How does treatment of ovarian cancer differ between younger and older women?

Submitted by Setsuko Chambers, MD

Response by Carol Howe, MD, MLS

Although epithelial ovarian cancer is primarily a disease of post menopausal women and "sixty-one percent of new cancer cases occur in women >65 years of age," (Villella & Chalas, 2005) women in this age group are dramatically underrepresented in the clinical trials upon which their treatment is based. Villella and Chalas (2005) discuss the many obstacles preventing enrollment of older women in clinical trials-which essentially contributes to the Catch-22 that prevents them from receiving the same aggressive treatment (surgical and chemotherapeutic) as younger patients because there are not enough standardized prospective randomly controlled trials proving that the benefit of such treatments outweigh the risks.

The reasons for age-related biases that have precluded enrolment of this population in clinical trials are complex. Some clinical trials require that only patients without a history of prior malignancies be enrolled. Other reasons for exclusion may be medical comorbidities, poorer performance status, physician prejudice regarding the patient’s ability to tolerate treatment and difficulty complying with conditions of the protocol [frequent testing, transportation issues, etc.]. (p.96)

Because of inherent physician bias, “clinical trials [which] often require greater than the standard dose intensity … such a treatment option may never be discussed with the geriatric patient” (p.97). Villella and Chalas compare the enrollment of geriatric patients in clinical trials with the enrollment of pediatric patients in clinical trials which is contrastingly quite high.

Elderly patients may have less family and social support to aid in the treatment process. The burden of regimented clinical trial procedures and high-dose, toxic regimens may be more difficult to handle and anxiety provoking. Some patients have external limitations, such as transportation. Many have partners, for whom they are the caretakers. These limitations are significant and solutions are costly. Providing an infrastructure to support the patient requires an extensive multidisciplinary team. (p.98)

In the absence of good prospective, randomized trials, much of the information we have about the diagnosis, evaluation and treatment of older women with ovarian cancer comes from retrospective analyses.

A consistent finding is that older women tend to present with more advanced stages of disease. Reasons for this include a decrease in the frequency of routine pelvic exams as women age. (Pignata & Vermorken, 2004) Also, “the symptomatology for ovarian cancer is non-specific and diffuse and in older women can be attributable to a variety of conditions, thus contributing to the delay of diagnosis”(p. 79).

More advanced stage of disease is associated with a poorer prognosis. As with every facet of this illness, it is difficult to determine what is cause and what is effect. Older women present with higher-grade malignancies and/but older women are also less likely to receive the aggressive surgery needed for optimal tumor debulking—which itself is a key prognostic factor. (“Maximal cytoreductive therapy is one of the most powerful determinants of survival in patients with stage III and IV ovarian cancer”[Pignata & Vermorken, 2004, p.79]).

Pignata & Vermorken (2004) discuss the fact that “ Unfortunately older patients underwent fewer operations [salpingo-oophrectomies, hysterectomies, and node dissections] as compared with those of their younger counterparts” (p.79). This occurred despite the fact that 1) “Elderly patients were less interested in the issues of sexuality and femininity and were less likely to question their doctors’ decision regarding surgery” (p.79); 2) They are just as interested in having definitive, aggressive surgery with a potential for cure as younger patients; and 3) Multiple studies have demonstrated that age and multiple comorbidities do not result in poorer surgical outcomes, thanks to improvements in surgical techniques including “early postoperative mobilization, autologous blood transfusions, intraoperative antibiotic prophylaxis, and the use of coagulator forceps” (p.79), “nutritional supplementation…improvement in anesthesia, intraoperative monitoring, blood banking and postoperative care” (DiSaia, 2002, p.490).

Pignata & Vermorken (2004) do caution that data reporting improved operative safety in elderly cancer patients is retrospective and therefore subject to selection bias—analyzing only those patients who were in fact selected ultimately for surgery and not the whole population of elderly patients with cancer, (again underscoring the need for prospective studies)! They also caution against extending their recommendations not to withhold surgical treatment in elderly patients to the subset of very elderly patients—those> age 80. They site the study by Cloven, Manetta, Berman, Kohler, & DiSaia (1999) which showed very significant morbidity and mortality in their small cohort of 18 patients—including 7 patients with post operative congestive heart failure, 3 with sepsis, 1 with aspiration pneumonia and 2 deaths—together with only a 25% rate of optimal debulking to less than 1 cm. If there are few clinical trials that include patients between 65 and 79, there are virtually none including patients greater than age 80. Even Cloven et al.’s (1999) small study is retrospective.

Uyar, Frasure, Markman, & von Gruenigen (2005) conducted a retrospective study which, in contrast to Cloven et al., did not find worse outcomes in the oldest old. The authors looked at 131 patients greater than 70 years of age dividing them into Group 1, ages 70-79, n=90; and group 2, ages ≥80, n=41. They found that significantly fewer patients in Group 2 underwent surgery when compared with Group 1 (60% vs. 90 %) and

only 46% received combination chemotherapy despite the fact that no significant difference as attributed to Charlson scores [“a scoring system to assess the impact of co-morbid medical conditions” {Uyar et al., p. 404}] or post-operative complication rates between age groups. More importantly, we did not observe a decrease in survival associated with age alone, even in the extreme elderly [>80 years]. (p.407)

Uyar et al. (2005) emphasize the heterogeneity of the elderly population, stress the importance of not relying on chronological age alone as a determinant of therapeutic plan—even in the oldest old, and urge the use of functional performance evaluations such as the Comprehensive Geriatric assessment to determine suitability for chemotherapy. The March 12th response to Dr. Chambers question regarding tools to evaluate how well elderly patients will respond to cancer chemotherapy is completely relevant to this discussion as well.

Pignata et al. (2004) address the fact that elderly ovarian cancer patients receive chemotherapy regimens that are subtherapeutic. Even more than surgery--, whether and how to treat elderly patients with chemotherapy-- is a matter of much debate and little data. Pignata et al. report that, although the percentage of elderly patients receiving chemotherapy is improving, “the rate of untreated patients increases with age” (p.80). They again cite the paucity of clinical studies and the selection bias inherent in the studies that have been done. Their conclusions:

It is the opinion of the authors that there is insufficient information in the literature to suggest the use of polychemotherapy for all elderly patients when basing the decision only on patient’s chronological age, particularly for the retrospective nature of the data available. The use of a multidimensional geriatric evaluation taking into account family support, mental status, the type and degree of disability and the presence of co-morbidities could be useful to in order to differentiate both frail patients, and those at high risk of toxicity from the rest of the elderly population. (p.81-2)

In their consideration of second-line treatment, Gronlund, Hogdall, Hansen, & Engelholm, (2002), similarly call for the use of performance status rather than chronological age to determine the individualized treatment plans.

In a multivariate Cox analysis, performance status at time of first-line treatment… performance status at time of second-line treatment…and response to second-line treatment…were found to be independent significant factors for overall survival whereas age (younger than 65 years vs. older than 65 years) yielded no independent information…No differences in the rate of postponement of treatment, neutropenia Grade 4, thrombocytopenia Grade 3-4, nor hypersensitivity reaction to either cytostatic agent [topotecan or paclitaxel-carboplatin] between older and younger patients were noticed. (abstract)

According to Pignata & Vermorken (2004)

The significant improvement in survival observed in ovarian cancer in the last decades is not evident in the population of elderly patients in which mortality has significantly increased. Starting from 1983, ovarian cancer mortality declined by 25% in younger American women but increased by 16% in those older than 65 years. The increase in ovarian cancer mortality is proportionally greater with increasing age and is maximal over 80 years of age. (p.78)

• Disease factors-- those that are inherent in the nature of the illness itself. Several authors, for example, have postulated differences in tumor behavior and biology in older vs. younger patients (mentioned by Pignata, & Vermorken [2004]; (Wimberger et al., 2006)]; and Gronlund et al. [2002]).
• Patient factors-- such as functional status or multiple co-morbidities.
• A combination of the two—for example the fact that most elderly patients present with a more advanced stage of cancer (discussed above).
• True age-related factors—such as decreased renal clearance, decreased cardiovascular reserve, or “age related declines in the number of hematopoietic stem cells and the ability of bone marrow to react to hematopoietic stress” (Uyar et al., 2005, p. 407).
• Physician factors such as unrecognized age bias, which can affect the treatments offered to the patient—including not only the chance for aggressive debulking surgery and polychemotherapy but also referral to gynecological oncologists or gero-oncologists. (Villella & Chalas, [2005])

System factors such as widely accepted restrictive selection criteria for clinical trials or the psychosocial infrastructure upon which participation in such trials depends.

Age alone is but one of many interacting factors. The literature is unanimous in advocating for more research so that we can begin to understand and address the unique needs of older patients with this disease—whose increasing numbers mirror the unparalleled growth of the elderly in our population.

References

Cloven, N. G., Manetta, A., Berman, M. L., Kohler, M. F., & DiSaia, P. J. (1999). Management of ovarian cancer in patients older than 80 years of Age. Gynecol Oncol, 73(1), 137-139.

DiSaia, P. J. C., W.T. (Ed.). (2002). Clinical gynecologic oncology (6th ed.). St. Louis, MO: Mosby, Inc.

Gronlund, B., Hogdall, C., Hansen, H. H., & Engelholm, S. A. (2002). Performance status rather than age is the key prognostic factor in second-line treatment of elderly patients with epithelial ovarian carcinoma. Cancer, 94(7), 1961-1967.

Pignata, S., & Vermorken, J. B. (2004). Ovarian cancer in the elderly. Crit Rev Oncol Hematol, 49(1), 77-86.
Uyar, D., Frasure, H. E., Markman, M., & von Gruenigen, V. E. (2005). Treatment patterns by decade of life in elderly women (> or =70 years of age) with ovarian cancer. Gynecol Oncol, 98(3), 403-408.

Villella, J., & Chalas, E. (2005). Optimising treatment of elderly patients with ovarian cancer : improving their enrollment in clinical trials. Drugs Aging, 22(2), 95-100.

Wimberger, P., Lehmann, N., Kimmig, R., Burges, A., Meier, W., Hoppenau, B., et al. (2006). Impact of age on outcome in patients with advanced ovarian cancer treated within a prospectively randomized phase III study of the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR). Gynecol Oncol, 100(2), 300-307.