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Editorial |
Division of Endocrinology, Diabetes, and Metabolism The Ohio State University Columbus, Ohio 43210
Address all correspondence and requests for reprints to: Dr. Lawrence S. Kirschner, The Ohio State University, 420 West 12th Avenue, Room 544, Columbus, Ohio 43210. E-mail: lawrence_kirschner{at}osumc.edu.
Adrenocortical carcinoma (ACC) is a disease that most physicians, including many endocrinologists, will rarely, if ever, treat during the course of their medical practice. The incidence of this disease is approximately one patient per million in the population worldwide (1), with the exception of regions of Brazil, where the incidence is approximately 10 times higher (2). ACC continues to carry a poor prognosis, with an overall 5-yr survival rate of less than 50% and rates of less than 20–25% for the approximately 60% of patients who present with advanced disease (3). As with most cancers, complete surgical removal at the time of diagnosis offers the best hope for rendering these patients free of disease. However, as the median size of ACCs at the time of diagnosis is still in excess of 10 cm, it is not surprising that gross or microscopic metastases are frequently present at the time of presentation. This clinical observation points out the inherent need for the development of new therapies targeting these residual cancer cells.
One of the major problems in dealing with ACC as a clinical disease is the longstanding view in the field that this cancer is poorly responsive to all treatments, including both cytotoxic chemotherapy and radiotherapy. This viewpoint has arisen from historical data over the past 50 yr, including institutional case series, small clinical trials, and expert opinion. For many years, the most hotly debated question regarding therapy for ACC was regarding the role of the adrenolytic agent mitotane, which was the most "effective" treatment available, with response rates in the 25–30% range (4).
Over the last few years, this reliance on historical precedent has begun to be replaced by data-driven treatment strategies. Part of the impetus for this push has come from Europe, where the availability of country-wide integrated networks for treatment has allowed a small number of centers in Italy, France, and Germany (among others) to develop specific expertise and specific treatment protocols for this rare disease. Another part of this drive comes from new understandings of the molecular mechanisms of disease and the desire to translate these data into more rational and effective treatment agents (5).
As these newer studies have developed, it has become clear that ACC can, in fact, be treated, although it remains fairly resistant to many (but not all) therapies. The first example of this was the development of a chemotherapy regimen by Berruti and colleagues in Italy, who showed that a regimen of etoposide, doxorubicin, and platinum in combination with mitotane (EDP/M, also known as the Berruti regimen) could produce clinical response rates up to 50% in advanced ACC patients, although complete remissions were still rare (6). This response rate was markedly higher than rates achieved with previous chemotherapy regimens and has held up remarkably well in a reanalysis of patient data 7 yr after the initial description (7). Fueled by these findings, a large, multicenter, international clinical trial is currently underway to compare this regimen with treatment with another moderately successful regimen, streptozotocin plus mitotane (SO, also known as Sz/M or the Khan regimen) (8), to define the standard of care for chemotherapy for this disease. Until patient accrual is completed, referral to this clinical trial, known as the FIRM-ACT study (www.firm-act.org), should be first-line therapy for any patient with a new diagnosis of advanced ACC. Using the FIRM-ACT data as a baseline, it will then be possible to assess properly the systemic effects of newer, molecular targeted therapies given in addition or instead of classical cytotoxic agents (5).
What, then, can be done for patients with nondisseminated ACC? This issue was recently addressed at a 2003 consensus conference on ACC held in Ann Arbor, MI (9), and is best subdivided into two distinct areas. First, what to do about patients that have isolated metastatic disease? Second, what is the role of adjuvant therapy after (presumably complete) primary tumor resection?
Regarding the patients with metastatic but limited disease, the data clearly indicate that repeat surgery with the intent to cure (i.e. complete metastasectomy) is beneficial for patients (10), both in terms of survival and for improving symptoms of hormone oversecretion. For patients that are not able to tolerate surgery, radiofrequency ablation appears to offer excellent local control for isolated metastases, particularly those that are less than 5 cm in diameter (11). Additionally, although it has not been widely discussed, there is good evidence in the literature that radiation therapy (XRT) is effective at providing significant local relief from the pain of bony metastasis (12).
For adjuvant therapy, the story is much less clear. The majority of the discussion at the Ann Arbor conference centered on the use of mitotane in the adjuvant setting, although irradiation was also discussed. Briefly, no recommendations were made regarding either treatment because there has not been enough data on this topic (9).
In this setting, the study of Fassnacht et al. (13) in this issue of JCEM occupies an important place in addressing the role of XRT as adjuvant therapy for ACC. In the paper, the authors report retrospectively on findings in 14 patients from the German ACC registry who underwent XRT to the adrenal bed as adjuvant therapy after primary resection of an ACC. Each of these patients was thought at the time of surgery to have a complete resection (R0), although subsequent pathological analysis suggested that true R0 status was obtained in only eight patients. As a control, the authors identified 14 patients matched closely to the XRT group in clinical characteristics but who had not received adjuvant radiation.
Although it was not clear that XRT would show benefit in this setting, the data convincingly demonstrated that radiation had a marked effect in reducing the rate of local recurrence, from 79% (10 of 14 control patients) to 14% (two of 14 XRT patients), recurrence rates that carried out essentially unchanged for 5 yr. This information seems quite promising and suggests that adjuvant XRT may have a place in the long-term planning of therapy for ACC. However, the bad news of the study is that overall mortality was not affected in these patients, with fewer than 20% in either group surviving past 5 yr.
In interpreting this study, it seems reasonable to ask how we can explain the very high recurrence rate in the cohort, particularly given (as the authors mention) that local recurrence is more typically observed in 50–60% of patients. Perhaps the best answer lies in the selection bias. It is doubtful that a group of experienced ACC physicians such as the authors would offer XRT to patients unless they were exceptionally concerned about local recurrence. As it turns out, the authors were quite good at predicting recurrence, as determined by the nearly 80% rate in the control group.
What are the take-home messages to be learned from this study? In the first place, it demonstrates (again!) that data from controlled studies (even case-control studies, such as this one) may provide different results from historical controls and opinion. As the authors point out, common practice had suggested that ACC was radioresistant (14). Although not definitive, the data presented in this paper refute this view and suggest the need for a prospective trial of adjuvant XRT in ACC. Given the massive effort (including research and patient care infrastructure) to recruit patients to the FIRM-ACT trial, one possibility would be to use the same mechanism to produce a separate study for patients in stage 1 or 2 of disease to test this question. In some ways, the goals of such a trial would closely parallel the goals of the current FIRM-ACT investigators: to dispel the myths surrounding ACC and replace them with prospectively earned facts regarding optimal treatment.
Second, this study highlights quite strongly the thing that most physicians caring for ACC patients fear the most: the likelihood that patients with this aggressive cancer will have micrometastasis even at clinically early stages of disease. Given that over half of the patients in each arm (eight for the XRT group, nine for control group) were in stage 1 or 2 of disease, this paper provides good support for the notion that these tumors spread early. Because XRT of the tumor bed prevented local recurrence, would irradiation of the paraaortic lymph nodes have a more pronounced effect on survival?
Finally, how does this study change the recommendations for the optimal therapy for ACC? The best algorithm for these new data is the one recently published in this journal by Allolio and Fassnacht (1), which includes the consideration of adjuvant XRT or mitotane, even in cases of complete resection of an ACC. Certainly, in cases where the tumor is large (e.g. 10 cm or greater) or has concerning features (e.g. high Weiss score and/or mitotic index), strong consideration should be given to adjuvant therapy, particularly in light of the low rate of observed complications. The caveat of this recommendation, however, is that this should optimally be carried out in the setting of a research study, so that any patient care data can contribute to the advancement of our understanding of the risks/benefits of such therapy.
In summary, the struggle against ACC continues to evolve at a significant pace. With a combination of XRT and radiofrequency ablation, we have adequate means to control ACC that occurs or recurs locally. The survival benefits of such treatment are not clear at present, although more studies to address this question directly are required. With these local therapies in place, we can again turn to the question of the optimal global (organism-wide) therapy and continue to work toward the development of chemotherapeutic regimens that will allow us to destroy small pockets of disseminated disease. When these modalities are used together, in combination with aggressive surgical management, we will have the potential to achieve both local and global control of this tumor, with the optimistic assessment that we may soon possess the tools to make inroads leading to reliably enhanced survival of ACC patients.
Footnotes
Abbreviations: ACC, Adrenocortical carcinoma; XRT, radiation therapy.
Received September 5, 2006.
Accepted September 7, 2006.
References
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