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Discussion
CrossMark
DR NANCY PERRIER (Houston, TX): The data are relatively strong with regard to the series size, but what is clear from your data is how weak we are in advancing the treatment of this disease. You confirm that we have had very little impact on cure over the last 50 years of this disease.
What you describe are factors determined for who received mito- tane, which is a reflection of practice pattern. Without clear inclu- sion criteria from mitotane therapy, we are merely retrospectively assessing the physician’s subjective choice of treatment. Those who died and did not receive mitotane likely died of disease, but of those who did receive mitotane, we cannot discern whether they died from disease or from the treatment itself. Death from treatment with this drug is possible and probable. Mitotane is an insecticide with a significant toxicity and pharmacokinetic chal- lenges that limit its effectiveness. The drug has a side effect profile that includes death.
The inconsistencies of close monitoring for therapeutic levels are of significant concern. This is a cytotoxic agent that causes adrenal cell death. Provision for meticulous care to balance the ravages of adrenal insufficiency from hypercortisolism, which is required for mandatory adrenocortical replacement when giving the drug, comparing and contrasting that with cytotoxic chemotherapy effects, or from death from advanced metastatic disease, is difficult. The therapeutic window is extremely narrow and dangerously close to the toxicity realm. I have several observations from the data.
The striking finding of a variability of treatment is apparent. Having data on only 15 patients who actually had documented therapeutic monitoring of the drug is concerning. There is also concern for mitotane overdose, plasma cortisol insufficiency, and aberrant vital hormonal function. Proper dosing of this drug
requires a tight regimen that needs meticulous management by both an endocrinologist and an oncologist familiar with the nuances of the pharmacokinetics. Even in experienced hands, this is difficult at best.
The National Comprehensive Cancer Network guidelines recommendation is indeed based on the assumption of achieving and maintaining therapeutic levels. Without having data on thera- peutic levels, this cannot be assumed.
We agree with the data showing that to date this work and others support that margin negative resection is the only independent predictor of a durable cure. Good surgery with complete extirpation is the solution. Good surgery alone is better than poor surgery plus drug. I applaud the conglomeration of data and I make the point that, again, in more than 50 years, we have not advanced this disease with mere treatment with a pesticide.
You report 13 institutions treating, on average, less than 2 patients per year. All result in occasional and varied care. You confirm that this simply is not the cure. I challenge all of us here to take a chance to change this into a transformative decision for health care.
This disease represents a disease that needs regionalization of care. To answer the question of how to cure it requires a prospec- tive, randomized clinical trial. The American College of Surgeons, along with national and international specialty societies, have made attempts to have this happen. This United States Adrenocortical Carcinoma Group can make this happen. You confirm that the retrospective attempt is simply not adequate. I challenge all of us to use this disease as an example to change our own behavior. We will only improve by designing centers with multidisciplinary care by experts who know these rare diseases. Endocrinologists, oncologists, and surgeons with volume and a chance to realize the nuances are necessary. With 209 cases, a randomized controlled trial with 100 patients in each arm over 20 years with follow-up may provide the answer.
We are no closer to understanding the mechanism of action of this drug, the advantages, or who should be put on this drug than we were before we put a man on the moon, revolutionized the microchip, interconnected the globe with the World Wide Web, or developed an artificial heart.
Our teams can instantaneously Facetime, but we cannot pro- vide consistent care. We can lead each other to improved guide- lines and concentrate this rare disease. To do this, we must be nimble. We need to do things differently. We need to change our own behavior. We need to take a step together with these data. We need to learn how neoadjuvant treatment and personal- ized molecular targeting and genomic profiles can affect the tu- mor cycles and regression, and transform borderline disease into resectable disease.
I hope that you have the confidence in these data to support that we should concentrate the care. My challenge to you is to maximize the power of the consortium, set the standard for how this should be done, and change the fact that 17% of the patients, at best, had recommended therapeutic levels, and concentrate care.
There are new therapies. The ATR 101 molecular target for ster- ile transferase, one pathway, is a clinical phase 1 trial at 3 institu- tions in the country. It is being led by the University of Michigan and Gary Hammer. We should enroll these patients in
that trial. We should administrate care with interest, experience, and volume.
DR CHARLES SCOGGINS (Louisville, KY): Dr Maithel has once again shown that he has mastered the art of collaborative research and has helped to develop a robust group of collaborators. Without this type of collaboration, rare diseases such as adrenal cancer would not be well studied, and it would be much more difficult to do trials.
Like other malignancies that you study, such as pancreatic cancer, adrenal carcinoma is in need of more effective adjuvant therapies. Monotherapy with an old drug like mitotane represents a therapeutic strategy with limited scope. Recent evidence points to a potential role for epidermal growth factor receptor (EGFR) inhibitors for adrenal cancer. I would be interested in your thoughts on multidrug therapies and novel therapies.
The decision on whether to use adjuvant mitotane appears to have been at the discretion of the treating physicians and, as such, introduces significant selection bias into your study. This makes drawing meaningful conclusions problematic. I wonder if you would comment further on this.
More patients in the mitotane group had higher stage disease. Is it possible that the lack of benefit seen by the mitotane was, in part, explained by the fact that the group who received it had more advanced tumors?
DR WILLIAM “BARRY” INABNET (New York, NY): Over the 25-year time frame of your study, we witnessed the introduction of laparoscopic techniques to the clinical realm. Surgeons now know that laparoscopic resection of known or suspected adrenocor- tical cancer can adversely affect outcomes and lead to higher recurrence.
When performing your data analysis, did you compare the first decade to the second decade with the hypothesis that there would be more laparoscopic adrenalectomies performed during the latter decade? Did the introduction of laparoscopic techniques in any way affect outcomes?
DR BARBARA GAINES (Pittsburgh, PA): I was struck when I was listening to this talk about a rare disease about the success of the pediatric oncologists taking on rare tumors. The incidence of Wilm’s tumors is about 500 new diagnoses a year; neuroblastoma is somewhere around that, maybe a little less. Through collaborative trials, they have been able to have significant success. I was just struck again about the opportunity, even with rare tumors, if we work together, to be able to find answers to these problems. I do think that the pediatric oncologists have really shown the success of that paradigm.
DR JOHN STEWART (Durham, NC): I was struck by the fact that this tumor is so rare, and your group has been able to put together quite an impressive series. However, moving forward, as Dr Perrier noted, it is important for us to understand molecular determinants of outcome. Are there efforts by the group to gather tumors through a central core lab to look at transcriptomic findings in order to better design therapies?
DR SHISHIR K MAITHEL (Atlanta, GA): Dr Scoggins asked about the different pathways that may be involved in tumorigenesis of adrenocortical carcinoma. This goes along with what Dr Perrier was saying as well. I believe that, for this disease, we have to move beyond the standard cytotoxic chemotherapies, and although it is a rare disease, include it in the modern era of personalization of cancer therapy, which we are trying to do for other solid and liquid tumors today.
It will require molecular profiling of these tumors and at- tempts to find the exact pathways that are involved in the devel- opment of these tumors to decide on the correct pathways to target. Specifically, EGFR is one target that has been investigated, as Dr Scoggins alluded to. There have been some promising data in cell lines. However, the data from human tumors have not shown any prognostic value for EGFR expression. Furthermore, investigators have not been able to demonstrate any consistent mutations in the EGFR pathway for adrenocortical carcinoma. So, whether or not that specific target will be effective remains to be seen.
As we study these tumors and describe their molecular profiles, we have to be careful of extrapolating data from advanced tumors to localized tumors that are resected and are further treated in the adjuvant setting. As we know from many other disease types, specifically colorectal cancer, tumor response to a specific therapy does not necessarily translate across disease stages.
One major difficulty in studying this tumor is its rarity. As I previously mentioned, there are only approximately 250 cases per year in the United States. This study was a 13-institution study over 20 years that compiled only 250 surgical cases. So the majority of adrenocortical carcinoma patients present with advanced disease that is beyond the scope of surgery. We have to be very careful, as we study this tumor, what we extrapolate to the patient with localized disease, whom we as surgeons will be seeing in our clinics.
It is unlikely there is any single pathway that will tie all of these tumors together. We have seen this multiple times. In countless studies looking at genomic profiles of solid tumors across different institutions and datasets, very rarely can you actually validate it and replicate a similar profile in a different patient population.
Dr Scoggins, regarding your concern about selection bias, I abso- lutely agree that this is a concern. In any retrospective series, there is no way to really overcome that, but I will say that it is the same selection bias that exists in 99% of papers and studies in the liter- ature that helped to train us.
In terms of the patients with higher-stage disease more likely to receive adjuvant mitotane, I once again absolutely agree that this goes back to the issue of selection bias. We attempted to account for that in multivariable regression analyses, as well as looking at high-risk and low-risk groups separately. When we analyzed the low-risk group, we still found no association of improved outcomes with adjuvant mitotane therapy.
With regard to Dr Perrier’s comments, I wholeheartedly agree with you, as well. We have to come together not just as an institution, but as a medical community, to treat this rare disease. It is definitely a limitation that we do not have data on the mitotane levels, and this raises caution about interpretation of the results. That being said, I also agree with you that a good R0 resection is the key.
Dr Perrier advocates for moving toward regionalization of care for this rare disease. In that vein, we have assembled several collab- orative research groups, starting with the Central Pancreas Consortium, as well as the United States Gastric Cancer Collabo- rative and the United States Extrahepatic Biliary Malignancy Consortium, and now this United States Adrenocortical Carcinoma Group. What this has done is bring like minds and academic inves- tigators together across institutions throughout the country to start studying these diseases. So far, we have been limited to retrospective series, but, it has created the foundation and the team to do exactly what Dr Perrier refers to, which is getting together and working toward conducting prospective trials.
On that same note, regarding the question of whether we are working toward doing molecular analysis of these tumors, the answer is absolutely yes. Within our US Gastric Cancer Collabora- tive, we have talked about centralizing tissue and doing molecular analyses. We are trying to overcome some of the logistic hurdles, including economic and institutional barriers, to do exactly that. That is definitely a goal of these collaborative efforts. I appreciate the comment about the success that the pediatric oncologists have demonstrated with rare diseases. We could, and should, definitely learn from them.
Finally, 19% of patients underwent a laparoscopic approach. Obviously, they were probably well selected for having smaller tumors. We found no difference in their survival in terms of recurrence or overall survival when compared with the open resection group. In terms of the timeline, we did not break it down by time periods. However, I would assume that the majority of the laparoscopic procedures were in the second half of the time period when skill and comfort with this tech- nique were greater.