Title: Presenters: Date:

Title: Side-effects of Ovarian Cancer Treatment

Presenter: Robert J. Morgan, Jr., MD, FACP Professor of Medical Oncology Department of Medical Oncology and Therapeutics Research City of Hope Comprehensive Cancer Center Assistant Clinical Professor, David Geffen School of Medicine, UCLA

Date: July 25, 2015

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Side Effects of Surgery

• Depend largely on the age at the time of surgery • Younger women will have an immediate surgical menopause • Post-menopausal women may experience only the side-effects of the surgery

if they have previously had menopausal symptoms that subsided.

• 12 months of amenorrhea (no menses) • Average age 51 • Primary ovarian function stops • Perimenopause

– Transition – Change from normal ovulatory cycles to complete cessation of menses – Marked by menstrual irregularity – May begin years prior to menopause – Onset of menopausal symptoms

What is Menopause?

• Hot flashes • Sleep disturbances • Vaginal dryness • Mood changes • Difficulty concentrating • Memory impairment • Bladder irritability/urgency • Changes in balance • Decreased interest in sex, possibly decreased response to sexual stimulation

Menopausal Symptoms

Vasomotor Symptoms (Hot Flushes) • Most often begin in perimenopause • Begin abruptly with surgery • Sudden onset reddening of the skin (head/neck/chest),

feeling of intense body heat, profuse perspiration Speroff

• Intervals vary (minutes to hours) • More frequent and severe at night • Generally stop spontaneously w/in few years, may persist for many years

– 12-15 % of women in 60’s – 9% of women after age 70 Casper

• Maintains collagen content – effects thickness and elasticity • Maintains mucopolysaccharides and hyaluronic acid – keep epithelial

surfaces moist • Maintains optimal blood flow • Keeps epithelium rich in glycogen

– Glycogen = substrate for lactobacilli, which convert glucose to lactic acid (creating acidic pH)

– Acidic environment protects against vaginal and urinary tract infections

Effect of Estrogen on Vaginal Tissue

Without Estrogen • Vagina loses collagen, adipose tissue

and ability to retain H20 • Labia and vulva lose fullness • Blood vessels narrow and secretions

from sebaceous glands decrease • Vaginal opening may narrow • Vaginal length may shorten

• With loss of glycogen, pH increases (generally > 5) – Environment less hospitable for lactobacilli – More susceptible to pathogens from skin and rectum

• Urogenital problems – Urgency – Dysuria – Abacterial urethritis – Recurrent UTIs – Urethral caruncles

Vaginal Atrophy

• Vaginal dryness • Pruritis (itching) • Discharge – yellow, malodorous • Dyspareunia (painful intercourse) • Vaginal bleeding or spotting • Unlike hot flushes, symptoms do not improve with time

Most Common Complaints

• Estrogen initially prescribed as treatment for vasomotor symptoms in 1960’s

• Use declined in mid 1970’s secondary to link to endometrial cancer • Use increased again in 1980’s when addition of progestin determined to be

protective • 1991: Nurse’s Health Study suggested that Estrogen decreased coronary

heart disease and death and had no effect on stroke • Indications expanded to include prevention of diseases of aging

Estrogen Replacement

Shifren JL, Schiff I. Role of Hormone Therapy in the Management of Menopause. Obstetrics and Gynecology; 2010: 115, 4: 839-855.

Estrogen thought to be the Fountain of Youth

• Organized by NIH in 1992 • Set of clinical trials • Primarily a trial of primary prevention of CV disease • Randomized, double blind, placebo controlled • 27,347 postmenopausal women • 40 US clinical centers

Estrogen First Replacement Therapy – Women’s Health Initiative

• Combined estrogen-progestin arm (16,608 either tx or placebo) • Statistically significant increase in breast cancer • Increase in CV events (CHD, stroke, venous TE)

• Estrogen only arm (10,739 s/p hysterectomy)

• Increased risk of stroke similar to combined arm • No increase or decrease in CHD • Trend towards increased risk of dementia and/or mild cognitive impairment • Reduction in hip fractures • No increase in breast cancer

..

Hormone Therapy- First Study Women’s Health Initiative

JAMA. 2002;288(3):321-333.

JAMA. 2004;291(14):1701-1712

• Overall hormones were associated with a greater risk of CHD instead of F of Y

• Analysis of data stratified based on age and time from menopause – No increased risk seen in women between 50-59 or in those within 10 years of

menopause – Stroke increased regardless of age and years since menopause – Breast cancer higher in women who initiated hormone therapy soon after

menopause (both regimens)

Analysis of Data from Women’s Health Initiative

Shifren JL, Schiff I. Prentice RL, et al. Benefits and risks of Postmenopausal Hormone Therapy When It Is Initiated Soon After Menopause.

American Journal of Epidiomology 2009; 170: 12-23Role of Hormone Therapy in the Management of Menopause. Obstetrics and Gynecology; 2010: 115, 4: 839-855. .

• For women with moderate to severe vasomotor symptoms, depending on individual risk, and patient’s willingness to accept risk, use the lowest dose of estrogen (with progesterone, if uterus intact) effective for the shortest amount of time possible.

So Can We Use Estrogen Replacement?

• Risk of Breast Cancer: – For estrogen/progesterone therapy, time is limited by the increased risk of breast cancer that is

seen with more than 3-5 years of use – For estrogen only, no sign of an increased risk of breast cancer was seen during an average of 7

years of treatment • Risk of Heart Disease/Stroke:

– Most healthy women below age 60 will not have an increased risk of heart disease with hormone therapy

– In women below age 60, risks of stroke and blood clots are less than 1/1000 women per year. • Risk of Ovarian Cancer

– Higher with hormone replacement and dependent on the duration of hormone replacement – However, the increased risk is very small

How Long?

• Abrupt withdrawal increases return of moderate to severe symptoms • Tapering dose of hormones lowers risk of recurrent symptoms • Weaning off

– Decrease to lowest dose first – Decrease by one pill per week, or – Skip 1 day, then 2 days, etc – Slower tapering may benefit women with recurrence

Cessation of Hormone Therapy

Alternative Therapies

• Lifestyle modifications – Keeping core temperature cool – Regular exercise, weight loss – Relaxation therapy/stress management/reflexology

• Isoflavone supplements: – Soy, red clover, black cohosh

• Acupuncture • Black cohosh

– may have estrogenic effect on breast – do not use in breast cancer pt

• Sexual activity – Improves blood supply – Preserves elasticity – Prevents introital narrowing

• Lubricants – K-Y Jelly – Astroglide – K-Y Liquid beads (silicone based)

• Replens – Long-acting moisturizer – Polcarbophil-based polymer, binds to vaginal epithelium, releases H20, produces moist film over

vaginal tissue – May restore normal vagina pH, does not affect cytology

• K-Y Silk-E • Feminease

– Contains mineral oil, glycerin, yerba santa

Vaginal Atrophy - Alternatives

Medications Used To Treat Menopausal Symptoms

• Anti-depressant classes (SSRIs such as Effexor) • Anti-epileptics (eg gabapentin) • Centrally Acting Anti-hypertensives (eg clonidine patches) • Plant-derived hormones (eg phytoestrogens)

• Are plant-derived hormones that are biochemically similar or identical to those produced by the body or ovaries

• Begin as soy products or wild yams, get converted to different hormones in the laboratory.

• Some use this term interchangeably between compounded bioidentical hormones – this is wrong.

Bioidentical Hormones

• Estrogen replacement – Premarin Cream, Estrace, Vagifem – Systemic and local are effective – Low vaginal doses usually do not reach serum levels sufficient to create systemic

side effects (endometrial stimulation) Bachman • Creams, rings, tablets similarly effective

Vaginal Atrophy – Treatment

• Menopause is defined as 12 months without periods • Surgically induced menopause is probable in women having surgery for ovarian cancer • Symptoms can start up to 10 years prior • Best Candidates for hormone therapy are women who:

– Are in their 50’s or younger – Had their last menstrual period within the last 3 years – Have moderate to severe symptoms

• Use lowest effective doses of hormones, for shortest duration possible • Take individualized risk factors into consideration (high blood pressure, diabetes,

smoking, excess weight, personal or family h/o blood clots) • Be wary of compounded hormones

Summary

Types of Systemic Therapy

• Systemic Therapy – Chemotherapy – Hormonal Therapy – Signal Transduction Agents – Immune Therapy

Primary Chemotherapy for Ovarian Cancer

• Intraperitoneal Cisplatin • IV Paclitaxel (Taxol)

• IP Paclitaxel

• The primary side effects of these agents depends on the chemotherapy drug • The IP procedure has been reported to have specific toxicity

Toxicity of IP Chemotherapy

• Local Effects – Abdominal distention – Pain – Low incidence of peritoneal infections – Difficulty with catheter placement – Catheter malfunction requiring revision – Constipation

Schematic of Method

Toxicity of Chemotherapy

• Nausea and vomiting • Myelosuppression (decreased blood counts) • Fatigue • Muscle Achiness • Asthenia (Just don’t feel good) • Neurotoxicity: Numbness and tingling of fingers and toes • Alopecia • Renal Failure if inadequate hydration

What to do about these side effects

• Good hydration following platinum • Growth factors such as neupogen/neulasta. These also cause bone aches • Analgesics

– NSAIDs – Tylenol – Narcotics

• Anti-nausea drugs – Steroids – Other combinations

Treatment of Toxicity

• Neuropathy often responds to Gabapentin (Neurontin) • Pregabalin (Lyrica) • Sometimes classical analgesics

Other Regimens used in Ovarian Cancer

• Carboplatin/Paclitaxel or Docetaxel – Given in several schedules

• Bevacizumab (Avastin)

Treatment of Toxicities of Therapy

• Carboplatin/Taxane is usually better tolerated than cisplatin • Less Nausea/Vomiting/Asthenia/Neurotoxicity • More Myelosuppression • Growth Factors only occasionally necessary • Anti-emetics are necessary

Bevacizumab

• Anti-angiogenesis Agent • Not specifically cytotoxic • Specific mechanism of action is not clear • Most Common Side-effects:

– Hypertension – Proteinuria – Thrombosis – Bleeding diathesis

Platinum-Sensitive

• Platinum-containing regimen • Platinum/paclitaxel or docetaxel • Platinum/Gemcitabine with or without Bevacizumab • Platinum/Liposomal Doxorubicin (Doxil)

Major Classes of Chemotherapeutic Drugs

• Alkylating Agents – Classical – Nitrosoureas – Platinum Agents (really platinating, not alkylating)

• Anti-metabolites • Anti-tumor Antibiotics

– Anthracyclines – Others

• Topoisomerase Inhibitors • Spindle Inhibitors- Many are plant alkyloids

Anti- Metabolites -- 5-Fluorouracil (5-FU) -- Methotrexate (Aminopterin) -- Gemcitabine (Gemzar) -- Temozolomide (Temodar) -- Pemetrexed (Alimpta)

Classes of Chemotherapeutic Agents

Major Side Effects

• Myelosuppression • Mucositis • Skin Sensitization • Methotrexate can cause toxicity to any organ system • Gemzar can sometimes cause lung infiltrates

Anti -tumor Antibiotics -- Doxorubicin (Adriamycin) -- Liposomal doxorubicin (Doxil) -- Daunorubicin (Daunomycin) -- Epirubicin -- Mitoxantrone (Novantrone)

Classes of Chemotherapeutic Agents

Major Side Effects

• Anthracyclines cause heart trouble when administered in high doses – Mainly need to keep vigilent and check heart function

• Mucositis/Sore Throat/difficulty swallowing – Can be helped by mouthwashes containing local anesthetics/antifungals – Sometimes Carafate slurries can help

Other Side Effects

• Liposomal Doxorubicin is a skin Sensitizer – Need to use a good sunblock

• Can cause constipation • Red skin rash over chest/arms • Hand:Foot Syndrome

– Alleviated by lanolin based creams such as Bag Balm or Udderly Smooth

Platinum-Resistent

• Usually single agents are recommended • A recent trial shows a benefit for the addition of bevacizumab to Liposomal

Doxorubicin, Paclitaxel, or Topotecan

Plant Alkyloids-Spindle Inhibitors -- Vincristine (Oncovin) -- Vinblastine (Velban) -- Paclitaxel (Taxol) -- Docetaxel (Taxotere) -- Vinorelbine (Navelbine) Plant Alkyloid-Topoisomerase Inhibitor --Etoposide (VP-16, Vepesid)

Classes of Chemotherapeutic Agents

Major Side Effects

• Paclitaxel, Docetaxel, Vinorelbine – All three spindle inhibitors – Primary side effects are myelosuppression and some neurologic toxicity

• Etoposide: primarily myelosuppression – Can cause secondary leukemias

Alkylating Agents -- Cyclophosphamide (Cytoxan) -- Ifosfamide --Melphalan (Alkeran)

Classes of Chemotherapeutic Agents

Work via DNA damage --Major cause of myelosuppression --Can cause lung toxicity —Ifosfamide can cause neurotoxicity

Methylene Blue can help acutely

Major Side-Effects

• Work via DNA damage – Major cause of myelosuppression – Can cause lung toxicity – Ifosfamide can cause neurotoxicity

• Methylene Blue can help acutely

Camptothecins Topoisomerase 1 Inhibitors -- Topotecan (Hycamptin) -- Irinotecan (Camptosar)

Classes of Chemotherapeutic Agents

Major Side Effects

• Camptothecins – Irinotecan

• Major side effect is diarrhea • Can cause myelosuppression

– Topotecan • Major side effect is myelosuppression • Can cause asthenia

Hormonal Agents

• Most have been developed as treatment for Breast Cancers but have activity for ovarian cancer

• Tamoxifen – Only side effects are weight gain and hot flashes – May increase thrombotic tendencies slightly

• Aromatase Inhibitors – Hot flashes – Bone and Joint aches (arthritis)

Hormonal Agents/Targeted Agents

• Medroxyprogesterone (Megace) – Weight Gain

• Olaparib

– PARP inhibitor: inhibits DNA repair – Myelosuppression is major side effect

Ovarian Cancer—Early Detection/Disease Recurrence

Follow-Up Study: Blood Samples

Updated study using Electronic Nose