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Phase III Randomized Placebo-Controlled Trial of Two Doses of Megestrol Acetate as Treatment for Menopausal Symptoms in Women With Breast Cancer: Southwest Oncology Group Study 9626
the breast treated with primary radiotherapy. Int J Radiat Oncol Biol Phys. 1986;12:1575-1582.
8. Madu CN, Quint DJ, Normolle DP, Marsh RB, Wang EY, Pierce LJ. Definition of the supraclavicular and infraclavicular nodes: implications
for three-dimensional CT-based conformal radiation therapy. Radiology. 2001;221:333-339.
not, open-label MA 20 mg was added to blinded study drug and continued for 3 months. Other menopausal symptoms were also assessed. Results.—Two hundred eighty eight eligible women were randomly assigned (286 eligible), of whom 85% were on tamoxifen, 40% had over 63 hot flashes/week, and 75% had vasomotor symptoms for $ 6 months. Success at 3 months was 14% on placebo, 65% on 20 mg, and 48% on 40 mg (both MA doses superior to placebo; P < .0001). Most successes at 3 months were maintained at 6 months (77% on 20 mg and 81% on 40 mg). Conclusion.—MA significantly reduced vasomotor symptoms with durable benefit over 6 months. MA 20 mg/d is the preferred dose. There was no significant impact on other menopausal symptoms.
breast cancer survivors were randomly assigned to 20 or 40 mg of megestrol acetate versus placebo for 3 months. After 3 months of treatment, women who did not experience benefit received open-label megestrol acetate at 20 mg for 3 months. Both 20 mg and 40 mg of megestrol acetate reduced symptoms by 75% in 65% and 48% of participants, respectively, compared to 14% of the placebo-treated women. These results are consistent with other studies demonstrating the efficacy of progestin agents in similar populations.1-3 While megestrol acetate was very efficacious in reducing hot flashes in breast cancer survivors, it is unlikely that the results of SWOG 9626 will change current practices. Since there is a remote chance that progestin will increase the risk of breast cancer recurrence,4 nonhormonal agents such as venlafaxine, paroxetine, or gabapentin should be preferred.5 However, if a woman remains symptomatic despite nonhormonal interventions, progestin should be considered. The best progestin dose and schedule is not known. SWOG 9626 and other studies support the use of megestrol acetate at 20 mg/day.1 The use of depot medroxyprogesterone acetate (MPA) as 500-mg intramuscular injections on days 1, 14, and 28 or a single administration of MPA at 400 mg also provides significant and sustained benefit.2,3 It would be of interest to study the effects
CHEMOTHERAPY Phase III Randomized PlaceboControlled Trial of Two Doses of Megestrol Acetate as Treatment for Menopausal Symptoms in Women With Breast Cancer: Southwest Oncology Group Study 9626 Goodwin JW, Green SJ, Moinpour CM, et al (Ozarks Regional Community Clinical Oncology Program, Springfield, MO; Pfizer Inc, New London, CT; Southwest Oncology Group Statistical Ctr, Seattle, WA; et al) J Clin Oncol 26:1650-1656, 2008
Purpose.—Prior progestin studies treating hot flashes in women have been short duration and single dose. This study tests the progestin megesterol acetate (MA) at two doses versus placebo over 6 months. Patients and Methods.—Patients with T1-3, N0-1, M0 breast cancer were eligible after completion of surgery and chemotherapy and at least 4 months of tamoxifen (if prescribed). Women were required to have at least 10 hot flashes of any severity or at least five severe episodes per week. Patients were randomly assigned to placebo, MA 20 mg, or MA 40 mg for 3 months. Success at 3 months was defined as completion of treatment with a $ 75% reduction in hot flashes from baseline. If success was achieved, drug treatment for another 3 months was given on the same blinded arm; if
Breast cancer survivors are more likely to report bothersome hot flashes compared to menopausal women owing to therapies that reduce breast cancer recurrence. Treatment options are also more limited for breast cancer survivors because of the concern that estrogenbased therapies may increase the risk of cancer recurrence. Several nonhormonal agents are available to reduce the number or severity of hot flashes, but these therapies are clearly not as efficacious as hormonal interventions. In the Southwest Oncology Group (SWOG) 9626 study,
Breast Diseases: A Year BookÒ Quarterly Vol 20 No 2 2009
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of low-dose progestin not only on symptom management but also on the risk of breast cancer recurrence. V. Stearns, MD
References 1. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med. 1994;331:347-352.
Tamoxifen Chemoprevention Treatment and Time to First Diagnosis of Estrogen Receptor– Negative Breast Cancer Shen Y, Costantino JP, Qin J (Univ of Texas M. D. Anderson Cancer Ctr, Houston; Univ of Pittsburgh, PA; Natl Inst of Allergy and Infectious Diseases, Bethesda, MD) J Natl Cancer Inst 100:1448-1453, 2008
Background.—Tamoxifen’s effect of reducing the risk of estrogen receptor (ER)–positive breast cancer is well established. Its effect on the time to first diagnosis of breast cancer has not been reported. We used information from the randomized, placebocontrolled Breast Cancer Prevention Trial (BCPT) to make that evaluation. Methods.—A total of 13 388 women enrolled in BCPT, of whom 174 were diagnosed with ER-positive tumors and 69 were diagnosed with ER-negative tumors. A flexible semiparametric cure rate model was used to assess the effects of tamoxifen vs placebo treatment on the time to disease diagnosis. Multivariable logistic regression, adjusted for age and tumor size at diagnosis, was used to assess the association between the
212
2. Loprinzi CL, Levitt R, Barton D, et al. Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol. 2006;24:1409-1414.
4. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.
3. Bertelli G, Venturini M, Del Mastro L, et al. Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study. Ann Oncol. 2002;13:883-888.
5. Hickey M, Saunders C, Partridge A, et al. Practical clinical guidelines for assessing and managing menopausal symptoms after breast cancer. Ann Oncol. 2008;19:1669-1680.
mammography detection rate and treatment with tamoxifen. All statistical tests were two-sided. Results.—The median times to diagnosis of ER-positive tumors were similar in both treatment groups (43 months for the placebo arm and 51 months for the treatment arm). Times to diagnosis of ER-negative tumors, however, differed between treatment groups, with median times to diagnosis of 36 months in the placebo arm vs 24 months in the tamoxifen arm (difference ¼ 12 months, 95% confidence interval [CI] ¼ 3 to 17 months, P ¼ . 037). ER-negative breast cancers in the tamoxifen arm were more likely than those in the placebo arm to be detected by mammography than by clinical breast examination alone after adjustment for age and tumor size, but the increase was only marginally statistically significant (odds ratio for mammography detection ¼ 4.68, 95% CI ¼ 0.86 to 25.32, P ¼. 073). No differences were found in the mammography detection rates for ERpositive tumors by treatment arm. Conclusion.—Although tamoxifen treatment does not reduce the incidence of ER-negative breast cancer, it may have advanced detection of such tumors by approximately 1 year,
compared with that in the placebo arm. The time to diagnosis of ER-positive breast cancer was similar in both treatment arms (Fig 1).
Breast Diseases: A Year BookÒ Quarterly Vol 20 No 2 2009
The positive results of the BCPT can be considered in more detail in terms of the types of tumors that were prevented. In the BCPT, the number of tumors diagnosed with 4 or more positive axillary lymph nodes was 11 (of 176 invasive cancers) in the placebo arm and 12 (of 89 invasive cancers) in the tamoxifen arm. The number of ER-negative invasive tumors was 31 in the placebo arm and 38 in the tamoxifen arm, yielding a rate of ER-negative tumors of 1.2 per 1000 women in the placebo group and 1.46 per 1000 women in the tamoxifen group (RR ¼ 1.22 [95% CI, 0.22-2.03]).1 In their methodologically innovative analysis of the BCPT, Shen and colleagues demonstrated that (a) the time to diagnosis for patients with ER-negative tumors was shorter in women who took tamoxifen than in women who did not take tamoxifen; (b) a higher proportion of ER-negative tumors found in women in the tamoxifen arm were smaller than 1 cm (39.5% vs 16.1% in the placebo arm;
8. Madu CN, Quint DJ, Normolle DP, Marsh RB, Wang EY, Pierce LJ. Definition of the supraclavicular and infraclavicular nodes: implications
for three-dimensional CT-based conformal radiation therapy. Radiology. 2001;221:333-339.
not, open-label MA 20 mg was added to blinded study drug and continued for 3 months. Other menopausal symptoms were also assessed. Results.—Two hundred eighty eight eligible women were randomly assigned (286 eligible), of whom 85% were on tamoxifen, 40% had over 63 hot flashes/week, and 75% had vasomotor symptoms for $ 6 months. Success at 3 months was 14% on placebo, 65% on 20 mg, and 48% on 40 mg (both MA doses superior to placebo; P < .0001). Most successes at 3 months were maintained at 6 months (77% on 20 mg and 81% on 40 mg). Conclusion.—MA significantly reduced vasomotor symptoms with durable benefit over 6 months. MA 20 mg/d is the preferred dose. There was no significant impact on other menopausal symptoms.
breast cancer survivors were randomly assigned to 20 or 40 mg of megestrol acetate versus placebo for 3 months. After 3 months of treatment, women who did not experience benefit received open-label megestrol acetate at 20 mg for 3 months. Both 20 mg and 40 mg of megestrol acetate reduced symptoms by 75% in 65% and 48% of participants, respectively, compared to 14% of the placebo-treated women. These results are consistent with other studies demonstrating the efficacy of progestin agents in similar populations.1-3 While megestrol acetate was very efficacious in reducing hot flashes in breast cancer survivors, it is unlikely that the results of SWOG 9626 will change current practices. Since there is a remote chance that progestin will increase the risk of breast cancer recurrence,4 nonhormonal agents such as venlafaxine, paroxetine, or gabapentin should be preferred.5 However, if a woman remains symptomatic despite nonhormonal interventions, progestin should be considered. The best progestin dose and schedule is not known. SWOG 9626 and other studies support the use of megestrol acetate at 20 mg/day.1 The use of depot medroxyprogesterone acetate (MPA) as 500-mg intramuscular injections on days 1, 14, and 28 or a single administration of MPA at 400 mg also provides significant and sustained benefit.2,3 It would be of interest to study the effects
CHEMOTHERAPY Phase III Randomized PlaceboControlled Trial of Two Doses of Megestrol Acetate as Treatment for Menopausal Symptoms in Women With Breast Cancer: Southwest Oncology Group Study 9626 Goodwin JW, Green SJ, Moinpour CM, et al (Ozarks Regional Community Clinical Oncology Program, Springfield, MO; Pfizer Inc, New London, CT; Southwest Oncology Group Statistical Ctr, Seattle, WA; et al) J Clin Oncol 26:1650-1656, 2008
Purpose.—Prior progestin studies treating hot flashes in women have been short duration and single dose. This study tests the progestin megesterol acetate (MA) at two doses versus placebo over 6 months. Patients and Methods.—Patients with T1-3, N0-1, M0 breast cancer were eligible after completion of surgery and chemotherapy and at least 4 months of tamoxifen (if prescribed). Women were required to have at least 10 hot flashes of any severity or at least five severe episodes per week. Patients were randomly assigned to placebo, MA 20 mg, or MA 40 mg for 3 months. Success at 3 months was defined as completion of treatment with a $ 75% reduction in hot flashes from baseline. If success was achieved, drug treatment for another 3 months was given on the same blinded arm; if
Breast cancer survivors are more likely to report bothersome hot flashes compared to menopausal women owing to therapies that reduce breast cancer recurrence. Treatment options are also more limited for breast cancer survivors because of the concern that estrogenbased therapies may increase the risk of cancer recurrence. Several nonhormonal agents are available to reduce the number or severity of hot flashes, but these therapies are clearly not as efficacious as hormonal interventions. In the Southwest Oncology Group (SWOG) 9626 study,
Breast Diseases: A Year BookÒ Quarterly Vol 20 No 2 2009
211
of low-dose progestin not only on symptom management but also on the risk of breast cancer recurrence. V. Stearns, MD
References 1. Loprinzi CL, Michalak JC, Quella SK, et al. Megestrol acetate for the prevention of hot flashes. N Engl J Med. 1994;331:347-352.
Tamoxifen Chemoprevention Treatment and Time to First Diagnosis of Estrogen Receptor– Negative Breast Cancer Shen Y, Costantino JP, Qin J (Univ of Texas M. D. Anderson Cancer Ctr, Houston; Univ of Pittsburgh, PA; Natl Inst of Allergy and Infectious Diseases, Bethesda, MD) J Natl Cancer Inst 100:1448-1453, 2008
Background.—Tamoxifen’s effect of reducing the risk of estrogen receptor (ER)–positive breast cancer is well established. Its effect on the time to first diagnosis of breast cancer has not been reported. We used information from the randomized, placebocontrolled Breast Cancer Prevention Trial (BCPT) to make that evaluation. Methods.—A total of 13 388 women enrolled in BCPT, of whom 174 were diagnosed with ER-positive tumors and 69 were diagnosed with ER-negative tumors. A flexible semiparametric cure rate model was used to assess the effects of tamoxifen vs placebo treatment on the time to disease diagnosis. Multivariable logistic regression, adjusted for age and tumor size at diagnosis, was used to assess the association between the
212
2. Loprinzi CL, Levitt R, Barton D, et al. Phase III comparison of depomedroxyprogesterone acetate to venlafaxine for managing hot flashes: North Central Cancer Treatment Group Trial N99C7. J Clin Oncol. 2006;24:1409-1414.
4. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.
3. Bertelli G, Venturini M, Del Mastro L, et al. Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study. Ann Oncol. 2002;13:883-888.
5. Hickey M, Saunders C, Partridge A, et al. Practical clinical guidelines for assessing and managing menopausal symptoms after breast cancer. Ann Oncol. 2008;19:1669-1680.
mammography detection rate and treatment with tamoxifen. All statistical tests were two-sided. Results.—The median times to diagnosis of ER-positive tumors were similar in both treatment groups (43 months for the placebo arm and 51 months for the treatment arm). Times to diagnosis of ER-negative tumors, however, differed between treatment groups, with median times to diagnosis of 36 months in the placebo arm vs 24 months in the tamoxifen arm (difference ¼ 12 months, 95% confidence interval [CI] ¼ 3 to 17 months, P ¼ . 037). ER-negative breast cancers in the tamoxifen arm were more likely than those in the placebo arm to be detected by mammography than by clinical breast examination alone after adjustment for age and tumor size, but the increase was only marginally statistically significant (odds ratio for mammography detection ¼ 4.68, 95% CI ¼ 0.86 to 25.32, P ¼. 073). No differences were found in the mammography detection rates for ERpositive tumors by treatment arm. Conclusion.—Although tamoxifen treatment does not reduce the incidence of ER-negative breast cancer, it may have advanced detection of such tumors by approximately 1 year,
compared with that in the placebo arm. The time to diagnosis of ER-positive breast cancer was similar in both treatment arms (Fig 1).
Breast Diseases: A Year BookÒ Quarterly Vol 20 No 2 2009
The positive results of the BCPT can be considered in more detail in terms of the types of tumors that were prevented. In the BCPT, the number of tumors diagnosed with 4 or more positive axillary lymph nodes was 11 (of 176 invasive cancers) in the placebo arm and 12 (of 89 invasive cancers) in the tamoxifen arm. The number of ER-negative invasive tumors was 31 in the placebo arm and 38 in the tamoxifen arm, yielding a rate of ER-negative tumors of 1.2 per 1000 women in the placebo group and 1.46 per 1000 women in the tamoxifen group (RR ¼ 1.22 [95% CI, 0.22-2.03]).1 In their methodologically innovative analysis of the BCPT, Shen and colleagues demonstrated that (a) the time to diagnosis for patients with ER-negative tumors was shorter in women who took tamoxifen than in women who did not take tamoxifen; (b) a higher proportion of ER-negative tumors found in women in the tamoxifen arm were smaller than 1 cm (39.5% vs 16.1% in the placebo arm;