News Briefs

OBTNJune 2008
Volume 2
Issue 6

Sorafenib Plus Dacarbazine Improves Progression-Free Survival in Patients With Advanced Melanoma, and Is Well Tolerated

There is currently no standard of care for patients with advanced melanoma. Dacarbazine is perhaps the most commonly used cytotoxic agent. Dacarbazine has a moderate toxicity profile. Treatment typically yields a low objective response rate (5% to 20%), a median progression-free survival (PFS) of 1.5 to 1.6 months, and no improvement in overall survival (OS).

Journal of Clinical Oncology

David F. McDermott, MD, Beth Israel Deaconess Medical Center, Boston and colleagues performed a multicenter, randomized, double- blind, placebo-controlled phase II study evaluating the efficacy and safety of sorafenib (Nexavar) combined with dacarbazine in patients with advanced melanoma. Results were published in the May 1, 2008 issue of .

Study enrollees (N = 101) were chemotherapynaïve patients with stage III (unresectable) or IV melanoma. Patients were randomized to receive either sorafenib plus dacarbazine (N = 51) or placebo plus dacarbazine (N = 50). On day 1 of a 21-day cycle, patients received intravenous dacarbazine 1000 mg/m2, for a maximum of 16 cycles. Sorafenib 400 mg or placebo was administered orally twice a day, continuously. The primary end point of the trial was PFS by independent assessment. Additional end points included OS, time to progression (TTP), objective response rate, PFS rates at months 6 and 9, duration of response, and change from baseline in ECOG performance status.




Median PFS in the combination therapy arm was 21.1 weeks, compared with 11.7 weeks in the dacarbazine monotherapy arm (hazard ratio [HR], 0.665; = 0.068). PFS was greater in the combination therapy arm at six months (41.0% vs. 19.5%) and nine months (22.2% vs. 12.2%). Median TTP was 21.1 weeks in the combination therapy arm, compared with 11.7 weeks in the dacarbazine monotherapy arm, resulting in an estimated HR of 0.619 (sorafenib plus dacarbazine/placebo plus dacarbazine; = 0.039). Median OS in the two arms was similar (45.6 wk vs 51.3 wk in the combination therapy and dacarbazine monotherapy arms, respectively;> 0.05). There was no significant difference in change from baseline in ECOG performance status.

The median duration of sorafenib treatment was 19.1 weeks, compared with 12.1 weeks for placebo. The median number of cycles of dacarbazine cycles in the combination therapy arm was five, compared with four in the dacarbazine monotherapy arm. The combination regimen was well tolerated and had a manageable toxicity profile.

The authors concluded that the combination of sorafenib and dacarbazine was well-tolerated and yielded an encouraging improvement in PFS in patients with advanced melanoma, and recommended further study of this combination.

Bevacizumab Can Be Added to Chemotherapy for Head and Neck Cancer

Journal of Clinical Oncology

Tanguy Siewert, MD, University of Chicago Cancer Research Center at the University of Chicago, in Illinois, and colleagues conducted a phase I doseescalation study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab (Avastin), when added to the standard FHX (fluorouracil, hydroxyurea, radiation therapy) chemoradiotherapy in patients with poor-prognosis head and neck cancer. Results were reported in the May 1, 2008 issue of .

Patients 18 years of age or older were eligible for the trial if they had histologically proven head and neck cancer. Enrollees could have either (1) recurrent, previously radiated disease without distant spread, or low-volume distant disease requiring locoregional palliation; or (2) no history pf previous treatment, with an estimated two-year survival < 10% with radiation. Prior radiotherapy had to be completed at least four months and/or chemotherapy at least one month before initiating treatment, and patients had to have recovered from adverse effects. Bevacizumab was escalated 2.5 to 10 mg/kg, fluorouracil 600 to 800 mg/m2 (120-hour continuous infusion), and hydroxyurea from 500 to 1000 mg (twice daily for 5 days), starting day 1. Treatment was repeated every 14 days for seven cycles. At the MTD, the cohort was expanded.

Forty-three patients were treated. Median overall survival was 10.7 months. One- and two-year survival rates were 49% and 28%, respectively. Median for patients not previously radiated (40.1 mo) was substantially greater than that for patients with prior radiotherapy (9.2 mo; P = 0.0046). Distant metastases were present in some patients in both groups. Further subgroup analysis was performed for patients with recurrent, nonmetastatic head and neck cancer who underwent re-irradiation (N = 29). Median survival in this group was 10.3 months, with one- and two-year survival rates of 41.4% and 17.2%, respectively (N = 29); the two-year cumulative incidence of death resulting from disease was 51.7%.

DLT was reached at level 3 (bevacizumab 5 mg/ kg, fluorouracil 800 mg/m2, hydroxyurea 1000 mg), with two grade 3 transaminase elevations and one grade 4 neutropenia attributed to the combination of chemotherapy with bevacizumab. For level 4, chemotherapy doses were reduced (fluorouracil 600 mg/2, hydroxyurea 500 mg), and bevacizumab escalation continued to 10 mg/kg. Treatment of six assessable patients resulted in one venous thrombosis; this dose level was expanded to 26 patients. Late complications included five patients with fistula formation (11.6%) and four with ulceration/tissue necrosis (9.3%). The incidence of serious toxicities, including hemorrhage, thrombosis, and death, was comparable to that before re-irradiation.

Targeted therapies for solid tumors are increasingly becoming integrated into clinical practice and may provide an incremental survival benefit with tolerable toxicity. Based on the results of their study, the authors concluded that bevacizumab can be integrated with FHX chemoradiotherapy at a dose of 10 mg/m2 every two weeks, with decreased chemotherapy doses because of neutropenia.

Tamoxifen May Be More Effective in Patients With Breast Cancer Who Have a Certain Genotype

Journal of Clinical Oncology

Journal of the National Cancer Institute

Adjuvant endocrine treatment with aromatase inhibitors has been shown to improve disease-free survival (DFS) compared with tamoxifen in postmenopausal women with estrogen receptor—positive (ER ) breast cancer. To explore whether this difference can be attributed to differences in tamoxifen metabolism, Rinaa S. Punglia, MD, MPH and colleagues at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, used a mathematical model to explore how genotype information affects therapy recommendations. They analyzed clinical data collected in the Breast International Group Trial 1-98 (BIG 1-98). This trial, published last year in , compared an aromatase inhibitor with tamoxifen in the adjuvant setting in postmenopausal women with ER breast cancer. Results of the analysis were published recently in .

The rationale for the analysis was based on the observation that levels of endoxifen, the active tamoxifen metabolite, vary with the number of mutant alleles, including the *4 allele, of the gene encoding cytochrome P450 2D6 (CYP2D6). The investigators created a Markov model to determine whether tamoxifen or aromatase inhibitor monotherapy maximized five-year DFS for patients with the wild-type CYP2D6 genotype (wt/ wt). Annual risks of recurrence with aromatase inhibitors and tamoxifen in patients breast cancer who were not selected by CYP2D6 genotype were derived from the BIG 1-98 trial. Genotype frequencies and the hazard ratio (HR) for cancer recurrence on tamoxifen among patients with the *4/*4 genotype relative to the wt/wt or wt/*4 genotypes (HR[*4/*4] = 1.86) were based on data from an analysis of the North Central Cancer Treatment Group trial of adjuvant tamoxifen.

With HR(*4/*4) = 1.86 and Eff(wt/*4) = 0.5, the five-year DFS of tamoxifen-treated patients with no mutations (wt/wt) was 83.9%, which is essentially the same as that (84.0%) for genotypically unselected patients who were treated with aromatase inhibitors. With greater HR(*4/*4) estimates, DFS with tamoxifen exceed that with aromatase inhibitors in wt/wt patients, even at lower assumed Eff(wt/*4) ratios.

This model suggests that among patients who are wild type for CYP2D6, 5-year DFS outcomes are similar to or perhaps even superior with tamoxifen than with aromatase inhibitors. The authors suggest that endocrine therapy tailored to CYP2D6 genotype might be considered for women who are newly diagnosed with breast cancer, particularly those who have concerns about either the relative toxicity or the increased cost of aromatase inhibitors.

Journal of the National Cancer Institute

Responding to the results of the analysis, experts recognize the clinical implications but caution against routine genotyping for all women who are considering tamoxifen treatment. In an editorial published in , Dr. Daniel Hayes, University of Michigan Comprehensive Cancer Center, Ann Arbor, and colleagues noted that similar studies have yielded mixed results. They do suggest, however, that “women who are taking tamoxifen should avoid the concomitant use of drugs that inhibit CYP2D6 activity if possible.”

NCCN Task Force Report: Breast Cancer in the Older Woman

The Journal of the National Comprehensive Cancer Network

Robert W. Carlson, MD, Stanford Comprehensive Cancer Center, Stanford, California, began his presentation on a recently released ‘NCCN Task Force Report on Breast Cancer in the Older Woman’ (proceedings of which are scheduled to be published in an upcoming supplement to JNCCN—) with some sobering demographic data. Americans older than 65 years are expected to double from 40 million in 2010 to 80 million in 2040.

The numbers cited above will lead to a large increase in breast cancer incidence among American women, reported Dr. Carlson. He stated that the medical community has a lot of catching up to do if they are going to meet the challenges associated with the upcoming spike in this disease.

Currently, for example, treatment data on women older than 70 years of age are often summed up in footnotes that simply acknowledge a lack of information. In fact, Dr. Carlson reported that the NCCN task force (which issued the report that he presented during the session covered herein), considered whether the NCCN Clinical Practice Guidelines for breast cancer should be expanded to include separate instructions concerning elderly patients. However, because women over age 70 are underrepresented in clinical trials, too few facts exist to gather evidence in support of more helpful recommendations.

Currently, the median age of women diagnosed with breast cancer is 61 years, a number likely to increase as baby boomers create a “ripple,” Dr. Carlson explained. In the context of breast cancer, advancing age increases the complications and challenges of care and treatment.

Decisions about cancer regimens are made more complicated because older women may need extra supportive therapies to survive the stress of cancer treatment, and also because lifespan is an issue. “The benefit of treatment has to be bigger in a relative sense to be ‘worth it,’ in an absolute sense, in the older patient, because of competing causes of death,” explained Dr. Carlson.

Comorbid conditions become more numerous as patients become older. A 64-year-old woman will already average just under three comorbidities. By the time that same patient reaches the age of 75, she will have, on average, more than four comorbid conditions. Roughly 24% of patients aged from 66 to 74 present with five or more comorbidities. By the age of 75, that percentage rises to 39%. The consequences of increasing ill-health are quantifiably severe. The life expectancy of a 65-year-old person with multiple comorbidities is over 10 years shorter than a relatively healthy (that is, evidencing no comorbidities) woman of the same age group. Aging also has an adverse effect on physiologic reserve and cognition.

When breast cancer treatment regimens are considered, another reason that age becomes a key factor is because elderly patients react to and process therapies in a different manner than their younger counterparts. Significant factors unique to the elder age group that should be taken into account include an increased disposition to dehydration, increased gastrointestinal toxicity, decreased bone marrow reserve, changes in renal function, and changes in hepatic function. “Renal blood flow decreases by 1% per year after age 50. Renal mass decreases by 25% to 30% across a life span, resulting in a decrease in functional nephrons and a decreased ability to concentrate and dilute,” reported Dr. Carlson. Changes in hepatic function include decreased liver volume, decreased hepatic blood flow, and decreased phase I reaction (mediated by p450).

Thus, it is important to assess the effect of advancing age by “a multidimensional, interdisciplinary patient evaluation that leads to the identification of patient problems and the development of a plan for resolving these problems,” advised Dr. Carlson. Geriatric assessments in oncology should be designed to “guide therapeutic decision making and identify signs of vulnerability,” he said, adding that a comprehensive assessment will enable clinicians to “identify and treat comorbidities, evaluate social support and cognition, evaluate nutritional status, and evaluate (potential) polypharmacy (-related) drug interaction (issues).”

According to Dr. Carlson, there is “a strong need for efficient tools to assess functional and physiological reserve.” Indeed, new tests are “desperately needed” to determine the physiologic age of the elder patient so that her physician can make wise recommendations regarding surgery, chemotherapy, and radiation, he said. Oncologists will look to geriatricians to abbreviate current tests that assess patient functioning. To be useful and practical in the realm of cancer treatment, tests that can take from two to three hours to administer must be distilled into fiveminute formats.

Not only do elderly patients have different sets of reactions to and circumstances surrounding their disease, they also, to some extent, have different disease. Aging even affects basic tumor biology. According to Dr. Carlson, “tumors in older women are associated with more indolent histology.” The proportion of tumors that are estrogen receptor (ER)—positive increases with age. “In women under the age of 65, 80% of tumors are ER positive,” reported Dr. Carlson, “Over the age of 65, 85% to 90% are ER positive.”

Owing to age-related variations in cancer presentation, progression, and therapeutic response, it is important, when evaluating research concerning the efficacy and safety of individual breast cancer therapies, to seek agespecific data. Dr. Carlson cited two recent adjuvant trastuzumab (Herceptin) trials as good examples of research that included a sufficient sampling of aged patients and were structured in a manner that lent themselves to elderspecific analysis. The trials (B-31 and N9831) enrolled 14,087 patients, 831 of whom were older than 65. The subsequent combined analysis broke down groups of patients by age group and was therefore able to demonstrate a “consistent benefit across most patient subgroups.” Clinicians were also able to assess potential risk factors (i.e., congestive heart failure, post AC LVEF) from an age-specific perspective.

Another useful research effort, according to Dr. Carlson, was a study in which 40 patients with breast cancer—20 who were under the age of 65 (mean 53; range 26—64) and 20 who were over the age of 65 (mean 71; range 65–80)&mdash;were treated with docetaxel (75 mg/m2 q 3 wk). Findings indicated that pharmacokinetics were the same in both the younger and older cohorts. However, the similarities between the two groups did not extend to tolerability. The older patient group was associated with an increased risk of grade 4 neutropenia (63% vs. 30% in the under 65 cohort) and febrile neutropenia (16% vs. 0%).

A number of circumstances make breast cancer therapy in the older adult a unique proposition. In concrete terms, this means that, “(as) competing causes of morbidity and death increase with age; the benefit of breast-conserving radiation therapy may decline with age; the benefit of chemotherapy declines with age while the toxicity of chemotherapy increases with age; (however,) the benefits of endocrine therapy persist with age,” concluded Dr. Carlson.

In closing, Dr. Carlson outlined several “research issues important to address over the next decade,” including:

• More ways to assess a patient’s “functional reserves”;

• Better understanding of patients’ priorities • Interaction of tumor biology and treatment;

• Physician attitudes toward older patients.

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