Survivorship Issues in Breast Cancer & Other Malignancies

Ann H. Partridge, MD, MPHDana-Farber Cancer Institute

September 24, 2019

Number of US Cancer Survivors: 1971-2010 in Millions

Based on data from Surveillance Epidemiology and End Results.

18 Million

2022

3 Million…

Survivorship Spans the Cancer Journey

Adapted from NCI, 2005

Optimal care of an individual patient differs along the continuum

Why is understanding and delivering appropriate follow-up important?

• Follow-up can detect problems that can be: – prevented, cured, or controlled

• Overuse and underuse (= poor quality) of medical resources for follow-up appears common in long-term survivors

Hensley et al, BCRT; 2005

4 Major Areas of Cancer Survivorship(TAKE-HOME Points)

1. Surveillance, screening and prevention of recurrence and new cancers

2. Identification and management of late and long-term effects

3. Recommendation and promotion of improvements of modifiable health behaviors

4. Coordination of care (provider-provider and patient-provider) to ensure that patient health needs are met

1. Surveillance for Disease

• Rationale for screening for recurrent cancer:– Detection of asymptomatic disease would improve

morbidity or mortality– Lead to earlier additional testing and potential early

intervention (e.g. lymphoma, testicular cancer)– Is cost-effective and safe in a population– Makes sense for that individual patient

6

7

Evidence for how breast cancer patients should

be followed for recurrence

GIVIO Investigators. JAMA.1994;271(20):1587-1592

Randomized controlled trial of 1320 with stage I-III breast cancer

Surveillance Strategy

Intensive

Standard

Every 3 months

history/PE

history/PE

Regular mammography

(

(

Annual testing

CXR, LFTs, bone scan, liver u/s

as indicated

% recurrences asymptomatic

31

21

% recurrences symptomatic

69

79

Time to recurrence

53.4 m

54.1 m

Overall survival (5 year)

80%

82%

Quality of life

=

=

Evidence for how breast cancer survivors should be followed for recurrence II

Intensive (CXR + BS) vs. STD Surveillance (n=1243)

Disease-Free Survival Overall Survival

Del Turco, et al. JAMA 1994

9

Important lessons learned in screening for breast cancer recurrences

• Most (~75%) symptoms not related to recurrence

• Most (~75%) recurrences heralded by symptoms• Only a minority (< 25%) of recurrences are detected in

asymptomatic patients

• Lab and radiology tests have significant false-positive rates excess evaluation and anxiety

• Patients can be educated about this

ASCO Guidelines for Surveillance after Early Stage Breast Cancer

History/physical exam Every 3-6 mos x 3 yearseliciting symptoms every 6-12 mos x 2 years

annually thereafter

Breast self-exam Monthly

Mammography Annually

Pelvic exam Annually, per gyn guidelines

Routine laboratory testing Not recommendedCBC, LFTs, automated chemistrystudies, tumor markers (CEA, CA15-3)

Routine radiological studies Not recommendedbone scan, CT scan, CXR,liver ultrasound

www.asco.org; see www.cancer.net for patient summary

http://www.asco.org/http://www.cancer.net/

Should Survivors UndergoBreast MRI Screening?

• 969 women with recent diagnosis unilateral breast cancer

• No clinical or mammographic evidence of contralateral disease

• MRI of contralateral breast lead to biopsy in 121 women (12.5%)

• Contralateral breast cancer in 30 of 969 (3.1%)

• Sensitivity: 91%, Specificity 88%Lehman et al., NEJM 2007

ACS Recommendations

Saslow et al., CA Cancer J Clin, 2007

Primrose JN, et. al. JAMA 2014;311:263-270

Evidence for CEA and CT Follow-up in Colorectal Cancer Survivors

1202 stage 1-3 dz randomized (2x2) to CT q 6-12 mos and/or CEA q3-6 mos

• Intensive follow-up by either CEA or CT increased the likelihood of detecting a recurrence that can be treated with curative intent

• No advantage seen to combining both strategies

• Absolute difference in the proportion of participants treated with curative intent was approximately 5% in the ITT analysis (8% in the “evaluable” subset)

Primrose JN, et. al. JAMA 2014

Evidence for CEA and CT Follow-up in Colorectal Cancer Survivors

ASCO Guideline Recommendations

• Medical history, physical examination, and CEA assay every 3-6 months for 5 years– 80% of recurrences occur during the first 2.0-

2.5 years and 95% by 5 years

• CT imaging annually for 3 years– no justification for surveillance PET/CT scan

testing

Meyerhardt et. al. J Clin Oncol 2013

Summary of Screening for Recurrence

- H & P- Mammography if

BCT/contralateral breast remains

- No imaging or bloodwork otherwise

- H & P- CEA q3-6 mos x

5 yrs- CT q12 mos x 3

yrs

- H & P- PSA q 6 mos x 5,

then q yr- DRE annually

- H & P- Chest scans q3-6

mos x 2yrs, then annually

- H & P- Scans and

bloodwork, tailored

- H & P- scans

and bloodwork, tailored

- H & P, pelvic- Scans and

bloodwork- tailored

New primary disease risk: update family history and re-visit genetics

• Survivorship care should entail updating family history and revisiting genetic issues – (re-) testing as needed

• Why?– Barriers to testing at diagnosis may have diminished– Testing is evolving– Patient and systems level indications for testing are

evolving

Ruddy et al, JCO 2016

Due to Either/All• menopausal

symptoms, infertility, sexual dysfunction

• osteoporosis • weight gain• cognitive impairment• fatigue• metabolic syndrome• psychosocial distress

Chemotherapy And Biologics

• neuropathy• secondary

leukemia• cardiac

dysfunction• Autoimmune

problems• GVHD

Hormonal Therapy• menopausal

symptoms• sexual dysfunction• myalgias,arthralgia• cataracts• Hyperlipidemia• Metabolic syndrome• uterine malignancies• vascular events

Local Therapy (Surgery and Radiation)

• Pain, numbness, lymphedema, restricted motion or weakness

• cosmetic breast or reconstruction changes

• cellulitis, nerve damage, rib fracture, pneumonitis

• heart disease, sarcomas, skin and other second cancers, lung fibrosis

• Site-specific problems (hypothyroidism)

Adapted from Nekhlyudov and Partridge, 2013

2. Long-term and Late Effects in Cancer Survivors

Local Therapy (Surgery and Radiation) Effects: Think Field/Site Specific Problems •COMMON:

–Pain, numbness, lymphedema, restricted motion or weakness, cosmetic issues

•LESS COMMON:–Cellulitis, nerve damage, bone fracture, pneumonitis, lung fibrosis

•MUCH LESS COMMON:–Heart disease, sarcomas, skin and other second cancers, lung fibrosis

–Systemic effects from site-specific treatment (e.g., hypothyroidism, hypogonadism)

Systemic Therapy: Take a Systems Approach

An Example: Effects of Androgen Deprivation Therapy

An Example: Effects of Androgen Deprivation Therapy

Metabolic and Cardiovascular Effects of ADT

• ADT is associated with unfavorable metabolic changes• No randomized trials have prospectively addressed cardiovascular risk

of ADT• Retrospective data are available from randomized trials and large

observational series

Nguyen et al, JAMA, 2011; O’Farrell et al, JCO, 2015

Men with ≥2 CV events, with the latest within 1 year of ADT, were at the highest risk of a CV event within the first 6 months of ADT

Among 4141 men from 8 randomized trials, CV death in men receiving ADT

versus control was not different

Management of Therapy Effects in Cancer Survivors: Hormonal Issues

• Cardiovascular health and metabolic syndrome– Optimize cardiac risks, lipids

• Bone health – Screen patients in high risk groups, treat as needed

• Hot flashes– HRT if appropriate, SS/SNRIs, Gabapentin

• Sexual dysfunction- ASK!– Often multifactorial– Treatment works

Mean Hot Flash Score Percent ReductionRandomized Trials

MPA 400 mg (n=94)

C Loprinzi, DL Barton, and colleagues. Mayo Clinic, Rochester, MN

Not superior to placebo:- Soy - Flaxseed - Black Cohosh - Mg oxide- Vitamin E

26

~25-50% of Survivors Report Sexual Dysfunction

• Management of Erectile Dysfunction

Process of Care Consensus Panel . Int J Impot Res. 1999

27

Sexual Dysfunction in Women

• Treatment depends on primary problem (often multifactorial)– ERT/Topical E2 if appropriate, or non-hormonal

water-based vaginal lubricants for dyspareunia– Vaginal dilation for stenosis– Consider medications for libido problems– Sex therapy; couples counseling, psychotherapy

• Comprehensive assessment and targeted intervention WORKS!Schover L et al., European Journal of Cancer, 2014; Ganz PA, et al. JNCI. 2000

Randomized Blinded Sham- and Waitlist-Controlled Trial of Acupuncture for Joint Symptoms Related to Aromatase Inhibitors

in Women with Early Stage Breast Cancer (SWOG 1200)

2

1

1

Assessment Week

0 6 12 24

Presented with permission, Hershman et al., SABCS 2017

Significant Improvement in Pain from True AcupunctureLinear Mixed Model - Worst Pain (BPI)

Presented with permission, Hershman et al., SABCS 2017

• Sustained over tapered treatment, and for 12 weeks beyond

• Toxicity minimal

Screening and Prevention of Late Effects

• Many unanswered questions- cardiac and bone health recommendations

• Secondary malignancies- e.g., lung after lung cancer, bowel and bladder after prostate

• HD or Lymphoma s/p chest irradiation-– 148 women with HD s/p chest RT age < 35, at least 8 years prior– Followed for 3 years with annual mammogram and MRI– 63 biopsies in 45 patients (30%)– 18 of 63 biopsies (29%) showed malignancy– Sensitivity 63% for MRI; 68% for mammogram– Sensitivity for both MRI and mammogram together: 95%– All but 1 of the image detected malignancies were pre-invasive or

sub cm and all were node negative

• Many studies ongoing and reporting out- e.g.:– ACE inhibitor etc. for prevention of cardiac complications after xrt,

anthracyline therapy– Low dose tamoxifen for prevention of breast cancer

(Ng et al, JCO 2013)

Fatigue

• Cancer-related fatigue (CRF)– Very common phenomenon among survivors (50-

80%)

– Rule out and treat other causes of fatigue• Pain, malnutrition, hypothyroidism, anemia, insomnia, and

depression, inactivity – Rx:

• Exercise, behavioral/psychotherapy• Complementary therapy • (Psychostimulants don’t seem to work!)

– Guidelines from NCCN at www.nccn.org and from ASCO at www.asco.org

Bower et al., JCO, 2014

http://www.nccn.orghttp://www.asco.org

Mental Health in Cancer Survivors • Depression and anxiety in survivors

– Associated with symptom distress, maladaptive coping

– Depression associated with heightened risk for premature mortality (RR 1.22-1.39) and cancer death (RR 1.18)

– Two studies have now documented increased rates of suicide among populations of long-term breast and testicular cancer survivors

• Screen, reassure, treat or refer as appropriate

• Guidelines from NCCN at www.nccn.org and from ASCO at www.asco.org

Andersen et al, JCO 2014

http://www.nccn.orghttp://www.asco.org

American Society of Clinical Oncology Recommendations on Fertility Preservation in People

Treated for Cancer

Eligible for proven fertility preservation method

Male: Female:sperm cryopreservation Embryo cryopreservation

Oocyte cryopreservationoophoropexy

•Assessment of risk for infertility•Communication with patient

• Patient at risk for treatment induced infertility-•Patient interested in fertility preservation options

Refer to specialist with expertise in fertility preservation

Investigational fertilitypreservation technique*

•

*Clinical trial participation encouraged

Eligible for proven fertility preservation method

Male: Female:sperm cryopreservation cryopreservation

conservative gynecologic surgeryoophoropexy

•Assessment of risk for infertility•Communication with patient

••Patient interested in fertility preservation options

Refer to specialist with expertise in fertility preservati

Investigational fertilitypreservation technique*

Cryopreservation of testicular or ovarian tissue

www.asco.org (Modified from Lee et al., J Clin Onc; 2006)

2012

Ovarian suppression2017?

Premature-Ovarian Insufficiency RateLower amenorrhea rates at 2 years with GNRh agonist

14.1%

GnRHa groupn=363

Control groupn=359

30.9%

OR* 0.38 (95% CI 0.26-0.57)p

Post-Treatment Pregnancy RateMore pregnancies in GnRH group

GnRHa Group: 37/359 (10.3%)vs.

Control Group: 20/367 (5.5%)

IRR* 1.83 (95% CI 1.06-3.15)p=0.030

Meta-analysis approach

GnRHa group

(n = 37)No. (%)

Control group

(n = 20)No. (%)

Age distribution, years≤ 40≥ 41

37 (100)0 (0.0)

20 (100)0 (0.0)

Estrogen receptor status PositiveNegative

6 (16.2)31 (83.8)

2 (10.0)18 (90.0)

*Incidence rate ratio (IRR)

Lambertini et al, JCO, 2018

Disease-Free Survival

Estrogen receptor-negative disease

HR* 1.17 (95% CI 0.62-2.20) HR* 0.95 (95% CI 0.64-1.42)

Estrogen receptor-positive disease

*Hazard ratio (HR) adjusted for age, estrogen receptor status, type and duration of chemotherapy administered and tumor stage pinteraction=0.867

Lambertini et al, JCO, 2018

Overall Survival

HR* 0.67 (95% CI 0.42-1.06)p=0.083

Median follow-up = 5.0 years (IQR, 3.0 - 6.3 years)

*Hazard ratio (HR) adjusted for age, estrogen receptor status, type and duration of chemotherapy administered and tumor stage

Lambertini et al, JCO, 2018

Pregnancy after Breast Cancer: Is it Safe?Most recent study: No differences in disease-free survival between pregnant group and matched

nonpregnant group.

Azim H A et al. JCO 2013;31:73-79

©2013 by American Society of Clinical Oncology

39

Pregnancy After Breast Cancer: When?

• Conventional wisdom is to wait at least 2 to 3 years, to get through early risk of recurrence period; receive optimal endocrine therapy

• No data to suggest harm in pregnancy sooner, though possibly less benefit from hormonal therapy if take for less than standard 5 years

• Ultimately the decision to get pregnant is a very personal one for a person with an uncertain future

Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsIVE

Breast Cancer

IBCSG 48-14 / BIG 8-13ALLIANCE # A221405

POSITIVE TRIALINTERNATIONAL PI: OLIVIA PAGANI

NORTH AMERICAN PI: ANN PARTRIDGE

The POSITIVE Trial: Endocrine therapy interruption for pregnancy in breast cancer patients

• Phase II trial designed to evaluate safety and pregnancy outcomes of interrupting ET for young women with ER+ disease who desire pregnancy

• Enroll 512 women,

3. Recommendation and promotion of improvements of modifiable

health behaviors

Behaviors to DROP or DECREASE

• Tobacco• Alcohol• High risk sexual

behavior• Illicit drug use

Behaviors to MAINTAIN OR INCREASE

• Physical activity• Prudent diet• Weight management

to ideal BMI

Energy balance matters for cancer survivors

• Risk of weight gain, obesity and metabolic syndrome in breast, colorectal, prostate, testicular, pediatric cancer survivors – Effect on cancer outcomes in breast, colorectal

and prostate survivors– Effect on cardiovascular and overall mortality

• Fortunately …– Physical activity, diet and attention to diabetic and

cardiovascular risk factors likely helps– Associated with lower risk of cancer recurrence

and deathLigibel and Meyerhardt, UpToDate, last accessed 3-30-15

Physical Activity and Breast Cancer Survivorship: Results from the Nurses’ Health Study

MET-Hrs/week

*p=0.05, # p

Dietary Patterns and Stage III Colon Cancer

11 1.1 10.7

1.3

0

0.5

1

1.5

2

2.5

3

3.5

4

1 2 3 4 5Quintiles of Dietary Pattern

Haz

ard

Rat

io fo

r Can

cer R

ecur

renc

e or

Dea

th

Prudent diet

1.22 2.2

3.9

Western diet

P, trend < 0.001

Meyerhardt, J. et al. JAMA 2007. 298(7):754-764.Other data suggest high glycemic load particularly risky

Chlebowski RT, et al. J Natl Cancer Inst. 2006;98(24):1767-1776.

WINS Study: Impact of Low-fat Diet on RFS in Breast Cancer Survivors

Womens’ Healthy Eating & Living Study (WHEL)

• RCT to ↑ fruit, vegetable, and fiber among breast cancer survivors -1537 intervention + 1551 controls

Pierce JAMA 2007http://libraries.ucsd.edu/locations/sshl/data-gov-info-gis/ssds/guides/whel-study.html

American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Survivors

• Achieve and maintain a healthy weight – If overweight or obese, limit consumption of high-calorie

foods and beverages and increase physical activity to promote weight loss

• Engage in regular physical activity– Avoid inactivity and return to normal daily activities as

soon as possible following diagnosis– Aim to exercise at least 150 minutes per week. – Include strength training exercises at least 2 days per

week.• Achieve a dietary pattern that is high in

vegetables, fruits, and whole grainsRock et al., CA Journal for Clin 2012

Alcohol and Breast Cancer Survival• Although studies consistent on alcohol and

getting breast cancer, survival studies mixed– Alcohol has mixed effect on overall survival– ↑ breast cancer risk, risk of recurrence– ↓ heart disease risk

=> Drinking in moderation safe

Future Directions

• Prospective exercise and weight loss studies ongoing

• Prospective RCTs ongoing testing NSAIDS in survivors

4. Coordination of care

(How can we deliver all of this care?!?!)

Treatment Summaries

and Survivorship Care Plans

53

Cancer Survivorship Care: New Tools are Available

Survivorship programs have suffered from a relative lack of prioritization

• Most patients don’t need all services

• One size does not fit all

Survivorship programs have suffered from a relative lack of prioritization

• Risk-based care has been advocated to overcome this– targeting the appropriate care to individual

patients, from the appropriate provider, at the most optimal times in the cancer care trajectory

– Ideally, there should be a minimum level of service along with a buffet of services

A Risk Stratified Approach:UK National Cancer Survivorship Initiative

Approx 70%

Approx 10%

Approx 20%

Conclusions • Cancer survivors face usual and unique issues in

follow-up which need to be addressed

• Lifestyle modifications should be part of standard follow-up recommendations

• Effective and efficient follow-up strategies are emerging to care for the growing number of survivors

Survivorship Issues in �Breast Cancer & Other Malignancies�Number of US Cancer Survivors: �1971-2010 in Millions Survivorship Spans the Cancer JourneyWhy is understanding and delivering appropriate follow-up important?4 Major Areas of Cancer Survivorship�(TAKE-HOME Points) �1. Surveillance for Disease�Slide Number 7Evidence for how breast cancer survivors should be followed for recurrence IISlide Number 9ASCO Guidelines for Surveillance after Early Stage Breast CancerShould Survivors Undergo�Breast MRI Screening? ACS RecommendationsEvidence for CEA and CT Follow-up in Colorectal Cancer SurvivorsEvidence for CEA and CT Follow-up in Colorectal Cancer SurvivorsASCO Guideline Recommendations Summary of Screening for Recurrence New primary disease risk: update �family history and re-visit genetics Slide Number 18Local Therapy (Surgery and Radiation) Effects: Think Field/Site Specific Problems �Systemic Therapy: Take a Systems Approach �An Example: Effects of �Androgen Deprivation Therapy An Example: Effects of �Androgen Deprivation Therapy Metabolic and Cardiovascular Effects of ADT Management of Therapy Effects in Cancer Survivors: Hormonal IssuesMean Hot Flash Score Percent Reduction�Randomized Trials~25-50% of Survivors Report �Sexual DysfunctionSexual Dysfunction in WomenRandomized Blinded Sham- and Waitlist-Controlled Trial of Acupuncture for Joint Symptoms Related to Aromatase Inhibitors in Women with Early Stage Breast Cancer (SWOG 1200)Significant Improvement in Pain from True Acupuncture�Linear Mixed Model - Worst Pain (BPI)Screening and Prevention of Late EffectsFatigueMental Health in Cancer Survivors American Society of Clinical Oncology Recommendations on Fertility Preservation in People Treated for CancerSlide Number 34Slide Number 35Slide Number 36Slide Number 37Slide Number 38Pregnancy After Breast Cancer: When?Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsIVE Breast Cancer��IBCSG 48-14 / BIG 8-13� ALLIANCE # A221405 � �POSITIVE TRIALThe POSITIVE Trial: Endocrine therapy interruption for pregnancy in breast cancer patients3. Recommendation and promotion of improvements of modifiable health behaviors Energy balance matters �for cancer survivorsPhysical Activity and Breast Cancer Survivorship: Results from the Nurses’ Health StudyDietary Patterns and Stage III Colon CancerSlide Number 46Womens’ Healthy Eating & Living Study (WHEL)American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Survivors�Alcohol and Breast Cancer SurvivalFuture Directions4. Coordination of care ��(How can we deliver all of this care?!?!)Slide Number 52Cancer Survivorship Care: New Tools are Available�Survivorship programs have suffered from a relative lack of prioritization�Survivorship programs have suffered from a relative lack of prioritization�A Risk Stratified Approach:�UK National Cancer Survivorship InitiativeConclusions