Larger Questions About Chemotherapy in Older Patients

Drs. Gillison and Chatta present an up-to-date review of the systemic treatments available to elderly patients with the most common types of cancer. The only point I might add in the context of their review is about recently reported, promising data on targeted therapies in acute leukemia patients. A large proportion of older patients have acute lymphocytic leukemia positive for a t(9;22) translocation (Philadelphia chromosome–positive ALL). This disease used to carry a very poor prognosis, but patients now significantly benefit from the addition of imatinib (Gleevec) or dasatinib (Sprycel) to a standard regimen. Also, with or without low-dose chemotherapy, imatinib or dasatinib can produce significant responses and prolong survival in patients not fit to receive intensive chemotherapy.[1] Likewise, in poor-prognosis acute myeloid leukemia (AML), hypomethylating agents might lead to better survival than intensive induction chemotherapy, thus providing welcome and well tolerated alternatives for older patients.[2]

Extrapolated Data

On a larger scale, the data presented by Gillison and Chatta raise another question: Since most data are extrapolated from younger patients, what are the benefits and the pitfalls of such an approach? I believe we can divide our extrapolation into two age zones: patients in their 70s, and patients aged 80 and above. Some direct data from large trials are available for most diseases in patients in their 70s; they are almost nonexistent for those above 80. For patients in their 70s, the data are obtained mostly from a posteriori subgroup analyses of large randomized trials. In some cases, there are enough data to allow a meta-analysis (for example, see reference 3). In other cases, as cited by the authors, the data are more difficult to interpret. In the Ramalingam a posteriori analysis of the Eastern Cooperative Oncology Group (ECOG) 4599 study, bevacizumab (Avastin) was not providing a survival benefit to older patients, and there were seven toxic deaths in the bevacizumab arm vs two in the control arm (P = .10). What should we conclude? Is this simply an underpowered analysis, and would survival be visible with larger numbers? Or conversely, would bevacizumab toxicity have been even more evident with larger numbers?

In order to avoid such conundrums, large randomized trials should be required to incorporate enough patients over age 70 to permit preplanned subgroup analyses of the relevant questions. If necessary, there should be oversampling of the older patients. At the very least, such results warn us against assuming that “just because it works in the young, it will work in an older patient.” More is not always better. Conversely, as standard treatments have proven feasible in at least a subgroup of older patients, systematic nihilism should be avoided.

Added Problem of Comorbidity

Although good sampling would constitute progress, it would not solve the other part of the problem, which is extrapolating study results to patients with more comorbidity, less functional reserve, or geriatric syndromes. The prevalence of these patients increases markedly with age. Yet patients in their 80s and older do develop cancer and are increasingly referred to oncology clinics. Here the evidence comes mostly from retrospective cohort studies. In specialized centers, geriatric oncology programs see a large enough cohort of patients with comorbidities to develop experience, and they also have available the multidisciplinary team, which can provide comprehensive oncogeriatic care. At our institution, we do believe such patients benefit from a comprehensive approach by an experienced team.[4]

Beyond the general case, the prevalence of cancer patients with comorbidities increases markedly with age, and here, too, data are sparse. Some small prospective studies have attempted to gather data on frail patients. For example, two studies addressed the treatment of frail patients with high-grade non-Hodgkin lymphoma.[5,6] Some retrospective studies provide data on patients with cognitive impairment (for example, see references 7 and 8). Yet these only scratch the surface of the problem. Specific prospective trials are urgently needed for the oldest old, with a sound stratification strategy for comorbidity.

Financial Disclosure:Dr. Extermann has received honoraria from Pfizer, Amgen, and Schering-Plough.

References:

References

1. Ottmann OG, Pfeifer H: First-line treatment of Philadelphia chromosome-positive acute lymphoblastic leukaemia in adults. Curr Opin Oncol 21(suppl 1):S43-S46, 2009.

2. Ravandi F, Issa JP, Garcia-Manero G, et al: Superior outcome with hypomethylating therapy in patients with acute myeloid leukemia and high-risk myelodysplastic syndrome and chromosome 5 and 7 abnormalities. Cancer 115:5746-5751, 2009.

3. Sargent DJ, Goldberg RM, Jacobson SD, et al: A pooled analysis of adjuvant chemotherapy for resected colon cancer in elderly patients. N Engl J Med 345:1091-1097, 2001.

4. Extermann M, Crane EJ, Boulware D: Cancer in nonagenarians: Profile, treatments and outcomes. Crit Rev Oncol Hematol Aug 29, 2009 (epub ahead of print).

5. Monfardini S, Aversa SM, Zoli V, et al: Vinorelbine and prednisone in frail elderly patients with intermediate-high grade non-Hodgkin’s lymphomas. Ann Oncol 16:1352-1358, 2005.

6. Soubeyran P, Khaled H, MacKenzie M, et al: Diffuse large B-cell and peripheral T-cell non-Hodgkin’s lymphoma in the frail elderly. Results of the EORTC 20992 trial with a progressive and cautious strategy. Presented at the 6th Meeting of the International Society of Geriatric Oncology. Geneva, Switzerland; Sept 29–Oct 1, 2005.

7. Gupta SK, Lamont EB: Patterns of presentation, diagnosis, and treatment in older patients with colon cancer and comorbid dementia. J Am Geriatr Soc 52:1681-1687, 2004.

8. Robb C, Boulware D, Overcash J, et al: Patterns of care and survival in cancer patients with cognitive impairment. Crit Rev Oncol Hematol Aug 24, 2009 (epub ahead of print).