Joanne E. Mortimer MD
Janet McElhaney MD
Elderly 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 more toxic in the elderly, who tend to be less resilient.
Cancers in the elderly 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 the elderly, whereas acute leukemias have a worse prognosis. In addition, because toxicities from therapeutic intervention may be more frequent in the elderly, 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 the elderly. 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 the elderly 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.
Once it has been determined that the cancer is not curable or that the patient is physically unable to tolerate aggressive therapy, the goal becomes palliation of cancer-related symptoms. Palliative care may involve the management of symptoms related to the cancer and its spread (eg, pain or shortness of breath from a pleural effusion) or may require preemptive therapy to avoid a more morbid complication resulting from untreated cancer. Radiation therapy to the spine to prevent spinal cord compression is an example.
It has consistently been shown that pain is not managed well in the elderly, especially women and minority populations. Cancer pain management should be tailored to the individual patient's pain needs. Initially, scheduled doses of acetaminophen (650 mg 4 times/day) combined with a short-acting opioid analgesic, such as oxycodone, may provide pain relief for 4–6 h. Acetaminophen potentiates the effect of the opioid analgesic when given in regular doses, so that lower doses of an opioid may be effective. Thus, acetaminophen/opioid combinations should be avoided unless they simplify pain management without disrupting the scheduled acetaminophen regimen. As the need for pain medications increases, short-acting opioid analgesics should be used for dose titration and then converted to a long-acting medication equivalent such as sustained-release morphine, oxycodone, and fentanyl to provide effective control of pain.
Constipation is an expected side effect of opioid analgesics, which cause paralysis of the myenteric plexus. A daily dose of a laxative is recommended for all patients when an opioid analgesic is initiated. Delirium and agitation are additional complications of opioid use that may be confused with adequate pain control. Sedative medications such as benzodiazepines can often paradoxically increase agitation as a result of worsening delirium. This problem can be minimized with lower and more frequent dosing of the opioid analgesics.
Fentanyl patches may provide more rapid drug delivery because of age-related atrophy of the skin; thus, lower dose patches may help to avoid delirium. Combinations of medications may be required, depending on the type of cancer pain being treated, and include antidepressant drugs and gabapentin, especially for neuralgic pain.
The incidence of breast cancer increases with age and plateaus in the seventh decade. In 1973, 37% of breast cancers were diagnosed in women older than 65; in 1995, that number increased to 46.7%. The natural history of breast cancer in the elderly is unique. When prognostic factors such as estrogen receptor (ER), histological grade, ploidy, p53, epithelial growth factor receptor (EGFR), and c-erb-b2 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 have life-threatening comorbid conditions. Second, physicians tend to treat the elderly less aggressively than younger individuals.
Primary Breast Cancer
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 trials designed to assess how cancers can best be managed.
Although modified radical mastectomy and breast conservation therapy with lumpectomy and radiation share similar survival rates, elderly women are less likely to undergo breast conservation therapy. Possibly some women chose 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.
For women with localized ER+ breast cancers, 5 years of adjuvant tamoxifen decreases the recurrence rate and incidence of contralateral breast cancers. In older women on tamoxifen, the incidence of venous thromobemboli and uterine cancer is higher than in younger women; however, the benefits of adjuvant tamoxifen outweigh the risks. An aromatase inhibitor such as anastrozole may be substituted in women for whom tamoxifen is contraindicated. When chemotherapy is indicated, the reduction in recurrence and survival advantage is identical to that observed in younger women.
Although one must weigh comorbid conditions when making treatment recommendations, appropriately administered adjuvant therapy has been shown to be 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+ breast cancers should receive adjuvant hormonal therapy, usually with tamoxifen. Chemotherapy should be considered for those women whose primary cancers are > 1 cm and ER–or her-2 positive and those with multiple node involvement.
Because the majority of breast cancers are ER+, hormonal therapy is the mainstay of treatment for advanced breast cancers. The aromatase inhibitors (anastrozole, letrozole, and exemestane) 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 have been shown to be as effective as combination chemotherapy. The humanized monoclonal antibody trastuzumab (Herceptin) is reserved for those patients whose cancers overexpress the her-2 protein. Trastuzumab is effective as a single agent and, when combined with initial chemotherapy, offers better a survival rate compared with chemotherapy alone.
Screening mammography have been shown to decrease breast cancer mortality in women aged 70–79. Screening mammography identifies early lesions in older women as effectively as in younger women. A single decision analysis and cost-effective study of mammography in women older than 69 demonstrated that survival
may be favorably affected by screening mammography. The American Geriatrics Society recommends annual screening mammography for women up to age 85, provided that their life expectancy is > 3 years.
Lung cancer is the leading cause of cancer death in both men and women. The majority of patients are older than 65. 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). Although older individuals are less likely to be referred for aggressive surgical procedures, a tissue confirmation of cancer and determination of histology provides important diagnostic and prognostic 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, elderly patients do experience more side effects from the chemotherapy used to treat lung cancer. This is especially true of myelosuppression.
Treatment is determined by the primary tumor histology (small cell or non-small cell) and disease stage (limited or extensive). Lung cancer confined to the primary tumor site and regional nodal drainage is considered to be limited stage. Spread outside this area is extensive stage and is incurable.
Small cell lung cancers comprise 15–20% of all lung cancer histologies. Thirty-three percent of patients have limited-stage disease, and treatment with both chemotherapy and radiation therapy is the standard of care. Concurrent chemotherapy and radiation produces a prolongation in survival. Median survival is 20 mo, 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 carboplatinum is administered every 21 days for 4–6 cycles. The optimal time for initiation of radiation therapy is the subject of some debate. However, 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 elderly 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 mo. 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 the elderly. The survival rates reported with these regimens appear comparable to those for younger patients using more toxic regimens.
Most newly diagnosed lung cancers are of non-small cell histology. 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. Similar to small cell cancers, limited-stage non-small cell lung cancers are treated with combined platinum-based chemotherapy and radiation therapy. Combined-modality therapy results in an improved survival compared with radiation alone, and elderly patients derive the same survival benefit from the combined modality approach as younger patients. 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 may provide palliation. Chemotherapy has been compared with best supportive care (pain management and radiation therapy to painful areas of disease). A small but significant survival advantage has been realized with chemotherapy. Newer agents such as vinorelbine and gemcitabine may be effective and are better tolerated than platinum-containing regimens. Single-agent vinorelbine has been shown to produce significant improvement in median survival, overall survival, and quality of life compared with best supportive care. Results are further improved when vinorelbine is administered in combination with gemcitabine. Chemotherapy should be offered to patients with extensive-stage non-small cell lung cancer, especially in 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.
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. Although only palliative, the addition of irinotecan to 5-FU and leucovorin produces a greater likelihood of tumor regression and possibly a longer survival than achievable with 5-FU and leucovorin alone. Oxaliplatin is the newest active agent used to palliate metastatic colorectal cancer. Neither irinotecan nor oxaliplatin-containing regimens have been specifically tested in the elderly population.
If the primary tumor is not removed, perforation, bleeding, and obstruction may develop, requiring emergency surgical intervention. Emergency operations performed in patients age 70 and older are associated with higher than expected morbidity and mortality.
The treatment of colorectal cancers in the elderly 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-fluorouracil (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. Possibly because this regimen is relatively nontoxic, adjuvant chemotherapy is appropriately administered to elderly patients.
Colonoscopy has been established as a cost-effective screening tool. The initial screening should begin at age 50 and is repeated every 10 years until age 85 years. If polyps are identified, the procedure should be repeated every 3–5 years.
Prognosis is related to the depth of invasion of the primary tumor, involvement of regional structures (eg, bladder or uterus), and nodal involvement.
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.
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.
The incidence of ovarian cancer increases with age, peaking at 80–84 years.
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 cytological examination of smears obtained from the cul-de-sac and diaphragms bilaterally.
The most effective initial chemotherapy combines paclitaxel with cisplatin or carboplatinum. 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 and identifying disease recurrence after initial treatment.
Chronic Lymphocytic Leukemia
Although chronic lymphocytic leukemia (CLL) is very responsive to chemotherapy and radiation therapy, early treatment intervention has never been shown to alter the survival. Therefore, treatment should be initiated only when symptoms are manifested: either B-symptoms (fever, night sweats, 10% weight loss over 6 mo) or symptoms from enlarged nodes. Symptoms referable to nodal enlargement may also be palliated with chemotherapy or localized radiation therapy. Oral alkylating agents combined with prednisone provide effective palliation of fever, night sweats, and weight loss.
Acute Nonlymphocytic Leukemia
The incidence of acute nonlymphocytic leukemia (ANL) increases with age and the prognosis is inversely related.
Overall, 75% of all patients receiving induction chemotherapy with cytarabine and an anthracycline will achieve complete remission; however, durable remissions are observed in only 30–40%. ANL in patients older than 40 is more aggressive and less amenable to therapy. In the elderly, ANL frequently develops after a history of myelodysplasia and cytogenetic abnormalities, such as deletions of chromosome 5 or 7. Leukemic cells from older patients are also more likely to express genes that confer drug resistance. These factors predict resistance to conventional induction regimens. Furthermore, treatment-related mortality during induction is as high as 25%. Thus, complete remissions are achieved in only 45% of older patients, and 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 not to offer induction therapy and to provide only palliative care.
Lymphomas with an indolent natural history based on the Revised European-American Classification of Lymphoid Neoplasms (REAL Classification) are listed in Table 30-1. 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.
The aggressive histologies are summarized in Table 30-1. More than 50% of the aggressive histologies develop in individuals older than 60, 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 alone.
Table 30-1. Lymphoma pathology.
For more than 2 decades, the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) has been the standard chemotherapy. Patients older than 60 are more likely to experience neutropenia and fever than 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. However, neither the complete response rate nor survival is improved by the administration of these costly agents.
It is expected that chemotherapy will produce complete remission of disease in the majority of patients, with 30–40% remaining disease free after 5 years. The benefits of chemotherapy are somewhat less for patients who are older than 60 or who have 1 or more comorbid medical conditions. Thus, conventionally administered CHOP chemotherapy remains the chemotherapy of choice in the elderly. Rituximab (Rituxan) is a chimeric monoclonal antibody directed against CD-20, a cell surface protein found on all non-Hodgkin's lymphomas that arise from B cells. The addition of rituximab to CHOP has achieved higher complete remissions and 2-year event-free and overall survivals compared with CHOP alone. Although rituximab is relatively nontoxic, it is extremely expensive. Before considering the combination of rituximab and CHOP chemotherapy as the new standard, additional data from confirmatory trials are needed. As we learn more about the biology of the malignant diseases, it is likely that such targeted therapies will produce a significant impact.
The diagnosis and treatment of prostate cancer has changed dramatically over the past 15 years as a result of prostate-specific antigen (PSA) measurement. This glycoprotein is produced almost entirely by the epithelial cells of the prostate. The Food and Drug Administration first approved the measurement of PSA in 1986 as a method for monitoring progression of prostate cancer. PSA declines after effective treatment for prostate cancer and increases with ineffective therapy. Similarly, recurrent or persistent elevations of PSA after initial treatment of localized disease are predictive of disease recurrence.
Screening & Prevention
Controlled trials to address the efficacy of PSA as a screening test are ongoing, and results are not expected for many years. Yet annual or biannual measurement of PSA has become part of a routine annual exam for men; the incidence and prevalence of prostate cancer has increased because of better detection. With screening, the lifetime risk for prostate cancer is 16%, and the risk of dying of the disease is 3.4%.
The American Cancer Society and American Urologic Society support annual screening, whereas others suggest that the decision to measure PSA be made on a case-by-case basis after discussion of the potential benefits
and harms of treatment if a cancer is diagnosed. Until data from the controlled trials are available, the use of PSA as a screening test is likely to continue.
The 5α-reductase inhibitor, finasteride has been shown to prevent or delay the onset of prostate cancer, especially low grade prostate cancers. Men assigned finasteride experienced fewer urinary symptoms but more frequent problems with sexual functioning. In weighing the risk and benefits, finasteride cannot be routinely recommended as chemoprevention.
The approach to men with PSA elevations and prostate cancer is summarized in Figure 30-1. PSA levels > 4.0 ng/mL are considered abnormal and should be followed by 4-quadrant transrectal biopsies. Because PSA elevations may be seen with any process that distorts the gland, including benign prostatic hypertrophy and prostatitis, only 25% of men with PSA elevations between 4–10 ng/mL will ultimately be diagnosed with prostate cancer. The probability that the patient has cancer increases with higher elevations of PSA. The PSA is extremely sensitive but lacks specificity. It is important to discuss the impact of making a cancer diagnosis in the asymptomatic patient whose PSA is elevated, because the normal tissue damage from surgery and radiation therapy may be greater than that produced by an indolent cancer.
As a result of PSA screening, most prostate cancer is diagnosed at an early stage when it is still confined to the gland. Treatment with radical prostatectomy or radiation therapy appears to provide comparable rates of local disease control and overall survival. It may be argued that nerve-sparing prostatectomy offers the advantage of preserving potency and providing an accurate pathological stage, and radiation therapy may be reserved for “salvage therapy” in the event of a local recurrence.
Watchful waiting is appropriate for men who have a limited survival. Treatment may be initiated when symptoms develop. Results achieved with watchful waiting are equivalent to those of radical prostatectomy. However, patients treated with surgery are less likely to die of prostate cancer.
Figure 30-1. General schema for prostate cancer treatment.
Patients with large tumors and those with symptoms of urinary obstruction should be offered surgery or radiation therapy.
For cancers that have advanced locally through the capsule or into the seminal vesicles, rectum, bladder sphincter (T3, T4), the combination of radiation with a luteinizing hormone-releasing hormone (LHRH) agonist may produce superior local control of disease and possibly a longer survival than radiation therapy alone. Similarly, patients with yet more advanced disease to pelvic nodes also benefit from the combination of radiation and hormonal therapy.
Widespread prostate cancer is initially managed with combined hormonal therapies. The addition of a 5α-reductase inhibitor such as flutamide in combination with bilateral orchiectomy or an LHRH agonist is more likely to control the disease and may prolong survival. A slight survival advantage has been achieved with the addition of an antiandrogen. With disease progression, cessation of flutamide may produce a hormone withdrawal response. Once the patient's disease has become resistant to hormonal therapy, chemotherapy may offer palliation. Single agents such as mitoxantrone or docetaxel provide palliation in select patients.
Complications associated with nerve-sparing prostatectomy include impotence and urinary incontinence. Definitive radiation therapy to control disease confined to the prostate gland is associated with bowel and bladder dysfunction, which slowly resolve over time; impotence; urinary incontinence; and diarrhea or urgency. Newer radiation therapy techniques that restrict the radiation field to the prostate gland (eg, brachytherapy implants) may offer effective local control with less toxicity than conventional whole pelvis external beam radiation.
Men undergoing radical prostatectomy are more likely to experience erectile dysfunction and urinary leakage but less likely to have urinary obstruction than patients treated with watchful waiting.
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