Phase II Evaluation of Cisplatin and Etoposide Followed by Mitotane at Disease Progression in Patients with Locally Advanced or Metastatic Adrenocortical Carcinoma
A Southwest Oncology Group Study
Stephen K. Williamson, M.D.1 Danika Lew, M.A.2
Gary J. Miller, M.D., Ph.D.3 Stanley P. Balcerzak, M.D.A Laurence H. Baker, D.O.5 E. David Crawford, M.D.3
1 Division of Clinical Oncology, University of Kan- sas Medical Center, Kansas City, Kansas.
2 Southwest Oncology Group Statistical Center, Seattle, Washington.
3 University of Colorado, Denver, Colorado.
4 Ohio State University Health Center, Columbus, Ohio.
5 University of Michigan Medical Center, Ann Ar- bor, Michigan.
Supported in part by the following PHS Cooperative Agreement grant numbers awarded by the Na- tional Cancer Institute, DHHS: CA38926, CA32102,
| CA04920, | CA27057, | CA37981, | CA96429, |
|---|---|---|---|
| CA04919, | CA46441, | CA46282, | CA22433, |
| CA58415, | CA58861, | CA45450, | CA35261, |
| CA35178, | |||
| CA12213, CA74647, | CA58882, | CA76462, | |
CA35192, and CA14028.
Address for reprints: Southwest Oncology Group (SWOG-8925), Operations Office, 14980 Omicron Drive, San Antonio, TX 78245-3217.
Received August 27, 1999; accepted November 18, 1999.
BACKGROUND. A previous Southwest Oncology Group study demonstrated a 30% response rate with the combination of cisplatin and mitotane in the treatment of patients with metastatic adrenocortical carcinoma. Several case reports suggested that the combination of etoposide and cisplatin may be an active regimen in this disease. Because of these reports of potential activity, the authors conducted a Phase II trial evaluating the combination of etoposide and cisplatin. Due to the lack of data regarding the objective response rates to mitotane, the authors planned to evaluate the response rate to mitotane after disease progression on etoposide and cisplatin in patients with no prior mitotane therapy.
METHODS. Patients with advanced, unresectable, or metastatic adrenocortical car- cinoma with objectively measurable disease or biochemical abnormalities received cisplatin, 50 mg/m2, intravenously on Days 1 and 2, and etoposide, 100 mg/m2, on Days 1, 2, and 3. Cycles were repeated every 21 days. At the time of disease progression, patients who had not previously received mitotane received 1000 mg orally 4 times a day along with cortisone acetate and fludrocortisone acetate.
RESULTS. Of the 47 patients entered onto the study, 45 were eligible. Nine patients had received mitotane previously and 36 had not. Objective responses were noted in 11% of patients (5 of 45 patients) (95% confidence interval, 3.7-24%). The median survival was 10 months. The most common toxic effects were hematologic, gastrointestinal, and neurologic. Only 16 patients with no prior mitotane therapy went on to receive mitotane at the time of disease progression. An objective response was noted in 13% of patients (2 of 16 patients). The most common toxic effects were edema and gastrointestinal effects.
CONCLUSIONS. The current study demonstrates that the combination of cisplatin and etoposide has minimal activity in advanced and metastatic adrenocortical carcinoma and other treatment strategies are warranted. Cancer 2000;88: 1159-65. @ 2000 American Cancer Society.
KEYWORDS: medical oncology, adrenal carcinoma, chemotherapy, etoposide, cis- platin.
A drenocortical carcinoma is a rare tumor with an incidence rate of 1-2 cases per 1 million population.1,2 Surgical resection is the treatment of choice for this tumor whenever possible. However, most cases are diagnosed at an advanced and unresectable stage.3,4 Stan- dard therapy for unresectable or metastatic disease has been with either mitotane, (0,P’-DDD), aminoglutethimide, metapyrone, and,
more recently, ketoconazole. The latter three agents are utilized for symptomatic relief of symptoms caused by hypercortisolism in functional tumors and have no antitumor effect.5,6 Mitotane is an adrenolytic and chronic administration of > 3 g/day results in adrenal atrophy and necrosis. This drug first was eval- uated in humans by Bergenstal et al. who noted “re- gression” of metastases in 7 of 18 patients and a re- duction in steroid levels in 7 additional patients.7 These responses lasted between 1.5-26 months. The National Cancer Institute sponsored the production and distribution of mitotane to individual investiga- tors, who were required to file complete case reports and periodic studies of the drug’s efficacy and safety. Three reports have been published summarizing the results of the data collected from 105 investigators.2,3,8 The primary problems with these studies were that uniform criteria for antitumor response were not ap- plied and any indication on the report forms of regres- sion in measurable disease was accepted as evidence of response. The first reports by Hutter and Kayhoe indicated a 34% response rate in measurable tumors and that approximately 70% of the 138 patients achieved a ≥ 50% decrease in hormone production.2 However, these authors also reported that survival in female patients who responded to mitotane was not statistically significantly different from those who did not respond. Only female patients were reported to have an improved survival compared with males. The number of males was too small to draw any significant conclusions.3
Using the same data base in a separate article on 115 patients, Lubitz et al. reported a 61% response rate in patients with measurable disease and an 89% re- sponse rate in reduction of steroid levels, with an average survival of 8.4 months.8 These results often have been compared with the 2.9-month survival re- ported by Macfarlane in 20 patients with untreated, inoperable disease.4 The survival reported by Macfar- lane is from the date of diagnosis. He also reported survival from the time of onset of symptoms in the same 20 patients as being an average of 13.2 additional months, with 4 patients living > 2 years.4 Because the natural history of this disease is so variable, and im- provements in diagnostic capabilities occur over time, comparing survival with historic data can be mislead- ing. Therefore, it is difficult to support a survival ben- efit for mitotane based on the above data.
To our knowledge there are several other recent reports using more standardized response criteria that do not support the results discussed earlier. These reports describe objective responses in < 20% of pa- tients, and when responses occurred, they were short- lived.9-13 The toxicity of mitotane is substantial, and
includes anorexia, nausea, emesis, lethargy, somno- lence, and rashes. In view of this, and the absence of any data indicating an effect on overall survival, it is important to search for more effective agents and to evaluate response prior to treatment with mitotane or other chemotherapeutic agents.
The literature is replete with case reports of vari- ous chemotherapeutic agents producing some re- sponses, but to our knowledge none with sufficient numbers to definitely conclude that any were active or worth pursuing further. There are several reports in- dicating that cisplatin has some activity, but this most likely is minimal.14,15 Etoposide has been demon- strated to be synergistic with cisplatin in an animal model.16 In addition, the combination of etoposide and cisplatin is active in refractory small cell carci- noma and germ cell carcinomas, suggesting therapeu- tic synergy. Johnson and Greco reported two patients who achieved partial remissions after one cycle of treatment with this combination.17 Hesketh et al. also have reported treating 4 patients with the combina- tion of etoposide, cisplatin, and bleomycin, with 1 patient achieving a complete response lasting 12 months, and another patient achieving a partial re- sponse.18 Results of Southwest Oncology Group (SWOG)-8325, which evaluated the combination of mitotane and cisplatin, demonstrated objective re- sponses in 30% of patients with a response duration of 7.9 months and a median survival of 11.8 months.19 Based on these initial observations, we proposed to evaluate the combination of etoposide and cisplatin in advanced and metastatic adrenal cortical carcinoma in patients with no prior therapy as well as in patients previously treated with mitotane. Patients with no prior treatment with mitotane and who progressed while receiving etoposide and cisplatin were evaluated for response to mitotane.
The primary objective of this trial was to assess the response rate of cisplatin and etoposide in the treatment of patients with advanced and metastatic adrenal cortical carcinoma. A secondary objective was to assess the response rate to mitotane after progres- sion on the above chemotherapy for patients with no prior treatment with mitotane. The final objective was to assess the qualitative and quantitative toxic effects of these treatments.
MATERIALS AND METHODS
To be eligible, patients were required to have a histo- logically confirmed diagnosis of adrenocortical carci- noma that was metastatic or residual local disease that was not amenable to further surgical resection. Pa- tients must have had either bidimensionally measur- able disease or evaluable disease comprised of an
elevation in 24-hour urinary 17-keto- or hydroxycor- ticosteroid. Prior chemotherapy other than mitotane was not allowed. Patients must have recovered from the effects of any prior therapy and have had adequate renal function (calculated creatinine clearance ≥ 60 mL/minute and serum creatinine ≤ 1.5 mg/dL), and hematologic status (leukocyte count ≥ 4000/uL, abso- lute granulocyte count ≥ 2000/uL, and a normal plate- let count). Patients had to have a SWOG performance status of 0-2. Pathology review by a central patholo- gist was required. Written informed consent was re- quired from all patients.
Patients with no prior mitotane therapy were scheduled to receive a combination of cisplatin and etoposide. Treatment was continued for a total of 6 months or until disease progression or excessive tox- icity occurred, at which time patients were reregis- tered and treated with mitotane. Patients with prior mitotane therapy were treated with the same cisplatin and etoposide regimen but were not treated with mi- totane at the time of disease progression.
To allow outpatient administration of the chemo- therapy, cisplatin was administered at 50 mg/M2 on Days 1 and 2 in 1000 mL of normal saline with 3 g of MgSO4 at a rate of 1 mg/minute. Patients were to receive at least 2500 mL of fluids on each day of cisplatin administration. Etoposide was administered at 100 mg/M2 over 1 hour on Days 1, 2, and 3. Cycles were repeated every 21 days provided the absolute granulocyte count was ≥ 2000/uL, platelet count was ≥ 100,000/uL, serum creatinine was ≤ 1.5 mg/dL, and calculated creatinine clearance was > 60 mL/ minute. Dose modifications were based on toxicity. If the creatinine clearance on Day 1 was > 50 mL/ minute but < 60 mL/minute, the dose of cisplatin was reduced by 25% on Days 1 and 2. If the creatinine clearance was ≤ 50 mL/minute then cisplatin was held for that course of therapy and was not readmin- istered until the calculated creatinine clearance was ≥ 60 mL/minute and the dose was reduced by 25% for subsequent cycles.
Etoposide dosages were modified based on gran- ulocyte and/or platelet nadirs from the previous cycle. Treatment was held if the granulocyte count was < 2000/uL or if the platelet count was < 100,000/uL on the day of treatment. Dosages of etoposide were re- duced by 25% if the platelet nadir was between 50,000-75,000/uL, if the platelet nadir was between 75,000-100,000/uL and the granulocyte nadir was be- tween 1000-1500/uL, or if the granulocyte nadir was < 1000/uL. Etoposide was decreased by 50% if the platelet nadir was < 50,000/uL, if the platelet nadir was between 50,000-75,000/uL and the granulocyte nadir was between 1000-1500/uL, or if the platelet
nadir was between 75,000-100,000/uL and the granu- locyte nadir was < 1000/uL. The dosage of cisplatin was reduced by 25% for any Grade 1 neurotoxicity and was held for neurotoxicity ≥ Grade 2 (NCI Common Toxicity Criteria).
Patients who had received no prior mitotane were reregistered at the time they developed progressive disease on etoposide and cisplatin. Patients were eli- gible for treatment with mitotane if their SWOG per- formance status was < 3, if they had a life expectancy of > 4 weeks, if they had recovered from the toxicity of prior therapy, if they continued to have measurable or evaluable disease, and if there were no plans for con- comitant radiotherapy. Mitotane was administered at a dose of 1000 mg orally, 4 times daily. The dose was escalated at 3-week intervals if no nausea and emesis occurred during the previous 3 weeks. This initially would be escalated to 2000 mg administered 4 times daily, then escalated to 2500 mg 4 times daily. All patients received concomitant cortisone acetate, 25 mg orally twice daily, and fludrocortisone acetate, 0.1 mg orally daily. Treatment was to continue for 8 weeks or until disease progression occurred. Dose modifica- tions of mitotane were allowed for neurotoxicity. If Grade 2 neurotoxicity occurred, mitotane was reduced by 50%. Mitotane was held for Grade 3 or 4 neurotox- icity.
Mitotane was reduced by 50% for any ≥ Grade 2 nausea and emesis. Mitotane was to be discontinued if any ≥ Grade 1 hepatic toxicity occurred that was not believed to be due to tumor. Treatment was to be discontinued if the patient experienced toxicity re- quiring more than two downward dosage adjust- ments.
Studies performed before therapy included a complete history and physical examination, complete blood count with platelets, urinalysis, and a calculated creatinine clearance. Twenty-four-hour urine collec- tions for determination of 17-ketosteroids and 17-hy- droxycorticosteroids were performed before therapy and also every 3 weeks if initially abnormal. Baseline chest radiographs and audiograms also were obtained and were repeated as clinically indicated. X-ray stud- ies or scans were performed every 3 weeks (6 weeks for computed tomography) to determine the size of mea- surable lesions.
Response and Toxicity Criteria
A complete response was defined as the disappear- ance of all clinical evidence of tumor on at least two successive evaluations. Partial response required a > 50% decrease in the sum of the products of the per- pendicular dimensions of all measurable lesions on at least 2 evaluations. Progressive disease was defined as
a > 50% increase in the sum of the product of mea- surable lesions over the smallest sum observed, or the appearance of new lesions. Stable disease was defined as not qualifying for partial response or disease pro- gression.
Statistical Analysis
Accrual was by a two-stage design with the assump- tion that the regimen would not be of interest if it were to have a true response rate of < 5%, but would be of considerable interest if it were to have a response rate of ≥ 20%. The study design had a power of 92% to detect a 20% response rate. Planned accrual was 40 eligible patients. Five or more responses from 40 pa- tients were required for the regimen to be judged to warrant further study. An adjustment for an actual accrual of 45 eligible patients required ≥ 6 responses to warrant further study.
RESULTS
The study accrued 47 patients between June 15, 1989 and December 1, 1995. Two patients were ineligible: 1 underwent tumor measurements > 14 days before registration and 1 had an insufficient creatinine clear- ance. Forty-four of the 45 eligible patients had mea- surable disease. Fifteen patients also were being fol- lowed with elevated tumor markers. Major treatment deviations occurred in three patients. One patient re- ceived aminogluthetamide in addition to the study treatment, and two had treatment delivered without dose modifications per protocol for hematologic tox- icities.
The patient characteristics are outlined in Table 1. Nine patients had prior treatment with mitotane. Forty-three patients had Stage IV disease and 40 pa- tients had a SWOG performance status of 0-1. Objec- tive responses were reported in 5 of the 45 patients. They were all partial responses, for an overall response rate of 11% (95% confidence interval, 3.7-24%). In addition to these five patients, there were three pa- tients with an unconfirmed partial response (respons- es had to be confirmed with a second evaluation 4 weeks after the response was documented). However, inclusion of these three patients with the responders would not alter the response rate significantly. Re- sponse could not be determined for eight patients and they were assumed to be nonresponders. Of these eight patients, one was a treatment-related fatality, two underwent one assessment followed by surgical resection of residual disease, one went off study early due to toxicity and was not assessed prior to death, one did not have consistent follow-up assessments, and three patients previously were noted to not have a confirmation of response. Of interest was one patient
| No prior mitotane (n = 36) | Prior mitotane (n = 9) | |||
|---|---|---|---|---|
| Age (yrs) | ||||
| Median | 46.5 | 30.0 | ||
| Minimum | 12 | 18 | ||
| Maximum | 72 | 46 | ||
| Gender | ||||
| Male | 17 | 47% | 6 67% | |
| Female | 19 | 53% | 3 | 33% |
| Race | ||||
| White (Non-Hispanic) | 32 | 89% | 7 78% | |
| Black (Non-Hispanic) | 3 | 8% | 1 11% | |
| Hispanic | 1 | 3% | 1 11% | |
| Measurable disease | ||||
| Yes | 35 | 97% | 9 100% | |
| No | 1 | 3% | 0 | 0% |
| Evaluable disease | ||||
| Yes | 10 | 28% | 5 56% | |
| No | 26 | 72% | 4 | 44% |
| Prior mitotane treatment | ||||
| Yes | 0 | 0% | 9 100% | |
| No | 36 | 100% | 0 | 0% |
| Stage | ||||
| III | 2 | 6% | 0 0% | |
| IV | 34 | 94% | 9 | 100% |
| Performance status | ||||
| 0-1 | 33 | 92% | 7 78% | |
| 2 | 3 | 8% | 2 22% | |
who had no response but whose disease remained stable after 20 cycles. The patient survived 61 months from the date of the initiation of treatment and 46 months from the time treatment was withdrawn. Of the 15 patients who also were followed with elevated biochemical markers, 9 had a ≥ 50% reduction from baseline levels.
Of the 36 eligible patients without prior mitotane, 17 went on to mitotane at the time of first disease progression after treatment with cisplatin and etopo- side as per protocol and 16 were evaluable. Of the 19 patients who did not go on to mitotane, 3 were early deaths; 1 patient progressed at Week 8 and was left on cisplatin and etoposide for a year and never received mitotane; 1 patient received carboplatin and etopo- side instead of mitotane at first disease progression; 1 patient received radiation therapy instead of mitotane at first disease progression; 1 patient with stable dis- ease after 20 cycles received no further therapy; 4 patients did not receive mitotane due to toxicity from cisplatin and etoposide; and 8 patients either refused the mitotane at first disease progression or did not return for follow-up. One patient received doxorubicin in addition to mitotane and this patient was not evalu- able for toxicity or response. The patient characteris-
| Mitotane at progression (n = 16) | ||
|---|---|---|
| Age (yrs) | ||
| Median | 45.0 | |
| Minimum | 13 | |
| Maximum | 61 | |
| Gender | ||
| Males | 7 | 44% |
| Females | 9 | 56% |
| Race | ||
| White (Non-Hispanic) | 15 | 94% |
| Hispanic | 1 | 6% |
tics for those eligible patients who received mitotane are outlined in Table 2. Objective partial responses were noted in 2 patients, for a response rate of 13%. Two other patients had stable disease. Two of 6 pa- tients with elevated biochemical markers had at least a 50% reduction from baseline levels.
Toxicity from etoposide and cisplatin therapy is noted in Table 3. There were two treatment-related fatalities. One patient did not have a dose reduction as per protocol and died from infection secondary to Grade 4 granulocytopenia, thrombocytopenia, and acute renal insufficiency. One patient died due to adult respiratory distress syndrome, for which the role of chemotherapy is unknown. Neutropenic sepsis also may have contributed to the death of this patient, who also had Grade 4 granulocytopenia. Hematologic tox- icity was the primary toxicity and granulocytopenia was the most common toxicity with 21 Grade 4 and 11 Grade 3 cases reported. Grade 3 and 4 thrombocyto- penia occurred in six patients. Grade 3 and 4 emesis occurred in five patients. Six of the 21 patients with Grade 4 toxicity discontinued therapy due to toxicity. Grade 3 neurotoxicity occurred in three patients.
The toxicity of mitotane included Grade 3 and 4 edema in two patients. Grade 4 thrombocytopenia occurred in one patient. Grade 3 nausea or emesis occurred in two patients. Grade 2 nausea and emesis occurred in five patients.
Pathologic materials were received from 40 pa- tients. The consultant pathologist confirmed the diag- nosis in all cases. No patient was declared ineligible due to pathologic review. Review also was conducted examining known prognostic variables and relating them to patient response. Unfortunately, there were too few responders to draw any significant conclu- sions. Three of the responders had confluent necrosis. This is the opposite of what one might have expected and suggests that this variable should be examined further as a prognostic factor. No responses were ob-
| Toxicity | Grade Unk 0 1 2 3 4 5 | ||||||
|---|---|---|---|---|---|---|---|
| Anemia | 0 | 20 | 10 | 11 | 4 | 0 | 0 |
| Creatinine increase | 0 | 37 | 4 | 4 | 0 | 0 | 0 |
| Diarrhea | 0 | 42 | 1 | 0 | 2 | 0 | 0 |
| Granulocytopenia | 0 | 11 | 0 | 2 | 11 | 21 | 0 |
| Hearing | 0 | 38 | 2 | 4 | 1 | 0 | 0 |
| Infection | 0 | 41 | 1 | 0 | 1 | 1 | 1 |
| Lung, other | 0 | 43 | 1 | 0 | 0 | 0 | 1 |
| Malaise/fatigue/lethargy | 0 | 35 | 5 | 1 | 4 | 0 | 0 |
| Nausea | 0 | 8 | 16 | 14 | 7 | 0 | 0 |
| Neuromotor | 0 | 42 | 1 | 0 | 2 | 0 | 0 |
| Paresthesia | 1 | 37 | 3 | 1 | 3 | 0 | 0 |
| Renal, other | 0 | 44 | 0 | 0 | 0 | 1 | 0 |
| Stomatitis | 0 | 39 | 3 | 3 | 0 | 0 | 0 |
| Thrombocytopenia | 0 | 27 | 6 | 6 | 3 | 3 | 0 |
| Emesis | 0 | 16 | 10 | 14 | 4 | 1 | 0 |
| Weakness | 0 | 37 | 4 | 3 | 1 | 0 | 0 |
Unk: unknown.
a Maximal toxicity experienced during treatment.
served in patients in whom the tumors were charac- terized as having atypical mitoses; the highest nuclear grades; poor differentiation; or prominent, frequent nucleoli. We also examined the survival times (date of registration to date of death) for the patients with available pathology data. Subsets were too small to make formal comparisons. The median survival for those with atypical mitoses (7 patients) was 6 months, and the median survival for those without atypical mitoses (13 patients) was 10 months. The median survival for those with confluent necrosis (14 patients) was 10 months, and the median survival for those without confluent necrosis (5 patients) was 5 months.
DISCUSSION
This study represents the second SWOG evaluation of chemotherapy in patients with adrenal cortical carci- noma. The rarity of this tumor requires a cooperative group approach to assess new therapeutic modalities in a reasonable time period. Even in a large coopera- tive group, it took 6.5 years to accrue an adequate number of patients for analysis to this trial. The cur- rent study investigated the utility of combined cispla- tin with etoposide. The secondary objective of the trial was to evaluate further the objective response rate to mitotane.
The objective response rate of 11% obtained with this combination does not represent an improvement over the 30% response rate obtained in the previous SWOG trial of cisplatin and mitotane. It is possible
that the addition of mitotane to cisplatin improved the response rate; however, the confidence intervals of both trials do overlap and therefore one can only state that the regimens do have some, albeit minimal, ac- tivity in this disease. Certainly it does not appear that the addition of etoposide results in any advantage over the use of cisplatin alone in this disease.
There may be several reasons for these findings. The first would be that the combination of mitotane with cisplatin may interact synergistically or to reverse an as yet unknown resistance mechanism. High levels of expression of P-glycoprotein have been found in both the normal adrenal gland and adrenocortical tu- mors.2º P-glycoprotein is a product of the mdr-1 gene, which is a 130- to 180-kilodalton plasma membrane phosphoglycoprotein that mediates multidrug resis- tance in cell culture by increasing efflux of the natural product chemotherapeutic agents. Bates et al. have demonstrated in vitro that this resistance can be re- versed with clinically achievable concentrations of mi- totane.21 This may be one reason for the lower re- sponse rate achieved in our trial compared with others utilizing similar agents but including the coadminis- tration of mitotane. For example, Bonacci et al. re- ported a 33% overall response rate with the combina- tion of etoposide and cisplatin administered with mitotane.22 In another clinical trial Berruti et al. eval- uated a regimen of doxorubicin, etoposide, and cis- platin given with mitotane in 28 patients with ad- vanced adrenal cortical carcinoma. They reported a complete response in 2 patients and partial response in 13 patients, for an overall response rate of 53.5%.23 Decker et al. reported the Eastern Cooperative Oncol- ogy Group experience with doxorubicin. They re- ported a 16% response rate in 19 previously untreated patients and a 0% response rate in 15 patients previ- ously treated with mitotane.24 From the limited data available, one might conclude that if chemotherapy is to be administered in these patients, the simultaneous administration of mitotane should be considered.
We also cannot exclude the possibility that the observed differences between these other trials and ours is simply due to the small numbers of patients in each of the trials, because the 95% confidence inter- vals of all of these trials overlap. Unfortunately, due to the limited number of patients with this disease, a randomized clinical trial testing these questions could never be performed.
We also tried to identify the response rate to mi- totane objectively. Unfortunately, > 50% of the pa- tients who would have been eligible to be crossed over to the mitotane arm did not. Although the objective response rate of 13% is low we did not achieve our accrual goal to assess this response rate accurately and
cannot make any meaningful conclusions. One could speculate that one reason that the response rate was so low is that patients had received prior chemother- apy and this may have induced some type of resis- tance mechanism, producing a lower response rate.
In this trial, pathologic review confirmed the di- agnosis from each participating institution. Patients were entered on this trial from 35 different institu- tions. No responses were observed among patients with atypical mitoses, high nuclear grade, poor differ- entiation, or numerous nucleoli per cell. Responses were found in patients with confluent necrosis. Re- cently, the topic of prognostic significance of patho- logic features for adrenocortical carcinoma has been examined in a series of 46 patients.25 In this series, as in the current series, the presence of mitotic figures was associated with poor outcome. However, intratu- moral hemorrhage also was found to be predictive of a poor prognosis, whereas we did not observe such an association in the current study. These observations point to a continuing need to evaluate prognostic factors that may predict for response to therapy and survival.
The median survival observed for patients in this study was 10 months and is similar to that noted in other trials.
The current study demonstrates that the combi- nation of cisplatin and etoposide has minimal activity in adrenocortical carcinoma and that other treatment strategies are warranted. From the available evidence, as discussed earlier, we would suggest that mitotane be administered concurrently with chemotherapy. Further evaluation of newer agents and treatment strategies is warranted.
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