Recurrent or Metastatic Disease in Select Patients With Adrenocortical Carcinoma
Aggressive Resection vs Chemotherapy
J. Christian Jensen, MD; Harvey I. Pass, MD; William F. Sindelar, MD; Jeffrey A. Norton, MD
· In a retrospective, nonrandomized comparison of patients with first recurrence of adrenocortical cancer, 18 patients were treated with chemotherapy (primarily mitotane) and 15 patients were treated with surgical resection plus similar chemotherapy. Surgical resection of recurrent adrenocortical cancer was often extensive, with morbidity in 20% of patients and no mortality. Mitotane therapy was Ineffective at controlling tumor growth. Median survival from the time of diagnosis for all patients was only 23 months and no patient was cured. Disease-free interval greater than 12 months was associated with prolonged survival, but it only occurred in six patients (18%), with a similar frequency in both treatment groups. Surgical resection of recurrent disease was associated with prolonged survival from the time of first recurrence. The potential benefit of this resection was evident in the 5 patients (33%) who were able to live greater than 5 years from the time of first recurrence with improvement in symptoms and signs of hypercortisolism. Although no patient with recur- rent adrenal cancer could be cured, resection of recurrent dis- ease was associated with a slight prolongation of survival and good palliation of Cushing’s syndrome. (Arch Surg. 1991;126:457-461)
A drenocortical carcinoma (AC), though fortunately rare, remains one of the most morbid and lethal of tumors.1 It comprises between 0.05% and 0.2% of all cancers: that is, approximately 2 per million in the world population. It occurs primarily in young children (5 years of age) and young adults, with a peak incidence in the fourth and fifth decades.1 In addition, these tumors commonly secrete high amounts of cortisol, and patients frequently present with Cushing’s syn- drome. Physician recognition and diagnosis of Cushing’s syn- drome is often delayed, because endogenous hypercortisolism itself is rare, the signs of hypercortisolism may occur in other disease processes, the changes may be subtle, and no particu- lar symptom or sign occurs in every patient.2 Without recogni- tion and proper management, Cushing’s syndrome by itself results in high rates of morbidity and mortality. Untreated patients with endogenous hypercortisolism of all types have a 5-year survival rate of only 50%, with most deaths resulting from infection or cerebrovascular disease.3 Thus, patients with AC have two potentially lethal diseases: an aggressive, invasive neoplasm and the hypercortisolism produced by it.
Because of its rapid growth, metastatic potential, and the insidious nature of Cushing’s syndrome, patients with AC often present with far advanced and/or metastatic disease. In fact, the weight of these tumors at initial resection is at least 100 g and is usually 5 kg.1 Furthermore, AC recurs with grim frequency and usually progresses inexorably to cause the
death of the patient.14 Besides surgical resection, there is no effective therapy for patients with AC. Chemotherapy has relied on mitotane and experimental phase 1 agents, but responses have been anecdotal, with no clear efficacy or docu- mentation of benefit in large groups of patients.6,6
Another problem in the surgical treatment of these patients is proper intraoperative and subsequent pathologic diagnosis of a malignant adrenocortical tumor. Histologic criteria are not able to distinguish benign from malignant adrenal neo- plasms, and the single best criterion seems to be the weight of the resected gland (>100 g is consistent with cancer).1 It is possible that inadequate operative identification or underesti- mation of the extent of invasion of tumor results in incomplete resection and inability to provide cure. Therefore, nearly every patient with AC will have development of recurrent and/or metastatic disease.1 Following initial complete resec- tion, patients have recurrences of disease in the local area plus lymph nodes (68%) and may have development of synchronous or metachronous metastases to the lung (71%), liver (42%), or bone (26%).” The common management question is what type of treatment to offer these patients with recurrent and/or metastatic disease when mitotane and other chemotherapy regimens have been ineffective.
Aggressive surgery and metastatectomy is a well-accepted strategy.&11 In addition, in patients with AC and hypercortiso- lism as in other hormone-secreting malignant tumors, resec- tion of all gross disease may markedly ameliorate the symp- toms and signs of hormonal excess and alleviate most of the morbidity associated with these hormonally functional tu- mors.12,13 Aggressive surgical resection with varying degrees of success has been reported in the literature in small numbers of patients with recurrent and/or metastatic adrenal can- cer.9,14-17 However, there is scant literature describing a large cohort of patients in whom aggressive surgical resection of recurrent AC has been attempted. Our bias and results in one patient18 have led us to attempt to aggressively resect locally recurrent and metastatic disease in patients with recurrent adrenal cancer in whom we believed preoperatively that we could eventually resect all identifiable disease with either a single or staged operative approach. We now attempt to ana- lyze our results in these patients by comparing them with a similar cohort of patients treated with chemotherapy alone.
PATIENTS AND METHODS Patient Selection
The records of the Clinical Center of the National Institutes of Health, Bethesda, Md, were searched for patients treated with a diagnosis of AC from 1965 to 1989. Some of these patients have been included in a previous report.18 Pathology reports, operative records, and charts were reviewed. Patients were selected for this study if they presented following complete (potentially curative) resection of the primary tumor and they subsequently had development of either locally recurrent and/or distant metastatic disease. Patients were entered into this study at the time of initial recurrence, the time of presentation to our institution. Patients in both groups had only one
Accepted for publication November 19, 1990.
From the Surgical Metabolism Section and the Thoracic Oncology Section, National Cancer Institute, National Institutes of Health, Bethesda, Md. Read before the 43rd Annual Cancer Symposium of the Society of Surgical Oncology, Washington, DC, May 21, 1990.
Reprint requests to Surgical Metabolism Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bldg 10, Room 2B07, Bethes- da, MD 20892 (Dr Norton).
previous operation that removed the primary tumor. Patients were excluded from this study if they had incomplete resection at the time of the original operation or if they presented originally with stage IV disease or distant metastases. The extent and amount of disease was estimated for each patient. Tumor location and burden was based on roentgenographic imaging of the tumor at either the National Insti- tutes of Health or the referring institution. Disease was scored by involvement of organ systems or viscera and by direct measurements when available. Patients treated with surgery also received chemo- therapy, usually mitotane. The patients were stratified by their treatment into surgery or nonsurgery group and analyzed for subse- quent survival. Operative complications were included in the analy- sis. Follow-up was obtained on each patient directly from the chart, by contact with the patient’s family or referring physician, or from the tumor registry in the patient’s community.
Therapeutic Regimens
The chemotherapeutic regimen of each patient was reviewed. The operative history of each patient was recorded, with particular atten- tion to the exact procedure or procedures required to resect locally recurrent and/or metastatic AC. The use of postoperative chemo- therapy was also recorded. The extent of the operation, including resection of involved tissues, was recorded. Operations for any com- plications were noted.
Statistical Analysis
Survival was calculated for all patients from the time of initial diagnosis and first recurrence. In an effort to evaluate comparability of surgical and chemotherapy groups, extent of disease was scored and analyzed by Fisher’s Exact Test. Disease-free interval (time from initial diagnosis to time of first recurrence) was divided into greater or less than 12 months and subsequent survival was analyzed independent of treatment group. Survival curves were constructed by the Kaplan-Meier method and analyzed for significant differences by a modification of the Kruskal-Wallis Test (Breslow Test).
RESULTS Patient Characteristics and Extent of Disease
Thirty-three patients with pathologically proved initial re- currence of adrenal cancer were identified for inclusion in this study. Long-term follow-up is complete on 32 of 33 patients.
One patient was unavailable for follow-up but was known to be alive with disease at 23 years following treatment. At the time of documented initial recurrence of AC, 18 patients were treated primarily with chemotherapy (chemotherapy group), and 15 patients were treated with chemotherapy and aggres- sive surgery (surgery group). The mean age of patients from each group was approximately 35 years and was not different between treatment groups (Table 1). Similarly, the percent- age of women, the disease-free interval, and the percentage of patients with Cushing’s syndrome, factors that might be expected to affect subsequent survival, were not different between the two treatment groups (Table 1). Finally, the extent of disease as measured by the proportion of patients with local recurrence, lymph node, liver, lung, or bone disease at presentation of initial recurrence of AC was not different between the two treatment groups, and, similarly, the pro- portions of patients with either stage III or stage IV recur- rent disease were not different (Table 1). Therefore, in regard to important prognostic patient characteristics and extent of disease at the time of presentation with recurrent AC, the patients in the surgery and chemotherapy groups were comparable.
Chemotherapy and Extent of Surgery
Mitotane, either alone or in combination with other agents, was the most frequently used single drug in both chemothera- py and surgery plus chemotherapy treatment groups, with 15 of 18 patients in the chemotherapy group and 13 of 15 patients in the surgery plus chemotherapy group receiving this drug (Table 2). A variety of other chemotherapy agents were used, and the proportions of each drug were again comparable in the two patient groups (Table 2), but agents appeared to be ineffective and minimal, if any, responses were seen. Anti- cortisol drugs were used in some patients in an attempt to control the symptoms and signs of Cushing’s syndrome. Again, the proportions of patients receiving these drugs were similar (Table 2).
The 15 patients in the surgery group underwent 32 opera-
| Table 1. - Patient Characteristics and Extent of Recurrent Adrenocortical Carcinoma by Treatment Group* | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Group | No. of Patients | Mean Age, y (Range) | Female, No. (%) | Cushing's Syndrome, No. (%) | Median DFI,t mo (Range) | No. (%) of Patients With Disease at Site on Entry | Stage,# | No. (%) | ||||
| Local | Lymph Node | Liver | Lung | Bone | ILt | IV | ||||||
| Chemotherapy | 18 | 37 (18-67) | 12 (67) | 12 (67) | 3.3 (0.5-43) | 10 (55) | 1 (6) | 7 (39) | 8 (44) | 2 (11) | 8 (44) | 10 (56) |
| Surgery | 15 | 35 (14-60) | 9 (60) | 13 (87) | 4.5 (0.8-24) | 8 (53) | 1 (7) | 5 (33) | 5 (33) | 0 (0) | 7 (46) | 8 (54) |
*There were no significant differences between surgery and chemotherapy groups by Fisher’s Exact Test. +DFI indicates disease-free interval (interval from time of initial resection to recurrent disease) in months. #Extent and stage of recurrent adrenal cancer at time of entry into the study.
| Group | No. of Patients | Chemotherapy Drug* | Anticortisol Drug | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Mitotane | Suramin Sodium | Fluorouracil | Doxorubicin | Etoposide | Cisplatin | Aminoglutethamide | Ketoconazole | RU 486 | ||
| Chemotherapy | 18 | 15 | 4 | 3 | 2 | 1 | 3 | 2 | 2 | 0 |
| Surgery | 15 | 13 | 1 | 4 | 1 | 3 | 1 | 2 | 1 | 1 |
*Total number of patients who were given a drug or had an operative procedure.
+One patient had more than one local reexcision.
One patient had more than one resection of part of the inferior vena cava.
§One patient had two separate liver resections.
|One patient had six different pulmonary resections.
tive procedures in an attempt to resect all locally recurrent and/or metastatic AC. The thoracoabdominal operative pro- cedures performed were major, potentially morbid, and life- threatening. Procedures included resection of part of or all of the involved organs, including the kidney and the inferior vena cava in five patients, the diaphragm in six patients, and part of the liver in eight patients (Table 2). In one patient, a right hepatic lobectomy was performed in combination with a partial duodenectomy, antrectomy, right colectomy, gastro- jejunostomy, and colostomy. In addition, 12 separate median sternotomies and/or thoracotomies were performed to re- move 68 malignant pulmonary nodules in seven patients, including one patient who had six different pulmonary resec- tions. One patient in the surgery group has been described in detail previously.15 One patient had massive blood loss (>60 U), and all other patients required either no blood or less than 10 U of blood. Three patients required reoperations in the postoperative period. One patient underwent reoperation for postoperative bleeding and two underwent reoperation for abdominal abscess. The mean postoperative hospital stay was 14 days. No patient died in the immediate postoperative period (within 60 days of surgery) and all patients were discharged from the hospital.
Survival
Overall survival for all patients in this study was only 22.8 months from diagnosis (Fig 1). All patients except one, who is still alive with disease, eventually died of AC. Survival from the time of initial diagnosis for patients in the chemotherapy group was not significantly different than survival from the time of initial diagnosis for patients in the surgery group (Fig 2). However, when measured from time of inclusion in this study and admission to our institution, that is, the time of first recurrence of AC, survival was significantly longer in pa- tients treated with chemotherapy plus aggressive surgical resection of recurrent disease than in patients treated with chemotherapy alone (Fig 3). The median survival from time of first recurrence was 27 months in the surgery group vs 11 months in the chemotherapy group (P <. 05). This slight pro- longation of survival was primarily due to five patients (33%) who were able to survive greater than 5 years from the time of first recurrence. In addition, these five patients had marked improvement in the signs and symptoms of Cushing’s syn- drome, indicating a clear benefit for this subset of the entire group.
The disease-free interval, that is, the length of time from initial resection to first recurrence (presentation at our hospi- tal), was not significantly different for patients in either the surgery or chemotherapy groups (data not shown). This fac- tor, however, was an important prognostic variable in pa- tients with recurrent AC and was associated with a signifi- cantly improved overall survival when the interval was greater than 12 months (P <. 05; Fig 4). However, only six (18%) of 33 patients had a disease-free interval greater than
| Resection: Extent of Surgery, No. | ||||
|---|---|---|---|---|
| Local | Kidney | Inferior Vena Cava | Liver | Lung |
| 8+ | 5 | 4+ | 7§ | 기 |
12 months; most patients in both groups had a short disease- free interval and poor prognosis. The influence of surgery and chemotherapy in patients with long disease-free intervals could not be assessed, because of too few patients in each treatment group who had a disease-free interval greater than 12 months. No other significant prognostic information was
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obtained when survival was analyzed as a function of age at diagnosis, tumor function, sex, or combinations of these vari- ables (data not shown).
COMMENT
Although AC occurs primarily in a young healthy popula- tion of patients who can generally tolerate aggressive surgery and chemotherapy, survival of patients with an initial diagno- sis of AC is poor, and survival of patients with a diagnosis of recurrent AC is limited to months.ª While surgical resection is the mainstay of treatment for patients with an initial occur- rence of localized AC,4,19 treatment options for patients with recurrent AC are few, and typically involve the use of mito- tane.1 This analogue of a common pesticide can cause atrophy and necrosis of normal adrenal tissue, and it may cause infarc- tion of large adrenal carcinomas.20 Its toxicity, however, is substantial and is often dose limiting.20,21 While mitotane has been reported to be helpful2 and occasionally even curative, its efficacy in larger numbers of patients has been unimpres- sive. 1,4,20,21,28,24 Specifically, mitotane appears to be no better than surgery alone for the treatment of patients with primary AC,25 does not have any efficacy in patients with large retro- peritoneal disease,21 and is not better than no treatment at all in regional or metastatic disease.4 Mitotane has also been advocated recently as an anticortisol agent and may help the medical management of hypercortisolism. Therefore, be- cause of the absence of any effective systemic therapy, we have pushed surgery to the limit in an attempt to rid patients of recurrent AC, with the hope that adjuvant mitotane thera- py, as suggested by some,” would prove effective.
Given the high morbidity of Cushing’s syndrome in patients with functional AC and the grim prognosis of AC in general, excision of locally advanced recurrent and metastatic AC has been advocated.’ This approach has been fortified by data showing improved survival with pulmonary metastatasec- tomy for other tumors, such as osteogenic and nonosteogenic
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sarcoma,10,27 and improved control of the symptoms and signs of patients with metastatic hormonally functional tumors. While the reported experience with resection of recurrent AC in the abdomen or metastatic to the lung is very limited (Table 3),5,14-19 occasional patients survive in excess of 10 years. These reports, however, are limited by their anecdotal na- ture, limited numbers of patients, limited long-term follow- up, lack of a cohort of patients with similar disease treated without surgery, and insufficient numbers of patients to cal- culate actuarial survival. The present study, therefore, is unusual.
Our data emphasize the grim prognosis facing patients with recurrent AC. Regardless of treatment, there were no cures, less than 20% 5-year survival, and a median survival from the time of diagnosis of less than 2 years. These dismal results are similar to results reported in a recent series from France.26 Despite the fact that this aggressive treatment included ex- tensive surgery, no patients were cured. Patients treated with aggressive surgery plus chemotherapy at the time of first recurrence, however, did survive longer than similar patients treated with chemotherapy alone (Fig 3). The sur- vival benefit was seen primarily in only one third of patients, who subsequently had greater than 5-year survival. In addi- tion, these patients were well palliated and free of symptoms and signs of endogenous hypercortisolism.
The time of first recurrence appears to be the appropriate time to begin the measurement of survival, because it was the time that these patients were first examined at our institu- tion. However, because the prolongation of survival by sur- gery was short and of limited duration, survival from the time of initial diagnosis was not improved (Fig 2). It appears that the malignant, progressive, and metastatic nature of the
| Source | No. of Patients | No. of Operations | Sites Resected (No.) | Median Survival, y | Status at Report |
|---|---|---|---|---|---|
| Cohn et al19 | 9 | 12 | Liver (4), kidney (3), lung (3), diaphragm (4), bowel (2), lymph nodes (1), mesentery (1) | 3.5 | 3 AWD, 5 NED, 1 DOD |
| Schteingart et al5 | 6 | 8 | Retroperitoneum (3), liver (1) | 2.5 | 1 Alive, 5 dead |
| Appelqvist et al" | 1 | 2 | Lung (3), retroperitoneum (1), pancreas/spleen (1) | 25.5 | NED |
| Appelqvist and Kostiainen17 | 1 | 2 | Lung (3) | 20.5 | NED |
| Linos et al14 | 1 | 1 | Liver (1) | 1.3 | AWD |
| Bradley22 | 1 | 2 | Liver (2) | 10 | DOD |
| Thomford et al® | 1 | NA | Lung (NA) | NA | NA |
*AWD indicates alive with disease; NA, not available; NED, no evidence of disease; and DOD, dead of disease.
cancer itself is the major determinant of survival in patients with recurrent AC, because the longer disease-free interval (>12 months) seen in a minority of patients was associated with prolonged survival regardless of treatment (Fig 4). The discouraging aspects of this analysis were that no patient with recurrent adrenal cancer was cured and that the duration of remission and prolongation of survival induced by surgery was only 11 months. The occasional, long-term survivor with recurrent adrenal cancer whose case was reported in the literature16,17,22 was also seen in our study as the longest survi- vor; this patient was alive with disease at more than 20 years following treatment with surgery and chemotherapy. Final- ly, mitotane by itself or in combination with other drugs did not appear to be effective in the treatment of these patients. At best, it provided a diminution in tumor growth, but few true responses and no cures were achieved. Although surgery appeared to provide only a minor benefit for these patients, it
was performed with 20% morbidity and no mortality.
In conclusion, the cure of patients with recurrent AC re- mains elusive, but aggressive surgical resection of recurrent disease may improve survival of selected patients in whom it can be performed. Disease-free interval or time to recurrent disease appears to be a very important prognostic variable. Patients with longer disease-free intervals may benefit more from aggressive surgical resection; however, the number of patients in this subgroup was too small to demonstrate a significant difference. One third of patients treated with re- section of recurrent adrenal cancer will survive greater than 5 years, and these patients will be well palliated from the symptoms and signs of hypercortisolism. However, overall survival of these patients is poor despite the use of aggressive reoperations to remove tumor and mitotane chemotherapy. This analysis does not support the use of mitotane, and better treatment regimens are needed.
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