Cancer Part 2: Diagnosis/Long-term Effects of Chemotherapy

Educational Objectives

The goal of this program is to improve long-term outcomes in patients with cancer. After hearing and assimilating this program, the clinician will be better able to:

1.   Recognize the signs and symptoms suggestive of common cancers.

2.   Work up and diagnose patients with suspected cancer.

3.   Detail the long-term effects of chemotherapy and radiation therapy in survivors of childhood cancer.

4.   Perform surveillance for adverse effects associated with chemotherapy and hormonal therapy in survivors of adult cancer.

5.   Manage chemotherapy-induced adverse effects in survivors of adult cancers.

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. Willis is on the Speakers’ Bureaus for Eli Lilly, GlaxoSmithKline, and Eisai Pharmaceutical. Dr. Pilz and the planning committee re­ported nothing to disclose.

Acknowledgments

Dr. Willis was recorded at the 16th Annual Essentials in Internal Medicine: Update on Principles and Practice, presented by the University of Texas Medical Branch, and held April 3-4, 2009, in Galveston, TX; Dr. Pilz was recorded at Topics and Advances in Internal Medicine, presented by the University of California, San Diego, School of Medicine, and held March 5-7, 2009, in San Diego, CA. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

The Cancer Work-up

Maurice Willis, MD, Assistant Professor of Medicine, Department of Hematology/Oncology, University of Texas Medical Branch, Galveston

Lung Cancer

History: smoking-related; onset of symptoms typically late in disease process (eg, after development of obstructive lesion); annual incidence »172,000; lifetime risk, 1 in 13 (men) and 1 in 18 (women); 15% survival at 5 yr

When to suspect: long-term smokers, especially those ³65 yr of age; pneumonia (obstructive lesion prevents patient from coughing up pneumopathogens); unexplained weight loss; new pleural effusion; onset of hoarseness (lesion may affect recurrent laryngeal nerve); new clubbing or osteoarthropathy (may be first sign of lung cancer)

Work-up: imaging  —  chest x-ray, followed by computed tomography (CT), if findings abnormal; physical examination  —look for clubbing or osteoarthropathy; perform cranial nerve examination and strength testing (Pan­coast tumors may cause miosis and hand weakness); laboratory tests  —  liver panel (elevations in alkaline phospha­tase or other liver enzymes may indicate metastasis to bones or liver); biopsy  —  bronchoscopy preferred procedure when lesion accessible; radiology-guided approach often helpful; risk for pneumothorax increases with depth of tu­mor; cytology  —  drain pleural effusion when present; send large sample for analysis (increases yield); after diagno­sis of cancer  —  liver panel (for signs of metastasis); CT of chest, abdomen, and pelvis; positron emission tomography (PET)-CT identifies resectable tumors; magnetic resonance imaging (MRI) of brain in patients diag­nosed with adenocarcinoma (high risk for brain metastasis); referral to oncologist

Lymphoma

When to suspect: prolonged unexplained itching; weight loss; night sweats; enlarged lymph node; lymph node pain after drinking alcohol (Hodgkin’s lymphoma); elevated level of lactate dehydrogenase (LDH); unexplained kidney stones (fast cellular turnover seen with aggressive lymphomas may cause formation of uric acid kidney stones)

Work-up: biopsy  —  fine-needle aspiration acceptable as first step, but entire node needed for typing; if whole node not accessible (eg, mediastinal lymph node), flow cytometry useful for typing; laboratory tests  —  levels of creati­nine, calcium (may be elevated), uric acid, and LDH; complete blood cell count; liver panel; imaging  —  CT of neck, thorax, abdomen, and pelvis; PET-CT (if available) has higher specificity and sensitivity than CT; outcomes  —  »80% of patients respond to chemotherapy

Multiple Myeloma

When to suspect: patient (typically in 50s or 60s) without history of immune compromise has recent history of mul­tiple infections (due to insufficient levels of functional immunoglobulins); unexplained bone pain or fractures; un­explained type-II renal tubular acidosis; elevated protein and decreased albumin levels; elevated level of calcium; black or Indian ethnicity

Work-up: levels of total protein and albumin; protein electrophoresis (using samples of serum and urine); bone sur­vey (radiographs of long bones); evidence of type-II renal tubular acidosis; referral  —  if multiple myeloma sus­pected but tests inconclusive, bone marrow biopsy warranted

Liver Cancer

When to suspect: chronic infection with hepatitis B or C virus (these patients should be screened every 6 mo); liver cirrhosis; sudden elevations in liver enzymes (not required for diagnosis); new-onset jaundice; liver capsular pain

Work-up: ultrasonography (US); a-fetoprotein (AFP) blood test (diagnostic if >400 ng/mL; refer to oncologist); bi­opsy required if US shows lesion, but AFP level not significantly elevated (lesion may be primary lymphoma or metastasis from primary cancer); referral  —  team approach recommended for identifying best course for manage­ment; patients may qualify for transplantation

Testicular Cancer

When to suspect: young men with testicular growths or tenderness or undescended testes

Work-up: US of testicles; assays for AFP and b-human chorionic gonadotropin (elevated AFP indicates nonsemi­noma [poor prognosis]); referral  —  urologist for removal of testicle; oncologist for chemotherapy and follow-up (required for patients with all stages of testicular cancer) and imaging

Prostate Cancer

Screening: among older men, often results in identification of indolent cancers; for black men with family history of prostate cancer, initiate screening in fifth decade; mortality rate higher among younger men (40-50 yr of age)

When to suspect: bone pain; elevated level of prostate-specific antigen (PSA; repeat test) or alkaline phosphatase (may indicate bone metastasis)

Work-up: repeat PSA test in 6 mo; digital rectal examination (DRE); bone scan for patients with high level of alka­line phosphatase or bone pain; referral to urologist  —  for possible biopsy; patients with persistently elevated PSA or nodule found on DRE

Colon Cancer

When to suspect: patient with multiple skin tags (may have familial polyposis syndrome); patients >50 yr of age; black or bloody stool; changes in bowel habits (eg, sensation of needing to defecate; constipation); acromegaly (high risk for polyps)

Work-up: colonoscopy; biopsy; CT of abdomen and pelvis; brain imaging if neurologic symptoms present; referral  —oncologist and surgeon to determine whether chemotherapy and/or radiation therapy required before sur­gery

Following Cancer Survivors

Surveillance: after neck irradiation  —  hypothyroidism; after breast irradiation  —  secondary sarcomas; after mantel irradiation (for lymphoma)  —  secondary sarcomas; breast cancer; after prostatectomy  —  rising PSA level indicates recurrence (radiation therapy may be curative); after anthracycline therapy  —  heart failure; early coronary artery disease (CAD); after treatment with bleomycin  —  late toxicities include lung scarring and respiratory failure (smoking accelerates); after colon cancer  —  annual screening for carcinoembryonic antigen (elevation may indi­cate recurrence)

Long-term Adverse Effects of Chemotherapy

Renate B. Pilz, MD, Professor of Medicine, Department of Hematology/Oncology, University of California, San Diego, School of Medicine

Survivors of Childhood Cancer

Population: »250,000 people in United States; cancers  —  »50% leukemias and lymphomas; »50% solid tumors; sur­vival rates  —  »78% overall; >90% for some leukemias

Childhood Cancer Survivor Study: enrolled patients who had survived childhood cancer ³5 yr; follow-up averaged 17 yr (up to 30 yr); patients had received chemotherapy and/or radiation therapy; findings  —  by 30 yr after diag­nosis, »40% of patients experienced severe, disabling, or life-threatening conditions (or death due to chronic ill­ness); incidence 8-fold greater, compared to siblings

Long-term effects: major joint replacement  —  50-fold increased risk (excluded patients who had joint replacement as part of therapy); also related to radiation therapy and long-term use of corticosteroids; secondary malignancies  —  15-fold increased risk; cancers of breast, lung, and thyroid most common; cancers common in radiation fields, but also occur in patients who receive only chemotherapy; malignancies usually hematologic in those who received only chemotherapy; screening important; heart problems  —  congestive heart failure (CHF) and/or cardiomyopathies may develop years after treatment with anthracyclines; 15-fold increased incidence; ra­diation may cause premature CAD; combination therapy likely increases risk; renal failure  —  typically develops soon after chemotherapy, then stabilizes; some patients require dialysis; »10-fold increased risk; amenorrhea  —  primary or secondary; associated with sterility and premature menopause; »4-fold increased risk

Recommended surveillance during adulthood: secondary malignancies (especially in radiation field; skin cancers often particularly aggressive in lymphoma survivors); premature CAD; late-onset cardiomyopathies (after anthra­cycline therapy); pulmonary fibrosis (after treatment with alkylating agents or bleomycin); endocrinopathies (eg, premature gonadal failure, hypothyroidism, osteoporosis, hypothalamic dysfunction)

Survivors of Adult Cancer

Long-term effects: chemotherapy  —  secondary malignancies; cardiomyopathy; neuropathy; pulmonary fibrosis; hormonal therapy  —  tamoxifen and aromatase inhibitors induce vasoactive symptoms (eg, hot flushes, night sweats); aromatase inhibitors associated with myalgias and arthralgias (may be severe; potential reason for discon­tinuing agent); tamoxifen associated with increased risk for thromboembolic events (risk increases slightly with aromatase inhibitors) and endometrial cancer (2- to 3-fold increase); both  —  combination therapy further increases risk; each associated with gonadal failure, infertility, sexual dysfunction, osteoporosis, fatigue, weight gain, and cognitive impairment

Secondary malignancies: typically myeloid malignancies (leukemias and myelodysplasia); early signs include low blood-cell counts and mild dysplasia; acute myelogenous leukemias associated with poor prognosis; onset  —  1 to 3 yr after chemotherapy; agents  —  alkylating agents (eg, cyclophosphamide [eg, Cytoxan]); anthracyclines (eg, doxo­rubicin [eg, Adriamycin]); etoposide (VP16); absolute risk  —  »5 in 1000 patients will develop myelogenous cancer 1 to 3 yr after standard adjuvant chemotherapy for breast cancer

Cardiomyopathy: agents  —  anthracylines; HER2/neu-antibodies (eg, trastuzumab [Herceptin]); onset  —  months to years; risk  —  dose-dependent; 5% of patients treated with doxorubicin and cyclophosphamide have decreased left ventricular function 1 yr after chemotherapy (often reversible), and 0.3% of patients experience congestive heart failure (CHF) or cardiac death within 3 yr; risk for CHF or cardiac death increases to 3% when trastuzumab therapy added; treatment  —  medical therapy addressing cardiomyopathy

Neuropathy: agents  —  platinum agents (used in treatment of testicular, lung, and colon cancers); taxanes (for breast and ovarian cancers); Vinca alkaloids (for lymphomas and leukemias) risk  —  dose-dependent; increased in patients with preexisting neuropathies; presentation  —  initially, numbness and tingling in fingertips and toes; may progress to pain and (rarely) motor neuropathy (potentially severe, requiring wheelchair); Raynaud’s disease common (usu­ally reversible); management  —  discontinue agents when symptoms clinically significant (eg, interfere with fine motor skills); symptoms typically improve with time; gabapentin improves pain in some patients; in-progress stud­ies looking at prevention

Gonadal and hormonal failure: agents  —  DNA-damaging agents (eg, alkylating agents, platinum agents); risk for sterility  —  dependent on dose (eg, occurs in 95% of men and women treated with high-dose chemotherapy with stem-cell rescue) and age (younger patients less likely to suffer permanent gonadal damage); fertility options  —sperm-banking recommended for young men; only invasive options available for women; amenorrhea or prema­ture menopause  —  amenorrheic women still need to use contraception; reversible in »50% of women <40 yr of age; rarely reversible in older women; only 8% of survivors of childhood cancers (requiring chemotherapy) have permanent amenorrhea; risk for premature menopause  —  risk increases with age at treatment; lowest for women who receive only hormonal therapy; highest for women who receive combination of hormonal and chemother­apy; managing menopausal symptoms  —  estrogens contraindicated in breast cancer survivors; hot flushes gener­ally resolve in 3 to 6 mo; medical therapy may improve symptoms; selective serotonin reuptake inhibitors (SSRIs) effective but interfere with action of tamoxifen (increasing risk for relapse); of SSRIs, venlafaxine pre­ferred (least effect on tamoxifen metabolism); megestrol (eg, Megace) improves hot flushes but associated with weight gain; gabapentin effective at higher doses, but sedating; vitamin E may help, but over-the-counter prepa­rations often already oxidized (ie, inactive); raloxifene, clonidine and soy shown ineffective

Osteoporosis: premenopausal women  —  chemotherapy-induced amenorrhea associated with decrease in bone min­eral density (BMD) comparable to natural menopause; addition of tamoxifen therapy further decreases BMD; postmenopausal women  —  tamoxifen therapy associated with increases in BMD (in setting of low estrogen, tamoxifen acts as partial agonist of estrogen receptors); aromatase inhibitors (more commonly used in postmeno­pausal women) associated with significant decreases in BMD and increased risk for fracture (screening recom­mended); prevention and management  —  smoking cessation; decreased intake of caffeine; exercise; supplementation with calcium and vitamin D; bisphosphonate therapy for women with low BMD before therapy or with decreasing BMD after initiation of therapy

Fatigue: very common; may last >6 mo; management  —  treat contributing factors (eg, insomnia, depression, hypo­thyroidism, hypogonadism, cardiopulmonary adverse effects of chemotherapy); exercise most effective; psychoso­cial interventions (eg, stress management) effective; speaker does not recommend psychostimulants

“Chemo-brain”: subtle cognitive deficits may persist up to 1 yr; poor correlation between self-reported problems and results on formal neuropsychologic testing; improves with time; management  —  reassurance; compensatory strategies; stress management; exercise; treatment for depression

Importance of exercise: studies show regular moderate exercise (30 min per day) associated with decreased rate of mortality among women with breast cancer; absolute risk decreased by 6%; relative risk decreased by 50%

Questions and answers: risk for fetal malformations  —  not significantly increased among women who wait 2 yr af­ter chemotherapy before conceiving; men recommended to wait ³6 mo after chemotherapy; fertility options  —  fertility treatment (eg, with donated eggs) sometimes successful in women with primary amenorrhea after treat­ment for childhood cancer; contraception after breast cancer  —  systemic estrogen contraindicated, but progester­one-based oral contraceptives and local estrogens (eg, intrauterine devices) acceptable; exercise  —  moderate exercise highly recommended; improves fatigue, cognitive deficits, vasomotor symptoms, and osteoporosis; mech­anism unknown; shown to reduce risk (prophylactically) for breast and other cancers; preventing cardiomyopathies  —  dexrazoxane given to patients receiving high-dose doxorubicin; unknown effect on outcome when used with adjuvant chemotherapy (eg, for breast cancer); radiation from imaging  —  potentially increases risk for cancer; CT important for staging and follow-up of cancer patients; effects minimized by reducing frequency and using noncontrast CT after baseline imaging with contrast CT

Suggested Reading

Carozzi FM et al: Molecular profile in body fluids in subjects enrolled in a randomised trial for lung cancer screening: perspec­tives of integrated strategies for early diagnosis. Lung Cancer Jul 29, 2009 [Epub ahead of print]; Coccaro M, Gallucci G: Late cardiac effects of adjuvant radiotherapy and chemotherapy in early breast cancer. J Clin Oncol 26:3288, 2008; Glass C: Role of the primary care physician in Hodgkin lymphoma. Am Fam Physician 78:615, 2008; Gurgan T et al: Pregnancy and assisted re­production techniques in men and women after cancer treatment. Placenta 29 (Suppl B):152, 2008; Hensley ML et al: American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants. J Clin Oncol 27:127, 2009; Holmes MD et al: Physical activity and survival after breast cancer diagnosis. JAMA 293:2479, 2005; Meadows AT et al: Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study co­hort. J Clin Oncol 27:2356, 2009; Oeffinger KC et al: Chronic health conditions in adult survivors of childhood cancer. N Engl J Med 355:1572, 2006; Sarrats A et al: Differential percentage of serum prostate-specific antigen subforms suggests a new way to improve prostate cancer diagnosis. Prostate Aug 7, 2009 [Epub ahead of print]; Shariff MI et al: Hepatocellular carcinoma: cur&