ELSEVIER
CLINICAL INVESTIGATION
ADJUVANT AND DEFINITIVE RADIOTHERAPY FOR ADRENOCORTICAL CARCINOMA
AARON SABOLCH, B.A.,* MARY FENG, M.D., KENT GRIFFITH, M.P.H., M.S., GARY HAMMER, M.D., PH.D., GERARD DOHERTY, M.D., AND EDGAR BEN-JOSEF, M.D.+
*University of Michigan Medical School, Ann Arbor, MI; Departments of Radiation Oncology, $Internal Medicine, and Surgery, University of Michigan, Ann Arbor MI; and +Biostatistics Unit, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI
Purpose: To evaluate the impact of both adjuvant and definitive radiotherapy on local control of adrenocortical carcinoma.
Methods and Materials: Outcomes were analyzed from 58 patients with 64 instances of treatment for adrenocor- tical carcinoma at the University of Michigan’s Multidisciplinary Adrenal Cancer Clinic. Thirty-seven of these in- stances were for primary disease, whereas the remaining 27 were for recurrent disease. Thirty-eight of the treatment regimens involved surgery alone, 10 surgery plus adjuvant radiotherapy, and 16 definitive radiotherapy for unresectable disease. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant recurrence, and overall survival.
Results: Local failure occurred in 16 of the 38 instances that involved surgery alone, in 2 of the 10 that consisted of surgery plus adjuvant radiotherapy, and in 1 instance of definitive radiotherapy. Lack of radiotherapy use was associated with 4.7 times the risk of local failure compared with treatment regimens that involved radiotherapy (95% confidence interval, 1.2-19.0; p = 0.030).
Conclusions: Radiotherapy seems to significantly lower the risk of local recurrence/progression in patients with adrenocortical carcinoma. Adjuvant radiotherapy should be strongly considered after surgical resection. @ 2011 Elsevier Inc.
Radiotherapy, Radiation oncology, Adrenocortical carcinoma, Adrenal glands, Adrenal cortex.
INTRODUCTION
Adrenocortical carcinoma (ACC) is a rare diagnosis, with an annual incidence of approximately 1 to 2 per million people (1,2). Given its rare nature, ACC has been a difficult entity to study, and its management continues to evolve. Although the mainstay of treatment is surgical resection (2-10), rates of local control after ostensibly complete resections range from 19% to 60% (3, 5, 7, 11), a fact that suggests additional approaches to locoregional and systemic control might have a role in disease management. Indeed, advances in systemic care have been seen with the adjuvant use of the adrenolytic agent mitotane (12), and its use has become increasingly common.
On the other hand, evidence for the efficacy of radiother- apy for local control has been lacking. The modality has his- torically been considered ineffective in the treatment of ACC, because small retrospective series have concluded, on the ba- sis of limited anecdotal evidence (9, 13-17), that ACC is
a predominantly radioresistant malignancy. However, since the publication of these reports, radiotherapy has seen significant improvements in both its planning and delivery, allowing higher treatment doses with greater precision. Given these recent advances, we hypothesized that modern- day radiotherapy would result in enhanced local control in the adjuvant setting. We also sought to determine the role of radiotherapy in unresectable disease and to identify poten- tial associations of patient, tumor, and treatment characteris- tics with local control and overall survival.
METHODS AND MATERIALS
After obtaining institutional review board approval, we reviewed the medical records of patients with ACC treated between January 1, 1989 and December 31, 2008 at the University of Michigan’s Mul- tidisciplinary Adrenal Cancer Clinic. This clinic was founded approximately 30 years ago to prospectively evaluate patients and collaboratively formulate treatment plans at a multidisciplinary
A. Sabolch and M. Feng contributed equally to this work.
tumor board. The clinic has recently been strengthened by the addi- tion of a formal Cancer Center Endocrine Oncology Program.
Patients were included in the analysis if they underwent surgical resection, resection with adjuvant radiotherapy, or radiotherapy with definitive intent. Patients who only received palliative radiotherapy were not included in the analysis. Using these criteria, 58 patients were identified, representing 64 individual instances of treatment. Five patients were treated for both primary and recurrent disease and were analyzed as distinct instances. Thirty-seven of these in- stances of treatment were for primary disease, whereas the remain- ing 27 were for recurrent disease. Patients were staged according to the tumor, lymph node, and metastasis guidelines detailed by the In- ternational Union Against Cancer and the World Health Organiza- tion in 2004 (18).
Forty-eight instances of treatment involved surgery, and 38 of these consisted of surgery without adjuvant radiotherapy. All but nine of the surgeries were performed at the University of Michigan. Thirty surgeries were for primary disease, and eight were for recur- rent disease. No surgical patients had macroscopically residual dis- ease. Of the 29 patients for whom margin status was available, resection was complete in 17, whereas there was either microscop- ically residual disease or tumor spillage in 12 patients.
Radiotherapy was used in 26 of the 64 instances of treatment, and 10 of these were in an adjuvant setting after surgery. Of these, three involved primary disease, and seven involved recurrent disease. Six- teen instances of treatment consisted of definitive radiotherapy for unresectable disease. Four of these involved primary disease and 12 recurrent disease. All radiotherapy was delivered at the Univer- sity of Michigan.
In the adjuvant setting, the target was the preoperative tumor volume and tumor bed. The draining lymph nodes were also treated in a minority of patients. In instances of definitive treat- ment, the target was the gross primary tumor. All but one of the adjuvant patients received external-beam radiotherapy, with a stan- dard fractionation schedule of 1.8-2.0 Gy per day. The remaining patient received low-dose brachytherapy, with catheters placed at the time of surgery. Adjuvant and definitive external-beam radio- therapy were delivered mostly with three-dimensional conformal techniques, although several recent patients received intensity- modulated radiotherapy (IMRT). An example of an IMRT plan used in the adjuvant setting is shown in Fig. 1. Figure 2 illustrates a definitive case.
Kaplan-Meier estimates of local control were generated for the entire population. Product-limit estimates for the probability of overall survival were calculated for those patients who received treatment for nonmetastatic primary disease, to identify a homoge- neous patient population from which to draw generalizable conclu- sions. The effects of patient, tumor, and treatment factors were modeled simultaneously using multiple variable Cox proportional hazards regression for associations with local recurrence, distant re- currence, and overall survival. Probability (p) values at or below 5% were considered significant.
Local recurrence was assessed using computed tomography. When treatment involved a metastasis, local recurrence was defined in relation to that site. For instances of definitive radiotherapy, local recurrence was defined as disease progression. For the entire cohort, the following variables were analyzed for associations with freedom from local failure: age at diagnosis, performance status, radiother- apy use, treatment site (adrenal gland/fossa vs. metastatic site), mi- totane use, and cytotoxic chemotherapy use. For those instances of treatment involving the adrenal gland or fossa, maximum tumor di- mension and disease stage were also analyzed.
RESULTS
Patient and treatment characteristics
In total, there were 58 patients included in our study: 37 women (64%) and 21 men (36%). Since several patients were treated at more than one site or for both primary and re- current disease, 64 unique instances of treatment were in- cluded in the analysis. Median follow-up for surviving patients was 72 months. Patient, disease, and treatment char- acteristics are presented in Table 1.
Thirty-three patients had functional tumors. Of these, 19 presented with an overproduction of cortisol, 2 with andro- gens, 1 with aldosterone, 1 with catecholamines, 9 with cor- tisol and androgens, and 1 with cortisol, androgens, and aldosterone.
For those instances of treatment involving radiotherapy, the median dose delivered in an adjuvant setting was 53.4 Gy, with a range of 45-57 Gy. For definitive treatments, the median dose was 39.2 Gy, with a range of 22.5-73.5 Gy. In addition to the primary treatment, 19 regimens incor- porated mitotane, 9 involved cytoxic chemotherapy, and 21 used both. Chemotherapeutic agents included gemcitabine, cisplatin, etoposide, adriamycin, and streptozocin.
Local recurrence
Local failure occurred in 16 of the 48 instances of treat- ment with surgery alone, in 2 of the 10 instances of surgery plus adjuvant radiotherapy, and in 1 of the instances of defin- itive radiotherapy.
When modeled simultaneously, lack of radiotherapy use was associated with 4.7 times the risk of local failure com- pared with treatment regimens that involved radiotherapy (95% confidence interval [CI], 1.2-19.0; p = 0.030; Fig. 3). Treatment to a metastatic site was associated with 4.1 times the risk of local failure compared with treatment to the adre- nal gland or fossa (95% CI, 0.9-18.3; p = 0.061), reaching only borderline statistical significance.
When considering only instances of treatment to the adre- nal gland or fossa (n = 50), maximum tumor dimension was found to be significantly associated with freedom from local failure. Tumors were dichotomized at 10 cm (median size of disease treated with both surgery and adjuvant radiotherapy). Those with tumors of a maximum dimension greater than 10 cm were 4.3 times more likely to fail locally than those with smaller tumors (95% CI, 1.5-13.0; p = 0.004; Fig. 4).
Distant recurrence
Of those instances of treatment to the adrenal gland or fossa (n = 50), seven involved patients who presented with metastatic disease at diagnosis. Of the remaining 43 instances of treatment, 20 (46.5%) eventually resulted in distant failure. Age at diagnosis, performance status, radiotherapy use, mito- tane use, cytotoxic chemotherapy use, tumor size, and dis- ease stage were tested for association with freedom from distant failure. No statistically significant associations were found.
A
B
C
D
>52.8 Gy
>43.2-52,8 Gy
>30.0-43.2 Gy
20.0-30.0 Gy
≥10.0-20.0 Gy
E
F
G
H
100
80
PTV
GTV
Volume (%)
60
40
20
0
Stomach Liver Kidneys Spinal cord Small bowel
0
40
60
Dose (Gy)
Regional Lymphatics
Esophagus
Rt. Kidney
Duodenum Liver
Spinal Cord
Tumor Bed
Lt. Kidney
Stomach
Small Bowel
A
B
C
D
PTV
GTV
>73.5 Gy
70-73.5 Gy
60-70 Gy
R
50-60 Gy
40-50 Gy
30-40 Gy
20-30 Gy
10-20 Gy
E
F
100
80
Volume (%)
60
40
Spinal Cord
Rt. Kidney
20
Lt. Kidney
Liver
Tumor
0
0
20
40
60
Dose (Gy)
80
Overall survival
Of those with primary disease treated to the adrenal gland or fossa, there were 33 nonmetastatic patients treated with cu- rative intent, 29 with surgery alone, 3 treated with surgery plus adjuvant radiotherapy, and 1 patient treated with definitive ra- diotherapy. The stage distribution was 3, 13, 10, and 7 for Stage I, II, III, and IV, respectively. The product-limit esti- mates for the probability of survival are shown in Fig. 5, strat- ified by disease stage. Of the following characteristics, age at diagnosis, performance status, disease stage, radiotherapy use, maximum tumor dimension, mitotane use, and cytotoxic chemotherapy use, only disease stage was significantly asso- ciated with overall survival (p <0.0001; Fig. 5).
Adverse events
Of the 26 instances of treatment involving radiotherapy, 13 resulted in Grade ≥2 acute toxicity (within 3 months of treat-
ment). Eleven of these events consisted of nausea and/or emesis. The etiology of these symptoms is difficult to ascer- tain because they may also be caused by mitotane, which was taken by 7 patients (6, 11, 12). There were also two events of late toxicity, one consisting of soft-tissue edema in the irradi- ated left flank and the other persistent pain within the treat- ment portal.
DISCUSSION
The main finding of this study is that adjuvant radiotherapy results in a significant reduction in the risk of local recurrence in patients with ACC. This is important because the rate of local recurrence in patients who undergo surgical resection is unacceptably high, even when margins are microscopically negative (3, 5, 7, 11). In fact, local failure at the adrenal fossa may account for approximately two thirds of all recurrences
| Characteristic | Surgery only | Surgery and RT | RT only | Total |
|---|---|---|---|---|
| Frequency | 38 | 10 | 16 | 64 |
| Female | 24 (63) | 5 (50) | 13 (81) | 42 (66) |
| Age at treatment (y), mean (SD) | 48.6 (13.0) | 49.4 (3.9) | 48.9 (13.2) | 48.8 (11.9) |
| Treatment site | ||||
| Adrenal gland | 36 (95) | 9 (90) | 5 (31) | 50 (77) |
| Bone metastasis | 2 (5) | 1 (10) | 11 (69) | 14 (23) |
| Disease type | ||||
| Primary | 30 (79) | 3 (30) | 4 (25) | 37 (58) |
| Recurrent | 8 (21) | 7 (70) | 12 (75) | 27 (42) |
| Functional tumor | 19 (50) | 6 (60) | 12 (75) | 37 (58) |
| Maximum tumor dimension of treated site (cm), mean (SD) | 12.2 (5.2) | 9.9 (5.1) | 13.2 (5.9) | 12.1 (5.4) |
| Stage of disease at initial diagnosis | ||||
| I | 4 (11) | 1 (10) | 0 | 5 (8) |
| II | 13 (34) | 4 (40) | 5 (31) | 22 (34) |
| III | 14 (37) | 3 (30) | 6 (38) | 23 (36) |
| IV | 6 (16) | 0 | 4 (25) | 10 (16) |
| Unknown | 1 (3) | 2 (20) | 1 (6) | 4 (6) |
| Chemotherapy | ||||
| Mitotane | 12 (32) | 5 (50) | 2 (13) | 19 (30) |
| Cytotoxic/s | 3 (8) | 1 (10) | 5 (31) | 9 (14) |
| Mitotane and cytotoxic/s | 10 (26) | 2 (20) | 9 (56) | 21 (33) |
| None | 13 (34) | 2 (20) | 0 | 15 (23) |
| RT dose (Gy), mean (SD) | 51.5 (4.7) | 42.9 (17.3) | ||
| Brachytherapy | 1 (10) | 0 | ||
| Acute RT toxicity | 6 (60) | 7 (44) | ||
| Nausea | 5 | 6 | ||
| Late RT toxicity | 1 (10) | 1 (6) |
Abbreviations: RT = radiotherapy.
Values are number (percentage) unless otherwise noted.
(8). Furthermore, our study shows that local recurrence is more likely at sites of treated metastasis or after the treatment of tumors larger than 10 cm. Both findings are novel and have not been previously demonstrated.
The potential role of radiotherapy in improving local con- trol has been overshadowed by early reports that prematurely dismissed the modality’s efficacy. Several investigators have stated that ACC is a predominantly radioresistant malignancy but relied on undocumented results for this conclusion (9, 13,
1.0
Freedom from Local Failure
0.8
0.6
Radiotherapy
0.4
0.2
No Radiotherapy
0.0
0
2
4
6
8
10
Time (years)
14). In those series with documented outcomes, radiotherapy was found to be ineffectual on the basis of experiences with 2-5 patients (15-17). Radiotherapy should not be discounted on the basis of such anecdotal evidence, particularly given the recent and rapid advances in radiotherapeutic techniques.
Indeed, several small studies have suggested that radio- therapy is efficacious, and recent consensus documents have acknowledged the modality’s potential role in ACC management (2). The usefulness of radiotherapy as a pallia- tive modality has been reported in several series, with symp- tomatic relief seen in 22-100% of patients (13, 19-27). Evidence of benefit in a nonpalliative setting has been scarce. Before the present study, the largest series in the literature included 14 patients who received adjuvant radiotherapy and found that radiation significantly improved local recurrence-free survival (11). Other evidence of efficacy has been sporadic anecdotal reports, often inter- spersed among larger series (20-24, 28).
Unfortunately, radiotherapy is used infrequently in ACC patients. Recent analyses of both the Surveillance, Epidemi- ology, and End Results program and the National Cancer Data Base have estimated that radiotherapy is used in 9.5- 11.7% of ACC treatments in the United States (1, 4, 29). Such sparse use is particularly concerning given the difficulty of attaining a complete surgical resection due to the location of these tumors. Although uninvolved margins are ideal (30), data from the National Cancer Data Base
1.0
Freedom from Local Failure
0.8
0.6
Tumor Size ≤10 cm
0.4
0.2
Tumor Size >10 cm
0.0
0
2
4
6
8
10
Time (years)
have shown that approximately 9% of surgical patients are left with microscopically residual disease, with a correspond- ing 21% 5-year survival rate (4). A further 10% of patients have grossly residual disease and a 10% 5-year survival rate (4). In such a context, the potential usefulness of radio- therapy in complementing surgery cannot be overlooked.
Our study also suggests that definitive radiotherapy should be strongly considered in cases for which surgical resection is not feasible. This is noteworthy considering that ACC is fre- quently quite advanced by the time it is discovered. Stage I disease, which is most amenable to resection, typically ac- counts for only 5% of initial diagnoses (1, 5, 9, 29, 31, 32), whereas approximately half of all patients present with Stage III or IV disease (1, 3, 9, 29). Even with advances in diagnosis and imaging, the last several decades have seen no corresponding drop in the proportion of those with late- stage disease (1). Likewise, there has been no decrease in me- dian tumor size at diagnosis over a similar time period (4, 29).
Another potential benefit of radiotherapy is that it can ad- dress disease in the regional lymphatics. Adrenocortical car- cinoma often spreads via lymphatic drainage (21), and one large, recent study indicated that lymph nodes are involved
1.0
0.8
Overall Survival
Stage I/II
0.6
0.4
Stage III
0.2
Stage IV
0.0
0
2
4
6
8
10
Time (years)
in approximately 15% of patients at diagnosis (33). Neverthe- less, regional lymph nodes are infrequently examined at sur- gery (4). It has been suggested that in addition to the adrenal bed, radiotherapy should include the bilateral periaortic lymph nodes (11, 34), a practice that we support.
Even when disease spreads beyond the adrenal fossa and regional lymphatics, there may still be a role for radiotherapy. Pulmonary and hepatic metastases are among the most com- mon sites of spread (3-5, 9, 18, 26, 29, 33), and advanced patients often have disease at both locations (24, 35). Approximately 18% of the instances in the present study involved the definitive treatment of metastases. Radiotherapy has a long-established role in the treatment of other pathologies at these anatomical locations and may prove to be a viable option for the treatment of limited met- astatic disease. This is further suggested by the fact that sev- eral studies have shown that surgical metastasectomy improves overall survival compared with those who only receive medical therapy (3, 9, 17, 36, 37).
Whether for the treatment of localized or metastatic dis- ease, radiotherapy is commonly used alongside mitotane. Al- though earlier studies concluded that mitotane was ineffectual (15, 27, 35, 38, 39), this changed with the publication of Terzolo et al. (12), and since then it has become an integral part of disease management. Nonetheless, the rate of relapse in patients treated with both surgery and mitotane was 49% (12), suggesting that further improvement in controlling recurrences is necessary even when mitotane is used. Interestingly, early preclinical evidence has suggested that radiotherapy and mitotane may act synergistically, an in- triguing possibility that awaits further investigation (40). In our series the use of mitotane was similar in the groups of pa- tients treated with surgery or surgery and radiotherapy (25% and 20%, respectively), thus the reduction in local relapse is likely independent from any mitotane effect. The administra- tion of mitotane often leads to nausea, emesis, and fatigue (6, 11, 12), adverse events that are difficult to distinguish from those of radiotherapy.
With regard to overall survival, there was no significant difference between those treated with radiotherapy versus those treated with surgery alone in our study. This finding is consistent with a previous report (11) and may indicate that locoregional control does not significantly influence sur- vival. However, the possibility remains that statistical signif- icance was not reached because of the small sample size, and a sufficiently powered study could have shown local control to extend survival.
Our study is subject to limitations common to retrospective analyses, such as the heterogeneity of patient characteristics and treatments. Patients included in this study were treated for either primary or recurrent disease, and the neoplasms of these two groups may have inherently different biologic characteristics. The radiotherapy group involved signifi- cantly more recurrent disease than the surgery group, a fact that would, if anything, predispose to worse outcomes given the typically aggressive nature of recurrent disease. Finally, surgical margin status was not consistently recorded in the
medical records to the extent that it could be included in our analysis. Nonetheless, it is likely that those who received ad- juvant radiotherapy had a higher incidence of positive mar- gins, which would be expected to predispose this group to higher rates of recurrence.
The strengths of our study include the relatively consistent approach to therapy, formulated by the Tumor Board of the University of Michigan Multidisciplinary Adrenal Cancer Clinic. This clinic, the largest of its kind in the United States, was founded approximately 30 years ago to provide a uniform and systematic approach to the treatment of ACC. All pa- tients were evaluated prospectively, and treatment plans were arrived at by consensus, a process that helped reduce
therapeutic variability between patients with similar disease characteristics. An additional strength is that our series is the largest of its kind in the literature (9, 13-17).
In conclusion, radiotherapy seems to significantly lower the risk of local recurrence in patients with ACC. Given the high rates of failure after surgical resection, adjuvant radiotherapy should be considered in all patients undergo- ing resection and is highly recommended in patients with locally advanced stage, large tumors, or after metastasec- tomy. Radiotherapy may also be effective in the definitive treatment of unresectable disease. Multi-institutional, pro- spective, randomized trials are warranted to confirm this benefit.
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