Peripheral Nerve Sheath Tumor - Online 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 cancer expert consultation service for assessing your treatment options. We converted your case reports into a structured summary to be reviewed by a medical oncologist and a surgical oncologist in the Pediatric Solid Tumor Disease Management Group at Tata Memorial Centre, and a surgical oncologist and a radiation oncologist in the Thoracic Disease Management Group at Tata Memorial Centre. We asked the following question(s) on your behalf: 1. Are additional diagnostic tests recommended at this time? 2. Is esophageal stenting recommended at this time? 3. Is surgery recommended at this time? 4. Is radiation therapy recommended at this time? 5. What is recommended at this time: chemotherapy or targeted therapy or immunotherapy or an alternate therapy? The TMC NCG Navya opinion is summarized as follows: 1. Mutation test for C-KIT/PDGFR expression is strongly recommended at this time. 2. Meanwhile, starting Tyrosine Kinase Inhibitor(TKI) with Imatinib 340 mg/m2 daily until disease progression or dose limiting toxicity is recommended. 3. Alternatively, Tyrosine Kinase Inhibitor(TKI) with Imatinib 340 mg/m2 daily along with oral metronomic chemotherapy with Cyclophosphamide and Etoposide may also be considered as an acceptable option at this time. 4. Additionally, 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 life) along with above recommended therapy is recommended at this time. The treating oncologists and physicians are best suited to determine the specifics of symptomatic treatment and best supportive care. 5. Given that the compression of the esophagus (food pipe) is close to the cricopharynx (throat region) (as mentioned in the CT chest dated December 31st 2018), upper endoscopy to assess the feasibility and safety of esophageal stenting margin, is recommended at this time. 6. If assessed feasible, then esophageal stenting to ease/relieve dysphagia (i.e. difficulty or discomfort in swallowing) may be considered at this time. This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page1 authority over the care of any individuals.

2. 7. However, if esophageal stenting is not feasible, then Percutaneous Endoscopic Gastrostomy (PEG) tube (an endoscopic medical procedure in which a tube is passed into a patient's stomach through the abdominal wall, most commonly to provide a means of feeding when oral intake is not adequate) is recommended at this time. 8. Additionally, given there are multiple metastasis in lung (i.e. presence of cancer cells/lesion(s) in the lung), further surgery and/or radiation therapy are not indicated/recommended at this time. We hope that the cancer 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 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. Oral metronomic chemotherapy with Cyclophosphamide 50 mg/m2 orally from day 1 to day 21, Etoposide 50 mg/m2 orally from day 1 to day 21 until disease progression or dose limiting toxicity is recommended. 2. After completing every two to three months of the recommended targeted therapy with Imatinib or Imatinib with Cyclophosphamide and Etoposide, assessment of response (i.e. whether the tumor(s)/lesion(s) in the body have decreased/not increased/increased) with CT scans with oral and chest/abdomen/pelvis or PET CT scan of the whole body is recommended. iv contrast of the 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. This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page2 authority over the care of any individuals.

3. ● Psychosocial − Social workers provide psychosocial assessment and supportive counseling for the child and family, and identify community services. ● Emotional − Child life specialists "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. provide skills in facilitating 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 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. anti-inflammatory drugs such as This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page3 authority over the care of any individuals.

4. Treatment constipation, and the use of dopamine receptor antagonists such as 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. includes rotation of different opioids, prevention of This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page4 authority over the care of any individuals.

5. 9. Seizures- Transmucosal antiseizure drug administration (eg, rectal diazepam) is an effective and relatively safe emergency treatment for 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 serious illness. The palliative care team can bring your child comfort in many ways. Further, treatment and supportive care. http://hospicecare.com/home/ offers information on symptomatic 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 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 Page5 authority over the care of any individuals.

6. CASE SUMMARY Expert Opinion ID Current Diagnosis Recurrent Peripheral Nerve Sheath Tumor Intra- Thoracic Malignant Age 14 Years 5 Months Old Gender Male First Presentation [February 2018] Complaint(s) Fever, Wt loss & lethargy [February 2018] FDG-PET CT 13.1*12.2*11.0 paramediastinal (SUV-8.67) involving RUL lung medial segment, RML and RLL lung; abutting RUL anterior segment pleura anteriorly, RLL lung pleura posteriorly, closely abutting and compressing SVC medially displacing SVC structures anteriorly compressing Rt main pulmonary artery, Rt superior pulmonary vein and Rt anterior lobar bronchus; Rt inferior pulmonary vein likely traverses through the mass; compressing trachea and esophagus and displacing to left; encasing Rt main bronchus and bronchus intermedius with resultant collapse or consolidative changes abutting T3-T6 vertebra posteromedially with erosive changes in anterior cortex. Few RML lung consolidative changes. Mild Rt pleural effusion. 5.2 cm superior mesenteric artery thickening. Lt lower anterolateral chest tissues and skin soft tissue thickening. Few b/l axillary LNs. [March 7th 2018] cm Rt lung/Rt mass , mediastinal in RLL lung; wall subcutaneous This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page6 authority over the care of any individuals.

7. Diagnosis Made By CT Guided Biopsy- Lung Mass [February 27th 2018] Malignant Disease Spindle Cell Tumor Note Mild nuclear irregularity and 1-2 hpf mitosis. Focal necrosis seen. Diagnosis Made By Slide/block Review- CT Guided Lung Biopsy [February 27th 2018] Malignant Disease Mesenchymal Tumor Cancer Grade III IHC- Positive Vimentin IHC- Negative EMA, CD117, CK, CD31, Desmin, Calretinin, Melan-A S100, SMA, CD34, ALK-1, Ki67 70-75% Note Possibility of fibrosarcoma Bone Scan Normal [March 3rd 2018] Diagnosis Made By Slide/block Review- CT Guided Lung Biopsy [March 6th 2018] Malignant Disease Malignant Tumor Peripheral Nerve Sheath IHC- Positive S100 IHC- Negative Desmin, Myogenin, EMA, SMA, CK Diagnosis Made By CT Guided Biopsy- Lung Mass [March 13th 2018] Malignant Disease Spindle Cell Sarcoma This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page7 authority over the care of any individuals.

8. Cancer Grade I IHC- Negative SOX10, S100, ALK, BETA-CATENIN, CD34, STAT6, DESMIN, TLE-1, EMA, DOG-1 Note Low grade Myofibroblastic Sarcoma and Low Grade Myxofibro Sarcoma are still the remaining possibilities. Inflammatory myofibroblastic Fibromatosis, Solitary Fibrous Tumor, MPNST and Spindle cell have been excluded tumor, GIST, Bone Marrow Aspiration (Right and Left Side) Mild Marrow Plasmacytosis (8%) [March 22nd 2018] Bone Marrow Biopsy Trilineage 2018] Hemopoiesis [March 22nd Prior Chemotherapy #1 Intent-Timing Therapy/Regimen Treatment Start Date March 23rd 2018 Treatment End Date May 2018 Curative-Definitive - Neoadjuvant A/Ifosfamide/Mesna: A(37.5)d1-d2/Ifosfamide(3000)d1-d3/M esna(600)_q21#2 4th Prior Surgery #1 Intent-Timing Curative-Definitive - Delayed Therapy/Regimen Right Postero-lateral Thoracotomy with Debulking Of Mass Surgery Date May 14th 2018 Surgery Notes 15*15 cm posterior mediastinal mass, adhered to RLL lung apical segment, infiltrating Rt paravertebral muscles and vertebra. Pathological Tumor Size (cm) 15*13*8 This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page8 authority over the care of any individuals.

9. Final Margins- Surgery 1 Negative (>10mm) Malignant Disease Spindle Cell Sarcoma, favour Peripheral Nerve Sheath Tumor FNCLCC Cancer Grade III IHC- Positive Vimentin, S100 (Focally Positive) IHC- Negative Desmin, Myogenin, CK, TLE-1, Bcl2, Alk-1 Note Few cells marked by SMA Pulmonary Infiltration Alveolar Parenchymal Yes Angio Invasion No Note Chondroid metaplasia noted focally. Prior Chemoradiation Therapy#1 Prior Chemotherapy #2 Intent-Timing Therapy/Regimen Treatment Start Date June 2018 Treatment End Date October 27th 2018 Curative-Definitive - Adjuvant C.iv/Dactinomycin/Vincristine: C.iv(1200)/Dactinomycin(2)/Vincristine( 1.36)_q21#7 1st Note During C2 and C3 Dactinomycin was not given due to ongoing RT Prior Radiation Therapy #1 Intent-Timing Therapy/Regimen Dose Fraction Treatment Treatment End Date July 2018 Start Date June 2018 Curative-Definitive - Adjuvant IGRT- Thorax 50 25 11th 19th This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page9 authority over the care of any individuals.

10. Diagnosis Made By Trucut [November 13th 2018] Biopsy- Mediastinal Mass Malignant Disease Malignant Tumor Cancer Grade III Diagnosis Made By Slide/Block Review- Mediastinal Mass Biopsy [November 21st 2018] Malignant Disease Malignant Tumor Peripheral Nerve Sheath Cancer Grade III IHC- Positive Vimentin, CK (Focally Positive), NF (Focally Positive) IHC- Negative CD99, CD45, S-100, Tdt, CD34,TLE1, EMA, Desmin Ki67 40% Second Presentation [November 2018] Complaint(s) Dysphagia, pain in neck/throat radiating to Rt arm [November 2018] FDG-PET CT Disease Rt extending paravertebral region at D2-D3 levels, pushing and compressing (SUV-5.6). Anterior mediastinal lesions (SUV-5.4), predominantly on Rt side, abutting SVC. D2 vertebral subtle erosion. FDG avid Lt proximal tibia lesion (SUV- 3.6). [November 12th 2018] Progression. FDG groove avid tracheoesophageal into lesion, and prevertebral esophagus This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate authority over the care of any individuals. Page 10

11. Note Flexible bronchoscopy with expandable metallic tracheal stent placed [December 8th 2018] CT Chest 6.3*5.8*4.1 cm anterior and superior mediastinal mass, abutting SVC and ascending aorta with loss of fat planes. 6.2*3.6*2.6 cm posterior lesion at the level of D2, D3 vertebrae, compressing esophagus with mild cortical erosion of anterior margin of D2-D3 vertebrae. Multiple 1.3*1.1 cm RLL subpleural location basal segment, b/l lung (R>L) nodules. interlobular septal thickening with RUL, RML lung areas of ground glassing. RML and RLL lung fibroatelectactic band. Multiple subcm paratracheal, subcarinal, b/l cervical LNs. [December 31st 2018] mediastinal RUL lung prevascular, b/l DICOM Link Click Here Prior Chemotherapy #3 Intent-Timing Therapy/Regimen Treatment Start Date December 2018 Treatment End Date Ongoing Palliative- Line 1st D/G.iv: D(75)d8/G.iv(1000)d1,d8_q21#1 18th Note TMC recommended C-KIT/PDGFR mutation test. Additionally, Imatinib + metronomic CTh recommended. stenting if feasible vs. PEG. No further surgery or RT. [January 4th 2019] NCG Navya Online Opinion Esophageal Note NGS Mutational Amplification- Alteration; CDKN2A/B Alteration loss; HMGA2- SMARCC2 Fusion; PTPN11 report- MSI- Stable; Low; Tumor CDK4 NF1 Burden- Equivocal; This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page11 authority over the care of any individuals.

12. subclonal; SUZ12 Alteration [January 9th 2019] C-Kit/ PDGFR Mutation Not Done Bone Marrow (Hematologic) Function Not Available Kidney (Renal) Function NotAvailable Liver (Hepatic) Function Not Available Heart (Cardiac) Function Adequate [March 15th 2018] LV Ejection Fraction 65% Functional Status- ECOG Score 3-4 General Condition Patient is completely on bed with c/o dysphagia and taking food via PICC Line This TMC NCG Online Expert Opinion Service, and Navya Network Inc., does not diagnose, treat, give orders, or have the ultimate Page12 authority over the care of any individuals.

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