Cancer and aging are related phenomena, as evidenced by the fact that 60% of cancer incidence and 70% of cancer-related mortality occurs in individuals older than 65. Treatment of cancer in the older adult represents a multidisciplinary effort, frequently integrating medical oncologists, geriatricians, radiation oncologists, and surgeons. As chemotherapy is a commonly used anticancer strategy, collaboration between the former two groups is of critical importance. Physiologic changes that accompany aging may alter the tolerance of chemotherapy, and geriatricians, primary care providers, and medical oncologists may play a role in co-managing related side effects. There are two distinct scenarios in which chemotherapy is applied: (1) the metastatic setting, where the principal goals of treatment are maintenance of quality of life (QOL), prolongation of survival, and decreasing disease-related symptoms; and (2) the neoadjuvant and adjuvant setting, where the goals of treatment are to decrease the risk of disease relapse and disease-related mortality.
The decision to administer chemotherapy is always dependent upon the goals of treatment, as well as the potential risks and benefits to the patient. With these goals in mind, the decision is made to pursue a specific chemotherapy regimen. In the adjuvant setting, polychemotherapy regimens are delivered to eradicate residual microscopic disease through the use of multiple agents with distinct mechanisms of action. In the metastatic setting, the goal is to control disease while maintaining quality of life. The approach to metastatic disease varies on the basis of the disease one is treating. For example, in the setting of breast cancer, studies have demonstrated that combination chemotherapy in comparison to single-agent sequential therapy produces higher response rates but no difference in overall survival. In contrast, even among adults older than 70, studies suggest that combination therapy represents a standard for metastatic lung cancer. Patient-related factors, such as performance status, can also inform the decision between single-agent and combination therapy. Numerous studies have also been performed across malignancies to optimize the dosing schedule of chemotherapy–notably, schedule may have a profound effect on efficacy. In the older adult, where transportation and compliance are often key issues, the chemotherapy schedule is of even greater importance. In this chapter, clinical vignettes (outlined in Table 9-1 ) are used to underscore general considerations for the use of chemotherapy in older adults.
G.R. is a 75-year-old man who presents to his primary care physician with persistent cough that has worsened over the course of 2 months. He is a nonsmoker, and has a past medical history notable only for mild hypertension, managed with a thiazide diuretic. A chest x-ray reveals multiple pulmonary nodules, up to 4 cm in size. He is referred to a medical oncologist, who orders further workup including imaging of the brain, chest, abdomen, and pelvis. CT of the chest reveals a 4 cm spiculated lesion in the right apex of the lung and several 1-2 cm lesions in the right lower, left lower, and left upper lobes. Other imaging studies show no evidence of distant disease. A CT-guided biopsy is performed of the 4 cm lesion in the right apex, and pathologic review of the specimen is consistent with non-small cell lung cancer, adenocarcinoma subtype. A biopsy is subsequently performed of a left lower lobe nodule, which confirms metastatic disease. The oncologist discusses with the patient the fact that the cancer is incurable and the goals of treatment are to prolong survival, minimize disease symptoms, and maintain quality of life. Ultimately, the patient elects to proceed with chemotherapy and receives a combined regimen of vinorelbine and gemcitabine. He visits his primary physician 1 week after his second cycle of therapy is completed and is neutropenic and febrile. He is admitted for IV antibiotics. Blood culture, urine culture, and chest x-ray finds no definitive source of the fever. Imaging of the chest after his second cycle suggests a response to treatment, with a decrease in size of all previously noted lesions.
| Case | Malignancy | Chemotherapy | Considerations in the Older Adult |
|---|---|---|---|
| 1 | Lung cancer |
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| 2 | Breast cancer |
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| 3 | Ovarian cancer |
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| 4 | Colon cancer |
| Management of diarrhea related to 5-fluorouracil and irinotecan |
| 5 | Breast cancer | Capecitabine |
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Discussion of Case 1
Older adults are largely underrepresented in oncology clinical trials, making it challenging in many scenarios to cite the benefit associated with chemotherapy within this demographic. However, several datasets are emerging to allow for an evidence-based approach in this population. The benefits of chemotherapy and best supportive care in comparison to best supportive care alone were described in the Elderly Lung Cancer Vinorelbine Italian Study Group (ELVIS) trial. In this study, 191 patients older than 70 with advanced non-small cell lung cancer were randomized to receive either best supportive care (BSC) or BSC along with vinorelbine chemotherapy. Patients receiving vinorelbine therapy were more likely to survive to one year (32% versus 14%). Toxicities commonly seen with vinorelbine (including neutropenia, anemia, constipation, and fatigue) were more frequent in the treatment group. Nonetheless, patients receiving vinorelbine were less likely to develop symptoms related to lung cancer and had less pain.
Once a decision to receive chemotherapy is made, then the specific regimen needs to be determined, as well as the decision of whether to give monochemotherapy or polychemotherapy. Prospective randomized trials reveal conflicting data. One prospective study randomized 120 patients aged 70 or older with advanced non-small cell lung cancer to either vinorelbine alone or gemcitabine with vinorelbine. Combination chemotherapy resulted in superior median survival (29 weeks versus 18 weeks, P < 0.01). However, these results were not replicated in a much larger study. In the Multicenter Italian Lung Cancer in the Elderly Study (MILES), the combination of gemcitabine and vinorelbine was compared to vinorelbine or gemcitabine alone in 698 patients older than 70 with non-small cell lung cancer. The study results demonstrated that combination chemotherapy did not improve survival as compared to use of a single agent. Furthermore, combination therapy led to increased rates of neutropenia, thrombocytopenia, vomiting, and fatigue. Notably, the side-effect profiles of gemcitabine and vinorelbine are slightly overlapping; as with vinorelbine, gemcitabine can lead to neutropenia, anemia and fatigue.
While the MILES study heralds caution for the combination of gemcitabine and vinorelbine, recent data from French Thoracic Oncology Intergroup trial 0501 (IFCT-0501) point to the potential efficacy of a distinct doublet regimen. In this phase III study, 451 patients between the ages of 70 and 89 were randomized to receive single-agent therapy (with either vinorelbine or gemcitabine), or monthly carboplatin with weekly paclitaxel. The Eastern Cooperative Oncology Group (ECOG) performance status (a clinical tool used to grade the generalized functional status of a cancer patient; Table 9-2 ) ranged between 0 and 2. Toxicities of both carboplatin and paclitaxel are described in detail subsequently (Case 9-3), and the doublet did elicit more hematologic toxicity than single-agent therapy. However, unlike the MILES study, significantly longer survival was observed in those patients who received doublet therapy as compared to a single agent. Thus, emerging data suggest the benefit of combination therapy among patients with good performance status.
| ECOG Performance Status | Description |
|---|---|
| 0 | Fully active and able to carry on all pre-disease performance without restriction. |
| 1 | Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. |
| 2 | Ambulatory and capable of all self-care but unable to carry out any work activities. Active more than 50% of waking hours. |
| 3 | Capable of only limited self-care, confined to bed or chair more than 50% of waking hours |
| 4 | Completely disabled. Cannot carry on any self-care. Confined to bed or chair. |
| 5 | Dead |
Recognizing the toxicity profile of chemotherapeutic agents allows for preemptive strategies to mitigate adverse effects. Given that both vinorelbine and gemcitabine are known to cause myelosuppression, growth factors could be used to decrease the risk of neutropenia and associated neutropenic sepsis. Several guidelines incorporate age-based risk stratification to aid the practitioner in appropriate use of growth factor therapy. In the current scenario, given the occurrence of neutropenic fever after the first cycle of chemotherapy, growth factors are recommended with any further use of the same regimen. Neutropenic fever should be recognized by the practitioner as an oncologic emergency; prompt administration of empiric antibiotic therapy and relevant clinical examinations (including, but not limited to, blood cultures, chest x-ray, and urine culture/analysis) are essential.
A.L. is a 70-year-old woman with a history of mild hypertension and hypercholesterolemia, well-controlled with metoprolol and lovastatin, respectively. On a recent visit to her primary physician, she pointed out a lump in her right breast, which was biopsied and which revealed the presence of invasive ductal cancer. She had a lumpectomy and a sentinel node biopsy, which revealed cancerous involvement of an axillary node. An axillary dissection was performed. On pathologic analysis, the patient was found to have a 4.5 cm invasive breast cancer (hormone receptor-positive, HER-2 negative) with 5 out of 12 lymph nodes examined involving tumor. A staging work-up revealed no evidence of metastatic disease. After visiting with her oncologist, she elects to receive adjuvant chemotherapy to decrease the risk of relapse and mortality from breast cancer. She receives doxorubicin and cyclophosphamide. After two cycles of therapy, she presents to her primary physician for a routine follow-up appointment. There, she notes having increasing shortness of breath and dyspnea on exertion. On physical examination, she is noted to have increased jugular venous distension and 2+ pitting edema in her lower extremities, bilaterally. Fine crackles are auscultated on pulmonary exam.
Discussion of Case 2
The patient described in this scenario has early stage (nonmetastatic) breast cancer; however, she has several risk factors placing her at a high risk of distant spread of the tumor, including lymph node positivity and tumor size. Adjuvant chemotherapy is given to decrease the risk of distant spread. In order to determine the magnitude of benefit from adjuvant chemotherapy, oncologists often turn to the Oxford Overview, a comprehensive meta-analysis of randomized trials of adjuvant chemotherapy in the setting of breast cancer. This landmark meta-analysis includes data from 33,000 patients enrolled in 194 randomized clinical trials. Across all strata of age, there is a clinical benefit from use of multiagent adjuvant chemotherapy; however, the proportional benefit declines steadily with age. Limitations of these data include the low proportion of older adults included in randomized clinical trials (less than 7% older than 70 years); therefore, the authors acknowledge that there are too few women older than 70 to be reliably informative as to whether it confers a survival benefit. However, over the past decade two prospective trials have been reported in older adults with breast cancer that have improved our evidence base. The French Adjuvant Study Group (FASG) 08 trial suggested that the combination of epirubicin and tamoxifen (as compared to tamoxifen alone) could delay recurrence of breast cancer in women older than 65 years with operable, node-positive disease. A more recent trial, Cancer and Leukemia Group B (CALGB) 49907, examined whether single-agent oral chemotherapy (capecitabine) could be used in place of standard, multiagent infusional regimens in patients older than 65 years with early-stage breast cancer. A survival advantage was found with use of standard polychemotherapy infusional regimens, suggesting this remains the standard of care.
Once the decision in Case 9-2 is made to proceed with adjuvant chemotherapy, the patient embarks on a regimen of doxorubicin and cyclophosphamide and develops clinical stigmata of congestive heart failure (CHF) shortly thereafter. The association between doxorubicin and CHF is well-documented, with a higher incidence of CHF at greater cumulative doses of doxorubicin. The association between increasing age and anthracycline-associated cardiac toxicity was evaluated in an analysis of 630 patients treated with doxorubicin, which demonstrated that increasing age was a risk factor for doxorubicin-associated CHF at cumulative doses greater than 400 mg/m. A SEER-Medicare analysis including patients with early breast cancer found that breast cancer survivors who had received an anthracycline-containing regimen had an increased risk of congestive heart failure in comparison to those who had not received an anthracycline or those who had not received adjuvant chemotherapy. Interestingly, this difference was most pronounced among women who were treated at ages 66 to 70, and was not observed in patients ages 71 to 90. This SEER-Medicare analysis identified several other important predictors of cardiac toxicity in older women, including the presence of hypertension, diabetes, or peripheral vascular disease. In contrast, a longitudinal cardiac assessment of patients enrolled in Southwest Oncology Group (SWOG) trial 8897 (comparing adjuvant chemotherapy for breast cancer with or without doxorubicin) suggested no significant deterioration in left ventricular ejection fraction (LVEF) over time with anthracycline therapy. The collective results of these studies can be incorporated into discussions with older patients considering anthracycline-based regimens. Furthermore, they may prompt a heightened awareness of potential cardiac toxicities in older adults and/or patients with specific comorbidities receiving these therapies.
Nonanthracycline alternatives to doxorubicin-cyclophosphamide adjuvant therapy are being studied. For instance, a randomized study (U.S. Oncology Trial 9735) compared doxorubicin-cyclophosphamide to docetaxel-cyclophosphamide (both regimens prescribed every 3 weeks for four cycles). In this study, superior disease-free and overall survival was observed with docetaxel-cyclophosphamide, and an update of these data suggested similar efficacy in older and younger patients. Among patients with HER-2-overexpressing breast cancer, the addition of the monoclonal antibody trastuzumab to conventional chemotherapy has shown immense clinical benefit in the metastatic and adjuvant setting. In the adjuvant setting, both anthracycline and nonanthracycline-containing regimens have been explored in combination with trastuzumab. A clinical trial compared adjuvant doxorubicin-cyclophosphamide followed by paclitaxel with or without trastuzumab to docetaxel, carboplatin, and trastuzumab. Notably, both trastuzumab-based regimens produced similar disease-free and overall survival, although patients receiving doxorubicin-cyclophosphamide had a numerically higher incidence of congestive heart failure. As a result of these data, there is increasing interest in studying nonanthracycline chemotherapy regimens in combination with trastuzumab, particularly for patients with cardiac comorbidity.
G.M. is an 80-year-old woman with multiple medical comorbidities (including hypertension, hypercholesterolemia, mild renal insufficiency, and diabetes) who reports several months of abdominal bloating and cramping, unrelieved with laxative use. On pelvic examination, she is noted to have some mild adnexal tenderness. Pelvic ultrasound reveals bilateral ovarian masses, both measuring 8 cm. She is subsequently taken to the operating suite for a total abdominal hysterectomy and bilateral salpingo-oophorectomy, and receives several omental biopsies and pelvic washings. On final pathologic analysis, she is found to have epithelial ovarian cancer, grade 2, and has stage II disease (i.e., confined to the bilateral ovaries). She meets with an oncologist, who recommends that she receive six cycles of intravenous carboplatin and paclitaxel chemotherapy. She begins treatment, and visits her primary physician for a routine follow-up after receiving three cycles of therapy. She notes having decreased sensation in her toes, and on pinprick examination, she appears to have decreased tactile sensation. Her neurologic exam is otherwise unremarkable. Her glycated hemoglobin level is within normal limits.
Discussion of Case 3
In Case 9-3, it is prudent to consider the patient’s comorbidities in the context of her current complaints. Given a clinical history including diabetes, ruling out any metabolic disturbances is critical. Paclitaxel and related taxane compounds are coadministered with steroids to prevent hypersensitivity reactions, and this may contribute to impaired glycemic control and worsening of diabetic neuropathy. Alternatively, the neuropathy could be a direct consequence of paclitaxel, which inhibits microtubule depolymerization and results in direct axonal injury.
The patient described in this case also has mild renal impairment. While renal impairment can certainly be associated with hypertension and diabetes, there is also an anticipated decrement in renal function with increasing age. Increasing age is paralleled by a decrease in renal blood flow, and a decrease in glomerular filtration rate of 0.75 mL/min per year is observed in most individuals older than 40. Care should be taken to use appropriate metrics to estimate renal function in the older adult. Formulas such as the Cockcroft-Gault and Jeliffe equations were validated primarily in cohorts of younger patients without renal disease. In contrast, formulas such as the Modification of Diet in Renal Disease (MDRD) equation incorporate age, and may therefore be more accurate in estimating renal function in this population. Precise calculation of the creatinine clearance is particularly important in the setting of carboplatin therapy, as the drug is dosed in a manner distinct from most other chemotherapeutic agents. Specifically, the dosing of carboplatin is calculated by multiplication of the creatinine clearance and the area under the concentration-time curve (AUC).
Outside of declines in renal function, multiple other physiologic changes accompany increasing age. Gastrointestinal absorption of oral agents may be compromised by decreased splanchnic blood flow, decreased secretion of digestive enzymes, and mucosal atrophy. Furthermore, hepatic metabolism may be affected by decreased levels of cytochrome P450. Alterations in endocrine axes, impaired cardiac function, and decreased bone marrow reserve may further affect the tolerance for chemotherapy in the older adult. Physiologic changes seen with aging may lead to intrinsic differences in pharmacokinetic profiles of chemotherapeutic agents in an older population. For instance, a study assessing paclitaxel (given at a standard dose every 3 weeks) demonstrated decreasing drug clearance with increasing age, and a concomitant increase
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