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Dose-Response Trial of Megestrol Acetate in Advanced Breast Cancer: Cancer and Leukemia Group B Phase III Study 8741

From the University of Maryland Cancer Center, Baltimore, MD; Cancer and Leukemia Group B Statistical Office, Durham, NC; Bowman Gray School of Medicine, Winston-Salem, NC; Dana-Farber Cancer Institute, Boston, MA; McGill Cancer Center, Montreal, Canada; State University of New York at Syracuse, Syracuse, NY; University of California at San Diego, San Diego, CA; and the Memorial Sloan-Kettering Cancer Center, New York, NY.

Address reprint requests to Jeffrey Abrams, MD, National Cancer Institute, 6130 Executive Blvd, EPN 741, Rockville, MD 20892–7436; Email AbramsJ{at}CTEP.nci.nih.gov

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
PURPOSE: To investigate whether dose escalation of megestrol acetate (MA) improves response rate and survival in comparison with standard doses of MA.

PATIENTS AND METHODS: Three hundred sixty-eight patients with metastatic breast cancer, positive and/or unknown estrogen and progesterone receptors, zero or one prior trial of hormonal therapy, and no prior chemotherapy for metastatic disease were prospectively randomized into three groups. The groups of patients received either MA 160 mg/d (one tablet per day), MA 800 mg/d (five tablets per day), or MA 1,600 mg/d (10 tablets per day).

RESULTS: Patient characteristics were well balanced in the three treatment groups. Three hundred sixty-six patients received treatment and were included in the analyses. The response rates were 23%, 27%, and 27% for the 160-mg, 800-mg, and 1,600-mg arms, respectively. Response duration correlated inversely with dose. Median durations of response were 17 months, 14 months, and 8 months for the 160-mg, 800-mg, and 1,600-mg arms, respectively. No significant differences in the treatment arms were noted for time to disease progression or for survival; survival medians were 28 months (low dose), 24 months (mid dose) and 29 months (high dose). The most frequent and troublesome toxicity, weight gain, was dose-related, with approximately 20% of patients on the two higher-dose arms reporting weight gain of more than 20% of their prestudy weight, compared with only 2% in the 160-mg dose arm.

CONCLUSION: With a median follow-up of 8 years, these results demonstrate no advantage for dose escalation of MA in the treatment of metastatic breast cancer.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
MEGESTROL ACETATE (MA), a semisynthetic, oral progestin with excellent gastrointestinal absorption, has demonstrated efficacy comparable to that of tamoxifen as first-line treatment in women with advanced breast cancer.¹ At the standard dose of 160 mg daily, side effects from MA are minimal and include nausea, vaginal bleeding and discharge, weight gain, and fluid retention. In a series of 908 patients treated at this dose, the only serious toxicities possibly attributable to MA were three cases of congestive heart failure, one case of pulmonary embolism, and one case of acute left-ventricular failure.²

Efforts to improve the activity of MA focused on dose escalation, an approach that has been widely pursued for cytotoxic agents but less so for hormonal therapies. Potential mechanisms that could explain improved antitumor effects from high-dose progestins include an enhancement of the direct cytotoxic effect of the hormone via the progestin receptor,³ additional direct cytotoxic effects on other related and important corticosteroid receptors,⁴ and an increase in the indirect effects of progestins by further suppression of the hypothalamo-pituitary-adrenal axis.⁵ Two phase III trials compared high versus standard doses of another progestin, medroxyprogesterone acetate, administered by intramuscular injection, and demonstrated improved response rates.^6,7 These encouraging results provided the impetus to initiate further trials to explore the dose-response effect of MA. However, not all investigators found higher doses to be more effective.^8,9

The superior oral availability of MA compared with medroxyprogesterone acetate led the Piedmont Oncology Association (POA) to perform a phase III trial in patients with metastatic breast cancer comparing high-dose (800 mg/d) with standard-dose (160 mg/d) MA. All but two of the 172 patients entered had one prior trial of tamoxifen therapy for either metastatic (74%) or adjuvant (26%) treatment. High-dose MA resulted in a superior complete plus partial response rate (27% v 10%, P = .005), time to treatment failure (median, 8.0 v 3.2 months, P =.019), and survival (median, 22.4 v 16.5 months, P = .04) when compared with standard-dose therapy.¹⁰

A phase I/II trial demonstrated that the dose of MA could be further escalated to 1,600 mg daily.^11,12 Although dose-limiting toxicity was not reached, substantial weight gain (median, 5.0 kg; range, 5.6 to 44 kg) occurred in 71% of patients at the 1,600-mg dose level, making further escalation difficult. Responses occurred at all dose levels in this trial, but the most promising results occurred in a subset of 27 patients who had progressed after treatment with standard doses of MA (160 mg/d). A 15% response rate (one complete response, three partial responses) was noted in this subset, and 10 patients (37%) had stable disease lasting a median of 5.4 months. Two of the objective responses occurred in women whose tumors had not previously responded to the standard MA dose.

These provocative results provided the rationale for the Cancer and Leukemia Group B (CALGB) to develop a randomized, three-arm, phase III trial design in which women with metastatic breast cancer received either standard-dose MA (160 mg/d), five times the standard dose (800 mg/d), or 10 times the standard dose (1,600 mg/d). A preliminary report of this trial has been presented.¹³

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Selection
Women at least 18 years of age and with histologically documented breast carcinoma and progressive metastatic disease were eligible. Other requirements included a performance status of 0 to 3, positive and/or unknown estrogen and progesterone receptors, and no prior or concomitant malignancy other than curatively treated in situ cancer of the cervix or basal cell carcinoma of the skin. Patients with metastatic disease that was either bidimensionally measurable or assessable were entered, but they were assessed separately. Only one prior hormonal therapy (drug or surgical manipulation) for adjuvant or metastatic treatment was permitted, excepting progestins, which were not allowed. Patients who responded to their initial hormonal therapy were required to wait 6 weeks off all therapy before entering the study to avoid confusion with a withdrawal response. This did not apply to surgical manipulations. Prior adjuvant chemotherapy was acceptable if the disease-free period off treatment was more than 1 year, but chemotherapy for metastatic disease was not permitted.

Brain, leptomeningeal, lymphangitic, lung, and extensive liver and bone marrow metastases were all causes for exclusion. Evidence of normal kidney, liver, and bone marrow function was required, and patients with serious medical problems (especially congestive heart failure, uncontrolled hypertension, or diabetes mellitus) and those with a history of thrombophlebitis or stroke were excluded. All participants had to sign an informed consent that had been approved by institutional review boards.

Treatment Evaluation
Before beginning treatment with MA, all patients had a chest x-ray, electrocardiogram, bone scan, and a liver/spleen scan or abdominal computed tomogram. Additional studies were performed as necessary to measure indicator lesions. Patients were initially evaluated for response and toxicity every 4 weeks, but this was changed to every 8 weeks for responding patients who were on treatment for long periods of time.

Treatment and Dose Modification
Patients were stratified according to prior hormone therapy (yes v no), prior adjuvant therapy (yes v no), and receptor status (estrogen- and/or progesterone-positive v both unknown). They were then randomized within each stratification subgroup to one of the following three treatment arms: (1) MA at 160 mg/d, one tablet per day; (2) MA at 800 mg/d, five tablets per day; and (3) MA at 1,600 mg/d, 10 tablets per day. To facilitate oral administration, Bristol-Myers Squibb Co (Princeton, NJ) provided specially prepared 160-mg tablets for this trial. A prior study in normal volunteers compared the pharmacokinetic profile of the 40-mg four-times-a-day dosage with the 160-mg investigational tablet. It demonstrated that the peak plasma concentrations, the extent of absorption (area under the curve), and the half-life (t 1/2) showed no significant differences. The bioequivalence of the 160-mg investigational tablet was 97% of the 40-mg four-times-a-day dosage.¹⁴ The recommended administration schedule was as follows: arm 1, one tablet at 8 AM; arm 2, one tablet at 8 AM, 12 PM, and 6 PM, and two tablets at 10 PM; and arm 3, two tablets at 8 AM and 12 PM and three tablets at 6 PM and 10 PM. No dose modifications were allowed for toxicity. Uncontrolled arterial hypertension, congestive heart failure, and thrombophlebitis were all causes for discontinuation of MA. Patients with weight gain and minor vaginal bleeding were encouraged to continue their treatment. If unacceptable side effects occurred in a responding patient, the patient was taken off the study drug and could then be treated with additional hormonal agents at the physician's discretion. After disease progression, patients were to be removed from MA and treated at the physician's discretion. For patients with rapidly progressive or life-threatening disease, chemotherapy was usually initiated, whereas further hormonal manipulations were considered for those with slower progression.

Study Design
The objective of this trial was to compare the response rates of the three treatment arms. The response rates were hypothesized to fall between 25% and 55%. A sample size of 100 patients per arm would yield at least an 80% power to detect a 17% additive difference, such as 30% versus 47%, between any two arms. Thus, with 123 patients randomized to the 160-mg arm, 124 to the 800-mg arm, and 119 to the 1,600-mg arm, there is better than 80% probability of detecting a 17% difference in response between any two arms.

Variables of Interest
We examined several demographic, pretreatment clinical, and treatment-related variables. These included: patient age, menopausal status, receptor status, performance status, measurability of disease, sites of involvement, number of involved sites, prior treatment, and time from initial diagnosis of breast cancer to first recurrence.

End Points
The study end points were response rate, response duration, time to disease progression, and overall survival. Definitions of response were assessed according to standard response criteria for patients with bidimensionally measurable disease.¹⁵ Briefly, a complete response was defined as the complete disappearance of all signs and symptoms of disease, including reossification of osteolytic lesions, for at least 30 days. A partial response was defined as a decrease of at least 50% in the product of the cross-perpendicular dimensions of all measurable indicator lesions, and no worsening of any existing lesion or the appearance of any new lesions, for at least 30 days. Stable was defined as less than a 50% reduction or less than a 25% increase in the product of the cross-perpendicular dimensions of all measurable lesions, with no new lesions for at least 60 days. For patients with assessable disease, symptomatic benefit but continued presence of lesions without the appearance of new lesions for at least 60 days qualified as stable disease. Progression was defined as an increase of at least 25% in the product of the cross-perpendicular dimensions of any measured lesion over the size present at entry, or for responders, the size at the time of maximum regression or the appearance of any new lesion. Those with only assessable disease were excluded from the assessment of partial responses.

Duration of MA response was measured from the date of complete or partial response, whichever occurred first, on MA until disease progression. Responders who were alive and disease-free were censored at their last follow-up visit. Time to disease progression was the date of study entry until the date of first disease progression or the date of last follow-up for patients who were alive and disease-free. Overall survival was the date of study entry until death due to any cause, or until date of last follow-up for survivors.

Statistical Methods
Survival curves were estimated by the Kaplan-Meier product limit method, whereas the log-rank test was used to compare two or more survival distributions. We used the Cox proportional hazards model initially to screen for individual variables potentially related to survival and time to disease progression. Subsequently, this method was used to identify sets of prognostic variables while controlling for the effect of other variables in the model.¹⁶

Comparisons between categorical variables were performed by the ² test. The Mantel-Haenszel ² test measures whether tumor response increases with increased MA dose (treatment arm). All P values are two-sided. We define statistical significance as P .05. We included data available as of February 1997. The median follow-up was 8.2 years.

Comparison with POA Trial
The POA kindly provided us with data from their previously published study.¹⁰ We included in analysis only variables that both our study and the POA study measured. We defined variables identically in the two studies, both pretreatment characteristics and end point measures.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Patient Characteristics
A total of 368 patients were enrolled from 23 CALGB main member institutions and their affiliates between June 1, 1987, and March 22, 1991. Of these, 124 patients were randomly assigned with equal probability to the 160-mg arm, 124 were assigned to the 800-mg arm, and 120 were assigned to the 1,600-mg arm. Two patients, one on the 160-mg arm and the other on the 1,600-mg arm, never received treatment. Twenty-eight patients did not meet the eligibility criteria. For the 160-mg arm (n = 7), reasons for ineligibility included the following: two prior hormone regimens (three patients), laboratory values out of range (one patient), less than 1 year from end of adjuvant treatment (one patient), visceral crisis (one patient), and prior chemotherapy for metastatic disease (one patient). For the 800-mg arm (n = 9), reasons for ineligibility included the following: two prior hormone regimens (3 patients), laboratory values out of range (one patient), less than 1 year from end of adjuvant treatment (three patients), and visceral crisis (two patients). For the 1,600-mg arm (n = 12), reasons for ineligibility included the following: less than 1 year from end of adjuvant treatment (two patients), visceral crisis (seven patients), prior chemotherapy for metastatic disease (one patient), estrogen- and progesterone-negative (one patient), and prior cancer (one patient).

In keeping with an intent-to-treat analysis, all treated patients (n = 366) were included in analyses. One patient received radiotherapy (RT) concurrent with MA therapy. She is excluded from analyses of MA response but included in analyses of other end points. Analyses (not shown) of all major study end points were recalculated using only eligible patients. No significant differences were found between these results and those based on the intent-to-treat principle.

Table 1 lists the pretreatment characteristics of participants by treatment arm. Patients on the three arms were well matched at pretreatment. Examination of baseline characteristics between white and nonwhite patients revealed no significant differences. The relatively small size of the nonwhite populations did not allow us to perform a separate analysis of outcome according to race.

Tumor Response and Duration of Response
Table 2 lists the maximum tumor response to MA therapy. Of the 365 total patients, 19 were missing follow-up tumor assessments. The most common reason for missing assessments was treatment termination before the scheduled 8-week follow-up evaluation. Reasons for early treatment termination included early death, toxicity, withdrawn consent, physician decision, and other complicating illness. Patients without repeat tumor assessments due to early death or MA toxicity were considered nonresponders and were included in response rate calculations. Other patients were considered to have nonassessable tumors and were excluded from response rates. Thus, response evaluation is based on 357 patients.

Ninety-one patients achieved a tumor response, that is, either a complete or partial response, while on MA. The response rates were 23%, 27%, and 27% for the 160-mg, 800-mg, and 1,600-mg arms, respectively. Results of the Mantel-Haenszel test show that response rate did not significantly rise with increasing doses of MA. The overlapping 95% confidence intervals indicate that treatment did not correlate with tumor response. Note that including nonassessable patients in response rates gave similar results as did excluding them.

Figure 1 shows the duration of response on MA for the 91 patients whose tumors responded to MA treatment. Dose did not correlate with achieving a response; however, dose did correlate with length of time in response. Of interest, the correlation was negative (P < .003), that is, the higher the MA dose, the shorter the time in response. Specifically, the median response duration was 17 months for patients on the 160-mg arm, 14 months for patients on the 800-mg arm, and 8 months for patients on the 1,600-mg arm.

View larger version (16K): [in this window] [in a new window]   Fig 1. Response duration by treatment arm (160-mg arm: - - -, n = 28, median = 17.1; 800-mg arm: — —, n = 32, median = 13.5; 1,600-mg arm: |Cv|Cv, n = 31, median = 7.8; P = .0028).

Time to Disease Progression
Figure 2 shows time to disease progression by treatment arm. Two patients from the mid-dose arm discontinued MA therapy before documented disease progression and subsequently received chemotherapy. Their disease progressed subsequent to chemotherapy. We censored these patients at the start of chemotherapy.

View larger version (16K): [in this window] [in a new window]   Fig 2. Time to disease progression by treatment arm (160-mg arm: - - -, n = 123, median = 8.3; 800-mg arm: — —, n = 124, median = 7.0; 1,600-mg arm: |Cv|Cv, n = 119, median = 8.1; P = .57).

Higher doses of MA did not prolong the time until disease progression. The median time to disease progression was 8 months for patients on the 160-mg arm, 7 months for patients on the 800-mg arm, and 8 months for patients on the 1,600-mg arm. These differences were not of statistical significance.

Univariate analysis of multiple pretreatment characteristics showed that age at study entry (P = .0001) and presence or absence of bone metastases (P = .007) correlated most highly with time until disease progression. Younger patients were at a greater risk of progressing compared with older patients (risk ratio = 1.03). Patients who had bone metastases had a risk of progressing that was 37% greater than the risk for those patients who did not have bone involvement (risk ratio = 1.37).

Other variables in this univariate analysis that also correlated, although weakly, with time until disease progression were prior hormone therapy (P = .01), total number of metastatic sites (P = .04), estrogen receptor status (P = .04), disease-free interval (P = .04), and patient race (P = .03). Variables that correlated with better prognoses included no prior hormone treatment, fewer metastatic sites, estrogen receptor-positive tumors, longer disease-free interval, and white race.

The following did not correlate univariately with time to disease progression: treatment arm; whether or not the patient received prior chemotherapy, RT, or tamoxifen; presence or absence of visceral metastases; progesterone receptor status; and performance score.

We also examined the relation of several variables simultaneously with time to progression. Table 3 lists data from the resulting multivariate model. Patient age (P = .0001) and prior treatment with hormonal agents (P = .0015) were strongly associated with time to disease progression. Of lesser importance were disease-free interval (P = .11), number of metastatic sites (P = .13), and performance score (P = .10).

Favorable characteristics included the following: no prior hormone treatment, older age, longer disease-free interval, fewer involved sites, and lower performance score.

Overall Survival
Treatment arm did not correlate with survival (Fig 3). The median survival from study entry was 28 months (low dose), 24 months (mid dose), and 29 months (high dose).

View larger version (16K): [in this window] [in a new window]   Fig 3. Overall survival by treatment arm (160-mg arm: - - -, n = 123, median = 27.8; 800-mg arm: — —, n = 124, median = 24.4; 1,600-mg arm: |Cv|Cv, n = 119, median = 28.6; P = .54).

As with time to disease progression, age at study entry (P = .0007) and presence or absence of bone metastases (P = .0005) correlated most highly with survival in univariate analysis. In addition, the number of metastatic sites (P = .0001) and performance score (P = .0001) were of statistical significance.

Again, younger patients had a higher risk of dying earlier compared with older patients (risk ratio = 1.02). The instantaneous risk of dying for patients with bone involvement was nearly 50% greater than that of patients without bone metastases (risk ratio = 1.49).

Prior hormone therapy (P = .01), estrogen (P = .03) and progesterone (P = .05) tumor status, prior RT (P = .05), and disease-free interval (P = .03) also correlated with overall survival. Better prognoses were correlated with the following: no prior hormone treatment, no prior RT, estrogen receptor-positive/progesterone receptor-positive tumors, and longer disease-free interval.

Treatment arm and whether or not the patient received prior chemotherapy and tamoxifen did not correlate with survival.

Table 3 lists data from the multivariate model for overall survival. Prior hormone treatment (P = .0002), patient age (P = .0001), number of metastatic sites (P = .0001), and performance score (P = .0001) correlated strongly with overall survival. Disease-free interval was of lesser importance (P = .04). Favorable characteristics included the following: no prior hormone treatment, older age, fewer involved sites, better performance score, and longer disease-free interval.

Comparison with POA Study
Table 4 lists the demographic profiles of POA patients compared with the CALGB patients. In general, POA patients were sicker at study enrollment than were the CALGB patients. On study entry, POA patients tended to have more extensive metastatic disease, worse performance status, fewer progesterone receptor-positive tumors, and more prior chemotherapy than did the CALGB patients.

About one half of the patients in the POA group had three or more metastatic sites, whereas only one third of the patients in the CALGB group had three or more sites (P < .001). Seventy-three percent of the POA patients had bone metastases, compared with 63% of the CALGB patients (P = .02). Only 30% of the POA patients had a performance score of 0 (normal functioning) compared with 55% of the CALGB patients (P = .001). The POA patients had fewer progesterone receptor-positive tumors than did the CALGB patients (68% v 79%; P = .02). Fifty-four percent of the POA patients had prior chemotherapy compared with 39% of the CALGB patients (P = .001).

Within the CALGB study, the treatment groups were comparable on pretreatment variables; however, within the POA study, the arms were not always comparable. In contrast to the POA 800-mg arm, the POA 160-mg arm had a higher incidence of visceral metastases (45% v 31%) and more sites of metastatic disease (29% v 13% with four sites). Thus, the POA patients randomized to the low-dose arm were, by chance, sicker at study entry than were those patients assigned to the 800-mg arm (data not shown).

Table 5 lists tumor responses of patients in the two studies by treatment arm. Patients in the low-dose arm of the POA study had considerably lower tumor response than did patients in any of the other arms. Overall survival did not differ by treatment arm in the CALGB or POA study. However, CALGB patients experienced longer overall survival compared with POA patients (Fig 4). In particular, patients in the low-dose POA arm had significantly worse survival compared with patients in the low-dose CALGB arm (P = .001). The moderate-dose POA and CALGB arms did not differ, a finding that indicates that the patients on these arms likely had reasonably similar pretreatment characteristics. Similarly, time to disease progression did not differ by study or by treatment arm (data not shown).

View larger version (20K): [in this window] [in a new window]   Fig 4. Overall survival by treatment arm (CALGB v POA) (CALGB 160-mg arm: |Cv|Cv, n = 123, median = 27.8; CALGB 800-mg arm: |Cv|Cv, n = 124, median = 24.4; CALGB 1,600-mg arm: |Cv|Cv, n = 119, median = 28.6; POA 160-mg arm: - - -, n = 87, median = 13.4; POA 800-mg arm: — —, n = 85, median = 21.1; P < .0001).

Toxicity in CALGB Study
Table 6 lists by treatment arm the maximum toxicities reported during MA. The table does not include adverse events reported during hormone therapy subsequent to MA.

Five patients died of causes that were possibly treatment-related, one on the mid-dose arm and four on the high-dose arm. The patient on the 800-mg arm had a proved pulmonary embolus. Of the four patients on the 1,600-mg arm, two died as a result of pulmonary emboli, one as a result of thrombosis of the right and left atria of the heart, and one as a result of gastrointestinal bleeding caused by warfarin therapy that the patient was taking because of a pulmonary embolus suffered on study.

There were 13 reported thrombotic events that were of at least grade 2 severity. Four of these events occurred on the 160-mg arm, three occurred on the 800-mg arm, and six occurred on the 1,600-mg arm. Six of these events were limited to lower-extremity thrombophlebitis, but there were five documented pulmonary emboli, one each on the 160-mg and 800-mg arms and three on the 1,600-mg arm. Although no statistically significant difference in incidence was apparent between the three arms, there was a trend toward more serious (grades 4 and 5) thrombotic events with increased MA dose.

Weight gain, the most frequently reported side effect, was noted in a substantial percentage of patients. Thirty-seven percent (37%) of patients on the low-dose MA arm reported a 5% weight gain above their prestudy weight. Nearly twice this proportion of patients reported a 5% weight gain in the moderate-dose (70%) and high-dose (66%) arms. Only 2% of patients in the low-dose arm reported a 20% weight gain, whereas 23% of the mid-dose and 20% of the high-dose patients reported more than 20% weight gain.

Other grades 3 and 4 toxicities that occurred in more than one patient included hepatic dysfunction limited to nonsymptomatic transaminase elevations, hyperglycemia, arterial hypertension, edema, skin rash, central nervous system changes characterized by Parkinson-like tremor and confusion, and peripheral nervous system and muscular-skeletal symptoms typified by extreme weakness in the lower extremities. Hematologic and gastrointestinal side effects were infrequent and generally mild. It is noteworthy that upon cessation of MA for disease progression, Addisonian crisis developed in a patient who had received MA on the 800-mg arm for 2 years. Her symptoms responded dramatically to corticosteroid replacement therapy.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Five- and 10-fold increases in the dose of MA, relative to the standard dose, did not improve the outcome for women with metastatic breast cancer in this study. Although most clinical outcomes (response, time to progression, and survival) were unaffected by the dose, the duration of response progressively decreased at the higher dose levels. A potential explanation for this finding may relate to the increase in weight gain and overall toxicity experienced by patients at the highest doses. This may have influenced both doctors and their patients on the higher-dose arms to stop treatment prematurely or at the first sign of progression. On the contrary, responders on the standard-dose arm had less weight gain and more tolerable side effects in general, which may have contributed to a tendency to remain on treatment longer, even if there was some evidence for progressive disease. A previously published quality-of-life study performed on a subset of the women entered in this trial demonstrated that, at 3 months, women treated with the standard dose reported an improved quality of life as measured by fewer side effects, better physical functioning, and less psychological distress.¹⁷ We examined the reasons for terminating MA among the responders by study arm. Progressive disease was clearly the dominant cause for stopping treatment on all arms, but toxicity and consent withdrawals were slightly more frequent at the higher doses.

The failure to demonstrate a dose response for MA in this trial supports an earlier finding that plasma progestin levels do not correlate with tumor response.¹⁸ Above a minimum threshold, the direct antitumor effects of progestins via the reduction of estrogen and progesterone receptors,^3,19,20 and their indirect effects through the suppression of adrenal production of sex corticosteroids,^5,21 are more dependent on the relative hormone sensitivity of the tumor cell than on the actual tissue or blood level of progestins. Nonetheless, this trial design could not totally disprove the possibility that high doses of progestins may, in select cases, act by other mechanisms, because patients who had progressed on standard doses were not treated at higher doses, as had been done in the pilot trial.¹² This theoretical possibility has less clinical value at present, however, because of the introduction of selective aromatase inhibitors for second- and third-line treatment that have less toxicity than high doses of MA but have similar or improved efficacy.²²

Contrary to the response data, the toxicity of MA correlated with the dose level. Only 19 grade 3 or greater toxic events occurred at the standard dose compared with 36 and 47 such events in the mid- and high-dose arms, respectively.

Thromboembolism was the leading cause of severe toxicity. Although standard-dose MA has not been shown to have an increased incidence of venous thrombosis or pulmonary emboli when compared with tamoxifen,² this trial raises concerns about a small but important increase in serious coagulation abnormalities, especially at the 1,600-mg dose. The precise mechanism of this hypercoagulability remains unknown but is likely to be similar to that seen with other sex corticosteroids.

An additional infrequent but nonetheless serious toxicity seen with MA was related to its corticosteroid-like effect resulting in hyperglycemia, hypertension, muscle weakness, and edema. The intrinsic corticosteroid activity of synthetic progestins has been appreciated ever since it was demonstrated that oral medroxyprogesterone acetate could protect adrenal function during treatment with aminoglutethimide.²³ However, at the higher dose levels used in this study, the corticosteroid effect of MA was exaggerated. Similar to the case cited in our study, reports of adrenal suppression after withdrawal from MA have become more frequent with the use of MA and other synthetic progestins for cancer cachexia.^24,25 Physicians should be alert to this side effect.

For the majority of women in this study, the most distressing side effect of MA was weight gain, and this was clearly dose-related. Few women in this study had such advanced breast cancer that they were cachectic or anorectic. Thus, substantial weight gain was undesirable. However, this effect of high doses of synthetic progestins on appetite stimulation and weight gain has been beneficial for some patients with advanced cancer, even in the absence of an antitumor effect.^26-30 The mechanism of this weight gain has not been demonstrated, although it does not seem to result entirely from the corticosteroid-like effects of MA.

Our finding of a lack of a dose effect for MA in advanced breast cancer stands in contrast to that reported previously by the POA. We found that the POA patients, at study entry, had more advanced cancer overall. It also seems that the stratification and randomization used by the POA failed to adequately balance the two treatment arms in regard to tumor burden. By chance, the patients in the POA 160-mg arm had more extensive disease than did patients in the 800-mg arm, and this may explain their inferior response rate. In contrast, patients on the 160-mg arm of the CALGB study had the expected response rate. It is likely that our larger sample size afforded better protection against imbalances in patient characteristics. The survival comparisons between study arms further support this hypothesis. Patients on the POA 160-mg arm had inferior survival compared with patients treated on the 160-mg CALGB arm, whereas patients on the POA and CALGB 800-mg arms had similar survival.

The discordant findings between our study and the POA trial may therefore be explained by the inferior response of patients on the POA control arm. The available evidence leads us to conclude that there is no reason to escalate the dose of MA for the palliative treatment of women with advanced breast cancer. Although progestins remain an important treatment option for hormone-sensitive disease, physicians prescribing MA for palliation of metastatic breast cancer should use the standard dose of 160 mg daily.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Other contributing institutions and grants include the following: University of Alabama (CA 47545), Southwestern Cancer Control Consortium Community Clinical Oncology Program (CA 45808), Bowman Gray School of Medicine (CA 03927), University of North Carolina at Chapel Hill (CA 47559), University of Chicago (CA 41287), The Medical Center of Central Massachusetts-Memorial Hospital (CA 37135), Dartmouth University (CA 04326), Duke University Medical Center (CA 47577), Dana-Farber Cancer Institute (CA 32291), University of Iowa Hospitals (CA 47642), State University of New York at Maimonides Medical Center (CA 25119), University of Maryland Cancer Center (CA 31983), University of Massachusetts Medical Center (CA 12449), McGill Cancer Center (CA 31809), University of Missouri-Ellis Fischel Cancer Center (CA 12046), Mount Sinai Hospital (CA 04459), Mount Sinai Hospital-Miami Community Clinical Oncology Program (CA 45564), North Shore University Hospital (CA 35279), New York Hospital-Cornell Medical Center (CA 07968), Rhode Island Hospital (CA 08025), Hematology-Oncology Associates of Central New York Community Clinical Oncology Program (CA 45389), State University of New York Health Science Center at Syracuse (CA 21060), University of Tennessee (CA 4755), University of California at San Diego (CA 11,789), University of California at San Diego-Kaiser Permanente Community Clinical Oncology Program (CA 45374), University of California at San Diego-South Nevada Community Clinical Oncology Program (CA 35421), Medical Center of Delaware Community Clinical Oncology Program (CA 45418), Washington University-Jewish Hospital (CA 47546), Walter Reed Army Medical Center (CA 26806).

	ACKNOWLEDGMENTS

 
We thank Bristol-Myers Squibb Co for supplying MA for this trial.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
1. Haller DG, Glick JH: Progestational agents in advanced breast cancer: An overview. Semin Oncol 13:2-8, 1986 (suppl 4)[Medline]

2. Schacter L, Rozencweig M, Canetta R, et al: Megestrol acetate: Clinical experience. Cancer Treat Rev 16:49-63, 1989

3. Allegra JC, Kiefer SM: Mechanisms of action of progestational agents. Semin Oncol 12:3-5, 1985 (suppl 1) [Medline]

4. Lundgren S, Kvinnsland S, Varhaug JE, et al: The influence of progestins on receptor levels in breast cancer metastasis. Anticancer Res 7:119-124, 1987[Medline]

5. Alexieva-Figusch J, Blankenstrin MA, Hop WCJ, et al: Treatment of metastatic breast cancer patients with different dosages of megestrol acetate: Dose relations, metabolic, and endocrine effects. Eur J Cancer Clin Oncol 20:30-40, 1984

6. Cavalli F, Goldhirsch F, Jungi F, et al: Randomized trial of low- versus high-dose medroxyprogesterone acetate in the induction treatment of postmenopausal patients with advanced breast cancer. J Clin Oncol 2:414-419, 1984[Abstract]

7. Pannuti F, Martoni A, Di Marco ARet al: Prospective, randomized clinical trial of two different dosages of medroxyprogesterone acetate (MAP) in the treatment of metastatic breast cancer. Eur J Cancer 15:593-601, 1979

8. Gallagher CJ, Cairnduff F, Smith IE: High dose versus low dose medroxyprogesterone acetate: A randomized trial in advanced breast cancer. Eur J Cancer Clin Oncol 23:1895-1900, 1987[Medline]

9. Della Cuna GR, Calciati A, Strada MRB, et al: High dose medroxyprogesterone acetate (MPA) treatment in metastatic carcinoma of the breast: A dose-response evaluation. Tumori 64:143-149, 1978[Medline]

10. Muss HB, Case LD, Capizzi RL, et al: High- versus standard-dose megestrol acetate in women with advanced breast cancer: A phase III trial of the Piedmont Oncology Association. J Clin Oncol 8:1797-1805, 1990[Abstract]

11. Tchekmedyian NS, Tait N, Aisner J: High-dose megestrol acetate in the treatment of postmenopausal women with advanced breast cancer. Semin Oncol 13:20-25, 1986 (suppl 4) [Medline]

12. Parnes HL, Abrams JS, Tchekmedyian NS, et al: A phase I/II study of megestrol acetate in the treatment of metastatic breast cancer. Breast Cancer Res Treat 18:171-177, 1991[Medline]

13. Abrams JS, Cirrincione C, Aisner J, et al: A phase III dose-response trial of megestrol acetate (MA) in metastatic breast cancer. Proc Am Soc Clin Oncol 10:33, 1992 (abstr 50)

14. Gaver RC, Pittman KA, Reilly CM, et al: Bioequivalence evaluation of new megestrol acetate formulations in humans. Semin Oncol 12:17-19, 1985 (suppl 1)

15. Hoogstraten B, Irewin L, Ahman D, et al: Breast Cancer: Suggested Protocol Guidelines for Combination Chemotherapy Trials. Bethesda, MD, National Institutes of Health, DHEW publication (NIH) 77-1192, 1977

16. Cox DR: Regression models and life tables (with discussion). J R Soc 34:187-220, 1972

17. Kornblith AB, Hollis DR, Zuckerman E, et al: Effect of megestrol acetate upon quality of life in a dose-response trial in women with advanced breast cancer. J Clin Oncol 11:2081-2089, 1993[Abstract/Free Full Text]

18. Hedley DW, Christie M, Weatherby RP, et al: Lack of correlation between plasma concentration of medroxyprogesterone acetate, hypothalamic-pituitary function, and tumour response in patients with advanced breast cancer. Cancer Chemother Pharmacol 14:112-115, 1985[Medline]

19. Tseng L, Gurpide E: Effects of progestins on estradiol receptor levels in human endometrium. J Clin Endocrinol Metab 41:402-404, 1975[Abstract/Free Full Text]

20. Chamness GC: Progestin action and progesterone receptors in breast cancer. Cancer Res 49:7176-7179, 1989[Free Full Text]

21. Blossey HC, Wander HE, Koebberling J, et al: Pharmacokinetic and pharmacodynamic basis for the treatment of metastatic breast cancer with high-dose medroxyprogesterone acetate. Cancer 54:1208-1215, 1984[Medline]

22. Buzdar A, Jonat W, Howell A, et al: Anastrozole, a potent and selective aromatase inhibitor versus megestrol acetate in postmenopausal women with advanced breast cancer: Results of overview analysis of two phase II trials. J Clin Oncol 14:2000-2011, 1996[Abstract/Free Full Text]

23. Nagel GA, Wander HE, Blossey HC: Phase II study of aminoglutethimide and medroxyprogesterone acetate in the treatment of patients with advanced breast cancer. Cancer Res 42:3440s-3444s, 1982 (suppl 8)

24. Leinung MC, Liporace R, Miller CH: Induction of adrenal suppression by megestrol acetate in patients with AIDS. Ann Intern Med 122:843-845, 1995[Abstract/Free Full Text]

25. Stoffer SS, Krakauer JC: Induction of adrenal suppression by megestrol acetate. Ann Intern Med 124:613-614, 1996 (letter) [Free Full Text]

26. Loprinzi CL, Ellison NM, Schaid DJ, et al: Controlled trial of megestrol acetate for the treatment of cancer anorexia and cachexia. J Natl Cancer Inst 82:1127-1132, 1990[Abstract/Free Full Text]

27. Tchekmedyian NS, Hickman M, Siau J, et al: Megestrol acetate in cancer anorexia and weight loss. Cancer 69:1268-1274, 1992[Medline]

28. Feliu J, Gonzalez-Baron M, Berrocal A, et al: Usefulness of megestrol acetate in cancer cachexia and anorexia. Am J Clin Oncol 15:436-440, 1992[Medline]

29. Simons JP, Aaronson NK, Vansteenkiste JF, et al: Effects of medroxyprogesterone acetate on appetite, weight, and quality of life in advanced-stage non-hormone sensitive cancer: A placebo-controlled multicenter study. J Clin Oncol 14:1077-1084, 1996[Abstract/Free Full Text]

30. Bruera E, Macmillan K, Kuehn N, et al: A controlled trial of megestrol acetate on appetite, caloric intake, nutritional status and other symptoms in patients with advanced cancer. Cancer 66:1279-1282, 1990[Medline]

Submitted April 10, 1998; accepted September 1, 1998.

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