing in cancer care and awareness of primary health care physicians to recognize bone sarcomas and avoid inadvertent inappropriate medical or surgical intervention is of paramount importance.
For Ewing’s sarcoma, tumor size >8cm was an additional prognostic factor, consistent with reported literature. [18-19] In the metastatic cohort, failure to complete treatment protocol, poor histological necrosis, tumours not amenable to local treatment and >10 metastases were also predictive of superior EFS on multivariable analysis. determinants of survival. This underscores the importance of multimodality clinics to identify tumors amenable to curative treatment and avoid overtreatment for patients with extensive disease. It has been previously observed that osteosarcoma presenting only with lung metastases have better survival outcomes than metastases at other sites [20].
The factors that emerged prognostically significant for our patients were similar to those described in data from centres using HDMTX-based protocols, indicating the wide applicability of our results. For non-HDMTX regimens, particularly prevalent in LMICs, data on prognostic factors are scarce with only few observational studies [21-23]. Histologic response to chemotherapy has been uniformly reported to be a predictive factor in these studies. A study from Brazil has additionally reported presence of metastases at baseline, primary tumor site and type of surgery (amputation vs. limb sparing) as prognostically significant [24]. Nevertheless, the lacunae for studies specifically targeting bone sarcomas in LMICs remains apparent. Smaller sample sizes of existing studies, observational nature, and non-uniformity of treatment protocols makes generalizability of these results challenging. A potential strategy to overcome these shortcomings include collaborative efforts with multi-institution studies to enhance understanding of osteosarcoma in LMICs. Importantly, several existing studies have included patients with both non-metastatic and metastatic tumors, with widely differing outcomes. We have addressed this limitation by separately analyzed homogenously treated populations of metastatic and non-metastatic osteosarcoma and Ewing’s sarcoma.
In our study, we developed separate prognostic models for non-metastatic and metastatic osteosarcoma and Ewing’s sarcoma based on the prognostic factors identified. We validated the risk score for non-metastatic osteosarcoma, and demonstrated effective discriminative ability for event-free survival between the three risk groups. For the other cohorts (metastatic osteosarcoma, and non-metastatic and metastatic Ewing’s sarcoma), we developed prognostic models depicted as nomograms, although validation could not be separately performed due to the limited sample size. Available prognostic models for risk stratification in osteosarcoma involve variable treatment modalities, clinician preferences, surgical expertise and chemotherapy protocols which precludes generalizability of these models. [25-28]. For Ewing’s sarcoma, existing models have largely utilized treatment-related factors such choice of local treatment, factors that vary in different centres due to individual clinician preference and expertise. [29-34] In developing our prognostic models, we have analyzed homogenously treated cohorts and reinforced the importance of baseline indicators of tumor aggressiveness, chemosensitivity as indicated by histologic response to chemotherapy, and general treatment-related factors unique to patients in LMIC settings, such as failure to complete treatment protocol and prior inadvertent treatment before referral to advanced oncology centres.
The prognostic models we report are important and unique as they are derived from a prospective analysis of homogenously treated AYA in a LMIC setting. The specific challenges faced by this vulnerable subset of patients has been stressed upon. The wide implications of our results include healthcare policy-making, in the context of need for early identification by appropriate awareness and training of primary care physicians and timely referral to sarcoma reference centres, and the importance of strategies to improve protocol completion by efforts such as targeted nutritional intervention, extended growth factor support and patient navigation facilities. Risk stratification of patients aids selection of patients who would benefit from aggressive treatment as well as those who may achieve comparable outcomes with less aggressive modalities with improved quality of life. Traditionally, escalation of treatment for patients with high-risk disease has been based on histologic response after completion of neoadjuvant chemotherapy [35-36]. Use of other important prognostic factors as described in our study may be used to identify patients who may benefit from a less intensive approach such as metronomic chemotherapy regimens and early incorporation of palliative care, particularly in resource-constrained settings [37-38].
The prognostic implication of common social challenges have been highlighted, including prior inadvertent treatment and the importance of compliance in the form of protocol completion. We did not analyze socioeconomic strata due to unavailability of uniform data, however, surrogate parameters including compliance as assessed by treatment duration and protocol completion, as well as prior inadvertent treatment were analyzed. Importantly, majority of our patients are constrained financially and socially and depend on financial aid from various government schemes for cancer treatment. Another study from India has evaluated location of primary residence of the patient and the distance of the residence from the hospital and not found prognostic significance for osteosarcoma [23].