Pharmacology of Antineoplastic Agents in Older Cancer Patients

December 1, 2000

People over the age of 65 are a fast-growing segment of the US population, and with the incidence of cancer increasing with age, the challenges of treating older cancer patients are also on the rise. Drs. Lichtman and Skirvin present a comprehensive review of the antineoplastic agents used in elderly cancer patients. They highlight the important factors of chemotherapy pharmacology in elderly cancer patients, with emphasis on the impact of physiologic changes-especially renal clearance-in dosing and toxicity. In addition, descriptions of significant toxicities are provided. The following additional issues should be considered.

People over the age of 65 are afast-growing segment of the US population, and with the incidence of cancerincreasing with age, the challenges of treating older cancer patients are alsoon the rise. Drs. Lichtman and Skirvin present a comprehensive review of theantineoplastic agents used in elderly cancer patients. They highlight theimportant factors of chemotherapy pharmacology in elderly cancer patients, withemphasis on the impact of physiologic changes—especially renal clearance—indosing and toxicity. In addition, descriptions of significant toxicities areprovided. The following additional issues should be considered.

Age Bias in Clinical Trials

Much of what we know about drug behavior and toxicities comesfrom trials conducted at academic medical centers and cooperative groups.Unfortunately, older persons are inadequately represented in both randomizedclinical trials and trials of new agents, thereby requiring information to beinferred from subgroup analyses with small numbers of elderly patients.

It has been shown that there is an age bias against offeringtreatment to older cancer patients, and that this barrier continues with entryinto clinical trials.[1] Moreover, elderly patients selected for trials maydiffer from other older cancer patients in the community because they have metstringent entry criteria in terms of comorbidity, performance status, and priortherapy history. Thus, it is difficult to know how to apply information fromsuch trials to the more general population of older cancer patients who may havemore comorbidities and poorer functional status. Trials with broad entrycriteria are needed in order to generate information that is relevant to thislarger group of older cancer patients.

Multiagent Regimens With Supportive or Protective Agents

As stated by Drs. Lichtman and Skirvin, single-agent therapiesand some novel agents have been well tolerated by the elderly cancer patients inwhom they were studied. For certain cancers, especially hematologicmalignancies, multiagent chemotherapy regimens are required for treatment.Although there is speculation of cumulative toxicity, there are limited data onthe outcome of elderly patients with these regimens, and further research isneeded.

However, the inclusion of supportive and cytoprotective agentsthat target the side effects and toxicity of chemotherapy may improve theoutcome of older cancer patients receiving more complex regimens. For example,hematologic growth factors, such as granulocyte colony-stimulating factor(Neupogen), granulocyte-macrophage colony-stimulating factor (Leukine), anderythropoietin (Epogen, Procrit), have been shown to decrease the degree ofmyelosuppression caused by chemotherapy. By doing so, older patients may be ableto receive full-dose, on-schedule treatments, thereby improving the chances of adesirable outcome.[2,3] Cytoprotective agents, such as dexrazoxane (Zinecard)and amifostine (Ethyol), have shown some benefit with cardiotoxicity andneuropathy, respectively.[4] However, these agents have not been well studied inthe older cancer patient cohort.

Toxicity

As noted by Drs. Lichtman and Skirvin, published descriptions oftoxicity have been very general. Toxicity is graded by a standard measurement intrials, whereby grades 3 or 4 are usually significant for citation.Traditionally, myelosuppression has been the most worrisome side effect ofchemotherapy agents—one that necessitates dose modification. However, in theolder person with a relatively limited reserve capacity in a number of organsystems, competing lower-grade toxicities may have an impact on recovery. Forexample, lower-grade mucositis, neuropathy, or fatigue may not be significantindividually, but together may result in a decline of nutritional and functionalstatus that affects physical recovery and also puts stress on both the caregiverand the patient’s social situation.

Other Antineoplastic Agents

Hormonal therapies for breast and prostate cancer are widelyused. Tamoxifen (Nolvadex) and the newer aromatase inhibitors are being used inolder women with breast cancer with few side effects.[5,6] Agents withalternative delivery methods, such as liposomal formulations of anthracyclines,have toxicity profiles that are different from the traditional anthracyclines;these may also be helpful in elderly patients. On the horizon are newer agentsdeveloped for specific molecular targets—such as STI-571, targeted against theBCR-ABL tyrosine kinase in chronic myeloid leukemia—which have shown promisein both response and toxicity profile.[7]

Polypharmacy

Drs. Lichtman and Skirvin describe the use of complementary andalternative medications as commonplace in the elderly, with concern regardingdrug-drug interactions. However, with more than 90% of ambulatory older personstaking at least one prescription medication (four drugs on average), the moreimportant focus should be on polypharmacy with conventionally prescribed andover-the-counter medications.[8] This phenomenon, with an obvious parallel tothe presence of comorbidity in elderly cancer patients, will likely influencethe outcome of older persons when the morbidity of cancer and chemotherapytreatment is added.[9] Of course, the addition of complementary and alternativemedications will further complicate the situation, and should therefore beconsidered as part of this evaluation.

Goals of Therapy

Ultimately, it is important to determine the goals of therapyfor the older cancer patient. Treatment evaluation and discussion differ forgoals of palliation, stabilization of disease, or cure. Any additionalinformation regarding quality of life, with or without antineoplastic treatment,would be helpful. Functional status, rather than age per se, may conditionpatient decisions about treatment. In select older patients, curative therapymay be quite appropriate, whereas in others, palliative or supportive therapymay be more suitable.

It should not be assumed that age alone will drive suchdecisions from the patient’s perspective. Indeed, a comprehensive geriatricassessment may aid both the clinician and patient in making treatmentchoices.[10] In some instances, for example, it appears that older patients arebetter able to cope with the psychological stresses of cancer treatment thanyounger patients.[11] The application of such approaches to cancer care is stillin its infancy, however, and the impact of its application on specific treatmentoutcomes remains to be demonstrated.

Conclusions

Although elderly cancer patients can tolerate and respond tomany antineoplastic agents just as well as their younger counterparts, manyquestions remain regarding appropriate therapy. Further clinical trials withmultiagent regimens, the incorporation of protective agents, inclusion of"less healthy" patients, and quality-of-life analyses in elderlycancer cohorts are needed to refine our knowledge.

References:

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2. Jacobson JO, Grossbard M, Shullman LN, et al: CHOPchemotherapy with G-CSF in elderly patients with intermediate grade lymphoma:Full dose intensity is possible (abstract 41). Proc Am Soc Clin Oncol17(41):11a, 1998.

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5. Jaiyesimi IA, Buzdar AU, Decker DA, et al: Use of tamoxifenfor breast cancer: Twenty-eight years later. J Clin Oncol 13:513-529, 1995.

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10. Cohen HJ: Management of cancer in older persons, in Perry M(ed): ASCO Education Book, pp 339-359. Alexandria, Va, American Society ofClinical Oncology, 1999.

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