CrossMark
Good news for patients with adrenocortical carcinoma from the ADIUVO trial
Veronika Zakharova/Science Photo Library
Published Online August 21, 2023 https://doi.org/10.1016/ S2213-8587(23)00231-0 See Articles page 720
Recently, a man aged 50 years came to my office. He had received surgery for a right-sided non-functional adrenocortical carcinoma measuring 11 cm in diam- eter and had been referred to discuss adjuvant treatment. Based on adrenal histology findings, he had a European Network for the Study of Adrenal Tumors (ENS@T) tumour stage II, which means no lymph node metastases, and a [18F]fluorodeoxyglucose-PET scan had ruled out distant metastasis.1 Fortunately, he had undergone oncological tumour resection resulting in complete resection. Nonetheless, his Ki67 proliferation index was 8% and, together with the tumour stage, he was at a 40-60% risk of recurrence within the next 5 years.2-5 “I heard about adjuvant treatment with mitotane, what do you recommend, doctor?” When I explained to him, that the adrenolytic agent mitotane would hopefully reduce the recurrence rates to 25-40%, but that he would not be able to drive a vehicle because of neurotoxicity during mitotane treatment, he interrupted me: “Sorry, doctor, I cannot take this drug, I have to drive a forklifter truck every day in my small enterprise, and stopping it would drive me out of business.” Reluctantly, I had to accept his choice.
Adrenocortical carcinomas are rare but very aggressive tumours with a prevalence of 0.7-2.0 cases per million population per year.6 The median overall survival of all adrenocortical carcinoma patients is about 3-4 years. Surgery is indicated for all non- metastatic adrenal carcinomas (ENS@T stages I-III), with R0 resection and intact capsule being the most important prognostic factors for cure. Surgical expertise is a key factor influencing local recurrences rates. However, even if treated by experienced surgeons, the majority of patients with ENS@T stage II and III tumours will eventually have a recurrence and die of their disease. Hence, adjuvant therapy with mitotane has received general endorsement by guidelines for patients with high-risk adrenocortical carcinomas, and treatment is also suggested for low to intermediate risk cases.6 Mitotane is a derivative compound of the insecticide dichloro-diphenyl- trichloroethane (DDT). It was first isolated from DDT in the 1940s, and after its successful use in a single
patient with adrenocortical carcinoma, it was launched to the market in the 1960s.7
In The Lancet Diabetes & Endocrinology, Massimo Terzolo and colleagues8 report the results of the ADVIUVO trial, a publicly funded, investigator-initiated, open-label, randomised trial in 91 patients with low to intermediate risk of adrenocortical carcinoma (resection status 0, ENS@T stage I-III, and proliferation index Ki67 ≤10%). The trial was done at 23 centres across seven countries between October, 2008, and December, 2018. According to this trial, the 5-year recurrence free survival rate was not significantly different between the 45 patients who received mitotane and the 46 patients who underwent surveillance alone (79% [95% CI 67-94] vs 75% [63-90]; hazard ratio 0-74 [95% CI 0-30-1.85]).
A similar improvement (with a marginal 2% difference between oral mitotane and observation) was found in a parallel prospective, observational study, which included patients eligible for the trial but who were reluctant to be randomly assigned.
This trial has several positive findings. First, it shows that the recurrence-free survival at 5 years in the placebo group was much better than previously reported (75% vs 40-60%). This difference is most likely due to a reporting bias of the retrospective older studies. Second, patients with low to intermediate risk of adrenocortical carcinoma can reliably be identi- fied with a widely available prognostication scheme based on adrenocortical carcinoma stage, resec- tion status, and Ki67 assessment. This information is paramount because it will pave the way to a more personalised management of patients with adrenocortical carcinoma. Finally, the trial suggests that adjuvant mitotane treatment does not have a major survival benefit over placebo in patients with low to intermediate risk of recurrence. This is in sharp contradiction with previous guidelines and recommendations based on expert opinion or retro- spective studies.6 As mitotane has a relevant toxicity profile at therapeutic levels, the authors of the ADIUVO trial argue that the observed side-effects associated with treatment (eg, toxicity and impact on quality of life) are key factors leading to their recommendation
of not treating patients at low risk of adrenocortical carcinoma in the future.
According to the initial hypothesis, 200 patients had to be randomly assigned to demonstrate a 15% significant improvement in recurrence free survival over 5 years. However, only 91 patients were randomly assigned, and the study had to be discontinued prematurely after 10 years. Is the high rate of refusals to participate in this randomised trial unusual? I believe not. It is intriguing that in the parallel ADIUVO Observational study almost half of the patients received mitotane, suggesting that the concept of randomisation as such was unacceptable. Patients with cancer dislike the idea that the choice of treatment would be based on chance. Moreover, acceptance is lower for trials such as ADIUVO with an active treatment arm compared with no treatment.9 This might have been the key reason for the trial not reaching the target sample size.
The open-label design was a consequence of the mode of action of mitotane. Because patients treated with mitotane are at risk of adrenal insufficiency and need preventive steroid treatment, similar steroid treatment in the surveillance group could have detrimental side-effects.
Finally, and despite some limitations, the results of the ADIUVO trial are another excellent example that retrospective studies should be generally abandoned and that prospective studies are feasible and should be favoured in rare diseases such as adrenocortical carcinoma. In conclusion, the findings from the ADIUVO
trial mean that patients similar to mine with a low to intermediate risk of recurrence could be spared a difficult choice between Scylla and Charybdis-either taking oral mitotane accepting severe and often intolerable side- effects or accepting a shockingly high recurrence rate and early death.
I declare no competing interests.
Martin Reincke martin.reincke@med.uni-muenchen.de
Medizinische Klinik und Poliklinik IV, Klinikum der Universität, Ludwig-Maximilians-Universität München, 80336 München, Germany
1 Fassnacht M, Johanssen S, Quinkler M, et al. Limited prognostic value of the
2004 International Union Against Cancer staging classification for adrenocortical carcinoma: proposal for a Revised TNM Classification. Cancer 2009; 115: 243-50.
2 Beuschlein F, Weigel J, Saeger W, et al. Major prognostic role of Ki67 in localized adrenocortical carcinoma after complete resection. J Clin Endocrinol Metab 2015; 100: 841-49.
3 Glenn JA, Else T, Hughes DT, et al. Longitudinal patterns of recurrence in patients with adrenocortical carcinoma. Surgery 2019; 165: 186-95.
4 Liang J, Liu Z, Zhou L, et al. The clinical utility of ‘GRAS’ parameters in stage I-III adrenocortical carcinomas: long-term data from a high-volume institution. Endocrine 2020; 67: 449-56.
5 Elhassan YS, Altieri B, Berhane S, et al. S-GRAS score for prognostic classification of adrenocortical carcinoma: an international, multicenter ENSAT study. Eur J Endocrinol 2021; 186: 25-36.
6 Fassnacht M, Tsagarakis S, Terzolo M, et al. European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 2023; 189: G1-42.
7 Corso CR, Acco A, Bach C, Bonatto SJR, De Figueiredo BC, De Souza LM. Pharmacological profile and effects of mitotane in adrenocortical carcinoma. Br J Clin Pharmacol 2021; 87: 2698-710.
8 Terzolo M, Fassnacht M, Perotti P, et al. Adjuvant mitotane versus surveillance in low-grade, localised adrenocortical carcinoma (ADIUVO): an international, multicentre, open-label, randomised, phase 3 trial and observational study. Lancet Diabetes Endocrinol 2023; published online Aug 21. https://doi.org/10.1016/S2213-8587(23)00193-6.
9 Jenkins V, Fallowfield L. Reasons for accepting or declining to participate in randomized clinical trials for cancer therapy. Br J Cancer 2000; 82: 1783-88.
Many years of life lost to young-onset type 2 diabetes
Years of life lost to diabetes is a metric that is receiving increasing attention given its potential use in health education and advocacy. People with diabetes have a loss of life expectancy of between 2.5 years and 12.9 years over the lifespan, as shown in multiple high-income populations.1
In this issue of The Lancet Diabetes & Endocrinology, the Emerging Risk Factors Collaboration show, by pooling data from cohorts in high-income countries, that loss of life is considerably greater in people who are diagnosed with type 2 diabetes at a younger age than in those who are diagnosed when older.2 For people in the USA, the group estimated that an
average of 6 years of life were lost in men diagnosed with diabetes at age 50 years, whereas 14 years were lost if diagnosed at age 30 years. In women, the corresponding losses were 7 years for diagnosis at age 50 years and 16 years for diagnosis at age 30 years.
These findings are of concern given that young- onset type 2 diabetes-usually defined as onset before the age of 40 years-is becoming increasingly common.3 In the 2013 Diabetes Atlas, the International Diabetes Federation estimated that 16% of cases of type 2 diabetes were diagnosed in people younger than 40 years. Studies from multiple sources suggest that this fraction could be increasing rapidly.4
CrossMark
Published Online September 11, 2023 https://doi.org/10.1016/ S2213-8587(23)00255-3 See Articles page 731
For the 2013 edition of the Diabetes Atlas see https:// diabetesatlas.org/atlas/sixth- edition/