Evidenced‐Based Practice for Symptom Management Facilitator John Hill, Jr. , MD DHMC ‐ Norris Cotton Cancer Center Panelists Mary Ellis, PharmD Exeter Hospital Elizabeth McGrath DNP, APRN, AGACNP‐BC, AOCNP, ACHPN DHMC ‐ Norris Cotton Cancer Center Danielle Fogg AOCNP Eastern Maine Medical Center – EMMC Cancer Care
Cancer and the Immune System • Immune systems response to cancer cells: Elimination Equilibrium Escape Compromised immune systems and immunosuppressive drugs
Cancer and the Immune System • Immune systems response to cancer cells: Elimination Equilibrium Escape Compromised immune systems and immunosuppressive drugs
Immune Checkpoint Inhibitors • Pathway responsible for maintaining self‐tolerance and homeostasis • To protect tissues from the immune response as well as prevent self autoimmunity • Cytotoxic T Lymphocyte Antigen (CTLA‐4) • Programmed cell death‐1(PD‐1)+Programmed cell death‐Ligand‐ (PD L‐1)
Immune mediated Adverse Effects • Pneumonitis • Colitis • Hepatitis • Nephritis and Renal Dysfunction • Skin Adverse Reactions
Immune Mediate Adverse Effects • Endocrinopathies Hypophysitis Adrenal Insufficiency Hypothyroidism Hyperthyroidism Type 1 Diabetes Mellitus Pancreatitis Thyroiditis
Immune Mediate Adverse Effects • Immune related adverse reactions include: Uveitis, Iritis, Pancreatitis, Facial and Abducens Nerve Paresis, Demyelination, Polymyalgia, Rheumatica, Autoimmune Neuropathy, Guillain‐Barré syndrome, Hypopituitarism, Systemic Inflammatory Response Syndrome, Gastritis, Duodenitis, Sarcoidosis, Histiocytic Necrotizing Lymphadenitis, Myositis, Myocarditis, Rhabdomyolysis, Motor Dysfunction, Vasculitis, Myasthenia gravis
Case 1 Presentation 24 y.o. male diagnosed with Stage IV Rectal Cancer with a solitary liver metastasis and extensive pelvic adenopathy 8/12~: 4 cycles of Folfox, with evidence of response 10/15 ‐ 11/12: EBRT/CI 5‐FU. The restaging CT showed slight decrease in the solitary liver lesion and decrease in the abd/pelvic LNs and no new areas of disease 1/13: He underwent ultralow anterior resection and hepatic metastatectomy pT3pN1bpM1
3/13: Post‐operative chemotherapy with Folfox/Avastin 8 cycles 10/13: He underwent resection and closure of the loop ileostomy. He had a very complicated post‐op course with bowel obstruction, pelvic abscess/infected hematoma (requiring exploratory lap and drainage). He was on TPN through a PICC catheter and developed fungal bacteremia treated with fluconazole 3/14: Radicular RLE pain. MRI in showed soft tissue involving the S1 neuroforamen, consistent with his symptoms and with recurrence of the cancer with a second hypermetabolic area in the left abdomen, felt to be consistent with metastatic disease Folfiri plus Bevacizumab 4 cycles. The RLE pain improved
5/14: CT scan showed a slight decrease in the left sided abdominal soft tissue nodule. The S1 area did not appear significantly changed 6/14: He was seen at Johns Hopkins‐ recommended stereotactic EBRT to the sacral lesion and then observation. If he had progressive intra‐abdominal or peritoneal disease, then could consider debulking and HIPEC 8/14: Received a short course of radiation to the S1 lesion, his symptoms improved but then worsened 11/14: CT scan showed the area appeared stable with no other areas of disease
12/14: PET scan showed uptake in the area and no evidence of disease elsewhere Treated with Folfox plus Panitumumab 4 cycles. He had response to therapy but due to SE changed to a maintenance regimen of Capecitabine plus Bevacizumab 4/16: Therapy was changed to Pembrolizumab due to clinical progression of disease with a rising CEA and worsening symptoms
5/18/16‐ C2 D1 “Due to worsening pain and declining functional status it was elected to initiate Pembrolizumab at his last visit 4/27/16. He is s/p cycle 1 and returns with his wife for consideration of C2. He has not felt well but finds it hard to describe. He has noted chills a/w sweating episodes. No fevers. More fatigue and he notes exertional fatigue with activities. Tried to wash the truck this morning and broke out in sweats. Felt shaky and very tired after that task. Skin is dry. Back and leg pain are no worse, continues oxycontin BID and oxycodone for breakthrough. He has been having headaches which is unusual for him. He is more short tempered, ‘I expected it to be different with this new chemotherapy’. ”
TSH 5/18/16 TSH was low @ 0.27mcUI/ml
Free T4 5/18/17 Free T4 high @ 5.12 ng/dl 5/18/16 TSH was low @ 0.27mcUI/ml
Free T3 5/18/16 TSH was low @ 0.27mcUI/ml Free T4 high @ 5.12 ng/dl
Total T3 5/18/17 Total T3 High @ 3.74 ng/ml 5/18/16 TSH was low @ 0.27mcUI/ml Free T4 high @ 5.12 ng/dl Free T3 High @ 51.03 mcIU/ml
Diagnosis • “noted to have symptoms and lab findings c/w immune modulated hyperthyroiditis r/t pembrolizumb • Spoke with Endocrinology who recommended starting Metoprolol 50mg daily and we will schedule an appointment for them to see in consultation next week • We will obtain a I‐131 Thyroid scan prior to that visit and additional thyroid function tests • We will proceed with C2 Pembrolizumab today”
I‐131 Thyroid Uptake Scan
Endocrinology • Scan/labs c/w silent thyroiditis • “tachycardic with high FT4 at 5.12 last week, switch atenolol to propanololLA 120 mg qd to help block T4 to T3 conversion in peripheral tissues until his HR <80 and FT4 trending back down to normal range, hopefully in the next 3‐4 weeks ”
Endocrinology • “Since he needs to stay on Pembrolizumab, he is likely switching to hypothyroid but also has risk of recurrent hyperthyroid, so we will continue to monitor TFTs closely.” • “He may need levothyroxine supplement in the future if he switches to hypothyroid and will stop Propanolol when FT4 is normalized”
Endocrinology Ref. Range 4/27/2016 5/18/2016 5/31/2016 6/8/2016 6/8/2016 6/29/2016 7/20/2016 16:20 12:22 14:35 13:25 13:25 13:35 13:12 T3, Total Range: 75 - 374 (H) 142 81 60 (L) 170 ng/dL Free T4 Range: 0.93 - 1.23 5.12 (H) 2.41 (H) 1.30 1.29 0.65 (L) 0.59 (L) 1.70 ng/dL TSH 0.27 - 4.20 1.35 0.01 (L) 0.01 (L) 0.01 (L) 0.01 (L) 16.73 (H) 51.03 (H) mcIU/mL TSI <=1.3 TSI <1.0 index Thyroperox Ab Range: <=34 13 IU/mL 6/8/16 Free T 4 wnl‐Propranalol d/c’d 7/20/16 TSH elevated‐LT4 supplement 150 mcg qd started
Pembrolizumab
Pembrolizumab
CEA
Resources Clinical Care Options http://bit.ly/2mYAImi
Case 2 Presentation DC: 56 y.o. female newly diagnosed Metastatic Melanoma to Left Lung History of Stage IIIA superficial spreading Melanoma to back. • S/P wide excision; One positive axillary node. • S/P negative completion axillary dissection. • Opted against adjuvant therapy Past Medical History • No Autoimmune disorders • History of Breast Cancer treated with neoadjuvant chemotherapy, mastectomy, post mastectomy radiation and endocrine therapy. No evidence of recurrence • History of Basal Cell Carcinoma
Case Presentation Recently presented with progressive dyspnea and cough with findings of a large left lung mass and large left pleural effusion. No other sites of disease. Core biopsy positive for Metastatic Melanoma. BRAF Wild‐Type. Immunotherapy with combined Ipilumumab/Nivolumab was offered as the best option for response . Discussion ensued regarding the high risk for Grade 3/4 adverse events. Combination Therapy: Incidence of Pneumonitis rises to 6% (about 4% with single agent) Incidence of Rash/Dermatitis rises to 23% (about 15% with single agent) Incidence of Colitis rises to 26% (about 20% with single agent)
Case Presentation Emphasis was placed on early reporting of symptoms: • Rash • Diarrhea • Weakness • Anything out of her norm Early reporting of symptoms can help minimize potential for grade 3/4 immune mediated side effects
Case Presentation February 7: Baseline CBC/D, CMP, TSH, Free T4 within normal limits Patient started first cycle of Ipilumumab/Nivolumab combined therapy February 16: Follow‐up telephone call to her revealed increased cough, mild increase in shortness of breath, and a new red, pruritic rash on upper back and chest. • Advised topical Hydrocortisone 1% BID for the rash and Cetirizine/Diphenhydramine for the pruritus • Ipilimumab/Nivolumab held
Case Presentation February 17: Patient called reporting rash quickly progressed to pruritic generalized erythroderma from her neck to her toes. No ulceration or breakdown. Also mentioned mild blurred vision. Advised Prednisone 40 mg PO daily. Rash resolved within 7 days. At Follow‐Up Appointment: • No lab discrepancies observed with repeat CBC/D, CMP, TSH, Free T4. • Mild blurriness to distant vision persisted • Discussed high risk for recurrent toxicity with resuming combined therapy • Rash and visual changes could be attributed to either agent: Similar toxicity profile for all of these agents. ‐ Opted to switch to single agent: Nivolumab based on personal experience with toxicities seen with Ipilumumab. Reinforced importance of close vigilance for recurrent rash or new or progressive vision changes
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