Ewings Sarcoma - Online Expert Cancer Consultation - Navya Care

1. Dear , Thank you for reaching out to Tata Memorial Centre (TMC) and nationally acclaimed experts of the National Cancer Grid (NCG). Navya is pleased to offer this online expert cancer consultation service for assessing your treatment options. We converted your case reports into a structured summary to be reviewed by a radiation oncologist in the Pediatric Solid Tumour Disease Management Group and an expert medical oncologist in the National Cancer Grid, a consortium of 206 cancer centers with the mandate to standardize cancer care nationally. We asked the following question(s) on your behalf: 1.What is recommended at this time: chemotherapy or an alternate treatment? 2.Is radiation therapy recommended? 3.Is surgery recommended? The TMC NCG Navya opinion is summarized as follows: 1.Chemotherapy either with Cyclophosphamide and Topotecan or Irinotecan and Temozolomide is recommended at this time. 2.After completing the recommended (usually 2 to 4 cycles) chemotherapy with Cyclophosphamide and Topotecan or Irinotecan and Temozolomide, assessment of response (i.e. whether the tumor(s)/lesion(s) in the body have decreased/not increased/increased) with ultrasound/CT/MRI scans with oral and iv contrast or PET CT scan is recommended. 3.If assessment of response shows complete response (i.e. absence of residual disease), radiation therapy to the lungs may be considered. 4.However, if it shows residual tumor (i.e. any presence of cancer cells/lesion(s) that remain after therapy such as surgery or chemotherapy), treating oncologist to assess feasibility and operability (i.e. treatable by surgical operation with a reasonable degree of safety and chance of success) with Metastasectomy (i.e. surgical removal of metastases, i.e. presence of cancer cells/lesions or tumours in lungs) is recommended. 5.If the assessment of response shows not favourable/ inadequate response/ progression (i.e. development of new cancer cells/lesion(s) or increase in size of existing lesion(s)/tumor(s) anywhere in the body, including the primary organ) then symptomatic treatment (i.e. therapy that eases symptoms such as pain, discomfort, etc) and supportive care (i.e. treatment given to prevent, control, or relieve complications and side effects and to improve comfort and quality of This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page 1 authority over the care of any individuals.

2. life) is recommended at this time. The treating oncologists and physicians are best suited to determine the specifics of symptomatic treatment and best supportive care. We hope that the expert opinion is helpful in determining the course of your treatment. Please discuss this opinion with your treating oncologist(s). Navya Evidence and Experience Engine is used to assess treatment options derived from clinical trials that pertain to your specific medical history and tumor characteristics as well as analysis of tumor board decisions of patients similar to you treated at internationally renowned tertiary care expert centers. Navya, who provides cancer online consultation, is pleased to provide the following information on treatment recommendation(s) per the Navya Evidence Engine, which includes the globally accepted guidelines for the treatment of cancers by National Comprehensive Cancer Network (NCCN); and the Navya Experience Engine based on the collective experience of experts at Tata Memorial Center and the National Cancer Grid. 1.Chemotherapy with either one of the following regimens is recommended: a.Cyclophosphamide 250 mg/m2, and Topotecan 0.75 mg/m2 daily for five days is recommended, along with Filgrastim 5 ug/kg. OR b.Irinotecan 10 to 20 mg/m2 from day one to day five, and day eight to day 12, and Temozolomide orally 100 mg/m2 from day one to day five, every three to four weeks (i.e. in a 21 to 28 day cycle). 2.If there is complete response, then radiation therapy to the lungs at a dosage of 18 Gy is recommended. 3.However, if there is residual disease, assessment for feasibility for Metastasectomy followed by radiation therapy to the lungs at a dosage of 18 Gy can be considered. Navya is pleased to provide additional information on symptomatic and supportive care. Supportive care focuses on managing the symptoms and offering as much comfort as possible. Disciplines required for the spectrum of palliative care needs of the child and family typically include a clinician, social worker, child life specialist, and religious or spiritual counsellor. Interdisciplinary teams can help ensure that the emotional, spiritual, physical, and practical needs of children and families are identified and met. ●Psychosocial − Social workers provide psychosocial assessment and supportive counseling for the child and family, and identify community services. This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page 2 authority over the care of any individuals.

3. ●Emotional − Child life specialists provide skills in facilitating "communication" with children through activities that assist with emotional distress, and can provide important understanding into the fears and wishes of the child. ●Spiritual − Religious/ spiritual counsellor support faith traditions and spiritual values that can comfort families as they face uncertainty, changes in medical status, loss, or grief, and promote hope and emotional healing. ●Physical − Clinicians can bring expertise in symptom management. It is always important to remember that physical symptoms improve with attention to each of the other three domains. Palliative care clinicians also can serve as facilitators between other healthcare providers and families, and can help coordinate medical care. Symptoms that may be expected and commonly used treatments that may be prescribed by treating oncologist(s) include the following: 1.Pain- Pain management varies depending upon the type, source, severity, and duration of pain. Mild pain can generally be adequately treated with acetaminophen and nonsteroidal anti-inflammatory drugs such as ibuprofen. Moderate to severe pain is generally treated with opioid agents (eg, morphine, hydromorphone, oxycodone, hydrocodone, fentanyl, methadone). The choice of opioid is dependent upon the intensity and duration of pain, preferred mode of administration, associated adverse effects, previous experience (if available), and preference of the patient and family. Oral analgesics should be used when possible to avoid painful routes of administration 2.Shortness of breath (Dyspnea)- Treating dyspnea is typically focused on identifying and treating the underlying cause. Causes of dyspnea include pulmonary disease (eg, pneumonia and primary interstitial disease), anemia, airway obstruction from tumor, and heart failure from cardiac disease. Opioids are the primary medical therapy used to alleviate persistent dyspnea despite maximal medical treatment of identified causes. Other useful interventions include a trial of oxygen, cool air from a fan or open window directed at the face, repositioning, hypnosis or other relaxation techniques, and lorazepam for associated anxiety. 3.Nausea and Vomiting- Medications can cause nausea, and it may be necessary to discontinue or replace them. As an example, opioids are a common source of nausea and vomiting, and also cause constipation. Treatment includes rotation of different opioids, prevention of constipation, and the use of dopamine receptor antagonists such as This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page 3 authority over the care of any individuals.

4. Metoclopramide or other medications such as Ondansetron. In addition, therapy for nausea and vomiting includes management of electrolyte abnormalities, managing mucositis, treating constipation, and the use of antiemetic therapy, if needed. 4.Fatigue- Treatment is generally focused upon the underlying cause of fatigue (eg, anemia). A multimodal approach to treatment may be most effective. Interventions include: a.Treatment of depression, anxiety, and/or sleep disturbance, if present b.Rest and frequent naps c.Modifying activities (including playing/socializing). d.Use of psychostimulants, such as methylphenidate, can be used to increase wakefulness. Given the short duration of action, the timing of doses can be controlled to coincide with important events during the day, such as visits with family and friends. 5.Anorexia and Weight Loss- Pharmacologic interventions that can increase appetite include megestrol acetate, cannabinoids, and corticosteroids. 6.Depression and Anxiety- Nonpharmacologic therapy includes child life specialists, child psychologists, or other trained experts are essential members of the team to assist children with expressing emotional symptoms of distress through age appropriate activities. In particular, guided imagery and hypnosis are effective tools in children with depression and anxiety. Psychopharmacologic treatment can be considered for children with symptoms of depression and anxiety that persist despite nonpharmacologic interventions or in those with more severe symptoms that meet diagnostic criteria for a psychiatric disorder. Options include: Benzodiazepines may have some short term benefit for anxiety symptoms. They should be used cautiously on a chronic basis, if at all, given the lack of evidence to indicate long term benefit and the development of dependence from long term use. 7.Delirium and Agitation- Medications that can help manage the symptoms of delirium and agitation include benzodiazepines and antipsychotic medications. 8.Anemia and Bleeding- Mucosal bleeding can sometimes be controlled with aminocaproic acid given orally or intravenously to inhibit fibrinolysis. Topical options include fibrin sealants. The tannins present in black teas can also help to stop bleeding. At home, patients can press a wet tea bag onto bleeding gums. More significant bleeding may require platelet transfusions. 9.Seizures- Transmucosal antiseizure drug administration (eg, rectal diazepam) is an effective and relatively safe emergency treatment for This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page 4 authority over the care of any individuals.

5. patients with prolonged seizures or seizure clusters in settings where intravenous access is not readily available. Palliative care teams can also provide a supportive environment and assist members of the health care team in managing their own distress. Provider distress is understandable and common when caring for a child with a serious illness. The palliative care team can bring your child comfort in many ways. Further, http://hospicecare.com/home/ offers information on symptomatic treatment and supportive care. If your treatment plan involves complex details such as a choice of immunotherapy vs targeted therapy or enrollment in a clinical trial or bone marrow transplant, etc., Please write to us at reports@navya.care We will prioritize a response based on clinical urgency as it pertains to your receiving on time care. Questions on managing ongoing side effects of cancer treatments such as pain, mouth sores, fever, infection, bleeding, etc. are only suited for in person examination with your local treating oncologist(s)/physician(s). These questions are not amenable to an online expert review. Navya Care is focused on assessing your cancer treatment options. If you are a financially underprivileged patient or receiving treatment under the General Category of any hospital, please reach out to us after you complete your current therapies (surgery or chemotherapy or radiation, etc.) We will assess your treatment response and continue to provide your next treatment plans at no cost. Please do not hesitate to write to us or call us with any questions. Sincerely, Gitika Srivastava This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page 5 authority over the care of any individuals.

6. CASE SUMMARY Expert Opinion ID Current Diagnosis Metastatic Ewing's Sarcoma Age 15 Years Old Gender Male First Presentation [2017] Complaint(s) Rt leg pain [November 21st 2017] MRI Pelvis/Lumbo Sacral Spine 8.0*7.2*6.0 cm sacral spinal canal central and Rt laterals sacral foramina lesion extending from S1 to S4 level. Widening of sacral foraminal- S2 and S3 with extension into presacral region on Rt and into posterior spinal region. Rt posterior spinal region at S2-S3 level necrotic area. S2,S3 and D4 involvement. [December 16th 2017] vertebral marrow Prior Surgery #1 Intent-Timing Curative Definitive Surgery Sacralization Excision Surgery Date December 18th 2017 Diagnosis Made By Trucut Biopsy- Sacral Tumor [December 19th 2017] Malignant Disease Round Cell Tumor Diagnosis Made By Slide/Block Review- Sacral Tumor Trucut Biopsy [December 26th 2017] Malignant Disease Ewing Sarcoma IHC- Positive CD99 This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page 6 authority over the care of any individuals.

7. IHC- Negative CD3, Pax-5, Synaptophysin, Desmin Prior Chemotherapy #1 Intent-Timing Therapy/Regim Treatment Start Date December 29th January 2019 Treatment End Date Response en VAC/IE: Vincristine(1.4)/ 2017 A(30)/C.iv(700)- >Etop.iv(100)/If osfamide(800) Curative Definitive- Induction Complete Response FDG- PET CT Partial response. Mild FDG avid sacral region (SUV-2.0). No e/o malignant lesions. [March 27th 2018] Prior Radiation Therapy #1 Intent-Timing Therapy/Regimen Treatment Start Treatment Date May 2018 End Date April 2018 Curative- Definitive Primary Target Site#32 Note RT doses not available. FDG- PET CT Complete response. Presacral region fat stranding with no e/o lesion. No e/o malignancy elsewhere [February 08th 2019] Note Patient was on follow up post CTh. Second Presentation [2019] Complaint(s) Rt leg pain [November 2019] FDG- PET CT Enlarged b/l tonsils (SUV-8.4). Non FDG avid- b/l maxillary thickening involving b/l maxillary and sphenoid sinuses. Non FDG avid- largest 1.2*1.1 cm b/l lung nodular lesions. FDG avid- largest This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page 7 authority over the care of any individuals.

8. 6.6*6.5*4.2 cm Lt costal pleura lesions (SUV-6.0) and 3.1*2.3*1.7 cm diaphragmatic pleura lesions (SUV-3.7). FDG avid- 2.4*2.4*1.6 cm pre tracheal LN (SUV-3.9). FDG avid- thymus (SUV- 3.4). Presacral fat stranding with no e/o lesions. No e/o malignancy elsewhere [November 11th 2019] Met : Lung Yes Diagnosis Made By Biopsy- Lung Lesion [November 14th 2019] Malignant Disease Small Round Cell Tumor IHC- Positive CD99/Mic2, Fli-1, Synaptophysin (Weak) IHC- Negative Desmin Clinical TNM Stage Stage IVB - Any T Any N M1b Bone Marrow (Hematologic) Function Adequate [November 9th 2019] Kidney (Renal) Function Adequate [November 9th 2019] Liver (Hepatic) Function Not Available Heart (Cardiac) Function Not Available Functional Status- ECOG Score 1 General Condition Patient is able to care for self, can bathe, can clothe, can walk and carry all independent activities assistance. Mild cough. without any Note Treating oncologist recommended RT at dose of 45 Gy#25 + 10.8#6 and CTh. This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page 8 authority over the care of any individuals.

9. Navya is a Cambridge, MA based company with offices in Bangalore, India. Navya is founded by graduates of Harvard University, MIT Sloan School of Management, and the Stanford School of Medicine. Navya’s innovative and scalable decision making system is a technology powered solution for complex medical questions. Navya’s software solutions are efficient engines to gather and synthesize individual goals of care, evidence specific to an individual medical case, and expert opinion, for evaluating treatment alternatives. Navya’s goal is to assist in bringing clarity to the complexity of evaluating treatment alternatives. Navya’s system collects the best available information and expertise from several worldwide sources relevant to a specific previously diagnosed medical case and assesses treatment decisions. For more information, please visit www.navya.care or call +91 80-61787700 or email gitika@navya.care Navya Network, Inc does not diagnose, prescribe medication, treat, or give orders, nor does Navya have the ultimate authority over the care of any individuals. Navya does not provide medical advice nor does its products, services, systems, projects, or programs constitute the practice of medicine, nursing, or any other health care profession. Any information provided by Navya as a result of use of Navya’s products, services, systems, projects, or programs is being provided solely for educational and informational benefit and should not be considered diagnosis, treatment or a substitute for professional medical advice. Use of Navya’s products, services, systems, projects, or programs does not establish a doctor-patient relationship. Navya encourages that individuals or patients using Navya’s products, services, systems, projects, or programs share any reports or other information generated by the use of Navya’s products, services, systems, projects, or programs with their treating health care provider. Use of Navya’s products, services, systems, projects, or programs is voluntary and any information communicated as a result of the use of Navya’s products, services, systems, projects, or programs is not intended to be, nor implied to be, and cannot and should not be used as a substitute for professional medical advice, diagnosis or treatment. Navya’s products, services, systems, projects, or programs are limited to the provision of consultative services with respect to known or previously-identified condition and neither Navya, nor its employees, consultants or agents with whom it contracts will diagnose, treat, give orders, prescribe medications or have any authority over the care of any individuals. Navya’s products, services, systems, projects, or programs will not involve any direct face-to-face encounters or physical examinations. Accordingly, individuals using Navya’s products, services, systems, projects, or programs are encouraged to share and discuss any information provided as a result of use of Navya’s products, services, systems, projects, or programs with their treating physician. The individuals or patients using Navya’s products, services, systems, projects, or programs will be the ultimate decision maker over their own care. This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page 9 authority over the care of any individuals.

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