Palliative Therapy for the Incurable Patient Sonali M

Palliative Therapy for the “Incurable” Patient Sonali M. Smith, MD Associate Professor, Section of Hematology/Oncology Director, Lymphoma Program The University of Chicago

Leading Sites of Cancer Cases and Death

Lymphoma Vital Statistics Total Cases Male Female Total Deaths Male Female USA 75, 190 40, 880 34, 310 20, 620 10, 510 10, 110 EU 52, 440 28, 043 24, 397 25, 906 13, 285 12, 261 8375 4471 3904 4212 2225 1987 Germany 10, 179 5203 4976 5260 2501 2759 Italy 10, 825 5906 4919 4675 2390 2285 8307 4515 3792 4507 2380 2127 France UK www. seer. cancer. gov; cancer mondial website

What is an “incurable” lymphoma? • Newly diagnosed: double hit • All indolent lymphomas and CLL • Relapsed/refractory aggressive lymphomas in the elderly • Multiply relapsed and/or refractory disease in the young • Mantle cell lymphoma • Most T-cell lymphomas

What is an incurable lymphoma? • 41 yo woman with MYC+BCL 2+ B-cell lymphoma unclassifiable (BCLU)Biology who progresses through DAEPOCH-R with a large breast mass • 78 yo man with MCL since 2005 s/p R-Hyper. CVAD, Cumulative bortezomib, BR, temsirolimus, toxicity DHAP who has persistent cytopenias due to marrow involvement • 92 yo man with DLBCL who relapses Advanced age 8 months after RCHOP (with dose reductions) • 67 yo woman with FL since 2008 who has no symptoms but with radiographic. Histology progression after 2 prior lines of therapy

MYC pos DLBCL: BCCA analysis • Patients with MYC pos DLBCL had inferior PFS and OS 66% PFS 31% • Even when excluding BCL 2 pos cases, MYC was an adverse prognostic factor • 2 of 12 (17%) of patients with MYC pos DLBCL had CNS recurrence compared to 4 of 123 (3%) of MYC neg DLBCL 72% OS 33% Savage Blood 2009

“Double hit lymphomas”: BCL 2 worsens prognosis of MYC pos lymphomas Prognostic factors for survival Age > 60 yrs PS > 1 High IPI BM pos BCL 2 protein pos R -CHOP Johnson Blood 2009

FL is an incurable lymphoma • Goals of therapy change over time • Selection of any treatment must reflect short- and long-term goals • Can be difficult to identify when patient should move to palliative care Swenson WT et al. J Clin Oncol. 2005; 23: 5019 -5026.

FL has multiple disease states… Treatment naive Sensitive Resistant Low tumor burden High tumor burden 1 st 2 nd or Relapse Low tumor burden High tumor burden Multiply relapsed/refractory …with different treatment goals

Age and prognosis IPI Age PS LDH >1 EN site stage FLIPI-1 Age LN sites >4 LDH Stage Hgb FLIPI-2 Age B 2 M BM + LN>6 cm Hgb MIPI Age PS LDH WBC (Ki 67) PIT Age PS LDH BM + The recurrent identification of age as an adverse prognostic factor implies that elderly patients are less “curable” overall

New agents challenge our definition of “incurable” and “untreatable”: HL example Median survival <8 months after relapse OS and PFS after ASCT in r/r HL Brentuximab vedotin Med survival 22 months Younes JCO 2012; Lavoie Blood 2005

When does the change to palliative approach occur? Living with cancer • • • Dying with cancer Loss of marrow reserve Worsening comorbidities due to disease Irreversible toxicity due to treatment Change in performance status Patient/family request

Domains of palliative care Domain Anxiety Depression Anorexia Pain control Nausea/vomiting Diarrhea Constipation

Emotional aspects of palliative care and impact on treatment goals Anxiety Generalized anxiety disorder Panic attacks • A state of feeling apprehension, uncertainty or fear • May lead to some level of dysfunction • A state of excessive anxiety or worry lasting ≥ 6 months • Impacting day-to-day activities • Sudden onset of intense terror, apprehension, fearfulness, terror or felling of impending doom • Usually occurring with symptoms (Shortness of breath, palpitations, Chest discomfort, Sense of choking, Fear of going crazy or losing control • Lasts 15 – 30 minutes 1. Up to 25% of cancer patients experience anxiety 2. Many develop PTSD 3. Barrier to improving the overall cancer experience

Anorexia Cachexia – wasting syndrome • • Lean tissue Performance status Altered resting energy expenditure Appetite Impact • • • ≥ 5% weight loss and poor prognosis Trend toward lower chemotherapy response rates Anorexia and poor prognosis QOL, function Affects caregivers Mac. Donald N, et al. J Am Coll Surg, 2003. Dewys WD, et al. Am J Med, 1980. Loprinzi CL, et al. JCO, 1994.

Timing of palliative care initiation • Generally done too late – 60% of cancer pts hospitalized in last month of life – 25% of US cancer pts die in the hospital – Median length of time between hospice referral and death is 33 days • Not clearly documented – Fragmented health care systems • Need better tools to recognize when patients have 6 months (not days, weeks) to live before making palliative care the dominant aspect of pt care – Only 32% of physicians accurately predicted shortened life expectancy – Consistently overestimated survival

Timing of shift to palliative care is important • Timely recognition of poor prognosis led to – less ‘aggressive’ end‐of‐life care – earlier hospice referrals – improved anxiety, less depression, and improved quality of life compared • Disconnect between patient desire and physician goals – Occasionally, disconnect between patient perceptions and reality Delayed recognition leads to increased suffering and increased socioeconomic burden

Model of palliative care Rocque, G. B. & Cleary, J. F. Nat. Rev. Clin. Oncol. 10, 80– 89 (2013)

Important tools when approaching pts with palliative intent • • Symptom control is key Steroids Radiation Multidisciplinary approach

Palliative care in the “incurable” patient: take-home points • Death from lymphoma is an important and still common occurrence • Many lymphomas are inherently or progressively incurable as defined by – Biology – Advanced age – Cumulative toxicities – Histology • Important to recognize when the goal of treatment is palliative – Symptom management is critical – Particularly challenging in indolent NHL – Need to discuss with patient/family – Need to clearly document the goals of treatment