MINI REVIEW
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New endpoints in adrenocortical carcinoma studies: a mini review
Matthieu Faron 1,2 . Livia Lamartina3 . Segolene Hescot4 . Sophie Moog3 . Frederic Deschamps5 . Charles Roux5 . Rosella Libe6,7 . Jerome Durand-Labrunie8 . Abir Al Ghuzlan9 . Julien Hadoux3 . Eric Baudin3
Received: 28 April 2022 / Accepted: 25 June 2022 / Published online: 23 July 2022 @ The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2022
Abstract
Purpose Adrenocortical carcinoma (ACC) is a very rare and aggressive malignant disease. Therefore, overall survival (OS) has long been considered as the best endpoint. Yet, a unique endpoint is not optimal to take into account the heterogeneity in tumor profile and the diversification of therapeutic option. The purpose of this mini review was to describe endpoints used in the past, present and future in the field of ACC.
Methods Pubmed and Clinicaltrial.gov were used to identify relevant studies.
Results Before year 2000 only three endpoints were regularly used: OS, recurrence-free survival (RFS) and response rate. These endpoints were used because ACC was seen as a homogeneous diseases with a high recurrence rate and low rate of long-term survival. Since 2000; along with the apparition of new class of drug, progression-free survival (PFS) has been more and more used. Other endpoints as “time to chemotherapy” or “Progression-free survival 2” were used to evaluate multimodal therapies or treatment with a delayed action. Finally, there is a hope that in the near future, quality of life along with other patient-reported outcomes may be used more frequently.
Conclusion While OS and PFS are currently the most used endpoints in ACC, new endpoints are needed to better take into account the challenges offered by different situations and treatment strategies.
Keywords Adrenocortical carcinoma . Endpoints . Surrogate . PRO . QOL
Introduction: endpoints in oncology trials
Purpose of endpoints
Overall survival (OS) (i.e., the time between randomization/ study initiation and death from any cause) has long been considered the best endpoint in oncology trials. At first glance OS seemed to have it all: it is very easy to define, highly reproducible and has a strong value from the patient point of
view. Yet, OS does not reflect well the complexity of the global management of patients in oncology. These past 10 years have seen the rise of “new” endpoints assessing other aspects of the treatments efficacy (tumor response, time to progression … ) or tolerance (quality of life (QOL), toxicities, etc. … ). Besides, from a statistical point of view, the power of a study relies on the number of “events” and in certain situation, waiting for the expected number of OS event may be too long opening the way for surrogates.
☒ Matthieu Faron Matthieu.faron@gustaveroussy.fr
1 Department de Chirurgie Oncologique, Gustave Roussy Cancer Campus, Villejuif, France
2 INSERM 1018, Equipe Oncostat, Université Paris Saclay, Gif-sur- Yvette, France
3 Service d’oncologie Endocrinienne, Département d’imagerie, Gustave Roussy, Villejuif, France
4 Service de Médecine Nucléaire, Institute Curie, Saint- Cloud, France
5 Service de Radiologie Interventionelle, Gustave Roussy Cancer Campus, Villejuif, France
6 Coordinator of the INCA-COMETE Network, Gustave Roussy Cancer Campus, Villejuif, France
7 Service d’Endocrinologie, Cochin Hospital, Paris, France
8 Service de d’onco-radiothérapie, Gustave Roussy Cancer Campus, Villejuif, France
9 Service d’anatomopathologie, Gustave Roussy Cancer Campus, Villejuif, France
Surrogates
The American Food and Drug Administration defines a surrogate as ”[ … ] intermediate endpoints that serve as substitutes for direct measures of how patients feel, func- tion, or survive” [1]. Yet, validating a surrogate is not as easy as it seems. A good surrogate for OS must: (1) be correlated to OS [2], (2) have a treatment effect on the surrogate correlated to the treatment effect on OS [3]. While the first point can be tested at the patient level in a single study, the second require several study to be evaluable.
Patient reported outcomes
Patient reported outcomes are defined as report that comes directly from the patient without interpretation of the patient response by the clinician. They constitute a critical com- plement to the clinician’s view and are becoming mandatory in oncology.
In oncology, no progress can be made without adequate endpoints. In this article we will elaborate why endpoints are difficult to study in adrenocortical carcinoma (ACC), which endpoints were used in the past, which endpoints are currently used and finally which endpoints are needed.
Story of endpoints in ACC: past, present and future
An “ultra-rare” cancer
Rare cancer are defined as having an incidence of less than 6/100,000 new cases per year. With 0.1-0.2/100,000, ACC is 30 times rarer (“ultra-rare”). With so few cases, rando- mized trials are expected to be hard to perform. Indeed, only three phase III trials have been published in the field of ACC [4-6]. Pharmaceutical companies are the promotors of most research on new drugs and are often reluctant to invest money for rare disease. Similarly, nonprofit organization or governmental agencies may prefer funding studies for fre- quent disease as the number of impacted patient is likely to be larger. Moreover, with such a rare disease, international collaboration only can achieve the statistical power neces- sary for phase III which increase the cost and complexity to get funding. Hopefully, the recent advent of “precision medicine” may offer potential answers by allowing to include ACC patient in larger trials. For instance, basket trials [7], are histology-agnostic protocols where patients are selected only by the presence of a specific mutation in the tumor.
With this limitation in mind, it becomes likely that most studies will rely on multi-centric and/or retrospective series. A major breakthrough in the field was the creation of
national networks (like the French INCA COMETE) and international networks like the European Network for the Study of Adrenal Tumor (ENSAT) in Europe (http://www. ensat.org/). The creation of these common databases allowed for a good estimation of “robust” endpoints like OS, while this may not be the case for other endpoint. Indeed, the candidate endpoint may not have been recorded for all patients (e.g., QOL) or in the same way in all centers (e.g., pathological response). Only prospective, large scale, cohorts will overcome these difficulties.
Endpoints in ACC: the past (before 2000)
Refining endpoints in the field of ACC has been neglected in the past because ACC was considered as a homogeneous disease with an extremely aggressive behavior. Indeed, classical pictures of metastatic ACC was a median OS between 1 and 2 years and a recurrence rate after surgery of 70% [8]. Based on such a rapid deleterious outcome, refinement in endpoints was not considered a priority.
OS is probably the most studied endpoint for ACC and one of the best for an aggressive cancer as disease pro- gression is likely the most frequent cause of death. Indeed, in the FIRMACT trial [4], deaths were classified as due to tumor progression in 91% of the patients. In the same line, recent large retrospective cohorts identified no difference between specific and OS [9, 10] confirming the validity of OS as a valid endpoint in ACC.
Along with OS, recurrence-free survival (RFS) has been one of the most used endpoints in older ACC studies. RFS has illustrated soon the high recurrence rate after a so-called curative surgery [8]. However, in contrast with OS, RFS robustness was limited in most studies by the absence of a clear pathological definition of ACC [11, 12] suggesting that benign or atypical adenomas may have been counted with ACC. Most, manuscripts lacked to describe the type and frequency of imaging used during follow-up. Therefore, only the most aggressive (i.e., clinically symptomatic) tumors were expected to be detected by such strategies. Finally, RFS has not been strictly demonstrated to be a surrogate of OS and subsequent analysis of the ADIUVIO trial may provide high quality data [5].
Radiological objective response rate (RR) was the third historically most studied endpoint. This endpoint was probably selected due to the need to identify cytotoxic agent able not only to control but also to reduce the tumor burden. RR is one of the oldest indicator of treatment effectiveness and has the advantages to be fast to determine. The most frequently used classification is the RECIST 1.1 [13]. Newer classification, not only based on tumor volume, like the Choi classification may be useful for some treatments [14]. RR have been shown to be related to OS in several studies for ACC [15-17].
| Endpoints | Comment |
|---|---|
| The past (before 2000) | |
| Overall survival | May be one of the best but too simple to capture the heterogeneity of the tumor |
| Recurrence-Free survival | Limited by no pathological definition and no standardized follow-up protocol |
| Radiological response (RR) | Most often with RECIST 1.1 |
| The present (2000-2020) | |
| R0 resection rate | Reproducibility need to be assessed |
| Time to second progression (PFS2) | For treatment with delayed action (mitotane) |
| Time to chemotherapy (TTC) | Loco-regional therapies as a way of delaying chemotherapy |
| Disease-free survival | The quality of the surgery |
| The future (>2020) | |
| Validated surrogate for OS (RR, PFS, RFS) | Shorter trial in low risk patients |
| Pattern of failure after resection | What to change for a better surgery |
| Quality of life | As the co-primary endpoint with a dedicated scale |
| Time to third systemic line? | For complex multimodal therapies including loco-regional treatment, mitotane and several chemotherapy |
Half of ACC are hormonally functional, and the hormone level is related to tumor volume and may be used a surrogate of treatment efficacy. Few studies have convincingly studied the relation between hormonal response and OS [15].
Endpoints in ACC: the present (2000-2020) and the future (>2020)
We identified five new challenges in ACC management illustrating the reason for the emergence of recent end- points. First, the demonstration of a certain degree of het- erogeneity in ACC prognosis best coined by ENS@T [18], and GRAS parameters [10]. Secondly, the renewed interest for mitotane based therapy [5]. Thirdly, the continuing insufficient rate of R0 resection at initial surgery [10]. Fourthly, the introduction of new therapeutic options (loco- regional therapies, immunotherapy) [6, 19] and strategies (neoadjuvant therapy). Finally, the need to study QOL and other patient-reported outcomes (PRO) (Table 1).
Individualization of subgroups of ACC with more indolent courses and prolonged survival challenges the pertinence of OS as the unique primary endpoint. Indeed, median OS of patients with unresectable modified ENSAT Stage IVA (i.e., no more than two metastatic sites) stage is 21 months [9]. In the same way, median OS time of 2-5 years have been reported in ACC responding to treatment which suggest again that good surrogates are needed [17, 20]. The recent investigation of several targeted therapies have popularized the analysis of progression-free survival (PFS) as the primary endpoint in ACC [21-24]. PFS based on RECIST with evaluation every 6 to 12 weeks depending on the treatment line is already the most used
| Endpoints | N= 35ª |
|---|---|
| Progression-free/recurrence-free survival | 21 (60%) |
| Radiological tumor response | 19 (54%) |
| Overall survival | 16 (46%) |
| Toxicities | 16 (46%) |
| Quality of life (QOL) (general scale QLQ-C30 in most) | 6 (17%) |
| Hormone level | 3 (9%) |
| biological | 2 |
| clinical | 1 |
| Time to QOL deterioration | 1 (3%) |
| Time to progression under second line | 1 (3%) |
| Duration of response | 1 (3%) |
aStudies can have more than one endpoint so percentage does not sum to 100%
endpoint in ongoing trials (Table 2). Another rising end- point in early-phase ACC trials is objective RR probably because these type of trial require an early endpoint in order to detect a signal of efficacy [19, 25, 26]. Although partial response has been shown to be correlated to OS in several studies, such achievement has not been reached for PFS yet.
In the absence of breakthrough with new drugs, a renewed interest has been observed for the “historical” mitotane ther- apy. Indeed partial response exists and potential gain in OS was suggested mainly by retrospective studies [27, 28]. Achieving a 14 mg/l plasma mitotane level is currently con- sidered as the best benefit over risk compromise for efficacy
[27] and the obtained level must be taken into consideration when evaluating the treatments. However, little is known about the median PFS of patients treated with mitotane and the first median PFS was reported in 2017 [28, 29]. These studies reported short median PFS of 3-4 months suggesting an insufficient antitumor action. However, delayed action is a well-known characteristics of this drug given as a mono- therapy. Indeed, partial response is most frequently observed between 3-6 months after treatment initiation [30]. Based on these results, it is probable that first progression under mito- tane therapy (PFS1) does not reflect the antitumor capacity of this agent [31] but second or third progression may be better indicators. We have reported a case report showing that four progression were observed before the patient experienced a very prolonged partial response [31]. To take this into account, we recently proposed to use second progression-free survival (PFS2) and time to systemic chemotherapy (TTC) as end- points [32]. In this study, we demonstrated a better correlation between PFS2 or TTC and OS than PFS1.
Complete (R0) resection is not achieved in all localized ACC patients and the rate of R0 resection did not progress in the recent years. Several factors explain this point including the absence of systematic referral of such patients in expert center which as demonstrated a clear benefit in other rare malignancies [33]. R0 resection of the primary has been demonstrated to be one of the most important prognostic parameter whatever the stage [10]. This implies that any sur- gical study need to incorporate the rate of R0 resection in its endpoints. Yet, the reproducibility of this endpoint remains to be explored. There is also an urgent need to better specify the pattern of abdominal failure after surgery. Indeed, the precise location of the recurrence can indicate why the treatment failed. For instance, local (tumor bed), lymph node or distant peritoneal recurrence may require different actions to be minimized and help to better define which surgery is needed.
Induction and neoadjuvant therapy are increasingly used in ACC patients and can have several goals: (1) obtain a tumor shrinkage rendering resectable a previously unresectable tumor, (2) to spare more organ during the surgical procedure, (3) to secure the rate of R0 resection, (4) to delay surgery to be able to adjust for extreme aggressiveness, (5) to be sure to be able to treat microscopic disease even in case of postoperative complication. Each of these goals may need its own endpoint and should be studied in the future. For instance, complete pathological response is rare and poorly reported in ACC [16, 20]. Well standardized partial and complete response classification may be useful as it has the potential to be major prognostic factor. Accurately evaluating this factor would be an argument to propose the surgical removal of residual dis- eases after neoadjuvant treatment.
While with an aggressive disease it may seem obvious that treatment efficacy is the most important endpoints, one can argue that if death is inevitable QOL is of utmost importance.
A recent systematic review by Steenaard et al. [34] illustrated that very few is known. Only six studies were identified representing 323 ACC patients. Most of the time ACC patients were mixed with other neuroendocrine neoplasia or with Cushing Syndrome. Only the FIRMACT trial [4] focused on ACC QOL. FIRMACT used the QLQ-C30 scale which is a general scale of QOL [35]. The QOL at baseline was lower than the general population. In this trial, although one regimen was superior on PFS, this oncological benefit did not translate into a QOL difference. Moreover, treatment like mitotane may greatly worsen the QOL for a little improvement in survival making Quality Adjusted Life Year an interesting endpoint to balance the benefit over the risk. Hormonal secretions may also impair QOL on their own. Two QOL scale (Tuebingen CD-25 [36] and CushingQoL [37]) can be used in functional tumor but were not specifically designed for ACC. It is desirable that QOL will be more and more present in future trials.
Conclusion
OS and PFS are currently the most used endpoints in ACC. New endpoints are needed to better take into account the challenges offered by different situations and treatment strategies. Finally, we hope that QOL and PRO will be more and more considered in the near future.
Author contributions The conception of the study was done by E.B. The literature search was done by M.F. The first draft of the manu- script was written by M.F. and E.B. and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest Directly related to the present work: E.B., M.F. and R.L. have served on an advisory board for HRA Pharma. S.H. received travel grant from HRA Pharma. Not related to the present work: J.H .: Board (IPSEN, Pharma Mar, Lilly, Roche, AAA), Travel support (AAA, IPSEN), Research: (Novartis). L.L .: tumor board (IPSEN, Bayer, EISAI), Honoraria (EISAI, LILLY), Travel Grant (AAA, Novartis). S.H .: Board (Eisai, AAA), Travel support (Ipsen, AAA), Research (HRA Pharma, Ipsen). E.B .: Expert board (Ipsen, Novartis, AAA, Pfizer, Hutchinson Pharma), Research grant: (Novartis, HRA), Principal investigator (Ipsen), Drug supply (Pfizer, AAA). M.F .: Board (HRA Pharma), Honoraria (VIFOR Pharma), Travel Grant (Novartis, Ipsen).
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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