JJCO Japanese Journal of Clinical Oncology
Original Article
The role of multimodal salvage therapy in the management of recurrent adrenocortical carcinoma
Toshiki Kijima DD*, Shohei Fukuda, Hiroshi Fukushima, Sho Uehara, Yosuke Yasuda, Soichiro Yoshida, Minato Yokoyama, Yoh Matsuoka, Kazutaka Saito and Yasuhisa Fujii
Department of Urology, Tokyo Medical and Dental University, Tokyo, Japan
*For reprints and all correspondence: Toshiki Kijima, MD, PHD, Department of Urology, Tokyo Medical and Dental University Graduate School 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail: tkijima@dokkyomed.ac.jp
Received 3 November 2022; Revised 19 December 2022; Accepted 23 December 2022
Abstract
Background: Adrenocortical carcinoma is an aggressive tumor which often recurs despite apparent complete resection. This study assessed the long-term outcomes for patients with recurrent adrenocortical carcinoma after multimodal salvage therapy with chemotherapy, chemoradiother- apy and surgery.
Methods: We retrospectively reviewed medical records of patients who had a pathological diagno- sis of adrenocortical carcinoma between 1996 and 2017. Kaplan-Meier curves were used to assess progression-free and cancer-specific survivals among all patients and cancer-specific survival among patients with tumor recurrence. Log-rank test was used to compare patient survivals by modality of salvage therapy (chemotherapy, chemoradiotherapy and chemotherapy/chemoradio- therapy plus surgery).
Results: Of 20 patients who underwent initial surgery, recurrence occurred in 14 (70%) with a median interval of 7.5 (range 1.0-12.6) months. Salvage therapy provided was chemotherapy only (n = 7), chemoradiotherapy (n = 2) and chemotherapy/chemoradiotherapy plus surgery (n = 5). Of the five patients who received salvage surgery, three underwent repeated resections. The potential benefit of multimodal salvage therapy was suggested in five patients (4 with chemotherapy/chemoradiotherapy plus surgery and 1 with chemoradiotherapy) who achieved durable disease control (cancer-specific survival from initial recurrence, 22-258 months). With a median follow-up of 25 months from recurrence, the 5-year cancer-specific survival rate was 58%. cancer-specific survival after recurrence was prolonged in patients with ≤ stage 3 disease, positive response to chemotherapy/chemoradiotherapy and salvage surgery.
Conclusions: Long-term disease control and survival could be achieved in highly selected patients with recurrent adrenocortical carcinoma using a multidisciplinary approach. Patients who had relatively limited recurrent sites and responded well to chemotherapy/chemoradiotherapy may be considered for salvage surgery on a case-by-case basis.
Key words: salvage surgery, radiotherapy, chemotherapy, multimodal therapy, recurrent adrenocortical carcinoma
Introduction
Adrenocortical carcinoma (ACC) is a rare and highly aggressive endocrine malignancy with an annual incidence of one to two cases per million (1). Complete surgical resection by qualified oncologic surgeons is the only potential curative treatment for ACC (2). There- fore, surgical resection is indicated for all patients with localized disease, and even for some metastatic patients in whom complete resection of all lesions seems feasible. The risk of recurrence, however, is as high as 60-80% even with complete initial resection (3,4). In addition, the optimal management of patients with recurrent ACC is poorly defined due to rarity of the disease.
The management of patients with ACC requires a multidisci- plinary approach, not only at presentation, but also at disease recur- rence and progression. Although there have been advancements in systemic chemotherapy (CT) through defining optimal combinations, this still has limited efficacy (5). Even though radiotherapy has been used in adjuvant settings and palliative settings for symptomatic patients with bone or brain metastases (6), ACC is generally consid- ered radio-resistant and the role of radiotherapy in the management of recurrent disease remains unclear. In line with these backgrounds, surgical resection still remains a valid treatment option for patients with recurrent ACC. In the literature, several retrospective studies suggested the possible advantages of surgical treatment for recurrent disease that include prolonged survival and palliation of Cushing’s syndrome (7-9).
This study assessed the long-term outcomes of patients with recurrent ACC receiving multimodal salvage therapy, including CT, chemoradiotherapy (CRT) and surgery, with a view to identify patients who might benefit from aggressive multimodal salvage therapy.
Methods
Design, setting and population
This was a single center, retrospective observational study approved by institutional review board (approval number M2019-132). We identified all patients who had a pathological diagnosis of ACC made after surgical resection or needle biopsy of primary tumor at Tokyo Medical and Dental University between 1996 and 2017.
Data collection
From the medical records, we collected the following information; demographics, tumor information including the European Network for the Study of Adrenal Tumours (ENSAT) stage (10,11), the size of primary tumor, hormonal status, the status of the tumor margins at initial surgery, tumor recurrence sites, disease-free interval and modality of salvage therapy (CT only, CRT and CT/CRT plus surgery).
Treatment
A CT, VP-16 + CDDP regimen (VP-16, 100 mg/m2 intravenously, on Days 1, 2 and 3, and CDDP, 50 mg/m2 intravenously, on Days 1 and 2, every 21 days) with mitotane (1000 mg/day, orally) (12) was used in our cohort. A CRT protocol consisting of two cycles of the same VP-16 + CDDP regimen were administered concurrently with external-beam radiation therapy of 40-50 Gy. After the confirmation of response to CR/CRT, salvage surgery was considered on a case- by-case basis and performed when complete resection of recurrent disease seemed possible.
Data analysis
Our primary outcomes were progression-free survival (PFS) and cancer-specific survival (CSS) after initial diagnosis in all patients, and CSS after initial recurrence in patients who recurred after initial surgery. Kaplan-Meier curves were used to compute time to event and the log-rank test was used to compare survivals according to the modality of salvage therapy (CT alone, CT and CRT, and CT, CRT plus surgery) and other clinical factors. All analyses were two sided, and a P value of < 0.05 was considered statistically significant. Analyses were performed with JMP 13.0 statistical software (SAS Institute, Cary, NC, USA).
Results
Patient characteristics
We identified 22 patients with pathologically confirmed ACC. Two patients were excluded because they could not receive initial surgery due to poor performance status and widespread metastases. Thus, 20 patients who underwent initial surgery for primary tumor, including four who had extensive resection of surrounding organs and two who had a concurrent metastasectomy were included in the study. The median age of all patients at diagnosis was 48 years (range 22-78). The median tumor size was 7.4 cm (range 5.2-15), and the ENSAT tumor stage was Stage II in 6 (30%), III in 12 (60%) and IV in 2 (10%) patients. Tumors were hormonally active in half of these patients, and most frequently experienced symptoms were abdominal pain and discomfort due to the large mass. The initial resection achieved pathologically negative margin status in 13 (65%) of the 20 patients. In addition, five (25%) patients received adjuvant mitotane therapy with median (range) duration of 6 (2-24) months (Table 1).
Survival outcomes after diagnosis in all 20 patients
The median follow-up from diagnosis in all 20 patients was 48 months. Median PFS and CSS from diagnosis was 10.9 months and not reached, respectively (Fig. 1A andB). No patients in Stage II had recurrence or died of disease. Patients in Stage III showed considerably fair CSS (5-year CSS 67%) in contrast to their short PFS (5-year PFS 13%) (Fig. 1C and D). All patients in Stage IV died of cancer in < 2 years.
Tumor recurrence and salvage therapy
Fourteen patients (14/20; 70%) had tumor recurrence. The median recurrence-free interval duration was 7.5 months (range 1.0-102). Of the 14 patients that developed recurrence, four had local recurrence, seven had distant recurrence and three had both local and distant recurrence. The sites of distant recurrence were the liver (n = 7), lung (n = 4) and bone (n = 3). All the 14 patients received CT with either mitotane or VP-16 + CDDP, or both regimens administered concurrently. CRT using VP-16 + CDDP or CDDP as single agent was delivered to five patients. Five patients received salvage surgery of whom three underwent repeated resections (2 surgeries in 2, 3 surgeries in 1) (Table 2). Overall, seven patients received CT only, two had both CT and CRT and five underwent CT and/or CRT plus surgery as salvage therapy for recurrent disease.
Cases with potential benefit of multimodal salvage therapy
Among the 14 patients with recurrence, potential benefit of multi- modal salvage therapy was evident in five patients (4 with CT and/or
Progression-free survival (%)
100
Cancer-specific survival (%)
100
80
80
60
60
40
40
20
20
0
0
0
50
100
150
200
250
0
50
100
150
200
250
Time from diagnosis (month)
Time from diagnosis (month)
Progression-free survival (%)
Cancer-specific survival (%)
100
100
80
5-year PFS rate
80
60
ENSAT stage
Il (n=6) :100%
60
III (n=12) :13%
5-year CSS rate
40
IV (n=2) :0%
40
ENSAT stage
Il (n=6) :100%
III (n=12) :67%
20
20
IV (n=2) :0%
0
0
50
100
150
200
250
0
0
50
100
150
200
250
Time from diagnosis (month)
Time from diagnosis (month)
Cancer-specific survival (%) m
Cancer-specific survival (%) 71
100
100
80
80
60
Response to CT/CRT PR or SD (n=8) PD (n=6)
60
40
40
Log-rank test p<0.01
Salvage therapy
CT/CRT plus surgery (n=5)
20
20
CT/CRT only (n=9)
Log-rank test p=0.05
0
50
100
150
200
250
0
0
0
50
100
150
200
250
Time from initial recurrence (month)
Time from initial recurrence (month)
| Age (year) | Variables | Median (range) or number (%) | |
|---|---|---|---|
| 48 | (27-78) | ||
| Gender | Male | 11 | (55%) |
| Female | 9 | (45%) | |
| Tumor location | Right | 10 | (50%) |
| Left | 10 | (50%) | |
| Tumor size (cm) | 7.4 | (5-15) | |
| Hormonal function | Glucocorticoid | 7 | (35%) |
| Mineral corticoid | 2 | (10%) | |
| Androgen/estrogen | 2 | (10%) | |
| Initial symptoms | Palpable mass | 8 | (40%) |
| Abdominal pain | 8 | (40%) | |
| Hypertension | 5 | (25%) | |
| Pyrexia | 4 | (20%) | |
| Cushing symptoms | 2 | (10%) | |
| cardiac insufficiency | 2 | (10%) | |
| ENSAT stage | II | 6 | (30%) |
| III | 12 | (60%) | |
| IV | 2 | (10%) | |
| Initial surgery | Adrenalectomy only | 14 | (70%) |
| With resection of | 4 | (20%) | |
| surrounding organ | |||
| With metastasectomy | 2 | (10%) | |
| Resection margin | Negative | 13 | (65%) |
| Microscopically positive | 6 | (30%) | |
| Macroscopically positive | 1 | (5%) | |
| Adjuvant therapy | Mitotane | 5 | (25%) |
ENSAT, European Network for the Study of Adrenal Tumours.
| Recurrence-free period (month) | Variables | Median (range) or number (%) | |
|---|---|---|---|
| 7.5 | (1-102) | ||
| Recurrence sites | Local only | 4 | (29%) |
| Distant only | 7 | (50%) | |
| Local + distant | 3 | (21%) | |
| Distant metastatic sites | Liver | 7 | (50%) |
| Lung | 4 | (29%) | |
| Bone | 3 | (21%) | |
| Other | 2 | (14%) | |
| Chemotherapy | Mitotane | 12 | (86%) |
| VP16 + CDDP | 11 | (79%) | |
| Chemoradiotherapy | 5 | (36%) | |
| Salvage surgery | 1st resection | 5 | (36%) |
| 2nd resection | 3 | (21%) | |
| 3rd resection | 1 | (7%) | |
CRT plus surgery and 1 with CT and/or CRT) who achieved long- term disease control with CSS from initial recurrence ranging from 22 to 258 months (Table 3 and Fig. 2). The interval from initial surgery
to initial recurrence was < 12 months in three of these five patients. One patient who achieved clinical complete response with CRT and CT (Case 2 in Table 3 and Fig. 2), survived > 10 years without any additional therapy. The remaining four patients underwent salvage surgery along with CT and/or CRT. Among them, two patients had two surgeries and one had three surgeries for recurrent disease. Among three patients who received CT and/or CRT before salvage surgery, one achieved partial response but the remaining two showed stable disease.
With a median follow-up from initial recurrence of 25 months, the 5-year CSS rate in the 14 patients with recurrence was 58%. CSS after recurrence was prolonged in patients with ≤ stage 3 disease, positive response to CT and/or CRT and salvage surgery (Table 4 and Fig. 1E and F).
Discussion
In this retrospective analysis of 14 patients with recurrent ACC, we identified five patients who achieved long-term disease control after multimodal salvage therapy which supports the potential role of aggressive management (including salvage surgery) for highly selected recurrent ACC. Among these five long-term responders, two patients had two surgeries each and one patient had three surgeries, implying that aggressive management may be applied even to patients with multiple recurrences. Among three long-term responders who received CT and/or CRT before salvage surgery, one achieved partial response and the remaining two had stable disease. This implies that salvage surgery could be considered, on a case-by case basis, for patients who either respond to therapy or have stable disease after CT and/or CRT.
The potential survival advantage of salvage surgery for recur- rent ACC has been proposed by several retrospective studies. In a retrospective multi-institutional study evaluating the role of surgery for recurrent ACC, Bellantone et al. reported a higher survival rate among patients who underwent salvage surgery compared with those who did not (8). When examining the outcomes of patients who underwent salvage surgery, Schulick et al. reported that patients with complete second resection survived longer than those with incomplete second resection (9). Dy et al. also reported the outcomes of surgery for recurrent ACC patients and found that patients with a disease-free interval > 6 months and complete second resection were more likely benefit from second resection (13). Although repeated salvage surgery seems to improve survival, its benefit is still difficult to ascertain from these non-randomized studies with bias in patient selection, for instance, no-surgery cohorts included patients with aggressive inoperable disease. Further research should investigate clinical characteristics that predict the patients who would benefit from salvage surgery.
A longer disease-free interval between the first operation and tumor recurrence has been assumed as one of the clinical predictors for favorable outcomes after salvage surgery. In concurrence with Dy et al. (prolonged survival in patients with >6 months of disease- free interval), Datrice et al. reported the patients with disease-free interval > 12 months had significantly longer survival after surgery for recurrent or metastatic ACC (14). In addition, experts recom- mend salvage surgery particularly for patients with a disease-free interval at least >4 months (15). Conversely, we found two patients with a short disease-free interval between the first operation and tumor recurrence and extremely long CSS after recurrence (Cases 1, 2 in Table 3). Based on our results, salvage surgery could be considered
Case 1 (1st. Local) CRT, CT, Surgery
Case 2 (1st. Local) CRT
Pre CRT
Post CRT
Pre CRT
Post CRT
Case 3 (1st. Liver) Surgery, CT
Case 3 (2nd. Liver) Surgery
Case 3 (3rd. Lung) Surgery
Case 5 (1st. Local) CT, Surgery, CRT
Case 4 (1st. Local) CT, Surgery
Case 4 (2nd. Local) Surgery
even in patients with a short disease-free intervals, provided that their recurrent sites were relatively limited and complete resection of all lesions seems feasible.
Our results also suggest that long-term disease control could be expected in patients with multiple recurrences if multiple salvage therapies are employed. Although reports on the outcomes of patients with multiple recurrences are limited, the study cohort of Schulick et al. included patients that had undergone multiple salvage surgeries up to seven times, illustrating the role of multiple resection in patients with multiple tumor recurrences (9). Based on our clinical experiences, salvage surgery could be considered for highly selected patients with multiple tumor recurrence to achieve long-term disease control.
In an attempt to select patients who will have a favorable outcome post-operatively, our approach proposes the use of CT and CRT with an evaluation of clinical response after 2 or 3 months of therapy. Patients with responsive or stable disease with no signs of newly developed tumor sites would then be considered for salvage surgery. The favorable outcomes achieved in our study advocate for salvage surgery selected patients with relatively limited recurrent disease and a good response to CT/CRT. Selection of candidate for aggressive salvage therapy based on the response to CT/CRT was also proposed by other group (13).
The maximum number of recurrent lesions which could be successfully treated with multimodal salvage therapy including surgery is an important consideration. Although we did not determine a clear indication for salvage resection and considered it on a case-by-case basis in this cohort, a retrospective evaluation showed that patients with three or fewer metastatic sites were treated with salvage surgery. Recent articles describing the utility of locoregional treatment for oligometastatic ACC reported that patients in Stage IVa (number of involved organs; 2) with ≤5 metastases or metastatic lesions with a maximum diameter of 3 cm had better response to locoregional treatment (16,17). Therefore, the response to CT/CRT, number of metastases and maximum metastatis diameter may need to be considered when discussing the salvage surgery.
This study had some limitations. This was a retrospective study with a limited number of selected patients, with the potential of selection bias and an inability to generalize our findings cannot be overlooked. The decision to administer salvage treatment for recurrent disease was determined on case-based discussion for each patient; no standardized procedures were employed. Although the current standard CT regimen for advanced ACC is mitotane plus EDP (VP16, doxorubicin and CDDP) (18), CT used in this cohort was VP16 plus CDDP (12). This was partly because patients received CT
| Age | Gender | ENSAT stage | Hormonal function | Initial resection | Recurrence sites | Interval from initial surgery to recurrence (month) | Salvage therapies for recurrent disease | Current Status | CSS from diagnosis (month) | CSS from initial recurrence (month) |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 47 | M | III | − | Adrenal tumor | 1st. Local 2nd. Chest wall | 2 | 1st. CRT (40 Gy with VP16 + CDDP): SD CT (VP16 + CDDP *1, high dose VP16 + Carbo *2): PR Resection (local recurrence) 2nd. CRT (50 Gy with VP16 + CDDP): PR Resection (chest wall) | NED | 260 | 258 |
| Kidney Liver | ||||||||||
| 2 28 | M | III | + | Adrenal tumor | 1st. Local | 2 | 1st. CRT (50 Gy with VP16 + CDDP): PR CT (VP16 + CDDP *2): CR | NED | 158 | 154 |
| 3 48 | M | III | + | Adrenal tumor | 1st. Liver | 7 | 1st. Resection (liver), CT (VP16 + CDDP *4) 2nd. Resection (liver) 3rd. | NED | 141 | 129 |
| Kidney | 2nd. Liver | Resection (lung) | ||||||||
| 3rd. Lung | ||||||||||
| 4 35 | F | III | − | Adrenal tumor | 1st. Local 2nd. Local | 102 | 1st. CT (VP16 + CDDP *4): SD Resection (local, kidney, spleen, pancreas) 2nd. Resection (local) | NED | 151 | 45 |
| 5 47 | F | + | Adrenal tumor | 1st. Local | 43 | 1st. CT (VP16 + CDDP *4): SD Resection (local), CRT (50 Gy with CDDP) | NED | 66 | 22 |
ENSAT, European Network for the Study of Adrenal Tumours; CRT, chemoradiotherapy; CT, chemotherapy; NED, no evidence of disease; CSS, cancer-specific survival; CR, complete response; PR, partial response; SD, stable disease.
Variables
ENSAT stage Recurrence sites Distant metastatic sites Response to CT/CRT
Intervention
ENSAT, European Network for the Study of Adrenal Tumours; CRT, chemoradiotherapy; CT, chemotherapy; CSS, cancer-specific survival; PR,
partial response; SD, stable disease; PD, progressive disease.
before the introduction of mitotane plus EDP therapy (i.e. Cases 1-4 in Table 3), and we still selected EP therapy with intent to provide multimodal salvage therapy, not to treat with CT only, since the introduction of this new regimen.
The rarity of ACC limits the possibility of clinical trials with prospective study designs; therefore, collaboration among large ter- tiary cancer institutions is warranted for future studies.
In conclusion, although recurrent ACC remains difficult to treat, long-term disease control and survival could be achieved in a subset of patients with relatively limited recurrent disease and response to CT/CRT using a multidisciplinary approach incorporating salvage surgery. Multimodal salvage therapy could be considered for highly selected patients on a case-by-case basis.
Conflicts of Interest
None.
Funding
None.
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P value
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