Prospective analyses of survival of patients with indeterminate lesions and unequivocal metastatic disease at presentation in Bone & Soft tissue sarcoma across all ages of patients presenting to BST DMG, agnostic of the intent of treatment and site of metastasis or burden of disease

BACKGROUND and RATIONALE

Metastases at presentation predicts worse event free and overall survival across sarcoma subtypes[1]. The predicted 5 year OS for osteosarcoma is 63% [2], for Ewing’s sarcoma is, 72% [3] Ability to achieve R0 resection with neo/adjuvant therapy and surgery portends better EFS and OS for all subgroups. Optimal triage of patients for intent of treatment, early onset palliative care referral, aggressive resection of oligo metastatic sites, timing of metastatectomy, balancing the morbidity of treatment with survival benefit and quality of life has not been systematically studied in a prospective cohort, particularly not in an Indian /LMIC cohort. Retrospective data fail to measure disease burden, reasons for triage, compliance, palliative care referrals as the dropout rate for this cohort of patients is high. It also suffers from selection, triage and reporting bias skewing the survival data. This is inherent due to the lack of consensus of optimal treatment strategy in this cohort. This is reflected in many published series all being retrospective, across sarcoma subtypes. These directly influence ‘value based care’, optimized for each patient with poorer predicted survival as compared to their non-metastatic peers. Prospective analyses of survival of patients with indeterminate lesions and unequivocal metastatic disease at presentation in Osteosarcoma, Ewing’s Sarcoma, Chondrosarcoma, Soft tissue sarcoma across all ages of patients presenting to BST DMG, agnostic of the intent of treatment, site of metastasis or burden of disease. The goal of this study is to assess differences in overall survival as predicted by metastatic burden at presentation.

AIMS AND OBJECTIVES

To measure overall survival in patients presenting with metastasis stratified by disease biology (Osteosarcoma/Ewing’s Sarcoma/Chondrosarcoma/Soft tissue sarcoma, Radiation induced sarcoma) agnostic to site, burden of metastasis, and intent of treatment (palliative vs curative)

Primary Objective: to measure median Overall Survival at 3 years from diagnosis of metastatic/indeterminate disease.

Secondary Objective: Quality of life measurements using EORTC QLQ 30 at baseline and subsequent in person or tele follow ups.

STUDY DESIGN

This is a single centre prospective observational cohort study.

SCHEDULE

Patients shall be screened and recruited after IEC approval and appropriate consenting. Since this is an observational study, patient follow up will align with standard of care. There shall be no additional follow ups for this study. Recruitment duration: 2 years after IEC approval

Follow up time: 3 years from accrual or death from any cause whichever first.

Study time: ~ 5 years

POPULATION AND SETTING

Patients who present to BST DMG outpatient clinics with indeterminate or unequivocal metastatic disease from biopsy proven bone or soft tissue sarcoma. The study shall recruit all patients regardless of their desire to complete therapy at TMH. We shall consent them for a brief telephonic follow up at 3 to 6 monthly intervals should they choose to avail care elsewhere. There shall be no additional intervention other than standard of care at the time of recruitment.

Inclusion Criteria

1. patient of any age/sex who presents with indeterminate lesions, or unequivocal radiological metastasis (including skip metastases), or biopsy proven synchronous metastatic disease in radiologically equivocal cases, at presentation, stratified for Ewing’s Sarcoma, Osteosarcoma (all subtypes), chondrosarcoma, Soft tissue sarcoma (round cell and NRSTS, including radiation induced sarcoma) irrespective of intent of treatment.

2. Histopathological confirmation of primary sarcoma diagnosis at TMH

3. Imaging review of standard of care staging investigations at TMH or documented radiology consensus at joint clinic appraisals for obvious metastases.

4. Indeterminate lesions based off validated radiologic criteria and consensus in multidisciplinary joint clinic (subcentimetre lesions, equivocal characteristics, minimal impact, not amenable to biopsy).

Exclusion criteria

1. Metachronous metastases (after a disease free/treatment free interval)

2. Absence of histopathological review at TMH

3. Absence of imaging review at TMH

INFORMED CONSENT

Patients matching inclusion criteria will be provided with a detailed patient information sheet. A screening and inclusion log shall be maintained by the study team. After their concerns are allayed, should they choose to participate, they shall be recruited in this study. Parents of minors and legally allowed representative shall consent for those unable to. We shall reinforce, that this is an observational study, which entails, that all investigations, treatment and follow up schedule shall be based on standard of care. No additional diagnostic, investigational or therapeutic interventions shall be made. Participation in this study shall not incur any additional cost, inconvenience or follow up. The study team shall record suitable variables as detailed below in the case record form. Patients will be requested to fill the validated quality of life questionnaire. The study team will seek out follow up information in person when a patient’s follow up is due or get in touch with them telephonically, via email or their preferred consented mode of messaging communication. The entire process will respect privacy and data breach concerns. Their follow up shall continue even when they choose to pursue recommended supportive care or treatment closer to their place of residence as is common in patients with metastasis and poorer expected survival.

Follow up

These patients will be followed up as standard of care for 24 months or until death from any cause, whichever first The usual protocol is 6 monthly after end of treatment. Any change of frequency of follow up or surveillance imaging shall be left to the discretion of the treating physician. Some radiation, chemotherapy, surgery, or related complications may warrant a shorter follow up period. This study shall not interfere with the treatment or follow up process.

Outcomes

Primary End point: Overall Survival at 3 years (death due to any cause) Survival in months (from date of diagnosis of metastatic disease to date of death/last patient contact/censored observation at the end of study period)

Secondary endpoints: QOL at baseline, during every hospital visit, then 3–6 monthly until end of study as measured by EORTC QLQ30.

Analysis

Analyses of primary and secondary outcomes stratified by histology, burden, indeterminate vs metastatic status, intent of treatment. Multivariate logistic regression models for biological and clinical factors associated with type of treatment and predicted probability of survival at 5 years using R version 3.0 or SPSS with appropriate plots/graphs.

Sample size considerations

All consecutive patients with indeterminate and metastatic disease shall be screened and recruited for 2 years from IEC approval. Approximately 200 patients with no upper limit or lower limit.

Data management

All study records will be kept with confidentiality in the investigators’ office or clinical research unit. Periodic audits will be performed by the investigators to ensure completeness and quality of data. Access to study documents will be available to the investigators and the Data Monitoring Committee.

Ethical aspects

The study will be conducted strictly as per International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines and the principles of the Declaration of Helsinki. An informed consent in the language of patient’s choice shall be administered.

Risk & Benefits

This study does not add or impose any risk to the participants. The outcomes of this study shall strengthen value based care in this set of patients, where expected treatment associated survival benefit may conflict with quality of life outcomes.

Feasibility

The annual outpatient load in the BST DMG is in the 1000s, we have 2 out-patient clinics per week. Based on historical data, up to 25% percent of our patients present with metastatic disease. We are not setting a sample size on this cohort, and shall screen all patients who fit the inclusion criteria.

Significance

This prospective study shall set benchmarks for data directed triage and optimal value based care in a cohort with relatively poorer overall survival in India and applicable to all LMIC nations. This will also act as a baseline for future cost effectiveness and health technology assessment studies.

Conflict of interest

The investigators declare no present or potential conflicts of interest in the conduct or outcome of this study

Budget

1. Source of funding

Intramural+ Extramural

|Items

5 th Year

|2. Salaries-personnel (Numbers) Study coordinator (Rs 25,000 x 5 yr)

1,500,000

|Equipment/hardware/Drugs and consumables/ clinical investigation/Hospitalization/any other expenditures

NA

|8.Miscellaneous (<5% of budget) Stationary

 20,000

|Grand Total

1,520,000/-

References

1]Cotterill SJ, Ahrens S, Paulussen M, Jurgens HF, Voute PA, Gadner 0H, Craft AW. Prognostic factors in Ewing’s tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing’s Sarcoma Study Group. Journal of clinical oncology. 2000 Sep 17;18(17):3108-14.

2]Gurney JG, Swensen AR, Bulterys M. Malignant bone tumors. Cancer incidence and survival among children and adolescents: United States SEER Program. 1975;1995(1999):99-110.

3]Grier HE, Krailo MD, Tarbell NJ, Link MP, Fryer CJ, Pritchard DJ, Gebhardt MC, Dickman PS, Perlman EJ, Meyers PA, Donaldson SS. Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermaltumor of bone. New England Journal of Medicine. 2003 Feb 20;348(8):694-701.