Surgery Alone May Be Best for Early Uterine Cancer

NCI Cancer Bulletin Publication Break Today's issue is the final one of 2008. On December 30, current subscribers to the NCI Cancer Bulletin will receive an e-mail message from Editor-In-Chief James Mathews announcing some exciting changes to the newsletter. These changes will debut when we resume publishing on January 13, 2009. If you are not yet a subscriber, go to http://www.cancer.gov/ NCICancerBulletin and submit your e-mail address on the left side of the page.

Most uterine cancers are diagnosed at an early stage, while still confined to the body of the uterus. In addition to surgery to remove the uterus and ovaries, some doctors perform lymphadenectomy (lymph node removal), external-beam radiation therapy (EBRT), or both, in the hope of preventing local recurrence. However, a large randomized trial, published online December 13 in The Lancet, showed no improvement in survival associated with lymphadenectomy or EBRT.

Investigators leading the international ASTEC study randomly assigned 1,408 women to receive surgery or surgery plus pelvic lymphadenectomy. Women in both groups at intermediate or high risk of recurrence were randomly assigned a second time to receive either EBRT or no EBRT.

In the lymphadenectomy arm of the trial, more women who underwent lymph node removal reported moderate or severe treatment-related side effects than women who had standard surgery. Five-year overall survival was 81 percent in the standard surgery group and 80 percent in the lymphadenectomy group.

Five-year recurrence-free survival was 79 percent in the standard surgery group and 73 percent in the lymphadenectomy group. Similar proportions of women in both groups had received postoperative radiation therapy. These results "show no evidence of benefit in terms of overall or recurrence-free survival for pelvic lymphadenectomy in women with early endometrial cancer. Pelvic lymphadenectomy cannot be recommended as routine procedure for therapeutic purposes outside clinical trials," concluded the authors.

To determine the effectiveness of EBRT, the results from the second randomization in the ASTEC trial were combined with those from a Canadian trial (EN.5) for a total of 905 participants. Similar proportions of women in the EBRT or no EBRT arms received brachytherapy, which was part of the standard treatment at several participating hospitals.

Both acute and late toxicity was greater in the EBRT group. No difference in overall survival was seen between the two groups. The 5-year recurrence-free survival was 84.7 percent in the EBRT group and 85.3 percent in the control group. EBRT did help prevent local recurrences, but only 35 percent of recurrences were isolated local recurrences. The authors concluded that "adjuvant [EBRT] cannot be recommended as part of routine treatment for women with intermediate-risk or high-risk early-stage endometrial cancer with the aim of improving survival."

Studies Assess the Economic Impact of Cancer Deaths

The estimated annual loss of productivity due to cancer deaths is the equivalent of approximately 1 percent of the 2007 U.S. gross domestic product, according to a new study published online December 9 in the Journal of the National Cancer Institute (JNCI). When the productivity costs associated with caregiving for cancer patients and household activities are factored in, the estimate nearly doubles.

Using a model based on a "human capital approach," which factors in the value of lost years of work due to premature mortality, Dr. Cathy J. Bradley and colleagues from Virginia Commonwealth University, the Massey Cancer Center, and NCI estimated that the total productivity cost in 2000 due to cancer mortality was $115.8 billion. Based on current mortality rates, that figure will jump to $147.6 billion by 2020. Incorporating caregiving expenses and household duties into the model raised the cost estimates of cancer mortality to $232.4 billion in 2000 and to $308 billion in 2020.

The authors also determined that, starting in 2010, reducing cancer mortality by 1 percent for the six cancers most costly in terms of lost productivity due to death - colorectal, breast, pancreatic, leukemia, brain, and lung (which had the highest cost for lost productivity) - would reduce the economic burden by approximately $814 million annually.

A companion study in the same issue of JNCI, led by NCI's Dr. Robin Yabroff from the Division of Cancer Control and Population Sciences' Health Services and Economics Branch, used a different method to assess the economic impact of death from cancer: the "willingness-to-pay" approach, which uses a previously published value of people's willingness to pay for one additional year of life, $150,000.

Compared to estimates based on the human capital approach, estimates of the cost associated with cancer mortality from the "willingness-to-pay" model were dramatically higher, $960.7 billion in 2000 and nearly $1.5 trillion by 2020.

In an accompanying editorial, Dr. Scott D. Ramsey from the Fred Hutchinson Cancer Research Center noted limitations to the methodologies used in both studies. Nonetheless, he acknowledged the use of these estimates to aid policymakers in deciding research priorities and assessing current investments, as well as helping insurers with coverage decisions.

Meta-analysis Highlights Progress in Treating Advanced Breast Cancer

Because randomized clinical trials of non-hormonal therapies for metastatic breast cancer tend to be small, it has been difficult for researchers to fully understand the survival benefits of different chemotherapy regimens and targeted treatments. To fill this knowledge gap, researchers led by Dr. John Ioannidis of the University of Ioannina in Greece performed a meta-analysis of 128 randomized clinical trials that compared at least two different regimens involving chemotherapy, targeted therapy, or both. Their results appeared December 9 in the Journal of the National Cancer Institute.

The researchers found that taxanes (such as paclitaxel and docetaxel) - in combination with novel chemotherapy agents, trastuzumab, or older treatment agents - provided the greatest decrease in mortality risk. Several other drug combinations and newer single agents provided "considerable survival benefits" compared with single-agent treatments using older drugs, stated the authors. Most of these regimens showed similar benefits when given as first-line or later therapy, indicating that several could be given in sequence to prolong survival.

These results show that "many classes of modern breast cancer therapy, including anthracyclines, taxanes, novel nontaxanes, and trastuzumab, either as monotherapy or as combination therapy, would produce tangible gains in absolute survival over older single agents, ranging from 4.2 to 12.5 months for a patient with an anticipated survival of 1 year treated with the reference standard alone," explained Drs. Philippe Bedard and Martine Piccart-Gebhart in an accompanying editorial.

"Several regimens [of newer agents] have shown effectiveness, and for some of them, the treatment effects are practically indistinguishable in magnitude," stated the authors. Therefore, choice of therapy should be tailored to individual patients, taking into account known side effects and the patients' overall health, they concluded.

Rituximab Improves Outcomes for CLL Patients

Two international phase III studies presented last week at the American Society of Hematology meeting in San Francisco show that advanced chronic lymphocytic leukemia (CLL) patients who received the monoclonal antibody rituximab (R) in addition to standard chemotherapy with fludarabine and cyclophosphamide (FC) had outcomes far better than those patients who received FC alone.

The first study included 817 previously untreated advanced CLL patients whose mean age was 61 years. They were randomized to receive six 28-day courses of either FC or FCR. After a median follow up of 25.5 months, the complete response rate in the FCR group was 52 percent, compared with 27 percent in the FC group. Progression-free survival was also higher in the FCR group, with 76.6 percent progression-free after 2 years versus 62.3 percent in the FC arm.

In the second study, 552 patients (mean age 63 years) with relapsed or refractory CLL were randomized to receive six 28-day courses of FC or FCR. Most of these patients had previously been treated with single-agent alkylator therapy, a purine analog therapy, or combination chemotherapy. Those in the FCR group had a median of 30.6 months without disease progression, compared with 20.6 months in the FC group. Complete response in the FCR group was nearly twice that of the FC group, 24 percent versus 13 percent.

While the overall response with rituximab was better in both studies, negative side effects were more common in the patients who received the drug, including diminished leukocytes and neutrophils. The incidence of these side effects was associated with age, sex, renal function, and the patient's relative health.

"While these studies clearly indicate that rituximab improves both response and progression-free survival when combined with FC, they do not address whether the addition of cyclophosphamide to fludarabine should become the standard chemotherapy platform for the treatment of CLL," cautioned Dr. Wyndham Wilson, head of the Lymphoma Therapeutics Section in NCI's Center for Cancer Research. "The increased toxicity associated with cyclophosphamide requires that physicians weigh the risks and benefits of FCR versus RF."