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 Cases Deaths Total 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 France 8375 4471 3904 4212 2225 1987 Germany 10,179 5203 4976 5260 2501 2759 Italy 10,825 5906 4919 4675 2390 2285 UK 8307 4515 3792 4507 2380 2127 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+BCL2+ B-cell lymphoma unclassifiable (BCLU) who progresses through DA-EPOCH-R with a large breast mass 78 yo man with MCL since 2005 s/p R-HyperCVAD, bortezomib, BR, temsirolimus, DHAP who has persistent cytopenias due to marrow involvement 92 yo man with DLBCL who relapses 8 months after R-CHOP (with dose reductions) 67 yo woman with FL since 2008 who has no symptoms but with radiographic progression after 2 prior lines of therapy Biology Cumulative toxicity Advanced age Histology

MYC pos DLBCL: BCCA analysis 66% 31% PFS OS 72% 33% Patients with MYC pos DLBCL had inferior PFS and OS Even when excluding BCL2 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 Savage Blood 2009

“Double hit lymphomas”: BCL2 worsens prognosis of MYC pos lymphomas Prognostic factors for survival Age > 60 yrs PS > 1 High IPI BM pos BCL2 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… Low tumor burden High tumor burden Treatment naive Sensitive Resistant Low tumor burden High tumor burden 1st or 2nd Relapse 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 B2M BM + LN>6cm Hgb MIPI Age PS LDH WBC (Ki67) 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 Brentuximab vedotin Med survival 22 months OS and PFS after ASCT in r/r HL 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 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 Lasts15 – 30 minutes Up to 25% of cancer patients experience anxiety Many develop PTSD Barrier to improving the overall cancer experience

Anorexia Cachexia – wasting syndrome Impact  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 MacDonald 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