Exercise-Based Rehabilitation Following a Diagnosis of Non-Small Cell Lung Cancer (NSCLC)

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2 Exercise-Based Rehabilitation Following a Diagnosis of Non-Small Cell Lung Cancer (NSCLC) Lee W. Jones, PhD Duke University Medical Center Cancer Survivorship Research: Recovery and Beyond Washington, DC

3 NSCLC epidemiology Incidence 250, , , ,000 50, , , , ,000 80,000 60,000 40,000 20,000 0 Breast Prostate NSCLC Colorectal Mortality Breast Prostate NSCLC Colorectal Second most commonly diagnosed malignancy in US (~15% of all diagnoses) Leading cause of cancer-related death (~20% of all deaths)

4 NSCLC survivorship Site 1975 (%) 2000 (%) % increase Overall Childhood Prostate Breast Colon Lung ~25% diagnosed with operable disease 3 & 5 yr survival rates: 58% and 49%, respectively (~26,000 >5 years) ~75% diagnosed with inoperable disease Median survival 8-10 months; 5-yr ~7%

5 NSCLC survivorship All forms of regional (pulmonary resection) and systemic therapies (chemotherapy, targeted therapy) associated with adverse toxicities Physical / functional toxicities leading to poor exercise capacity Poor exercise capacity predisposes to other common age-related diseases, poor symptom control, and likely premature death

6 What is exercise capacity? Pulmonary function (O 2 diffusion) + Cardiac function (Q, Hb concn,, SpO 2 ) + Vascular integrity + Skeletal muscle function (oxidative capacity, fiber type distribution) = Exercise capacity

7 Exercise capacity assessment Symptom-limited, cardiopulmonary exercise test Peak oxygen consumption (VO 2peak ml. kg.-1 min -1 )

8 NSCLC continuum Diagnosis Surgery Advanced Disease Death 1. Pre-Surgical Setting 2. Post-Surgical Setting 3. Advanced Setting

9 Pre-Surgery

10 Pre-surgical setting Surgery best option for cure - patients present with significant comorbidities that complicates treatment process Selection for resection weighed against risk of perioperative morbidity & mortality Strong inverse relationship between VO 2peak and surgical complications <15 ml.kg. -1 min -1 high risk of complications <10 ml.kg. -1 min -1 very high risk of complications Interventions to improve VO 2peak prior to resection to lower complications (2 studies)

11 1. Safety and efficacy of presurgical aerobic training (Jones et al. 2007) Stage I-IIIA FEV 1 >1.1L Sx candidate Baseline CPET, PFT, & Blood Cycle ergometry VO 2 for 4-66 wks Presurgery CPET, PFT, & Blood n=20 Jones et al. Cancer 2007

12 Results 18 (90%) completed the study 72% adherence (30 ± 27 sessions) No SAEs; 2 AEs ml.kg.min ( 17%) 2.7 ml.kg.min ( 16%) VO 2 (ml.kg.min) Jones et al. Cancer Baseline Presurgery Postsurgery

13 2. Pre-operative pulmonary rehabilitation on VO 2peak (Bobbio et al. 2008) 12 pts with COPD & VO 2peak 15 ml.kg. -1 min -1 4-wk rehabilitation program (5d.wk -1, physical therapy breathing exercises, aerobic and resistance tx, 90min.d -1 ) Bobbio et al. European J Cardio-Thoracic Surgery 2008

14 Results 12 (100%) completed the study Adherence not reported AEs not reported Variables Pre-Intervention (n=12) Post-Intervention (n=12) Mean Change (%) VO 2peak, ml.kg. -1 min ± ± (17%) VO 2peak, ml.min ± ± (16%) VO 2peak, ml.kg. -1 min -1 at anaerobic threshold 10.1 ± ± (25%) Workload, W 65 ± ± (17%) Oxygen Pulse, ml/bpm 9.3 ± ± (17%) Bobbio et al. European J Cardio-Thoracic Surgery 2008

15 Pre-surgical setting - summary Intensive exercise-based rehabilitation safe & well-tolerated Effective at improving exercise capacity Limited number of studies Effects on surgical complications unknown Challenges Adequate time-frame to exert training effect in US system? Exercise during induction therapy / smokers? Large RCTs required to investigate surgical complications

16 Post-Surgery

17 Direct treatment effects Surgery ~30% VO 2peak following pneumonectomy ~15% - 20% VO 2peak following lobectomy Adjuvant chemotherapy / radiation / targeted therapy Indirect treatment effects Physical inactivity (deconditioning) ~75% of post-surgical NSCLC do not meet CDC/ACSM guidelines Weight loss (poor prognostic factor) Coups et al. Cancer Epidemiol Biomarkers Prev, 2009

18 The Multiple-Hit hypothesis Adjuvant Therapy Direct Effects Early Lung Cancer Diagnosis Decreased Functional Reserve Exercise Capacity Symptoms, Morbidity & Mortality Indirect Effects Physical Inactivity & Weight Loss Jones et al. J Am Coll Cardiol 2007

19 VO 2peak and survival in lung cancer Association between VO 2peak and overall mortality in 398 operable NSCLC patients: CALGB months follow-up; 294 (74%) deaths All Patients VO 2peak (ml. kg. -1 min -1 ) < >17.3 P for trend Median, Mths year survival, % Adjusted* Referent *adjusted for age, gender, performance status, and FEV 1 Jones et al. Cancer, In Press

20 1. Inpatient rehabilitation program after lung resection (Spruit et al. 2006) 10 pts post-tx NSCLC with COPD 8-wk in-patient rehabilitation program (multi-modal program including cycle ergometry) Improvements in 6MWD and peak exercise capacity Spruit et al. Lung Cancer 2006

21 2. Post-operative respiratory rehabilitation after lung resection (Cesario et al. 2007) 25 pts >tx for NSCLC vs. 168 refusing rehab 8-wk in-patient rehabilitation program (multi-modal program including cycle ergometry) Improvements in 6MWD relative to patients refusing rehabilitation Cesario et al. Lung Cancer 2007

22 3. Safety and efficacy of aerobic training in postsurgical NSCLC patients Stage I-IIIB ~42% receiving CT ~53% male Baseline CPET, PFT, & Urine Cycle ergometry VO 2 for 14 wks Postintervention CPET, PFT, & Urine n=20 Jones et al. Cancer 2008

23 18 (90%) completed the study 85% adherence No SAEs; 3 AEs ml.kg.min ( 7%) 18 VO 2 (ml.kg.min) ml.kg.min ( 1.7%) +1.7 ml.kg.min ( 10%) Baseline 14 wks VO 2 (ml.kg.min) 15 Baseline 14wks Jones et al. Cancer Chemo No Chemo

24 Post-Surgical Setting - Summary Intensive exercise-based rehabilitation safe & well-tolerated >sx Effective at improving exercise capacity, QOL, & fatigue Exercise limited effects during chemotherapy Only 3 studies; small N; no RCTs Many questions remain unaddressed Mechanism(s) of poor VO 2peak Most efficacious type of exercise Effects on systemic biomarkers

25 Randomized trial of optimal type of aerobic training in NSCLC (NCI) Aerobic Training Alone Cycle ergometry, 3d.wk, 20-45mins, 50-75%, 16 wks Post-Sx Completed therapy Sedentary N=160 Stratified by gender & smoking status Resistance Training Alone Combined Aerobic & Resistance Training Attention Control Machine weights, 3d.wk, 20-45mins, 50-75%, 16 wks Combined Tx, 3d.wk, 20-45mins, 50-75%, 16 wks Progressive stretching, 3d.wk, 20-45mins, 16 wks Jones et al. BMC Cancer, 2010

26 Endpoints Primary VO 2peak Secondary Physiological mediators (pulmonary, cardiac, vascular, muscle function) Patient-reported outcomes (e.g., QOL, fatigue, sleep, neurocognition) Systemic (host) related factors ( omic approaches) Adverse events (CTCAE v.4.0) N=25 on trial Jones et al. BMC Cancer, 2010

27 Advanced Disease

28 Advanced Disease Majority of NSCLC patients present with inoperable disease Present unique challenge from exercise-based rehabilitation perspective Significant concomitant disease Aggressive combination therapy Metastatic disease Pulmonary obstruction Deconditioned High-risk of exercise-related adverse event Exercise could offer significant benefit

29 VO 2peak assessment Only 105 from 470 (22%) were deemed eligible 47 (44%) consented to CPET 23% exercise-induced EKG abnormality Exercise Training Studies Temel et al. J Thorac Oncol, week multi-modal structured program 20 underwent baseline testing; 11 (55%) completed No deterioration in 6MWD Jones et al. Lung Cancer, 2007

30 Conclusion (1) Role of exercise following a NSCLC is understudied but has significant promise, particularly in operable disease Future directions Elucidation of physiological mechanisms underlying poor VO 2 Investigation of the most appropriate exercise prescription for NSCLC pts Observational studies examining association between self-reported PA as well as objective measures and survival

31 Conclusion (2) Future directions (cont) Correlative science and translational (basic science) studies to identify mechanisms underlying exercise NSCLC progression relationship Exercise may represent an important component of multidisciplinary management following a NSCLC diagnosis

32 Acknowledgements Collaborators Duke Exercise-Oncology Team Miranda West, Whitney Hornsby, Beth Fowler, Kim Duren, Amy Lane Funding Agencies Participating Patients

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