44: Common Cancers

Older patients with cancer provide a unique challenge to the oncologist, whether the intent is cure or palliation of symptoms. Curative therapy may require aggressive and potentially morbid operations, radiation therapy, or chemotherapy. Such aggressive approaches are often more toxic in older patients, who tend to be less resilient.

Cancers in older patients may demonstrate a distinct natural history that differs from that of younger patients. For example, breast cancers tend to have a more favorable prognosis in older populations, whereas acute leukemias have a worse prognosis. In addition, because toxicities from therapeutic intervention may be more frequent in older patients, more severe modifications in therapy may be required. Although radiation therapy is generally well tolerated, alterations in the radiation fields and doses may be necessary to decrease toxicity without significantly compromising efficacy.

Most of the antineoplastic agents are cytotoxic to rapidly dividing cells and are not specific for cancer cells. This lack of specificity results in myelosuppression, mucositis, and hair loss. In general, older patients experience more frequent and more severe normal tissue toxicities. Both the peripheral neuropathy from vincristine and the cardiotoxicity from doxorubicin develop at lower cumulative doses than is typically seen in younger patients. Similarly, mucositis from the combination of 5-fluorouracil (5-FU) and leucovorin is also more common and more severe in older patients. Alterations in renal and, to a lesser extent, hepatic function occur with age and should be considered in the selection and dosing of chemotherapy. Agents such as methotrexate, cisplatin, and bleomycin are normally excreted by the kidney and may produce excessive toxicity in older adults if administered in conventional doses. With an awareness of the normal aging physiology and knowledge of the pharmacology of antineoplastic agents, chemotherapy may be safely administered. Because most clinical trials have enrolled mostly younger individuals, evidence-based data that addresses the challenges of cancer treatment in the older population, is often lacking. Thus, in the addition to current age-based recommendations, life expectancy, functional status, and the patient’s preferences and goals of care should be taken into consideration when making decisions regarding cancer screening and treatment in the older population.

Diagnosis-specific therapies are described in the sections below. If it has been determined that the cancer is not curable or that the patient is unable to tolerate aggressive therapy, the goal becomes palliation of cancer-related symptoms, which may include, but are not limited to, nausea, dyspnea, and pain. Cancer pain management should be tailored to the individual patient’s pain needs and may require nonpharmacologic interventions such as radiation therapy. Attention should be paid to the effective management of potential complications of pain management such as constipation and delirium (see Chapter 11, “Geriatrics & Palliative Care,” and Chapter 54, “Managing Persistent Pain in Older Adults”).

General Principles in Older Adults

The median age for the development of breast cancer is 61 years. The incidence of breast cancer increases with age and plateaus in the seventh decade. In 1973, 37% of breast cancer were diagnosed in women older than 65 years. Between 1996 and 2000 that number increased to 44.2% with 22.5% ≥75 years. The natural history of breast cancer in older populations is unique. When prognostic factors such as estrogen receptor (ER), histologic grade, ploidy, p5p3, epithelial growth factor receptor (EGFR), and human epidermal growth receptor 2 (HER2) status are assessed, it appears that tumors become less aggressive with advancing age. Despite this, 60% of breast cancer-related deaths involve women 65 years of age and older. The high mortality rate may be explained by several factors. First, breast cancer is a common disease in this age group, and patients often have life-threatening comorbid conditions. Second, physicians tend to treat older patients less aggressively than younger individuals.

Primary Breast Cancer

Treatment

Treatment recommendations should be made on an individual basis, taking into consideration comorbid conditions and expectations of therapy. Whenever possible, patients should be encouraged to participate in clinical trials designed to assess how cancers can best be managed.

Breast Conservation Therapy

Although modified radical mastectomy and breast conservation therapy with lumpectomy and radiation share similar survival rates, older women are less likely to undergo breast conservation therapy. Possibly some women choose mastectomy because they find the 6–7 weeks of daily radiation treatments for breast conservation cumbersome. It has also been shown that physicians are less likely to offer breast conservation therapy to older women.

Data suggest that, after surgical removal of the primary cancer, tamoxifen without radiation therapy may be adequate in select patients. However, by eliminating breast irradiation, ipsilateral breast cancer recurrences are more common and are generally treated by mastectomy for local control of the primary cancer. Despite the higher rate of “in-breast” recurrences, the survival for women treated with this less-aggressive approach is identical to that among women treated with conventional surgery and radiation therapy. Resection of the primary tumor and administration of tamoxifen may be appropriate for select women with small, ER+ breast cancers, and a finite life expectancy. Older women with a favorable long-term outlook should be treated as aggressively as younger women.

Adjuvant Therapy

For women with localized ER+ breast cancers, 5 years of adjuvant endocrine therapy decreases the recurrence rate and incidence of contralateral breast cancers. In older women on tamoxifen, the incidence of venous thromboemboli and uterine cancer is higher than in younger women; however, the benefits of adjuvant tamoxifen outweigh the risks. Adjuvant aromatase inhibitors (anastrozole, letrozole, and exemestane) are generally prescribed in postmenopausal women. When chemotherapy is indicated, the reduction in recurrence and survival advantage is identical to that observed in younger women. Less-toxic chemotherapy regimens are less effective than conventional chemotherapy.

Although one must weigh comorbid conditions when making treatment recommendations, appropriately administered adjuvant therapy is cost-effective. In the absence of severe comorbidities, the guidelines for adjuvant therapy are identical to those used to treat younger women. Women with ER+, node-negative breast cancers should have the primary tumor submitted for the 21-gene, Oncotype Recurrence Score, which is helpful in identifying patients who will benefit from chemotherapy in addition to endocrine therapy. Chemotherapy should be considered for those women whose primary cancers are >1 cm and ER− or HER2-positive, and for those with multiple node involvement. The addition of the humanized monoclonal antibody trastuzumab (Herceptin) to conventional chemotherapy is associated with an improved survival and should be used despite a higher incidence of cardiac toxicity in woman older than age 65 years and in patients with hypertension.

Metastatic Disease

Treatment

Because the majority of breast cancers are ER+, endocrine therapy is the mainstay of treatment for advanced breast cancers. The aromatase inhibitors have achieved a higher rate of tumor regression and a longer duration of efficacy and have replaced tamoxifen as first-line therapy for metastatic disease. In ER− disease and cancers that are hormone resistant, chemotherapy may provide effective palliation. Newer, less-toxic single agents such as oral capecitabine are as effective as combination chemotherapy. In women with newly diagnosed HER2-positive breast cancer, anti-HER2 therapy is added either to an aromatase inhibitor in hormone receptor-positive disease or to chemotherapy in hormone receptor-negative of hormone refractory disease. Combined anti-HER2 therapy with trastuzumab and pertuzumab with chemotherapy has been shown to further improve survival compared to trastuzumab and chemotherapy alone.

Screening

A systematic review conducted by the U.S. Preventive Services Task Force (USPSTF) in 2009 led to recommendations for biennial film mammography for women ages 50–74 years; there was insufficient evidence to recommend screening mammography for women age 75 years and older. However, screening mammography decreases breast cancer mortality in women aged 70–79 and identifies early lesions in older women as effectively as in younger women. A single decision analysis and cost-effectiveness study of mammography in women age 70 years and older demonstrated that survival may be favorably affected by screening mammography. Given the heterogeneity of health, particularly in the older-than-75-years population, recommendations should be based on age and health status. For example, the American Geriatrics Society recommends screening mammography in women up to age 85 years, provided that their life expectancy is at least 4 years.

General Principles in Older Adults

Lung cancer is the leading cause of cancer death in both men and women. The majority of patients are older than 65 years. Cancers arising from lung parenchyma are categorized as either small cell or non–small cell (adenocarcinoma, large cell, squamous cell, bronchoalveolar cell, or mixed histologies). A tissue confirmation of cancer and determination of histology provides important diagnostic, prognostic, and therapeutic information. Prognosis is also related to the stage of disease, performance status, gender, and patient’s ability to tolerate adequate treatment. Although age is not an independent prognostic factor, older patients do experience more side effects from the chemotherapy used to treat lung cancer. This is especially true of myelosuppression.

Treatment

Treatment is determined by the primary tumor histology (small cell or non–small cell) and disease stage (limited or extensive). Staging work-up should include an fluorodeoxyglucose positron emission tomography (FDG-PET) scan and MRI of the brain.

Small Cell Lung Cancer

Small cell lung cancers comprise 15% of all lung cancer histologies and 30% of these patients have disease confined to the hemithorax of origin, the mediastinum or supraclavicular nodes. In this “limited stage” disease, concurrent chemotherapy and radiation prolongs survival. Median survival is 20 months, and 20% of patients remain free of disease after 5 years. Because anthracycline-based chemotherapy regimens appear to be more toxic and are probably less effective, etoposide with cisplatin or carboplatin is administered every 21 days for 4–6 cycles. Overall survival and local control of the primary tumor are greater when radiation is initiated with the first cycle of chemotherapy. It has been shown that older patients are more likely to require delays in chemotherapy or dose reductions as a result of toxicity. Yet, despite the need to modify chemotherapy, the likelihood of response to treatment and overall survival are similar to that for younger patients treated with higher doses of chemotherapy. The efficacy of treatment does not appear to be compromised by these alterations in therapy.

For patients with extensive-stage disease, chemotherapy prolongs the median survival from 6–8 weeks to 8–10 months. Patients who are able to receive ≥4 cycles of chemotherapy appear to have a better survival than those who receive fewer cycles. Such data should be viewed with caution because it is possible that the patients who were able to tolerate “more” chemotherapy had a better prognosis. New regimens that are less dose intensive and toxic are being tested in older populations. The survival rates reported with these regimens appear comparable to those for younger patients using more toxic regimens.

Non–Small Cell Lung Cancer

The majority of lung cancers are of non–small cell histology and 10% are identified in patients who are nonsmokers. With the development of newer targeted agents, systemic therapy is further individualized based on the presence or absence of target markers such as EGFR and anaplastic lymphoma kinase (ALK) mutations. Rarely, patients have a solitary nodule that may be removed surgically for cure. Appropriate staging includes a mediastinoscopy with nodal sampling before removal of the primary tumor. If nodal metastases are identified, the patient is diagnosed with limited-stage disease and treated accordingly. Adjuvant chemotherapy and radiation therapy may be indicated in patients with selected tumors following definitive resection. Fit older patients with locally advanced disease that is not amenable to surgical resection will benefit from concurrent chemotherapy and radiation therapy, although they experience more myelosuppression. In older patients, chemotherapy doses are often attenuated because of declining performance status or because of an increased incidence of mucositis or myelosuppression.

In metastatic non–small cell lung cancer, chemotherapy has been shown to palliate symptoms and improve quality of life in the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS trial). In patients >70 years of age, the combination of carboplatin with paclitaxel was compared to either single agent vinorelbine or gemcitabine. Although the combination was associated with more side effects, survival was significantly prolonged. Chemotherapy should be offered to patients with extensive-stage non–small cell lung cancer, especially those who have not lost weight and have a good performance status. Although lung cancer is most often fatal, meaningful improvement in survival and quality of life can be achieved. By modifying chemotherapy doses and schedule, toxicity can be minimized without compromising efficacy. In contrast to younger patients, the addition of bevacizumab to carboplatin and paclitaxel in advanced non–squamous cell cancers had no impact on progression free or overall survival in patients age >65 years. In treating cancers with the EGFR mutations, the single agent erlotinib appears to be as effective as other first-line single agents and is associated with increased side effects when used as second- and third-line therapy. Studies of the newer targeted agents are being tested in older populations.

Screening

Although still controversial, in 2012, the American Cancer Society and the American College of Chest Physicians recommended that adults between the ages of 55 and 74 with at least a 30 pack-year history of current or prior cigarette use receive annual low-dose CT scans of the chest to screen for lung cancer. The USPSTF has not updated its 2004 recommendation that there is “insufficient evidence for or against screening asymptomatic persons for lung cancer.”

Rectal Cancer

The natural history of rectal cancer differs from colon cancer. Because the rectum lies in close proximity to the sacral plexus, uterus, bladder, and prostate, a wide radial margin is often difficult to obtain with surgery, and local recurrences are common. To prevent local disease recurrence, 5-FU in conjunction with radiation therapy is administered either before or after surgical resection. In the Medicare population, the advantages of combined-modality treatment of rectal cancer are similar to those observed in younger patients.

Metastatic Colorectal Cancer

Although most large bowel cancers metastasize to the liver, the pattern of disease recurrence differs somewhat depending on whether the primary tumor arises from the colon or rectum. The drainage of the colon is via the portal vein, and the liver is the most common site, and possibly the only site, of metastasis. Because the inferior mesenteric vein receives drainage from the rectum, systemic metastasis to sites in addition to the liver may develop.

Metastatic colorectal cancer is generally incurable. However, resection of liver metastases may provide long-term disease-free survival for select patients. 5-FU–based regimens may provide both improved quality of life and prolongation in survival. The oral agent capecitabine is better tolerated than 5-FU, and is equally effective in this population. The addition of irinotecan to 5-FU and leucovorin produces improvement with a greater likelihood of tumor regression and possibly a longer survival than is achievable with 5-FU and leucovorin alone. Bevacizumab is a component of first-line chemotherapy, but has not been specifically studied in older patients who tend to experience more thrombotic and thromboembolic events with this agent.

If the primary tumor is not removed, perforation, bleeding, and obstruction may develop, requiring emergency surgical intervention. Emergency operations performed in patients age 70 years and older are associated with higher-than-expected morbidity and mortality.

The treatment of colorectal cancers in older patients does not differ from that for younger individuals. Surgical resection of the primary tumor has been the mainstay of treatment, even in patients with metastatic disease. For patients with newly diagnosed cancers, the resection specimen provides important staging information.

When the regional nodes are involved, 32 weeks of adjuvant 5-FU and leucovorin is recommended. In this setting, the leucovorin is administered not to “rescue” the patient from chemotherapy toxicity (as with methotrexate), but to potentiate the antitumor effect of 5-FU. In the Medicare population, a regimen of adjuvant 5-FU and leucovorin has been shown to reduce the risk of death by 27%, an advantage equivalent to that demonstrated in younger patients. The addition of oxaliplatin to 5-FU+leucovorin was not found to improve survival in patients older than 70 years, although it is superior to 5-FU+leucovorin in younger patients (Adjuvant Colon Cancer Endpoints [ACCENT] trial). Possibly because this regimen is relatively nontoxic, adjuvant chemotherapy can be appropriately administered to older patients.

Colonoscopy has been established as a cost-effective screening tool. The initial screening should begin at age 50 years and is repeated every 10 years until age 85 years. If polyps are identified, the procedure should be repeated every 3–5 years. As with any screening test, the decision to screen should weigh life expectancy and goals of care with the potential risks and benefits of screening. For a more detailed approach to decision making regarding screening see Chapter 3, “Goals of Care & Consideration of Prognosis,” and Chapter 8, “Prevention & Health Promotion.”

Prognosis is related to the depth of invasion of the primary tumor, involvement of regional structures (eg, bladder or uterus), and nodal involvement.

General Principles in Older Adults

More than 66% of pancreatic cancers develop in individuals 65 years of age and older. Even when it appears that the disease is confined to the organ, few patients survive 5 years.

Treatment

Pancreaticoduodenectomy may provide long-term survival for a small percentage of patients. However, the complications of the procedure are significantly higher in patients 70 years of age and older.

Pain is a common and debilitating problem in patients with pancreatic cancer. Even if the patient is found to have unresectable disease at the time of surgical exploration, palliation of pain and prevention of future pain may be achieved by neurolysis of the celiac ganglion.

If the disease is localized to the pancreas but not resectable, combined chemotherapy and radiation therapy may provide both palliation and a slight survival advantage. Candidates for such an approach should be carefully selected because this therapy is toxic. Once the disease has metastasized, palliation is the goal of any intervention. Single-agent gemcitabine has been shown to improve quality of life, with superior pain control and a modest survival advantage.

General Principles in Older Adults

The incidence of ovarian cancer increases with age, peaking at 80–84 years. There are no widely accepted screening modalities, and in 2012, the USPSTF recommended against routine screening for ovarian cancer.

Treatment

Most women present with advanced stages of the disease and are treated with surgery and chemotherapy. Ideally, patients should undergo surgery for both staging and treatment. A total abdominal hysterectomy with bilateral salpingo-oophorectomy and surgical debulking of visible tumor should be performed. Staging also includes nodal sampling, and cytologic examination of smears obtained from the cul-de-sac and diaphragms bilaterally.

The most effective initial chemotherapy combines paclitaxel with cisplatin or carboplatin. Although chemotherapy is effective and relatively nontoxic, older women are less likely to receive treatment. The serum marker CA-125 is an excellent indicator of disease and is of value in monitoring the efficacy of chemotherapy.

Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia and its incidence rises with age. As many as 50% of patients are asymptomatic at the time of diagnosis. The clinical course may be indolent, and chemotherapy or radiation may be reserved until the patient becomes symptomatic. The natural history of CLL is defined by the initial stage at diagnosis, cytogenetics, and tumor markers. Although CLL is not curable, chemotherapy may delay the course of the disease and improve quality of life. Treatment should be initiated only when symptoms are manifested: either B-symptoms (fever, night sweats, 10% weight loss over 6 months) or symptoms from enlarged nodes. Symptoms referable to nodal enlargement may also be palliated with chemotherapy or localized radiation therapy. A number of combination chemotherapy regimens are effective in controlling the disease. In frail older patients, the oral alkylating agent, chlorambucil, was found to be as effective as intravenous fludarabine.

Acute Nonlymphocytic Leukemia

The incidence of acute nonlymphocytic leukemia (ANL) increases with age and the prognosis is inversely related.

Of all patients treated, 70% of individuals go into remission and these are durable for 15–20% of those who achieve a complete remission. ANL in patients older than 40 years is more aggressive and less amenable to therapy. In older people, ANL frequently develops after a history of myelodysplasia and adverse cytogenetic abnormalities, which predict a poor outcome. Leukemic cells from older patients are also more likely to express genes that confer drug resistance. These factors predict resistance to conventional induction regimens. The treatment-related mortality during induction is as high as 25% and complete remissions are achieved in only 45% of older patients; long-term remissions are rare. When lower doses of chemotherapy are used to minimize treatment-related complications, the remission rate is significantly less as well.

Patients and their families should understand that the treatment for ANL is toxic and relatively ineffective. Whenever possible, patients should be referred to oncologists who enter patients in clinical studies that address improved methods of supportive care and innovative regimens. For frail and elderly patients with significant comorbidities, it is reasonable to provide only palliative care.

Indolent Histologies

Lymphomas are classified as Indolent, Aggressive and Highly Aggressive based on the WHO Classifications of Tumours of Haematopoietic and Lymphoid Tissues. As with CLL, treatment of low-grade lymphomas does not appear to alter the natural history of the disease, even though the disease is sensitive to treatment.

Chemotherapy and radiation therapy are reserved for the treatment of symptoms produced by the disease.

Aggressive Histologies

More than 50% of the aggressive histologic subtypes develop in individuals older than 60 years, and age >60 years has been identified as a poor prognostic factor by the International Prognostic Factors Project.

Patients with stage I and stage II disease are treated with chemotherapy and radiation therapy, and, regardless of age, have a favorable prognosis. Patients with more advanced-stage disease (stage III and stage IV) are treated with chemotherapy with or without the anti-CD20 antibody, rituximab.

For more than 2 decades, the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard chemotherapy. Patients older than 60 years are more likely to experience neutropenia and fever than are younger patients. However, when doxorubicin has been deleted from the regimen or the dose has been attenuated, the efficacy has been significantly compromised. After the first cycle of chemotherapy, the use of colony-stimulating factors will decrease the incidence of neutropenia.

It is expected that chemotherapy will produce complete remission of disease in the majority of patients, with 30% to 40% remaining disease free after 5 years. The benefits of chemotherapy are somewhat less for patients who are older than 60 years or who have 1 or more comorbid medical conditions. The addition of rituximab to CHOP has been shown to further improve disease outcome and survival and is the new standard of care in this population.

For Prostate Cancer, see Chapter 40, “Benign Prostatic Hyperplasia & Prostate Cancer.”

National Cancer Institute’s Surveillance Epidemiology and End Results database. http://seer.cancer.gov/index.html

U.S. Preventive Services Task Force. http://www.uspreventiveservicestaskforce.org/adultrec.htm