Late effects in Cancer Survivorship

MARYAM B LUSTBERG MD MPH

CHIEF OF BREAST ONCOLOGY

YALE CANCER CENTER

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Agenda

• Introduction to late effects
• Late effects by cancer type: breast cancer, prostate, testicular and colorectal cancer

Introduction to late effects

Cancer survivors in the USA

Tonorezos et al JNCI, 2024

Key definitions

• Definitions
• Short-term sides effects occur during treatment
• Long-term side effects begin during treatment and continue after the end of treatment
• Examples: ovarian failure, infertility, neuropathy
• Late effects are symptoms that first appear months or years after treatment has ended.
• Examples: heart failure, osteoporosis, and second cancers

Seasons of Survivorship

Fitzhugh Mullan MD, NEJM 1985

Graduate from U. of Chicago in 1968

NCCS founded in 1986

Why study late effects?

• Find ways to prevent or mitigate effects
• Know the “what” to look for and the “why” and “how”
• Increase understanding of pathophysiology

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• Give better information to patients and families at time of diagnosis and during follow-up

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Potential Late Effects

• Can look at these in several ways

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• By disease
• By type(s) of treatment
• By system affected

Any system can be affected…..

• Cardiac
• Pulmonary
• Gastrointestinal
• Urinary tract
• Musculoskeletal
• Neurologic
• Neuropsychologic

• Endocrine
• Gonadal
• Male
• Female
• Growth
• Thyroid
• Hematologic
• Immunologic
• Second Malignancies

Late effects of Cancer Treatment

Potential Late Effects

Chemotherapy?

Anthracyclines

Alkylating agents

Epipodophyllotoxins

Anti-metabolites

Vinca alkyloids

• By disease
• By type(s) of treatment
• By system affected

Radiation

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Amount?

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Location?

Both?

Non-cancer late and long-term effects

Chemotherapy

• Cardiac dysfunction (doxorubicin, daunorubicin, trastuzumab)
• Pulmonary fibrosis (bleomycin)
• Neuropathy (vincristine, vinblastine, paclitaxel, docetaxel, oxaliplatin, cisplatin)
• Hearing loss (cisplatin)
• Premature menopause, infertility (cyclophosphamide, nitrogen mustard)

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Global Considerations of late effects

• Psychosocial
• Post-traumatic stress
• Family/peer relationships
• Social and societal function
• Financial
• Insurance?
• Educational
• Learning ability?
• Recurrence of primary disease

NCI Office of Cancer Survivorship, 2022

Breast cancer late effects

A real life clinical situation

• 45 yo woman is diagnosed with lymph node positive breast cancer in 2010
• Germline testing reveals BRCA 1 alternation
• Treated with anthracycline chemo (doxorubicin/cyclophosphamide plus paclitaxel)
• Axillary dissection and bilateral mastectomies and later BSO
• She is cured of her breast cancer she is told

A real life clinical situation continued

• Short term: She has hair loss, nausea, neuropathy, hot flashes and symptoms of menopause and cognitive changes
• Long term: she struggles with persistent neuropathy and some mild memory changes
• Late effects: 1 year after treatment ended, lymphedema symptoms

In affected side presented

Late Effects of Breast Cancer Treatment

• Lymphedema
• Cardiac dysfunction
• Premature ovarian failure
• Infertility, bone loss, menopausal symptoms
• (side effects of endocrine treatments)
• Osteoporosis –related to treatment
• Secondary malignancies
• Cognitive dysfunction
• Sexual side effects

Pedersen et al, J Nat Cancer Inst, 2022

Risk factors for secondary malignancies

Wood M E et al. JCO 2012;30:3734-3745

Genetic Predispositions

Garber JCO, 2005

Increased risk of second malignant neoplasms in children and AYA survivors

Lee JS. Cancer 2016.

Genetic Predispositions (Continued)

Garber JCO, 2005

Subsequent Primary Cancers

Using SEER data of 1.54 million cancer survivors (mean age, 60.4 years; 48.8% women), follow up 7.3 years.

• Male survivors (excluding those with prostate cancer)
• Higher incidence (11%) and mortality (45%) from a subsequent primary cancer.
• Most common subsequent cancers were lung, prostate, bladder/urinary, colorectal.
• Female cancer survivors
• Higher incidence (10%) and mortality (33%) from a subsequent primary cancer.
• Most common subsequent cancers were breast, colorectal, uterine.

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Sung H et al. JAMA 2021

Secondary Malignancies After Breast Cancer Treatment

• Chemotherapy-Related
• Treatment related MDS, AML - <1%
• Alkylating agent (Cytoxan) – latency 5-10 yrs
• Topoisomerase II inhibitor (Adriamycin) – 1-5 yrs
• Tamoxifen – Uterine Cancer
• Relative risk 2-4 – highest in obese, post-menopausal, prior HRT
• P-1 study – 56 uterine malignancy/6700 women
• 8 excess cases/10,000 women at 10 years
• Annual pelvic exam; if bleeding – U/S, biopsy
• Radiation Therapy – Slight increased risk in sarcomas, angiosarcoma of the breast, lung cancers (primarily in smokers)

Matesich SM, Semin Oncol 2003;30(6):740

MDS and Leukemias from PARP inhibitors

Lancet Haematol 2021; 8: e122–34

Compilation of data from 28 clinical trials from patients with breast, ovarian, colorectal, prostate, gastric , melanoma, NSCLC

Results

• . The incidence of myelodysplastic syndrome and acute myeloid leukemia across PARP inhibitor groups was 0·73% (95% CI 0·50–1·07; I²=0%, χ² p=0·87; 21 events out of 4533 patients)
• Across placebo groups was 0·47% (0·26–0·85; I²=0%, χ² p=1·00; three events out of 2774 patients
• median treatment duration was 9·8 months
• Median latency period since first exposure to a PARP inhibitor was 17·8 months
• Of 104 cases that reported outcomes, 47 (45%) resulted in death.

Morice et al. Lancet Haematol 2021; 8: e122–34

A real life clinical situation continued

• Short term: She has hair loss, nausea, neuropathy, hot flashes and symptoms of menopause and cognitive changes
• Long term: she struggles with persistent neuropathy and some mild memory changes
• Late effects: 1 year after treatment ended, lymphedema symptoms

In affected side presented ; 5 years after initial diagnosis presented with recurrent metastatic triple negative breast cancer. Initially responded to chemo and then transitioned to olaparib PARP inhibitor. Excellent response; In year 2, developed persistent cytopenias c/w therapy related MDS

Late recurrences

• Risk of recurrence for ER+ breast cancer persists for decades after diagnosis
• More than 50% of recurrences are after 5 years from diagnosis
• Even patients with node negative T1c tumors have persistent 1% risk/year for decades after diagnosis

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• Extending adjuvant endocrine therapy is limited by appreciable side effects as well as limited efficacy

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• Molecular residual disease detection via ctDNA is associated with high risk of recurrence in the adjuvant setting
• Parsons HA, et al. Circulating tumor DNA association with residual cancer burden after neoadjuvant chemotherapy in triple negative breast cancer in TBCRC 030. Annals Oncology 2023; 34(10): 899-906.

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Pan et al NEJM, 2017

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Minimal residual disease (MRD) and associations with outcomes

PS15-05: Breast Cancer Patients with High-Risk Disease Characteristics have Proportionately Higher Risk of Mortality from Non-Breast Cancer Related Causes in both Non-Metastatic and Metastatic Disease

Mehta L et al Circulation, 2018

Optimizing care: primary and secondary CV risk reduction

Kidane, Ruddy et al Mayo Clinic Proceedings, 2024

Optimize metabolic health, body composition and fitness

Cardiac Disease

Anthracycline chemotherapy- Congestive heart failure (CHF)

• Cumulative, dose dependent
• Up to 1% risk for standard breast CA doses
• Latency period up to at least 5 yrs in adults
• Latency period noted up to 25 years in pediatric patients
• Risk factors –HTN, CAD, mediastinal radiation, taxol, trastuzumab, young or old age (<18, >65)
• Can cause permanent structural damage
• 87% improve with ACE-I, beta blocker

Tallaj, J Heart Lung Transplant 2005;24:2196

Anthracycline toxicity is dose dependent

Saleh et al, Heart Failure Reviews, 2021

Cardiac Disease

• Trastuzumab
• Class 3 or 4 CHF in 1-4% (adjuvant studies)
• Occurs during treatment –typically reversible
• Radiation
• Mediastinum, left chest
• Children treated for Hodgkin’s lymphoma
• 7.2x higher risk for fatal cardiovascular events
• Adults treated for breast cancer, lymphoma, germ cell tumor
• Late effects- pericardial disease, restrictive CM, early CAD, conduction abnormalities
• Onset 5-10 years after treatment

Darby et al. NEJM<, 2013

Prostate cancer/testicular cancer

Atsushi Tanaka et al. J Am Coll Cardiol CardioOnc 2019; 1:307-309.

_{2019 The Authors}

Atsushi Tanaka et al. J Am Coll Cardiol CardioOnc 2019; 1:307-309

Late Effects of Prostate Cancer

• Erectile dysfunction
• Incontinence
• Androgen Deprivation Therapy
• Used for metastatic or high risk, localized disease
• Predisposes to:
• Obesity, diabetes, cardiovascular disease, decreased bone density

Leufgens, radiotherapy and oncology, 2021

Metabolic health and prostate cancer

Heart health calculator

Testicular cancer

• Testicular cancer is one of the most curable solid tumors, whether it occurs unilaterally or bilaterally
• Cisplatin neurotoxicity and nephrotoxicity
• Bleomycin pulmonary toxicity
• Etoposide is used as a major treatment modality in this disease (this chemotherapeutic agent is associated with acute leukemia)
• there may be some elevation in risk of leukemia following successful therapy
• when radiation therapy is used in the primary management of testicular cancer, there may be elevated risks for other neoplasms in the pelvis.

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Leufgens et al, Radiotherapy and Oncology 156,2021

• Asymptomatic abnormalities of PFT are common
• Can progress and become symptomatic as a late effect 

About 10 years post-chemotherapy, I noticed that my exercise tolerance was decreasing. It was harder and harder to keep up with friends on our long runs. I felt more fatigued overall. I went from running 10 miles to 7 to 5 to now barely being able to complete 2 miles. My chest would feel tight, as if a vise was clamping down on my ribs. Running up short hills in my neighborhood, which I had routinely done in the past, felt like I was ascending Mount Everest without supplemental oxygen or Sherpa support.

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When I brought this up to my primary care physician, he looked perplexed. I’m young(ish), no family history of heart disease, non-smoker, healthy weight, and only enjoy a hard cider once a week. He performed an EKG in the office, just to double check to make sure I wasn’t crazy. When my heart rhythms started throwing out inverted T-waves, his eyes got larger. He said that I didn’t fit the description of someone who should be experiencing these symptoms.

Colorectal cancer late effects

Later treatment Effects: Colorectal Cancer

• Ostomies
• Effect self-image
• Sexual relationships
• Chronic, persistent diarrhea
• Rectal cancer risk for stool incontinence, decreased rectal compliance
• Associated with surgery, increased if RT
• Urinary and sexual dysfunction nerve damage
• Decrease pelvis bone density secondary to pelvic radiation

Chronic neuropathy

Oxaliplatin

Putting it all together

Rapidly evolving therapeutic landscape

Mean there are more toxicities and late effects to understand and tackle

Immunotherapy

https://www.cancer.gov/news-events/cancer-currents-blog/2019/cancer-immunotherapy-investigating-side-effects

Late effects of immunotherapy are not known fully.

ASCO 2012

Cancer survivorship domains span multiple areas

Health

Promotion

Models of survivorship care delivery

• These models are not widely adopted, and evidence-based recommendations to guide implementation are required.

• Nurse-led and primary care provider-led models may produce cost savings to cancer survivors and healthcare systems

Chan et al J. Cancer Surv, 2021

Ruddy et al. Cancers 2020, 12(12), 3737

Summary

• Monitoring for late effects of cancer treatment is an important part of survivorship care
• Individualized based on patient and treatment factors
• Effective monitoring require patient education, communication among providers

Lustberg et al Nature Reveiws, 2023

Thank you!

MARYAM.LUSTBERG@YALE.EDU