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