Adrenocortical Cancer
Melissa Wandoloski, Bsª, Kimberly J. Bussey, PhDª, Michael J. Demeure, MD, MBAa,b, *
KEYWORDS
· Adrenal · Adrenocortical cancer · Molecular oncogenesis
· Surgery . Endocrine tumors
INCIDENCE AND PRESENTATION
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy causing up to 0.2% of all cancer deaths. Its annual incidence is 1 to 2 per million people. ACC typically is diagnosed during one’s fourth and fifth decade of life, but it can also be seen in childhood.1 Women are afflicted more often than men, at a ratio reported at 1.5:1.2,3 In southern Brazil, the inci- dence of ACC increases up to 12 per million per year where childhood ACC is more prev- alent due to the frequent occurrence of the associated germ-line p53 mutation. 1-6 Benign adrenocortical adenomas are discovered in a much higher proportion of the population, typically through diagnostic imaging for nonadrenal-related reasons. Unfortunately, it can be difficult to ascertain whether some of these “adrenal incidentalomas” will ultimately develop into a malignant tumor or remain a benign mass.2-4,6-8
Many ACC patients have no symptoms until their tumors reach a large size and cause symptoms due to a mass effect and compression of nearby structures. Symptoms in these cases are typically vague and include abdominal fullness, nausea, obstipation or early satiety, weight loss, weakness, fatigue, or fever.1 In about 40% to 60% of patients, increased hormone production results in symptoms that lead to the diagnosis of an adrenal tumor.1,2 Malignant adrenal tumors can secrete a variety of steroids, steroid precursors, and mineralocorticoids.1,3,7 As many as 75% of ACC are associated with occult hypercortisolism demonstrable with hormone testing only. A lesser proportion of patients will present with overt Cushing syndrome. The behavior of benign adrenal tumors may be distinguishable from malignant ACC based on their profile of cortico steroid and androgen production. Cosecretion of androgens and cortico steroids by an adrenal tumor is suggestive of malignancy. Benign, functional adrenal tumors normally secrete only one class of steroids. This distinction is of only limited clinical utility, as patients with ACC may harbor nonfunctioning tumors.3 At the time of diagnosis most ACC patients
This work supported by a grant from the ATAC fund.
a Translational Genomics Research Institute, Clinical Translational Research Division, TGEN 445 N. Fifth Street, Phoenix, AZ 85004, USA
b Scottsdale Healthcare Shea Medical Center, Virginia G. Piper Cancer Center, 10460 N. 92nd Street, Suite 200, Scottsdale, AZ 85260, USA
* Corresponding author. Scottsdale Healthcare Shea Medical Center, Virginia G. Piper Cancer Center, 10460 N. 92nd Street, Suite 200, Scottsdale, AZ 85260. E-mail address: mdemeure@tgen.org (M.J. Demeure).
have become symptomatic, but this is not until relatively late into the course of their disease. At diagnosis most patients present with a large tumor and disease advance- ment. Metastases are present in more than half of the patients with ACC.2,3,7
EVALUATION OF ADRENAL TUMORS INCLUDING INCIDENTALOMAS
Adrenal masses discovered by imaging such as ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT) done for nonadrenal reasons are considered to be “adrenal incidentalomas.” Adrenal incidentalomas have been de- tected for 20 years, but their incidence is increasing rapidly due to a more frequent use of diagnostic imaging techniques.9-13 The incidence of incidentalomas of the adrenal gland is approaching 3% in middle-aged adults and 10% in the elderly. The overall occurrence rate is about 4% to 6% in those patients who undergo abdominal imaging studies with CT or MRI.9,14 Although most of these adrenal masses prove to be nonfunctioning adenomas, it has been reported that approximately 6% of adrenal incidentalomas are functional tumors; 5% cortisol secreting, and 1% sex hormone or aldosterone producing.14 As a result, evaluation of hormone activity and an assess- ment of the potential for malignancy are important in diagnosing the nature of the mass. 10,12-14 Although rare, pheochromocytomas and aldosterone-producing tumors can also present in patients with no overt symptoms.10
To examine tumors that are clinically asymptomatic but might be hormonally active, the authors use an overnight dexamethasone (1 mg) suppression test to assess cortisol production. 11,12 Plasma cortisol levels less than 5 µg/dL are normal and levels more than 5 to 10 µg/dL are abnormal, with a 15% false positive rate.11 It has been reported that up to 12% of subjects with adrenal incidentalomas have had tumors with pathologic cortisol production. It is also possible that a functional tumor would not produce sufficient cortisol to cause Cushing syndrome but could produce enough cortisol to cause hypertension, diabetes mellitus, or obesity. These patients should be further assessed for adrenalectomy. “Pre Cushing syndrome” and “Subclinical Cush- ing syndrome” are terms used for healthy patients with cortical-producing tumors, but without the overt signs or symptoms allowing for a diagnosis of Cushing syndrome. 12 Particularly in hypertensive patients, plasma aldosterone concentration and plasma renin activity should be assessed.11 An increased aldosterone to renin ratio suggests primary hyperaldosteronism, although the optimal cutoff value is not yet established.
Tumor size is the most significant factor in distinguishing benign and malignant adrenal incidentalomas.11,13,14 ACC has been identified in 2% of tumors smaller than 4 cm, 6% of tumors of 4.1 to 6 cm, and 25% of tumors larger than 6 cm. 11,13 Consequently, tumors 4.0 cm and greater have the highest risk for malignancy and should therefore be considered for removal.11,13,14 Moreover, any patients whose tumors increase in size over a 6-month period should be considered for surgery because this finding is also suggestive of the presence of a malignant adrenal tumor. 14
Although characteristics such as an irregular border or heterogeneity seen on more common imaging techniques can be useful tools in characterizing adrenal masses, [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) may become a valuable technique in discriminating between benign and malignant lesions. FDG is taken up by active metabolic cells and is used to recognize metastasis. FDG-PET has been shown to be up to 100% sensitive in identification of lesions. However; FDG-PET should not substitute for other imaging but should be used in combination with other common imaging techniques.11 [ 123I]Iodometomidate (IMTO) has been identified as a highly specific radiotracer that can be used for adrenal imaging. IMTO binds to Cyp11B enzymes that are highly expressed in adrenocortical
originating tissue only. The uptake has been shown in both animals and humans at a faster rate and lower dosage, with a longer half-life than with other imaging. The specificity of this tracer is therefore a potentially useful tool for the diagnosis of adrenal lesions. The reliability and cost-effectiveness of FDG uptake warrant further study in the evaluation of potentially malignant adrenal masses.10-12 Close serial observation of a patient’s adrenal tumor over time with advanced imaging remains the best current method of accurately diagnosing adrenal incidentalomas. 14
PATHOLOGY
ACC typically present as a large heterogeneous mass with an average size of 10 cm, irregular margins, and areas of necrosis, and may exhibit vascular, local, or capsular invasion. The tumor may also extend into the renal vein or vena cava (Fig. 1).1,3,5 In general, the benign tumors weigh up to 50 g whereas malignant tumors weigh more than 100 g.1
Due to the significant difference in the prognosis of adrenocortical adenomas and carcinomas, an accurate pathologic diagnosis is paramount. Although this distinction is often straightforward, as is the case when one has proven metastases, there are times when the diagnosis of these tumors can be difficult. Pathologists rely on the various pathologic features of the tumor as detailed in the Weiss criteria.2-4,7,8 The Weiss score catalogs 9 different histologic features: high mitotic rate, atypical mitoses, high nuclear grade, low percentage of clear cells, necrosis, diffuse architec- ture of the tumor, capsular invasion, sinusoidal invasion, and venous invasion. 1,3,4,6 A Weiss score of 1 is given to features that are present and a score of 0 is given to absent features. 3,6 A total score less than or equal to 2 is classified as an adrenocor- tical adenoma, and a score of 3 or more is suggestive of an ACC.4,6 However, a score of 2 or 3 is commonly considered ambiguous, requiring other criteria to classify the tumor, and others believe some of the 9 criteria are not reliable measurements.2-4,6,7 More recently, some investigators have advocated the use of adjunct pathologic diagnostic tools to facilitate a more accurate diagnosis. Suggested markers of a malignant adrenal tumor include insulinlike growth factor 2 (IGF-2) overexpression, allelic loss at 17p13, increased Ki-67, and cyclin E expression via immunohistochem- istry.1,3,4,6 Other investigators, including most recently Giordano and colleagues and de Reynies and colleagues, have shown gene sets identified by expression array that
purport to distinguish malignant from benign adrenal tumors.4,15 Furthermore, some gene sets, particularly those related to cell cycle regulation, have been associated with high-grade ACC and a poor prognosis.3,5-7
MOLECULAR ONCOGENESIS Genomics
The changes that underpin the development of benign and malignant adrenal tumors are still relatively undefined. From a classic cytogenetics perspective, adenomas are almost always diploid with a loss of a sex chromosome and potential rearrangement of chromosome 7, whereas carcinomas can be diploid with single chromosomal gains, or have highly aneuploid DNA content due to complex numerical and structural rear- rangements.16 Comparative genomic hybridization (CGH) studies have revealed that adenomas in adults generally have few if any changes, and the number of aberrations accumulates as a function of tumor size. No specific changes have been identified, however, that reliably distinguish adenomas from ACC. Five studies report the results of applying conventional CGH to ACC.17-21 The abnormalities detected are present in 50% to 60% or less of the tumors examined in each series, and no single aberration has been reported in higher prevalence. There is also a great deal of heterogeneity within tumors and between studies. However, taken as a whole ACC demonstrate gains of 4p16, 5p15, 5q12-13, 5q32-qter, 9q34, 12q13, 12q24, and 19p. Regions of loss include 1p21-31, 2cen-q21, 9p, and 11q24-qter. Similar data emerge from array CGH studies in which instead of metaphase chromosomes as the hybridization target, the samples and controls are hybridized to DNA microarrays. This method permits a resolution that is limited only by the genomic distance between 2 probes on the array. The authors’ group reported that among 25 tumors there were overall gains within chromosomes 5, 6q, 7, 8q, 12, 16q, and 20. Losses were found within chromo- somes 1, 2q, 3, 6p, 7p, 8p, 9, 10, 11, 13q, 14q, 15q, 16, 17, 19q, and 22q.22 It was also demonstrated that amplifications of 6q, 7q, 12q, and 19p and losses of 3, 8, 10p, 16q, 17q, and 19q were significantly associated with poor survival.22
Expression Microarrays
Recent studies have shown gene expression patterns that can be used to distinguish adenomas from carcinomas. 4,5,7,15,23,24 Giordano and colleagues demonstrated that genes showing differential expression in ACC compared with adenoma or normal adrenal are enriched for cell cycle progression. This study also identified 12q and 5q as chromosomal regions with evidence of enrichment for overexpressed genes in ACC, whereas 11q, 1p, and 17p had evidence of enrichment for underexpressed genes. Both Giordano and colleagues and de Reynies and colleagues reported that amongst ACC, hierarchical clustering revealed 2 clusters that corresponded to better and worse prognosis.4,15 In the Giordano group study, the clustering was associated with mitotic index, suggesting an approximate grouping by grade. In addition, the genes differentially expressed in the poor prognosis cluster were enriched for the G2/M transition. Given the enrichment for cell cycle genes, and mitosis in particular, and because the mitotic index is one component of tumor grade, one might expect that the approximation of grade by gene expression data was due to the mitotic index component. To check for this, the study employed a Cox proportional hazards model incorporating tumor grade, log of the mitotic index, and the gene expression data from the first principal component. Mitotic index was not significant whereas grade and the principal component were significant. This result suggests that the gene expression data contain information beyond what is captured by grade.15 De Reynies and
colleagues identified a 2-gene signature, PINK1 and BUB1B, as being predictive of overall survival. A patient was predicted to have a poor prognosis if analysis of their tumor sample by quantitative polymerase chain reaction showed the delta crossover threshold of BUB1B minus the delta crossover threshold of PINK1 to be less than 6.32.4
Inherited Syndromes: Li-Fraumeni
Further clues to the molecular oncogenesis arise from the observation that ACC occurs in the context of two inherited syndromes, Li-Fraumeni and Beckwith-Wiede- mann. Li-Fraumeni syndrome is caused by a germ-line defect in the tumor suppressor gene, TP53, which encodes p53. Patients with Li-Fraumeni syndrome have a higher susceptibility to breast carcinoma, soft tissue sarcomas, brain tumors, osteosarcoma, leukemia, and ACC. Some argue that diagnosis of ACC, particularly in a child, is suffi- cient to warrant testing to determine the patient’s p53 mutation status.25 The spec- trum of germ-line mutation for Li-Fraumeni families with one or more cases of ACC shows a shift outside of the normal hot spots in the DNA-binding domain. Sixty percent of kindreds with ACC have mutations that cluster in a region of the p53 protein within non-DNA binding loops, the b-sheet skeleton, and the oligomerization domain.26 TP53 has been reported to be mutated in approximately 25% of sporadic ACC cases.3 Loss of heterogeneity (LOH) for 17p has been reported in 85% or more of ACC,27 further supporting the role of p53 aberrations in the pathogenesis of ACC. In Brazil, a unique germ-line mutation at R337H has resulted in an increased inci- dence of ACC of 4 to 6 per million but does not result in Li-Fraumeni syndrome in most patients, giving rise to 1 in 10 carriers developing ACC. In keeping with the distribution of ACC-associated mutations in Li-Fraumeni, R337H is a pH-sensitive mutation local- ized to the oligomerization domain.28 Polymorphisms in TP53 may play a role in the development of ACC as well. In a study of Polish ACC patients, the proline allele of the R72P polymorphism was more prevalent in patients with ACC than in normal controls, suggesting that it may contribute to ACC susceptibility.29
Inherited Syndromes: Beckwith-Wiedemann
ACC also occurs as part of the constellation of tumor types seen in the overgrowth syndrome, Beckwith-Wiedemann. The disease arises from the misexpression of genes from an imprinted domain on 11p15.5, usually due to paternal uniparental dis- omy (2 copies of 11p15.5 from the father without any contribution of the region from the mother) or an imprinting defect that silences the genes on the maternal chromo- some. Patients generally have overexpression of IGF-2 and a lack of maternally expressed genes such as H19, KCQN1, and CDK1N, which encodes p57kip. Two regions in the imprinted domain have been implicated in the variation of the tumor spectrum (ie, the types of tumors associated with the disease) of this disease. The te- lomeric region encompasses paternally expressed IGF-2 and maternally expressed H19. Abnormalities that lead to the lack of H19 expression and overexpression of IGF-2, such as paternal uniparental disomy or aberrant methylation of H19, give rise to Beckwith-Wiedemann syndrome with a preponderance of Wilms tumor. The centromeric region of the 11p15 imprinted domain includes the LIT1 transcript of the KCQN1 gene and CDKN1C, the gene that encodes p57kip. Hypomethylation of LIT1 or mutations in CDKN1C have been implicated in Beckwith-Wiedemann syndrome with a tumor spectrum that is skewed toward embryonal tumors such as rhabdomyosarcoma, hepatoblastoma, gonadoblastoma, and ACC.30 p57kip is a known negative regulator of cell cycle progression, making it a prime candidate for a tumor suppressor in this region.
Insulinlike growth factor 2
One of the most common features of ACC is an overexpression, either at the RNA or protein level, of IGF-2. Approximately 90% of ACC demonstrate overexpression of IGF-2 and LOH for the IGF-2 locus has been found in 95% or more of ACC.3 In micro- array studies of gene expression, IGF-2 and associated binding proteins are consis- tently identified as differentially expressed in ACC compared with normal adrenal tissue or adenomas, with most studies identifying IGF-2 as upregulated. It is hypoth- esized that overexpression of IGF-2 forms a positive autocrine loop that promotes cell proliferation, which is selected for in the ACC. However, the role of IGF-2 overexpres- sion in tumorigenesis is unclear. Targeted knockouts of H19 that when maternally in- herited lack H19 expression and overexpress IGF-2 do not demonstrate evidence of increased cancer incidence unless crossed into a background that confers an increased risk in and of itself.31,32 For example, in the APCmin background, IGF-2 over- expression as a consequence of maternally inherited H19 knockout results in twice as many tumors as the APCmin background alone.33 In contrast, targeted overexpression of IGF-2 by transgene insertion (ie, inserting an exogenous copy of IGF-2 while leaving the endogenous imprinted domain intact and maintaining normal expression of the genes in the region) does lead to an increase in tumors in mice. The diversity of the tumor sites, including tissues that express the transgene as well as those that do not, coupled with a long latency (most tumors are seen after 18 months), suggests that IGF-2 overexpression may be tumor promoting but not tumor initiating.34 It is worth noting that none of these models include ACC as a tumor type to which the mice are prone. That said, inhibition of IGF1R, the primary receptor for IGF-2, has been shown to reduce cell proliferation and viability in preclinical studies.35,36
OPERATIONS FOR ADRENOCORTICAL CANCER
The major predictor of long-term survival is presentation with either stage I or II disease, and the ability to undergo complete resection of tumor (Fig. 2). Adrenalec- tomy can be conducted in the supine or decubitus position. In the era before laparo- scopic adrenalectomy, retrospective studies showed a flank approach was associated with a shorter hospital stay and quicker recovery than was associated
1
n total = 113
.9
Cumulative Survival
.8
.7
.6
.5
Stage II (n=52)
.4
Stage I (n=5)
.3
.2
Stage III (n=12)
.1
Stage IV (n=44)
0
0
12 24 36 48 60 72 84 96 108 120
Months after First Resection/Diagnosis
with a transabdominal approach. For potentially malignant tumors, however, a trans- abdominal approach is favored because one can fully stage the abdomen, and one has better exposure for control of major vessels and for resection of adjacent organs when needed. The transabdominal approach can be conducted via a midline, parame- dian, or extended subcostal incision. For very large tumors, a thoracoabdominal inci- sion may be necessary. A multidisciplinary team of surgeons may be required for a cancer with intracaval tumor thrombus that on occasion can extend all the way into the right atrium. Before operation one should assess for subclinical excess of cortisol production and administer exogenous steroid replacement as appropriate. Postoperatively, one should taper hydrocortisone slowly, guided by recovery of the pituitary-adrenal axis, which can take up to 6 months.37
On the right side, care is taken to fully mobilize the duodenum by a Kocher maneuver and hepatic flexure of the colon by division of its retroperitoneal attach- ments. One then must fully divide the ligamentous attachments of the right lobe of the liver and identify the vena cava behind the liver, and the site of the junction of the right adrenal vein and the inferior vena cava. The adrenal vein typically enters the vena cava directly from the medial aspect of the tumor but may enter the vena cava on its posterior aspect. One should also be aware of potential accessory adrenal veins that may drain into the right renal vein. Routine nephrectomy is not required, but the tumor may directly invade the kidney or involve its vascular supply, making complete or partial nephrectomy necessary. On occasion, a right adrenal cancer may directly invade the right lobe of the liver. In this setting, a liver-hanging maneuver or transection of the liver has been described as a technique to fully obtain vascular control of the adrenal tumor and facilitate en bloc resection.38
On the left side, the splenic flexure of the colon is reflected inferiorly by dividing its attachments to the retroperitoneum and the spleen. The omentum is divided to allow entry into the lesser sac. If the tumor is relatively small, one may prefer to leave the spleen attached to the diaphragm and divide the retroperitoneum along the inferior aspect of the body and tail of the pancreas to expose the left adrenal gland. Down- ward retraction on the left kidney helps expose the adrenal gland, allowing for division of its superior and posterior attachments. Although typically the vascular supply is derived medially, extensive and large collateral vessels may form in this area, requiring one to proceed cautiously. If the adrenal tumor is large one may choose to divide the leinophrenic attachments to allow one to rotate the spleen and tail of the pancreas medially. If there is direct invasion of the pancreas, a distal pancreatectomy and sple- nectomy may be required for en bloc complete tumor resection. One then seeks expo- sure of the left adrenal vein as it enters the left renal vein to ligate this vessel. The posterior attachments and the attachments to the left kidney are then divided. Again, nephrectomy is not required unless there is direct invasion of the kidney or its vascu- lature by the tumor. On either side, one should resect enlarged regional lymph nodes, as lymphatic metastases portend a poor prognosis.
The best prognostic indicators for adrenocortical cancer are complete resection of tumor and an early stage at diagnosis (Table 1). Although anecdotal complete remis- sions have been observed with chemotherapy, a complete surgical resection is the only modality that offers a realistic prospect for cure. Overall 5-year survival for patients who undergo a complete resection is 32% to 48%. Given that laparoscopic approaches to the adrenal gland have become routine in the resection of benign func- tional adrenal adenomas, the optimal surgical approach to cancerous adrenal tumors has been debated. Admittedly, prospective randomized comparative trials of open and laparoscopic approaches have not been done. Caution is urged, stemming from the potential for tumor dissemination and a concern for tumor fracture, and
| Table 1 Staging of adrenocortical cancer (Macfarlane) | ||
|---|---|---|
| Stage | T, N, M Staging | Criteria |
| 1 | T1, N0, M0 | Tumor <5 cm Node negative No local invasion No metastases |
| 2 | T2, N0, M0 | Tumor >5 cm Node negative No local invasion No metastases |
| 3 | T3, N0, M0 or T1-2, N1, MO | Presence of local invasion without involvement of adjacent organs or mobile, nodal metastases |
| 4 | T4, N0, M0 or T3, N1, M0 or T1-4, N0-1, M1 | Invasion of adjacent organs, fixed positive lymph node metastases, or presence of distant metastases |
this mitigates against the use of laparoscopic adrenalectomy if one suspects an adrenal tumor is malignant. Retrospective series suggest a higher risk of local recur- rence and peritoneal carcinomatosis if a primary ACC had been resected via the lapa- roscope. The transabdominal open approach helps limit the risk of tumor fracture and therefore tumor spillage is reduced.
MITOTANE
No proven chemotherapeutic regimen exists for the treatment of ACC, and the toxicity of the only approved compound, mitotane (o,p’-DDD or 1,1-dichloro-2-(o-chlorophenyl)- 2-(p-chlorophenyl)ethane), is often severe and dose limiting. An isomer of the pesticide DDT, mitotane is an agent that is directly toxic to adrenocortical cells. The biochemical mechanisms of action for mitotane are not well characterized, although it is thought to work after hydroxylation by a mitochondrial cytochrome P450 enzyme and subsequent conversion to an acyl chloride that is cytotoxic.39 Cytotoxicity ultimately results in mito- chondrial disruption and necrosis.40 The primary metabolites of mitotane are o,p’-DDA and o,p’-DDE. Investigations of the localization of 3-methylsulfonyl-DDE, a metabolite of DDT, and mitotane demonstrated that both compounds accumulate in the zona fas- ciculata and the zona reticularis, but not in the zona glomerulosa.41 The activity of mito- tane is dependent on the 1,1-dichloro structure; conversion of this moiety to a methyl group significantly reduces activity.42 Investigations of the protein profile of H295R cells and steroid production after mitotane exposure suggest that the cytochrome P450 enzyme involved in the initial activation step acts upstream of the steroidogenic cascade.43
The first report of mitotane use in patients with ACC was presented by Bergenstal and colleagues in 1959.44 The therapeutic value of mitotane is dependent on achieving sufficiently high blood levels of the drug, but the therapeutic window is narrow.45 Side effects of mitotane are predominantly gastrointestinal, neurologic, and cutaneous. Gastrointestinal disturbances occur in about 80% of patients and include anorexia, nausea and vomiting, and diarrhea. Central nervous system side effects occur in approximately 40% of patients. These side effects are often severe enough to require discontinuation of treatment.
Unfortunately, even after apparently curative operation, up to 85% of patients with ACC will eventually relapse. Repeated resections where possible have been recom- mended, as patients who are able to undergo complete resection of their recurrent disease or metastases fare better than those who do not, albeit in retrospective, non- randomized series (Fig. 3). Because of the high rate of recurrence, there is a great need for effective adjuvant chemotherapy. The adjuvant use of mitotane remains controversial despite an article published in 2007. In this article from groups in Germany and Italy, the investigators studied a multi-institutional group of 177 patients. Forty-seven patients in Italy who received mitotane were compared with control groups in Italy and Germany who did not receive mitotane. In this series, the use of mitotane conferred a prolonged recurrence-free survival of 42 months compared with 10 and 25 months for the 2 control groups. Mitotane dosing was 3 to 5 g daily for 20 patients and 1 to 3 g daily for 27 patients, and both groups seemed to benefit. This article has been criticized because the patients were treated in 8 Italian centers and 47 German centers over a prolonged period of 20 years. Although this report is of a relatively large series in a rare disease, the fact remains that this is a nonrandom- ized, uncontrolled, retrospective analysis. Furthermore, there was no stratification based on surgical technique or status of surgical margins.
UNRESECTABLE DISEASE
In 20% of ACC cases, patients are unresectable due to disease advancement. The 5-year survival rate in patients with stage IV disease is between 16% and 38%.1,3,4,6,7 Mitotane, alone or in combination with cytotoxic drugs, remains the stan- dard therapy for nonresectable metastatic adrenocortical cancer. In a study led by the Eastern Cooperative Oncology Group, 22% of patients responded to mitotane treat- ment and experienced prolonged median survival of 50 months compared with 14 months for nonresponders. 46 These findings were confirmed in a later study by a group of investigators from MD Anderson Cancer Center (Fig. 4).47 Van Slooten and colleagues showed an increase in survival or tumor regression in 57% of patients who had mitotane serum levels greater than 14 ug/mL, with complete remission in one patient.48 However, no patient with a mitotane serum level less than 10 µg/mL had a significant response to chemotherapy. Other studies have failed to show
1
n total = 47
.9
Cumulative Survival
.8
Complete Second Resection (n = 32)
.7
.6
.5
.4
3
.2
1
Incomplete Second Resection (n = 15)
0
0
12 24 36 48 60 72 84 96 108 120
Months after Second Resection
1.0
0.8
Percent surviving
0.6
0.4
0.2
- Nonresponders (DP)
Responders (CR/PR+DS)
0.0
0
24
48
72
96
120
144
168
192
Follow-up (months)
a response.27,49 Chemotherapeutic strategies using mitotane in combination with other standard agents have been reported, with mixed results. In a study of 35 patients using mitotane in combination with doxorubicin, vincristine, and etoposide, a 22% response rate was reported and there was no evidence for improved survival over mi- totane alone.50 The most promising regimen thus far has been a combination of doxo- rubicin, etoposide, and cisplatin in conjunction with mitotane. The investigators reported that in 72 patients with metastatic disease, 5 responded completely and 30 had partial response, for an overall response rate of 48.6%. The median time to progression and overall survival of the entire cohort were 9.1 and 28.5 months, respec- tively, with responders having approximately double those values.51 This regimen is currently under investigation in an international multicenter phase III trial comparing it to mitotane and streptocozin, known as the FIRM-ACT study.
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