Oncologic Issues

From the 40th Annual OB/GYN Spring Symposium, sponsored by the   Medical University of South Carolina

Educational Objectives

The goal of this program is to improve the management and prevention of gynecologic cancers, including those oc­curring  during pregnancy. After hearing and assimilating this program, the clinician will be better able to:

1.   Describe short- and long-term effects of chemotherapy and radiation therapy in pregnant women and their fe­tuses.

2.   Assess risks and benefits of techniques for maternal cancer surveillance.

3.   Explain evidence for the timing of therapies for pregnant women with cancer.

4.   Recognize “red flags” suggesting that patients should be tested for Lynch syndrome or hereditary breast and ovarian cancers.

5.   Describe risks for gynecologic cancer in women who are BRCA1- or BRCA2-positive.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Mutch has received research grants from Eli Lilly and Co and Genentech. Dr. Hunter-Hicks and the planning committee reported nothing to disclose.

Acknowledgments

Drs. Mutch and Hunter-Hicks were recorded at 40th Annual Ob/Gyn Spring Symposium, held March 23-25, 2009, in Charleston, SC, and sponsored by the Department of Obstetrics and Gynecology, College of Medicine, the Office of Con­tinuing Medical Education, and the College of Nursing of the Medical University of South Carolina. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Cancer in Pregnancy

David G. Mutch, MD, Ira C. and Judith Gall Professor of Obstetrics and Gynocology, and Chief, Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, MO

Incidence of cancers: »19% of all mortality in women 15 to 34 yr of age; most common  —  breast, melanoma, thyroid (not usually life-threatening), cervix, central nervous system (CNS) tumors, leukemia, and lymphoma; »3500 cases complicate pregnancies each year

Age and cancer: <15 yr of age  —  leukemia and CNS tumors more common; sarcomas and preinvasive lesions of cervix; 15 to 34 yr of age  —  leukemia; cancers of breast and cervix; Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL); cancers of bone and connective tissue; 35 to 54 yr of age  —  breast, colorectal (mostly rectal), cervical, and ovarian

Diagnosis: risk due to chest x-ray negligible; avoid fluoroscopic barium enema; computed tomography (CT) of abdo­men and pelvis  —  exposes patient to half of recommended limit (5 rad); ultrasonography (US)  —  safe; if tests be­yond US required, magnetic resonance imaging (MRI) preferred over radiographic tests to avoid radiation

Chemotherapy: Cardonick (2004)  —  chemotherapy probably safe in second or third trimester; breastfeeding contra­indicated; avoid myelosuppression at term; do not deliver infant immediately after chemotherapy (mother can metabolize drugs, but infant may not)

Management: most drugs cross placenta; mechanisms similar to those of radiation (eg, crosslinking of DNA, inhib­iting viability of rapidly dividing cells); avoid most chemotherapies, especially antimetabolites, in first 2 to 3 wk

Complications: neonatal  —  consider immunosuppression and hemorrhage at delivery; childhood  —  increased risk for delay in psychomotor development; secondary neoplasias (not well-documented); infertility

Data: children of breast cancer patients  —  patients received combined-modality therapy during pregnancy; off­spring had normal neurologic and physical development; no evidence of increased risk for cancer; limitations  —  small numbers; moderately long follow-up

Take-home messages: if chemotherapy necessary in first trimester, use single agent (eg, anthracycline, vinca alka­loid); avoid multiagent therapy close to delivery; avoid iatrogenic prematurity;  breastfeeding contraindicated

Radiation therapy: effects depend on gestational age and dosage; inverse square law  —  first trimester dose to pelvis when treating breast »6 rad; as fetus grows, it nears site of irradiation (exposure to portion of fetus will increase ex­ponentially); dose and volume  —  determine complications; eg, 10,000 cGy to few millimeters of fetus harmless, but 600 cGY to whole fetus lethal; effects according to age  —  “all or nothing” during peri- or preimplantation; struc­tural abnormalities during organogenesis; CNS defects or neurologic issues (eg, microcephaly, mental retardation) later in pregnancy; teratogenesis  —occurs with low threshold during early development; fetus becomes more resistant as it develops; risk of developing cancer increased by 40%, but risk remains negligible due to low absolute magnitude of risk for childhood cancer; take-home message  —  radiation therapy almost always contraindicated

Cervical cancer: pregnancy  —  no effect on prognosis or fetus; 1 to 13 cases per 10,000 pregnancies; bleeding main symptom in 30% of patients; pregnant women 3 times more likely to be diagnosed with stage 1 disease (because of regular examinations); dysplasia  —  can occur in £5% in some populations; no evidence of increased incidence of human papillomavirus expression; abnormal Papanicolaou test  —  evaluate as in nonpregnant patient; perform col­poscopy; directed biopsy required for all gross cervical lesions; endosurgical curettage probably contraindicated

Colposcopy in pregnancy: Economos (1993)  —  612 patients; detected all cases of invasive cancer; cone biopsies performed only when invasive cancer cannot be ruled out

Cone biopsies: Averette (1970)  —  180 patients; 14% with blood loss of >400 mL; margins contained abnormal cells; 1 in 20 resulted in premature birth and/or fetal demise; if biopsy unavoidable, loop electrosurgical excision pre­ferred procedure

Delay of therapy: studies indicate that delay of several weeks does not alter prognosis; route of delivery  —  insufficient data to make recommendation; few case reports of metastases to episiotomy site

Breast cancer: second most common pregnancy-associated malignancy (includes cancers diagnosed in first year postpartum); course of disease unaltered by pregnancy; linear relationship between woman's risk for breast can­cer and age at first full-term birth (decreased risk if <30 yr of age); some data suggest multiple births associated with decreased risk

Diagnosis: difficult because breasts double in volume during pregnancy; mammography  —  safe, but shielding diffi­cult; Memorial Sloan-Kettering Cancer Center (MSKCC)  —  only 25% of patients underwent imaging before bi­opsy; sensitivity of imaging significantly diminished; 118 patients with pregnancy-associated breast cancer and 269 controls; pregnant patients 2.5 times more likely to have metastatic disease; significantly lower chance of stage 1 disease

Evaluation: if patient has "triple negative findings", ie, benign clinical condition, imaging features, and pathology on fine needle aspiration (FNA) or core biopsy, follow-up only until end of pregnancy; MSKCC study  —  19 of 23 cases not diagnosed until after pregnancy, yet 52% had symptoms before pregnancy; symptoms often missed, with resulting delay in diagnosis; increased incidence of poor prognostic variables observed; in 154 patients with pregnancy-associated breast cancer, 26% had inflammatory disease vs 9% in controls

Therapy: surgery  —  safe during pregnancy; radiation therapy after surgery  —  if required, give as early in pregnancy as possible, or wait until after delivery (in speaker’s opinion, can delay for 15-30 wk); chemotherapy  —  if re­quired during first trimester, discuss pregnancy termination; administration during second and third trimesters appears relatively safe; no teratogenicity because organogenesis complete; consider effects on CNS develop­ment and potential for intrauterine growth retardation and preterm labor; MD Anderson study  —  women with median of 4 cycles of chemotherapy during pregnancy; no maternal deaths; 3 patients with preterm labor; no congenital malformations; 1 episode of fetal neutropenia postpartum and 2 of 24 infants had alopecia; long-term effects  —  few known; 1 twin developed 2 malignancies (second twin unaffected) after 17-yr follow-up; effects on mother’s future offspring unknown

Pregnancy after breast cancer: not associated with higher mortality; multiple studies show no significant increase in risk for breast cancer; no difference in rate of spontaneous abortion; 2-yr rule  —  frequently recommended wait before conception; no biologic basis; however, chemotherapy may affect fertility

Endometrial cancer: rare during pregnancy, but most reported cases have favorable outcomes

Ovarian cancer: only 2% of ovarian masses associated with pregnancy malignant; as most adnexal masses func­tional or pregnancy-related, avoid surgical exploration unless patient has significant findings on US; if unavoidable, wait until 32 wk, when neonatal mortality and morbidity similar to that of full-term infants

Histologic types of cancers: germ cell tumors most common; general management  —  if <6 cm, observe; avoid elec­tive surgery until 16 to 21 wk gestation; wait until fetal lungs mature; data show low risk for malignancy and tor­sion

Colorectal cancers: 64% rectal vs 36% colonic; opposite of that seen in general population, but may reflect detection bias; colon cancer  —  does not appear to adversely affect pregnancy; avoid radiation therapy; chemotherapy  —  low efficacy (not worth risk)

Leukemia: reported outcomes uniformly poor; start chemotherapy immediately; distribution  —  61% acute myeloid; 28% acute lymphoblastic; 7% chronic myelogenous; survival without treatment  —  median 2 mo

Lymphoma: incidence low (but unknown); exact treatment not known; HL  —  775 patients (»3% pregnant); NHL  —  exceedingly rare; study  —  50 pregnancies associated with HL; 38 live births; prognosis varies during course of pregnancy; pregnancy delays treatment of NHL in »60% of patients; maternal outcomes  —  39 of 90 mothers alive and disease-free 21 mo after delivery; 4 alive with disease; 47 died median 6 mo after delivery; delay of therapy not advisable

Thyroid cancers: evaluate surgically during pregnancy; radionuclide scan  —  contraindicated; US  —  safe; FNA  —  most important tool; most cancers well-differentiated; treatment delay appropriate and safe

Melanoma: may be most common malignancy during pregnancy; excise suspicious lesions

Screening for Ovarian and Uterine Cancer

Verda Hunter-Hicks, MD, Clinical Associate Professor, Department of Obstetrics and Gynecology, University of Missouri Medical School, and Director of Gynecologic Oncology, Resource Center for Gynecologic Oncol­ogy, Kansas City, MO

Women with cancer: annually, 50,000 fewer cases than in men; gynecologic malignancies  —  10% of all cancers

Endometrial cancer: mortality  —  currently 20% vs <10% 20 yr ago; obesity  —  major cause of increased incidence and advanced disease; due to excessive estrogen production in adipose tissue; genetic predisposition and age also increase risk; screening tests  —  no routine or standard screening test for asymptomatic patient; hallmark abnormal bleeding; not seeing patients as early in disease process as previously

Ovarian cancers: include fallopian tube and peritoneal carcinomas; similar diagnosis, treatments, and risk factors; risk factors  —genetic predisposition; nulligravidity and decreased fertility likely coexist with genetic predisposi­tion; increasing age; screening  —no adequate tests; patients report vague abdominal symptoms for 6 to 9 mo; trans­vaginal US may fail to identify abnormality; patients present with ascites within 2 to 3 wk of diagnosis with advanced stage III

Hereditary Cancer Syndromes

Overview: relatively common, eg, hereditary breast and ovarian cancer (HBOC), Lynch syndrome; result from inher­ent genetic defects; increase risk of developing second cancer; early identification in family members may aid pre­vention; hallmarks  —family clustering of specific types of cancers among siblings and across multiple generations; younger age at first diagnosis, compared to families with nonhereditary cancers; multiple cancers in single person (eg, breast and ovarian, uterine and colon); mutations typically in tumor supressor genes; breast cancer  —  5% he­reditary; ovarian cancer  —  18% hereditary; refer all ovarian cancer patients for genetic counseling; uterine cancers  —  5% hereditary; genetic vs hereditary  —  all cancers genetic in origin, but not all hereditary (ie, most can­cers due to age-associated loss of ability to repair genetic errors); in hereditary cancers, specific mistakes occur in regular pattern

Breast cancer (BRCA) gene: 0.25% of cases familial; 3% to 5% of cases BRCA-error positive; BRCA mutation prevalence  —  in general population, 1 in 500; in eastern European Ashkenazi Jews, 1 in 40; carried in men and women; <5% of BRCA carriers identified; risk for cancer over time greatly increased in individuals with known BRCA mutation

Ovarian malignancies: no better screening test for prevention or early diagnosis than testing for BRCA genes; BRCA1 and BRCA2 positivity and risk  —  risk highest with BRCA1 carriers (40% by age 70 yr); risk associated with BRCA2 lower than with BRCA1, but still higher than in general population (even at 50 yr of age)

Women at risk for HBOC: influence on treatment decisions  —knowing BRCA gene carrier status may affect choices (eg, trastuzumab [Herceptin] for human epidermal growth factor receptor 2-positive breast cancer); prognosis of BRCA carriers with breast cancer  —  BRCA1 carriers have more adverse prognoses than noncarriers; with BRCA2, prognosis similar to that for sporadic breast cancer; BRCA-related ovarian cancer  —  fare better than noncarriers; counseling  —  determine whether appropriate to test for BRCA gene mutations or Lynch syndrome; determine whether patient candidate for prophylactic surgery; physician pitfalls  —  underestimation of preva­lence, cancer risk associated with BRCA mutations, and efficacy of prevention strategies (eg, prophylactic sur­gery); inadequate preventive screening and maintenance; identification of noncarriers; evaluating patients with new diagnosis  —reconstruct family history to determine need for genetic testing

Red flags for referral to counseling and testing: breast cancer in family member <50 yr of age; all ovarian cancer patients (regardless of age or family history); multiple primary cancers in same patient; any male breast cancer;  breast cancer or ovarian cancer in woman with Ashkenazi Jewish heritage;  ³3 blood relatives with breast or ovarian cancer, regardless of age  

Lynch syndrome: endometrial cancer  —  most frequent extracolonic cancer; median age at diagnosis »60 yr; female carriers more likely to develop endometrial before colon cancer; inheritance  —  autosomal dominant; usually ³2 generations affected; indicators  —  presence of endometrial cancer; cancers at young age; genetics  —  error in mis­match repair gene; 2-hit theory  —  patients develop cancer more readily after first genetic “hit”; family history  —  may be multiple cancers, including those of urinary tract; multiple generations, up to third-degree relatives; colorectal polyps

Red flags: any patient with colon or uterine cancer <50 yr of age; any patient with multiple Lynch syndrome-related cancers, regardless of age (colon, uterus, ovary, gastric, biliary, pancreas, renal pelvis, and CNS); any patient with Lynch syndrome-related cancer and suspicious history; tumors of small intestine or renal pelvis

Management: increased surveillance; colonoscopy and preventive surgery of uterus and ovaries; colonoscopy  —  starting at 20 to 30 yr of age in affected families, depending on earliest age of malignancy diagnosis; abnormal bleeding  —  associated with endometrial or ovarian cancer; transvaginal US or cancer antigen 125 testing with en­dometr