Adrenocortical Cancer: A Molecularly Complex Disease Where Surgery Matters
Eden C. Payabyab1, Sanjeeve Balasubramaniam2, Maureen Edgerly3, Margarita Velarde3, Maria J. Merino4, Aradhana M. Venkatesan5, Harshraj Leuva6, Thomas Litman7, Susan E. Bates6,8, and Tito Fojo6,8
Abstract
The development of new therapies has lagged behind for rare cancers without defined therapeutic targets. Adrenocorti- cal cancer is no exception. Mitotane, an older agent consid- ered “adrenolytic,” is used both to control symptoms in advanced disease and as adjuvant therapy after surgical resec- tion. Molecular characterization of adrenocortical cancer has deepened our understanding of this genetically complex dis- ease while identifying subgroups whose importance remains to be determined. Unfortunately, such studies have yet to demonstrate a therapeutic target for drug development, and to date, no targeted therapy has achieved meaningful out- comes. Consequently, first-line therapy for metastatic disease remains a combination regimen of etoposide, doxorubicin, and cisplatinum established in a randomized clinical trial. In addition to evaluating recent studies in adrenocortical
cancer, we raise one critical clinical issue-the risk of peri- toneal dissemination following laparoscopic resection of adrenocortical cancer. In a retrospective case series of 267 patients referred to the NCI for the treatment of recurrent or advanced adrenocortical cancer, we found extensive peri- toneal dissemination in 25 of the 45 patients (55.6%) who had undergone laparoscopic resection, compared with only 7 of the 222 patients (3%) who had undergone an open resection (P < 0.0001). Although this has been debated in the literature, our data argue for an end to laparoscopic resection of adrenocortical cancers to avoid peritoneal dis- semination, a complication of laparoscopy that is uniformly fatal. Clin Cancer Res; 22(20); 4989-5000. @2016 AACR.
See all articles in this CCR Focus section, “Endocrine Cancers: Revising Paradigms.”
Introduction
Adrenocortical cancer is a rare malignancy with an estimated incidence of 1.5 per million per year. Its prognosis remains poor, with average survival from diagnosis of approximately 14.5 months and 5-year survival of approximately 10% to 25%. Patients can be asymptomatic or can present with symptoms from a large, locally invasive primary tumor. Biochemical evidence of hormone excess can be found in approximately 50%, and approximately 10% to 20% can present with systemic manifestations of endocrine hypersecretion including hirsut- ism in females, gynecomastia in males, or Cushing syndrome. A
1Surgery Branch and Thoracic & GI Oncology Branch, NCI, NIH, Bethesda, Maryland. 2Division of Oncology Products 1, OHOP, CDER, U.S. Food and Drug Administration, Silver Spring, Maryland. 3Medical Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. 4Laboratory of Pathology, Center for Cancer Research, NCI, NIH, Bethesda, Maryland. 5Department of Diagnostic Radiology, Divi- sion of Diagnostic Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas. 6James J. Peters Veterans Adminis- tration Medical Center, Bronx, New York. 7Medical Biostatistics, Uni- versity of Copenhagen, Copenhagen, Denmark. ªDivision of Medical Oncology, Department of Medicine, Columbia University Medical Cen- ter, New York, New York.
Note: Current address for E.C. Payabyab: Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia.
Corresponding Author: Tito Fojo, Division of Medical Oncology, Department of Medicine, Columbia University Medical Center, New York, NY 10032 and James J. Peters VA Medical Center, Bronx, NY 10468. E-mail: atf2116@cumc.columbia.edu doi: 10.1158/1078-0432.CCR-16-1570
@2016 American Association for Cancer Research.
multidisciplinary approach to treatment is essential as the disease presents many management challenges. Several recent reviews provide in-depth summaries (1-5).
Because of the rarity of adrenocortical cancer, it was only in 2004 that the International Union Against Cancer defined TNM criteria and published the first staging classification for adrenocortical cancer. An evaluation published in 2008 using data from 416 patients in the German Adrenocortical Cancer Registry found some limitations with the existing clas- sification and proposed a newer staging system (ref. 6; Table 1). In this classification, stage III adrenocortical cancer is defined by infiltration of surrounding tissues/organs including tumor thrombus in the venous system and the presence of positive lymph nodes; stage IV adrenocortical cancer is restricted to patients with distant metastases. The survival curves shown in Fig. 1 demonstrate that long-term survival occurs rarely when presenting with metastatic disease.
Whole-Genome Sequencing in Adrenocortical Cancer
Two recent studies have reported genomic characterization of adrenocortical cancers (7, 8). The first reported the exome sequence of 45 adrenocortical cancers and validated the results in an independent cohort of 77 adrenocortical cancers (7). The authors identified alterations in known driver genes including CTNNB1, TP53, CDKN2A, RB1, and MEN1 as well as alterations in genes “not previously reported in ACC” including ZNRF3, DAXX, TERT, and MED12. Two distinct molecular subgroups were reported as having “opposite
CCR FOCUS
| Stage | UICC/WHO 2004 | ENSATª 2008 |
|---|---|---|
| I | T1, N0, M0 | T1, N0, M0 |
| II | T2, N0, M0 | T2, N0, M0 |
| III | T3, N0, M0 | T3-4, NO, MO |
| T1-2, N1, MO | T1-4, N1, MO | |
| IV | T3, N1, M0 | Any M1 |
| T4, NO-1, MO | ||
| Any M1 |
Abbreviations: M0, no distant metastases; M1, presence of distant metastasis; NO, no positive lymph nodes; N1, positive lymph nodes; T1, tumor ≤5 cm; T2, tumor >5 cm; T3, tumor infiltration in surrounding tissue; T4, tumor invasion in adjacent organs; UICC, Union Internationale Contre le Cancer. ªAlso venous tumor thrombus in vena cava or renal vein.
outcomes,” and this will need to be validated before such subgroup stratification can inform clinical management. The second study expanded “the catalog of known ACC ‘driver genes’ to include PRKAR1A, RPL22, TERF2, CCNE1, and NF1” (8). Data currently available in the TCGA portal (9) ratify some but not all of these alterations while adding yet others. The provisional data from The Cancer Genome Atlas (TCGA) iden- tify TP53 alterations in 20% of tumors, a number similar to the 16% reported by investigators in the complete series of 122 adrenocortical cancers in the discovery (45) and validation (77) samples. Although these observations are interesting, common sense argues against such a diverse group of genes having critical “driver” roles in this disease. Were this diverse a group of genes so important as to be etiologic “actionable drivers” critical for disease development, one would expect the inci- dence of adrenocortical cancer to be higher than one per one million. Regardless, none of the alterations provide clear leads that can change treatment paradigms given our current drug armamentarium. The provisional TCGA data leave unanswered the likelihood of any efficacy for developing immunothera-
pies-if one assumes the paradigm that tumors with a high mutational load are more likely to benefit. Recognizing the tentative value of this emerging paradigm and that it is unlikely to be the only explanation for why tumors respond to immune therapies, one can see as shown in Fig. 2-generated using a uniform TCGA dataset-that although the mutational load of adrenocortical cancers is higher than many common tumors, it is lower than the burden found in the tumors that have thus far been shown to have reproducible response rates to immune therapies. Rigid clinical assessment is needed, and trials should be performed in patients with molecularly well-characterized tumors.
Multidisciplinary Management of Adrenocortical Cancer
The management of adrenocortical cancer requires a multidis- ciplinary effort. Because it is a rare disease, data from randomized trials are generally lacking, but the lack of rigorous evidence opens the door to haphazard treatment approaches. The options avail- able include surgical resection at the time of the initial presenta- tion or at a subsequent relapse, oral mitotane, intravenous che- motherapy, radiofrequency ablation (RFA), cryoablation, and palliative radiation. Although an occasional patient will have a sustained remission from combination chemotherapy or oral mitotane, surgery remains the only proven curative option for a patient with adrenocortical cancer and it must always be aggressively considered both at presentation and at relapse. We discuss the controversy of the surgical approach last.
Mitotane
Mitotane, also known as o,p’-DDD, is a unique chemothera- peutic originally identified as an adrenolytic agent in the early 1960s (10). Marketed as an orphan drug, it is an isomer of DDD, an organochlorine no longer registered for agricultural use in the
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United States. Along with DDE, DDD is a major metabolite and environmental breakdown product of DDT, the protagonist of the 1962 book Silent Spring by Rachel Carson that cataloged the environmental impacts of widespread DDT spraying in the United States. In the book, Carson alleged that DDT and other pesticides had been shown to cause cancer and were a threat to wildlife (11). Its publication is regarded as a seminal event in the environmen- tal movement and led to a public outcry and a ban on the agricultural use of DDT. Banned initially in the United States and eventually worldwide, DDT was formally prohibited under the Stockholm Convention on Persistent Organic Pollutants. In this context, it is interesting that a switch of one of the para- chlorines in DDD to the ortho-position, to generate (RS)-1- chloro-2-[2,2-dichloro-1-(4-chlorophenyl)-ethyl]-benzene, is the only difference between mitotane and the banned compound, and that this close relative of known carcinogens is used in the therapy of adrenocortical cancer. Mitotane is approved by the FDA for the “treatment of inoperable adrenal cortical carcinoma of both functional and nonfunctional types” and is used in patients who have persistent disease despite surgical resection, who are not surgical candidates, or who have metastatic disease. Mitotane is also used to treat Cushing disease in dogs, where it is used to decrease cortisol production by controlled destruction of adrenal tissue. Importantly, despite its approval nearly 50 years ago, its mechanism of action remains unknown. It is clearly an adrenal cytotoxic agent, and, as such, it directly suppresses the adrenal cortex; however, it also modifies the peripheral metabolism of steroids. Reductions in 17-hydroxycorticosteroids and increased formation of 6-B-hydroxycortisol are among the changes that have been reported (12).
Mitotane was originally assessed in an era when quantitation of tumor was less precise and often relied on clinical exams. With investigators possibly influenced by the improvement in symptoms of hormone hypersecretion that were erroneously thought to represent tumor reduction, it is likely that the activity of mitotane was overestimated. Regrettably, we do not have a prospective assessment of activity with modern imaging modalities and only retrospective data to inform the value of targeting threshold serum concentrations. For exam- ple, a retrospective analysis evaluating the correlation of the currently used mitotane threshold of 14 mg/L with tumor response concluded there was value in targeting 14 mg/L, albeit with low sensitivity and specificity values of 65% and 69%, respectively (13). Considering the possible selection bias that encumbers all retrospective analyses, such low specificity and sensitivity values must be viewed cautiously, although they provide some support to clinicians who strive for such levels. To be sure, in a small percentage of patients, mitotane can cause tumor regressions, but its tumoricidal activity is limited and its clinical utility and value is primarily as an antihormonal agent. In a patient whose tumor produces an excess of hor- mones, mitotane is indispensable and should be started as soon as possible and continued indefinitely. Even if a patient with a hormone-producing tumor experiences disease progres- sion on imaging studies, mitotane should be continued as an antihormonal agent serving as a foundation to which other antihormonal agents may be added.
Mitotane has also been used in the adjuvant setting, following surgical resection of adrenocortical cancers. Retrospective studies, including several small studies and one modest-sized study,
| Agent(s) | Target | Patient number | ORR | PFS | Comment | Reference |
|---|---|---|---|---|---|---|
| Erlotinib + gemcitabine | EGFR (1) | 10 | 0 (0/10) | <3 months | EGFR expression in the nine tumors evaluated; six strong, two average, one weak | Quinkler et al. (19) |
| Figutumumab | IGFIR (1) | 14 | 0 (0/14) | <12 weeks | Moderate changes in glucose levels seen in most patients; most had increased insulin secretion that stabilized at study end | Haluska et al. (20) |
| Bevacizumab + capecitabine | VEGF (1) | 10 | 0 (0/10) | 59 days | In a preliminary analysis, the majority of >160 adrenocortical cancers showed VEGF and VEGFR staining by immunohistochemistry | Wortmann et al. (21) |
| Paclitaxel + sorafenib | VEGF (1) | 10 | 0 (0/10) | <8 weeks | Tumor progression in nine patients at the first assessment led to premature interruption of trial | Berruti et al. (22) |
| Sunitinib | VEGF (1) | 38 | 0 (0/38) | <8 weeks | Authors concerned that concomitant mitotane might have negatively impacted outcome | Kroiss et al. (23) |
| Everolimus | mTOR | 4 | 0 (0/4) | <3 months | Interaction with mitotane, multiple signaling pathways, and/or downstream IGFR effectors considered as explanations | Fraenkel et al. (24) |
| Cixutumumab (IMC-A12) | IGFIR (1) | 20 | 5% (1/20) | 6 weeks | Given with mitotane; starting dose 2 g daily, with adjustments according to levels and symptoms | Lerario et al. (25) |
| Axitinib (at NCI) | VEGF (1) | 13 | 0 (0/13) | 5.48 months | Majority could not tolerate dose higher than starting dose of 5 mg orally twice daily | O'Sullivan et al. (26) |
| Linsitinib (OSI-906) | IGFIR (1) | 90 | 3.3% (3/90) | 44 days | Tolerability not an issue as linsitinib very well tolerated | Fassnacht et al. (27) |
| Nine targeted therapy studies | Various | 209 | 1.9% (4/209) | <8 weeks | Disappointing results |
NOTE: (1) indicates overexpression in adrenocortical cancer.
suggest that adjuvant mitotane, when continued indefinitely, can at a minimum delay and possibly prevent a recurrence of disease (14, 15).Ongoing studies will hopefully better define those who may experience benefit-an important distinction as mito- tane is well tolerated by only a fraction of patients, whereas the majority of patients find it a difficult therapy that affects the quality of their lives. Pending the outcome of ongoing efforts, patients who present with large tumors, uncertain margins, and many of the histopathology findings described by Weiss (16) as well as a Ki67 index higher than 10% to 15% should receive mitotane. According to current ESMO guidelines, “There are no data regarding the optimal duration of adjuvant mitotane; we recommend that adjuvant mitotane should be administered for at least 2 years since the greatest frequency of disease recurrence is expected within this time frame … The treatment duration should be assessed individually, taking carefully into account the cost/benefit ratio” (17).
Systemic chemotherapy
Systemic options for metastatic adrenocortical cancer are currently limited to combinations of cytotoxic intravenous chemotherapy with oral mitotane. Of the agents studied, the combination of cisplatin, etoposide, and doxorubicin intrave- nously every 28 days plus daily oral mitotane (EDP + M) was compared with intravenous streptozocin every 21 days plus daily oral mitotane (S + M) in an international randomized study that enrolled 304 patients-a remarkable feat in a rare disease (18). This study, known as the First International Randomized Trial in Locally Advanced and Metastatic Adreno- cortical Carcinoma Treatment Trial (FIRM-ACT), found signif- icantly better rates of response (23.2% vs. 9.2%; P < 0.001) and PFS (5.0 months vs. 2.1 months; HR = 0.55; P < 0.001) with EDP plus mitotane than with streptozocin plus mitotane as
first-line therapy. The absence of a statistical difference in overall survival (14.8 months vs. 12.0 months; P = 0.07) was likely confounded by the crossover that occurred as evidenced by the similar result with both regimens in first or second line- an observation that also suggests these two regimens are not cross-resistant and may be administered in succession if a response is not achieved with the first regimen. Finally, the observation of similar but not identical rates of toxic events has translated for those who treat this disease as support for the use of EDP as the preferred first-line regimen. We would emphasize that the EDP regimen uses cisplatin, and that although a majority of patients with adrenocortical cancer have undergone a nephrectomy, renal complications were not observed. Thus, the drug of choice should remain cisplatin pending published data with carboplatin.
The FIRM-ACT trial was published in 2012, more than a decade after the enthusiasm surrounding imatinib in chronic myeloid leukemia ushered in the era of “targeted therapies.” Now 16 years after the start of that era, the verdict on targeted therapies in adrenocortical cancer has been tendered, and, unfor- tunately, it can only be characterized as disappointing (Table 2; refs. 19-27). VEGF inhibition, attempted in three separate clin- ical trials (bevacizumab + capecitabine, sunitinib, and axitinib) that together enrolled a total of 61 patients with adrenocortical cancer, was an unequivocal failure given that no single patient had an objective RECIST response. But possibly more disap- pointing was the failure of three agents targeting the IGF2 - IGF1R axis: figitumumab, cixutumumab, and lisitinib. High levels of expression of IGF2 signaling predominantly through IGF1R in adrenocortical cancers as compared to adenomas and the normal adrenal have emerged as one of, if not the most, significant finding in several studies examining expression pat- terns in adrenocortical cancer (ref. 28; Fig. 3). The results,
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summarized in Table 2 (19-27), serve as a reminder of the refractory nature of this disease and emphasize the continued need for better therapies. The failure of targeted therapies also confirms the view that single-agent therapies are unlikely to succeed in meaningful ways in the management of hard-to- treat solid tumors such as adrenocortical cancer. This lesson should deter us from attempting to target “actionable muta- tions” with single agents, given that a randomly chosen single agent is no more likely to succeed, especially agents that in their approved indication have achieved only marginal to modest gains. There remains no better option than enrollment in a clinical trial in which data can be appropriately gathered and lessons learned.
Interventional radiology as a treatment modality
In the multidisciplinary management of adrenocortical can- cer, both RFA and cryoablation can be seen as adjuncts to surgery or as stand-alone modalities to eradicate recurrences (29). RFA and cryoablation can be performed in lieu of a surgical intervention, but only if complete tumor eradication can be achieved. Embolization as an adjunct to reduce tumor size and vascular supply prior to a surgical intervention is seen as valuable, albeit not based on randomized data. Emboliza- tion, either with chemotherapy-loaded beads or radioparticles, needs formal evaluation, but offers promise.
Radiotherapy
Increasing evidence suggests that administering palliative radiotherapy to patients with metastatic disease can be bene- ficial. However, its use other than for palliation is not sup- ported by data nor is its administration to the surgical field. Adjuvant radiation was not found to be beneficial in initial studies. Although later studies, possibly using better techni- ques, claim better outcomes with little toxicity, there are no convincing randomized data that ionizing radiation can erad- icate microscopic disease, but there is certainty harm will occur, given the marginal benefit of such an approach in other solid
tumors (30, 31). Surgery remains the only curative option, and radiotherapy is not an adequate substitute. Postoperative radio- therapy should only be considered in a patient with known positive margins after surgery performed by a highly qualified surgical oncologist or in a patient in whom a reoperation is deemed not possible.
The roles and the approach to surgical resection
Although mitotane, chemotherapy, thermal ablation, cryoa- blation, and radiotherapy can have a role in treatment, surgery remains the only curative modality (32, 33). Open exploration performed by a qualified surgical oncologist-never a general surgeon-seeking to achieve a curative (RO) resection remains the most common and was for years the only surgical approach. Complete open resections of local disease, not debulking proce- dures, should be the approach at the time of the initial surgery, given survivals of less than 1 year in patients with incomplete resection (2, 32, 33).
But increasing experience with laparoscopic resection of incidentally discovered adrenal adenomas, referred to as adre- nal incidentalomas, has prompted some to attempt a similar minimally invasive approach in the management of adreno- cortical cancers-a practice whose merits have been argued in the literature (Table 3; refs. 34-49). It is not surprising that surgeons, leveraging their experience with benign adrenal masses that can be readily addressed with a simple laparo- scopic resection, adopted a similar surgical approach to adre- nocortical cancers. However, the long-term safety of this approach is unproven, and as our data will show, it has a high likelihood of resulting in peritoneal carcinomatosis, nearly always a lethal complication. Although some argue a laparoscopic approach can be used in selected patients by experienced surgeons, the occurrence of peritoneal dissemina- tion, a lethal complication, in patients undergoing laparoscop- ic resection should discourage any approach other than an open resection. Indeed, laparoscopic resection should never be performed when adrenocortical cancer is suspected. We
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| Reference | Number of patients | Procedure (months follow-up), OA/LA | Results | Conclusion | Comment |
|---|---|---|---|---|---|
| Gonzalez et al. (35) | 160 | 154/6 (all = 28) | Tumor bed initial recurrence OA 35%/LA 50% First recurrence in peritoneum OA 8%/LA 83% | LA for ACC associated with high risk of PC. OA remains standard of care for patients with an adrenal cortical tumor with ACC in the differential. | Small number of LA. Included patients who underwent adrenalectomy before referral as well as patients who underwent operation at reporting institution, and all six LA had surgery performed elsewhere |
| Brix et al. (37) | 152 | 117/35 [129ª]/[23ª] (32)/(64) | Disease-specific survival No difference using matched pairs approach (HR 0.79; P = 0.55) or multivariate analysis (HR 0.98; P = 0.92) RFS Not different (HR = 0.91; P = 0.69) Frequency of tumor capsule violation and PC comparable | LA performed by an experienced adrenal surgeon is justified for potentially malignant adrenal incidentalomas and for selected cases of stage I/II ACC. | Retrospective analysis. Erroneous to infer LA is safe. Only 23% began as LA and 12/35 (34%) of LA were converted to OA. Conclusion applies only to experienced adrenal surgeon and selected, potentially malignant stage I/II ACC. |
| Leboulleux et al. (38) | 64 | 58/6 (All = 35) | Risk of PC OA 27%/LA 67% P = 0.016 | Increased risk of PC after LA for ACC. Whether related to inappropriate surgical approach or insufficient experience needs prospective clarification. | Numbers undergoing LA too small. PC diagnosed within 2 months after initial surgery considered as present since initial diagnosis. Recurrences in the adrenal bed, stuck to the peritoneum, and classified as local recurrences. |
| Miller et al. (39) | 156 (stage 1/ II/III) | 110/46 (All = 37) | Recurrence OA 40%/LA 85.7% P = 0.07 Median time to first recurrence OA 29.5 months/LA 11.7 months P = 0.002 Positive margins; intraoperative spill OA 16%/LA 30% P = 0.04 | OA superior to LA for ACC based on completeness of resection, site and timing of initial tumor recurrence, and survival in stage II. Intraoperative evaluation insensitive for detection of stage III. | Poorer LA outcomes despite unbalanced against OA. Median tumor size LA 7.4 cm (median stage, II) and OA 12.0 cm (median stage, III). |
| Porpiglia et al. (41) | 43 (stage I/II) | 25/18 (38)/(30) | Median RFS OA 18 months/LA 23 months P = 0.8 No differences in pattern of recurrences No differences in OS P = 0.3 | OA and LA might be comparable in terms of RFS for patients with stage I and II ACC when principles of surgical oncology are respected. | Only 43/63 eligible analyzed. Unclear if single institution surgical experience. |
| Lombardi et al. (43) | 156 | 126/30 (40)/(50) | Time to recurrence OA 27 months/LA 29 months P = 0.839 | Operative approach does not affect oncologic outcome of patients with localized (stage I/II) ACC if principles of surgical oncology respected. | A total of 278 patients identified and report only the 156 who had an R0 resection for stage I/II ACC. Authors acknowledge possible bias is patient selection in retrospective analysis. |
| Fossa et al. (44) | 32 (stage I/II/III) | 15/17 (NA)/(NA) | Median PFS OA 8.1 months/LA 15.2 months Not significantly different Violation of tumor capsule and/or intraoperative spill OA 2/LA 5 | LA seems to offer short-term advantages and similar long-term outcome compared to OA in patients with resectable ACC stage I/II/III. | Authors acknowledge LA patients had significantly smaller tumors (8.0 cm) than OA (13 cm; P = 0.002); also differences in stages favored LA (P = 0.06). Two LA converted to OA and scored as LA. Two peritoneal recurrences and two port-site recurrences in LA. |
| Cooper et al. (45) | 302 | 210 + 46/46 35 + 38/29 | Cox regression model adjusting for pathologic T stage, recurrence-free and overall survivals were longer for OA than LA (RFS, P < 0.0001 and OS, P < 0.0001) | Despite performing LA in patients with smaller tumors, LA associated with higher rates of recurrence, particularly PC. For known or suspected ACC, benefits of OA outweigh short-term benefits of minimally invasive LA. | No LA performed at reporting institution. Tumors resected via LA significantly smaller (median 8 cm) than those resected by OA (median 12 cm at outside hospital; 12.3 cm at reporting institution); P < 0.0001. Only 15.2% of patients with PC could undergo surgical resection consistent with 35.9% of all patients with any recurrence (P = 0.0004). |
Abbreviations: ACC, adrenocortical cancer; LA, laparoscopic adrenalectomy; OA, open adrenalectomy; PC, peritoneal carcinomatosis; RFS, recurrence-free survival. ªIn 12 of 35 patients of the LA group, surgery was converted to open surgery with no impact on the clinical outcome.
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| Laparoscopic resection | |||
|---|---|---|---|
| Recurrence with carcinomatosis | Recurrence without carcinomatosis | No carcinomatosisª | |
| Number | 25 | 13 | 20 |
| Female/male | 20 F; 5 M | 6 F; 7 M | 12 F; 8M |
| Age at diagnosis, years | |||
| Median | 49.7 | 52.8 | |
| Range | 23.7-80.2 | 26.9-74 | |
| Time to recurrence, months | |||
| Median | 8.4 | 12.8 | 21.0 |
| Range | 1.6-42.7 | 1.1-36.9 | 1.1-103.7 |
| Overall survival from diagnosis, months | |||
| Median | 26.8 | 37.8 | 52.7 |
| Range | 4.1-129.7 | 3.0-121.9 | 3.0-121.9 |
ªIncludes 13 with recurrence but without carcinomatosis and 7 without recurrence.
reviewed data on 267 patients with recurrent or advanced adrenocortical cancer who had undergone resection of adre- nocortical cancer and who had been referred to the NCI over a period of 15 years. We defined peritoneal carcinomatosis as multiple sites of recurrence on the peritoneal surface spatially separate from the site of surgery, involving areas that would not have been considered part of the surgical field and would not have been considered a local recurrence. Among the 267 patients, 45 had undergone a laparoscopic resection, and 25 of these 45 (55.6%) presented with a pattern of widespread peritoneal dissemination, as shown in Fig. 4A. In comparison, peritoneal dissemination was seen in only 7 of the 222 (3%) patients who had undergone an open resection (RR 17.62; 8.12-38.22; P < 0.0001). In those who had undergone an open resection, the pattern of local recurrence more often resembled the examples shown in Fig. 4B, with localized peritoneal implants limited to the area near the resection. The occurrence of peritoneal dissemination, as shown in Table 4, was associ- ated with a poor prognosis, with a faster time to recurrence and a shorter survival. Trying to discern if peritoneal seeding might
| Laparoscopic resection | |||
|---|---|---|---|
| All patients (45) | (+) Peritoneal carcinomatosis (25) | (-) Peritoneal carcinomatosis (20) | |
| Tumor size (cm) | |||
| Range | 2.3-20 | 3.5-19 | 2.3-20 |
| Mean | 8.37 | 8.5 | 8.19 |
| Median | 8.0 | 8.0 | 8.0 |
| Capsule disruption | 7 | 5 | 2 |
| Tumor fragmented | 5 | 4 | 1 |
| Open resection | |||
|---|---|---|---|
| All patients (191ª) | (+) Peritoneal carcinomatosis (8) | (-) Peritoneal carcinomatosis (183) | |
| Tumor size (cm) | |||
| Range | 1-28 | 6-25 | 1-28 |
| Mean | 12.6 | 13.5 | 15.5 |
| Median | 11.6 | 11 | 11.6 |
aFull information not available for all 220 patients who underwent open resection. Data are for 191 patients with full information.
have occurred as a complication of the surgical approach used, we examined the surgical and pathologic reports for possible clues. Our findings, summarized in Table 5, found no evidence that the seeding that occurred was because of the handling of the specimen. Specifically, this was not peritoneal seeding incited by morcellation of the tissue or disruption of the capsule. Neither descriptions of the operative procedures nor the gross pathologic descriptions indicated the tumor had been handled in any systematic inappropriate manner or led to disruption of the capsule with possible seeding of the peritoneal cavity-although an occasional case did have dis- ruption of the capsule. Instead, routine handling of the tumor had led to inadvertent peritoneal seeding, and we could find no systematic error that could be brought to the attention of those performing these laparoscopies. We would stress that because this patient series represented referrals to a tertiary center, we cannot comment on the incidence of recurrence following laparoscopic resection versus open resection, because we do not have “denominators.”
We recognize the prevalence of incidentally discovered small adrenal masses is high. An NIH State-of-the-Science Conference Statement on the “Management of the Clinically Inapparent Adrenal Mass (Incidentaloma)” noted “the preva- lence of clinically inapparent adrenal masses detected at autopsy is less than 1% for ages younger than 30 years and increases to 7% in those 70 years of age or older.” And with an annual incidence of 1.5 per one million for adrenocortical cancer, the overwhelming majority of incidentally discovered adrenal masses will be benign (50). Thus, we are not suggest- ing laparoscopic approaches be abandoned. However, we would argue strongly that when one is dealing with a likely adrenocortical cancer only, an open procedure should be done without a diagnostic biopsy, as these also risk seeding tumor and often cannot differentiate benign from malignant (51-53). In this regard, as shown in Table 5, the overwhelming majority of these masses would not have appeared on imaging studies as benign adenomas that on pathologic analysis were proven to be carcinomas. With a median size of 8 cm, these were clearly not adenomas. Thus, one can expect that this lethal complication can be avoided. But we would also caution that some surgeons may consider this as a complication of others who may have been careless in their technical approach and think it will not happen to them. However, no one can guarantee laparoscopic removal of a large adrenocortical can- cer will not result in spillage-intraoperative tumor spill rates as high as 50% even by an experienced laparoscopic surgeon have been reported, consistent with our own findings (38, 39). The important thing to note is that although we cannot predict any individual outcome, the majority of these cases were localized adrenocortical cancers that had a good chance of being cured surgically. Instead a surgically curable cancer recurred as an incurable, fatal problem.
We acknowledge that some recognize peritoneal carcinoma- tosis as a risk of laparoscopic surgery, yet believe this technique can be considered in a selected group of small adrenocortical cancers without evidence for invasiveness that are judged as only potentially malignant. They argue that surgical oncologists strictly respecting principles of oncologic surgical treatment can safely perform laparoscopic surgery. Although we respect that opinion, we disagree with it given our own experience that unequivocally shows disseminated peritoneal carcinomatosis
CXCR4 expression
Tumor tissue
Normal tissue
Adrenal
Bladder
Blood
Brain
Breast
Cervix
Colon
Endometrium
Esophagus
Head/neck
Kidney
Liver
Lung
Ovary
Pancreas
Prostate
Skin
Small intestine
Stomach
Testis
Thyroid
Uterus
Vulva
0
2,000
4,000
6,000
8,000
10,000
12,000
1,000
2,000
3,000
4,000
5,000
6,000
7,000
0
8,000
@ 2016 American Association for Cancer Research
CCR Focus
AAGR
as a lethal complication of laparoscopic procedures. Review of the available literature shows others have raised the potential for this complication, but that there has been disagreement regarding the advisability of laparoscopic resection of known malignant adrenal tumors. Notably, two of the three largest studies have warned of peritoneal carcinomatosis as a compli- cation of laparoscopic surgery (35, 45). The third study advo- cated the use of laparoscopic resection of selected adrenocor- tical cancers, summarizing the surgical and oncologic outcome
in 152 adrenocortical cancer patients managed at the time of initial presentation with either an open adrenalectomy or a laparoscopic resection (37).The authors concluded laparoscop- ic adrenalectomy was not inferior to open adrenalectomy, if the cancer was localized and less than 10 cm in diameter. This data, not fully mature at the time of publication, must be viewed cautiously given that (i) extensive preselection occurred with only 23% of tumors less than 10 cm in maximum diameter initially approached laparoscopically and one third of these
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converted to open, and (ii) results in specialized tertiary referral centers have very limited to no applicability in the general community. In addition, a higher incidence of positive margins and more rapid recurrence have been reported with laparo- scopic resections. Finally, a systematic review of laparoscopic surgery for different cancers concluded, “There is no prospective randomized series to guide or endorse the use of laparoscopic resection for adrenocortical carcinoma or malignant pheochro- mocytoma” (40). With regard to patients with adrenocortical cancer, our data, summarized in Table 4, show that peritoneal carcinomatosis results in a more rapid recurrence and inferior overall survival. This may not be surprising, as peritoneal dissemination means fewer surgical or interventional options going forward.
As to what might be causing the occurrence of peritoneal carcinomatosis, ongoing studies are looking at possible interac- tions between the membrane chemokine receptor CXCR4, and its ligand CXCL12, responsible for the homing of stem cells to the bone marrow. As Fig. 5 demonstrates, expression of CXCR4 is high in the normal adrenal and higher in adrenocortical cancers than in the majority of tumors; and surprisingly, CXCL12 is expressed at very high levels on the peritoneal surface (T. Fojo; unpublished data).
Finally, as more data on adrenocortical cancer accumulate, an aggressive surgical posture may emerge as the preferred option at the time of relapse, especially in patients with less aggressive clinical presentations, slower growing tumors, and sensitivity to chemotherapy (54, 55). Although metastasectomy is likely to be of value, one must remember all or the majority of studies reporting the value of salvage metastasectomy have an inherent bias: Those undergoing surgery likely have more limited disease, a better performance status, and possibly tumors whose biology might be considered “more indolent.” It is likely, however, that the literature will eventually validate that carefully planned metastasectomy can bring benefit to patients.
Conclusions
Management of patients with adrenocortical cancer requires a multidisciplinary team comprised of medical, sur-
gical, and radiation oncologists; interventional radiologists; and endocrinologists. Surgery is the only curative option, remains the cornerstone for managing adrenocortical cancer, and must always be aggressively considered both at presenta- tion and at relapse. At the time of the initial presentation, only an open procedure should be conducted. We describe the occurrence of lethal peritoneal carcinomatosis following lapa- roscopic resection of adrenocortical cancers and only rarely after an open resection. As part of a multidisciplinary effort, other options are available for deployment along the course of disease. Mitotane’s greatest attribute is its ability to interfere with steroid hormone metabolism, and it should be continued indefinitely when dealing with a hormone-producing tumor. Chemotherapy with a combination of etoposide, doxorubicin, and cisplatin is the preferred first-line option, but new para- digms are needed and referral to clinical trials should be strongly encouraged. Radiotherapy should be reserved for pal- liative indications. In some patients, RFA and cryoablation likely have value.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors’ Contributions
Conception and design: S. Balasubramaniam, M.J. Merino, S.E. Bates, T. Fojo
Development of methodology: S. Balasubramaniam, M.J. Merino, T. Fojo Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): E.C. Payabyab, S. Balasubramaniam, M. Edgerly, M. Velarde, M.J. Merino, A.M. Venkatesan, T. Fojo
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): E.C. Payabyab, S. Balasubramaniam, M. Edgerly, A.M. Venkatesan, H. Leuva, T. Litman, T. Fojo Writing, review, and/or revision of the manuscript: S. Balasubramaniam, M. Velarde, M.J. Merino, A.M. Venkatesan, S.E. Bates, T. Fojo Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): E.C. Payabyab, M. Edgerly, M. Velarde Study supervision: M. Velarde, T. Fojo
Received July 12, 2016; revised August 22, 2016; accepted August 24, 2016; published online October 14, 2016.
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