Outcomes in non-metastatic treatment naive extremity osteosarcoma patients treated with a novel non-high dosemethotrexate-based, dose-dense combination chemotherapy regimen ‘OGS-12’

Bajpai, Jyoti; Chandrasekharan, Arun; Talreja, Vikas; Simha, Vijai; Chandrakanth, M V; Rekhi, Bharat; Khurana, Sachin; Khan, Anisur Rahman; Vora, Tushar; Ghosh, Jaya; Banavali, Shripad; Gupta, Sudeep

doi:10.1016/j.ejca.2017.08.013

Cited by 38 publications

(57 citation statements)

References 44 publications

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“…In the given context, a non-HDMTX–based regimen containing the three most active chemotherapeutic agents for osteosarcoma treatment was devised at our center. 12 The provision of sequential doublets in the regimen is to make it more dose dense so as to potentiate the tumor-cell kill based on the Norton and Simon hypothesis. 13 Dose-dense chemotherapy with antiangiogenic and proapoptotic properties has shown proof of concept in landmark trials.…”

Section: Introductionmentioning

confidence: 99%

Outcomes in Treatment-Naïve Patients With Metastatic Extremity Osteosarcoma Treated With OGS-12, a Novel Non–High-Dose Methotrexate–Based, Dose-Dense Combination Chemotherapy, in a Tertiary Care Cancer Center

Bajpai

Chandrasekharan

Simha

et al. 2018

JGO

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PurposeMetastatic osteosarcoma is largely treated with high-dose methotrexate (HDMTX)–based therapy, especially in the pediatric population. This mandates complex pharmacokinetic monitoring in a costly inpatient setting to mitigate unpredictable serious toxicities. Hence, a non-HDMTX–based regimen is worth exploring, especially in India and low- and middle-income countries.Materials and MethodsAll consecutive treatment-naïve patients with metastatic osteosarcoma were prospectively treated on the novel OGS-12 protocol consisting of sequential doublets of doxorubicin, cisplatin, and ifosfamide. Four cycles were administered as neoadjuvant therapy followed by planned curative intent surgery and metastasectomy when feasible, followed by four cycles of adjuvant chemotherapy. Baseline characteristics, histologic response, event-free survival (EFS), overall survival (OS), and toxicity data were prospectively collected.ResultsThree hundred seventeen patients were enrolled onto the OGS-12 protocol from 2011 to 2014, of whom 80 (25%) had metastatic disease; median age was 17 years. The majority of patients were nutritionally challenged with high-risk features. At presentation, 83% of patients (66 patients) had lung metastases. After neoadjuvant chemotherapy, 57% of patients were histologically good responders. Four-year EFS and OS rates were 24% and 27%, respectively, in the intent-to-treat population and 27% and 29%, respectively, in the per-protocol analysis. Significant grade 3 or 4 toxicities were febrile neutropenia (51%), thrombocytopenia (36%), and anemia (54%). Histologic response was an independent predictor for EFS and OS in patients who underwent surgery. Surgical intervention was found to be significant for survival in univariable analysis.ConclusionThe novel, low-cost, non-HDMTX–based, dose-dense OGS-12 regimen has shown comparable outcomes to international standards in metastatic osteosarcomas and is worthy of wider clinical application. An aggressive multimodality approach may result in long-term survival in a select group of patients and, hence, is worth considering.

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Section: Introductionmentioning

confidence: 99%

Outcomes in Treatment-Naïve Patients With Metastatic Extremity Osteosarcoma Treated With OGS-12, a Novel Non–High-Dose Methotrexate–Based, Dose-Dense Combination Chemotherapy, in a Tertiary Care Cancer Center

Bajpai

Chandrasekharan

Simha

et al. 2018

JGO

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“…We have taken corrective steps to ensure better compliance including improved communication to patients, thus helping improve upon survival. 8,10,21,22 The OGS-12 protocol resulted in good HR in 58% patients, which is similar to HDMTX-based regimens such as MSKCC (65%), Cooperative German-Austrian-Swiss osteosarcoma study group (COSS) protocol (43%), and INT0133 (48%) [23][24][25] and to non-HDMTX-based regimens such as OS-99 (61%) and OS-91 (51%), including those from India. 1,[26][27][28] Good histological response was similar with all the three protocols; however, the survival was better with OGS-12 protocol.…”

Section: The Results Of the European And American Osteosarcoma Studymentioning

confidence: 93%

“…Poor compliance to treatment and inadvertent prior treatment by non‐oncologists is rampant in LMICS and affect ultimate outcomes. We have taken corrective steps to ensure better compliance including improved communication to patients, thus helping improve upon survival …”

Section: Discussionmentioning

confidence: 99%

“…This was then compared with a standard HDMTX regimen (Supporting Information S1). Institutional review board's permission was obtained.…”

Section: Methodsmentioning

confidence: 99%

“…This was then compared with a standard HDMTX regimen (Supporting Information S1). 10 Institutional review board's permission was obtained. In the OGS-12 protocol, intention-to-treat (ITT) analysis was carried out in all the enrolled patients, and patients who were lost to follow-up were censored.…”

Section: Introductionmentioning

confidence: 99%

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Osteosarcoma journey over two decades in India: Small steps, big changes

Bajpai

Chandrasekharan

Simha

et al. 2019

Pediatric Blood & Cancer

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Background The management of osteosarcoma is challenging especially in lower‐income and middle‐income countries, and there is an unmet need to evolve efficient and sustainable chemotherapy regimens. Methods We compared the outcomes in nonmetastatic osteosarcoma patients treated with three sequential non‐high‐dose methotrexate‐based combination chemotherapy protocols at a single tertiary care center over two decades. The first protocol, OGS‐99, involved dose‐intense, alternating dyads of three drugs: doxorubicin (Dox), cisplatin (CDDP), and ifosfamide (Ifo). The second protocol, OGS‐99 enhanced, included OGS‐99 drugs with etoposide and enhanced supportive care. The OGS‐12 protocol involved dose‐dense administration of eight sequential dyads of Dox, CDDP and Ifo, universal growth factor prophylaxis and targeted nutritional support. Event‐free survival (EFS), overall survival (OS), and toxicity were reported using a retrospective chart review in the OGS‐99 and OGS‐99 enhanced protocols and prospectively in the OGS‐12 protocol. Results A total of 41, 94, and 385 treatment‐naïve, consecutive, nonmetastatic patients with extremity osteosarcoma were treated with the OGS‐99 (2000–2005), OGS‐99 enhanced (2010), and OGS‐12 (2011–2016), respectively. At a median follow‐up of 19, 86, and 39 months, the five‐year EFS rates were 38%, 50%, and 62% in the OGS‐99, OGS‐99 enhanced, and OGS‐12, respectively. The corresponding rates of five‐year OS were nonevaluable, 60% and 77%, respectively, with acceptable rates of grade 3–4 toxicities: febrile neutropenia (40%), thrombocytopenia (36%), anemia (51%), and 1% deaths related to toxicity. Conclusions Sequential selection of an intelligent, dose‐dense chemotherapy regimen together with enhanced supportive care resulted in marked improvement in outcomes of nonmetastatic osteosarcoma and this “small steps—big changes” model deserves wider recognition and usage.

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Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies

Shen

Lan

et al. 2023

MedComm

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Osteosarcoma (OS) is a highly prevalent bone malignancy among adolescents, accounting for 40% of all primary malignant bone tumors. Neoadjuvant chemotherapy combined with limb‐preserving surgery has effectively reduced patient disability and mortality, but pulmonary metastases and OS cells' resistance to chemotherapeutic agents are pressing challenges in the clinical management of OS. There has been an urgent need to identify new biomarkers for OS to develop specific targeted therapies. Recently, the continued advancements in genomic analysis have contributed to the identification of clinically significant molecular biomarkers for diagnosing OS, acting as therapeutic targets, and predicting prognosis. Additionally, the contemporary molecular classifications have revealed that the signaling pathways, including Wnt/β‐catenin, PI3K/AKT/mTOR, JAK/STAT3, Hippo, Notch, PD‐1/PD‐L1, MAPK, and NF‐κB, have an integral role in OS onset, progression, metastasis, and treatment response. These molecular classifications and biological markers have created new avenues for more accurate OS diagnosis and relevant treatment. We herein present a review of the recent findings for the modulatory role of signaling pathways as possible biological markers and treatment targets for OS. This review also discusses current OS therapeutic approaches, including signaling pathway‐based therapies developed over the past decade. Additionally, the review covers the signaling targets involved in the curative effects of traditional Chinese medicines in the context of expression regulation of relevant genes and proteins through the signaling pathways to inhibit OS cell growth. These findings are expected to provide directions for integrating genomic, molecular, and clinical profiles to enhance OS diagnosis and treatment.

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Outcomes in non-metastatic treatment naive extremity osteosarcoma patients treated with a novel non-high dosemethotrexate-based, dose-dense combination chemotherapy regimen ‘OGS-12’

Cited by 38 publications

References 44 publications

Outcomes in Treatment-Naïve Patients With Metastatic Extremity Osteosarcoma Treated With OGS-12, a Novel Non–High-Dose Methotrexate–Based, Dose-Dense Combination Chemotherapy, in a Tertiary Care Cancer Center

Outcomes in Treatment-Naïve Patients With Metastatic Extremity Osteosarcoma Treated With OGS-12, a Novel Non–High-Dose Methotrexate–Based, Dose-Dense Combination Chemotherapy, in a Tertiary Care Cancer Center

Osteosarcoma journey over two decades in India: Small steps, big changes

Targeting signaling pathways in osteosarcoma: Mechanisms and clinical studies

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