Muscle Density not Mass predicts for Survival in Newly Diagnosed … · 2019-06-07 · Background...
Transcript of Muscle Density not Mass predicts for Survival in Newly Diagnosed … · 2019-06-07 · Background...
Muscle Density not Mass predicts for Survival in Newly Diagnosed Epithelial Ovarian
Cancer
Dr Lucy Dumas
Clinical Research Fellow Gynaecology Unit
Royal Marsden NHS Foundation Trust
Disclosure
I do not have any conflicts of interest to declare.
Background 1.
• Around half of all new diagnoses of ovarian cancer are in women over the age of 651
• Outcomes are disproportionately poor with advancing age2,3
• Multifactorial; late presentation and more advanced stage at diagnosis, increased comorbidities, under-treatment, adverse tumour biology
• Need for better predictive and prognostic biomarkers1. NCIN. Trent Cancer Registry, the National Cancer Intelligence Network's lead registry in England for gynaecological cancers. Overview of Ovarian Cancer in
England: Incidence, Mortality and Survival. Available fromhttp://www.ncin.org.uk/publications/data_briefings/a_profile_of_ovarian_cancer_in_england2. Dumas L1, Ring A2, Butler J1, Kalsi T3, Harari D3, Banerjee S4. Improving outcomes for older women with gynaecological malignancies. Cancer Treat
Rev. 2016 Nov;50:99-1083. Dumas L, Bowen R, Thomas K, Gore M and Banerjee S. A Retrospective Review of Treatment Patterns, Toxicity Rates and Survival Outcomes in Women
over the age of 65 across two UK Cancer Centre. Poster 31 SIOG 2018
Background 2.
• Sarcopenia (loss of muscle mass, quality and function) is increasingly prevalent in older adults1
• Association with frailty but relationship complex and remains unclear2,3
• Can be readily assessed on routine CT
• Loss of muscle mass has been shown to be associated with poorer survival outcomes4
1. Cruz-Jentoft, A.J., et al., Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing, 2010. 39(4): p. 412-23.
2. Williams, G.R., et al., Frailty and skeletal muscle in older adults with cancer. J Geriatr Oncol, 2018. 9(1): p. 68-73.3. Wilson, D., et al., Frailty and sarcopenia: The potential role of an aged immune system. Ageing Res Rev, 2017. 36: p. 1-10.4. Shachar, S.S., et al., Prognostic value of sarcopenia in adults with solid tumours: A meta-analysis and systematic review. Eur J Cancer, 2016. 57: p. 58-67
Primary Objective
• To assess whether sarcopenia, in women over the age of 65 being considered for first line treatment of ovarian cancer, as defined by:
a) Skeletal muscle index (SMI) < 38.5 cm2/m2 and/or
b) Muscle density of 41HU or less
is associated with poorer progression-free and overall survival
Retrospective case review (Local Institutional Approval): Royal Marsden NHS Foundation Trust
• August 2009-December 2015• Newly diagnosed epithelial ovarian cancer• 65 years or older at time of diagnosis• Baseline CT CAP available for review
n=208
Excluded (n=29)- No suitable CT baseline for analysis (non-contrast/muscle area not fully visualised at L3), - no height/weight data available
CT images assessed OsiriX software (two blinded assessors)
n=179
Demographic, treatment detail and outcome data collected
Baseline, mid-treatment and end of treatment CT CAP assessed
Methods
Imaging analysis
• CT chest abdomen pelvis anonymised and saved to DICOM format for analysis on OsiriX software
• Skeletal muscle area (SMA cm2) at the level of L3
• Psoas, erector spinae, quadratus lumborum, transverse abdominus, external and internal obliques and rectus abdominus
• Height-standardised value of skeletal muscle index (SMI) derived (cm2/m2)
• Two assessors blinded to the clinical data evaluated SMA and subcutaneous adipose tissue area (SAT) using CT Hounsfield unit ranges of -29 to +150HU and -150 to +50HU respectively
• 10% of regions of interest (ROIs) generated verified by independent assessor
Results
Patient characteristics 1.• Mean age at diagnosis 73.4 (65-94)
• Mean BMI 25.7 (13-52), Mean BSA 1.69 (1.3-2.2)
• 35.8% SMI <38.5cm2/m2 , 78% mean muscle density <41HU
Association of increasing age and muscle density
Association of increasing age and muscle mass
-0.27 (p=0.012)0.05 (p=0.397)
Patient characteristics 2. <HU41
n=140 (%)>HU41
n=39 (%)Total
n=179 (%)p-value
FIGO stage 3/4 84.3 74.4 82.1 0.152ECOG PS 2/3 32.8 15.4 29.0 0.034
High grade serous 72.9 79.5 74.3Endometrioid 4.3 5.1 4.5Clear Cell 2.9 0.0 2.2 0.258
Carcinosarcoma 6.4 7.7 6.7Low grade serous 4.3 0.0 3.4
Cardiovascular disease 35.7 17.9 31.8 p=0.035Hypertension 42.9 28.2 39.7 p=0.098Polypharmacy 42.9 30.8 51.4 p=0.163
Respiratory disease 11.4 7.7 10.6 p=0.503Diabetes 11.4 10.3 11.2 p=0.837Osteoarthritis 5.7 12.8 9.3 p=0.130
Patients with low muscle density were more likely to be performance status 2/3
Treatment received
• 95.5% patients underwent chemotherapy • 49.4% Neoadjuvant• 39.3% Adjuvant • 13.0% Palliative
• 65% received platinum-doublet chemotherapy
• 73.4% patients underwent debulking surgery (primary or interval)• 71.9% of whom deemed optimally debulked
No statistically significance between treatment rates according to muscle density
Progression-free survival by baseline muscle density
16.6 months (median)
HR 1.57 (p=0.039; 95%CI 1.024-2.306)
13.3 months (median)
Overall survival by baseline muscle density
31.0 months (median)
56.6 months (median)
HR 1.98 (p=0.04; 95%CI 1.029-3.835)*
*Adjusted for Age, FIGO stage and Debulking status
However…
•No significant relationship with SMI • (HR 0.86, p=0.465; 95%CI .0582-1.281)
Chemotherapy tolerance<HU41 (n=131) >HU41 (n=39) Total (n=170) p value
n % n % n %
≥Grade 3 non-haematological toxicity 41 31.3 8 20.5 49 28.8 0.192
≥Grade 2 haematological toxicity 39 29.8 11 28.2 50 29.4 0.851
Completed 6 cycles 106 80.9 36 92.3 142 83.5 0.092
Early discontinuation of chemotherapy 25 19.1 3 7.7 28 16.5 0.092
Discontinued chemotherapy due to toxicity
16 12.2 0 0 16 9.4 0.001
Hospital admission during chemotherapy 46 35.1 9 23.7 55 32.5 0.185
Dose delay > 2 weeks 101 77.1 26 66.7 127 74.7 0.188
Trend towards increased rate of poorer chemotherapy tolerance in patients with low muscle density
Risk of Grade ¾ non-haematological toxicities and early chemotherapy discontinuation with reducing muscle density
Univariate OR 0.96 (p=0.039; 95% CI 0.923-0.998) Univariate OR 1.04 (p=0.049; 95% CI 1.000-1.099 )
Conclusions
• Reduced muscle density in a population of older women with newly diagnosed ovarian cancer is significantly associated with poorer overall survival• Loss of muscle density an earlier event than loss of muscle mass• More closely related to function/strength
• Reduced muscle density is associated with a trend towards poorer chemotherapy tolerance
• Absolute muscle mass (SMI) does not appear to be related with survival
Limitations and further work
• Retrospective
• Heterogeneity of cohort
• No availability of frailty/geriatric assessment
Future work:• Prospective validation of these findings
• Prospective studies evaluating sarcopenia alongside GA as well as serum biomarkers of frailty/inflammation
• Incorporation of sarcopenia as a non-invasive biomarker into interventional clinical studies and….ultimately, routine clinical practice
With thanks to…
Supervisory team and colleagues:
Professor Andrea RockallDr Susana Banerjee (Primary supervisor)
Dr Nina TunariuDr Elena Serena
Statistical support:
Mrs Karen ThomasMr Kyriakos Kouvelakis
And of course, our patients and their families