Adjuvant Radiation Therapy Improves Local Control After Surgical Resection in Patients With Localized Adrenocortical Carcinoma
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Aaron Sabolch, MD,* Tobias Else, MD, Kent A. Griffith, MPH, MS,* Edgar Ben-Josef, MD, Andrew Williams, BS, Barbra S. Miller, MD, Francis Worden, MD,# Gary D. Hammer, MD, PhD, and Shruti Jolly, MD*
*Department of Radiation Oncology, Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, “Division of Endocrine Surgery, Department of General Surgery, and Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan Hospital and Health Systems, Ann Arbor, Mchigan; Center for Cancer Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Mchigan; University of Michigan Medical School, Ann Arbor, Mchigan; and $Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
Received Aug 28, 2014, and in revised form Dec 8, 2014. Accepted for publication Jan 9, 2015.
Summary
This is the largest study to date on adjuvant radiation therapy for adrenocortical carcinoma, which is an area of significant controversy. Using a cohort design, pa- tients treated with surgery followed by adjuvant radia- tion therapy were retrospec- tively matched to a cohort treated with surgery alone on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane. Local
Purpose: Adrenocortical carcinoma (ACC) is a rare malignancy known for high rates of local recurrence, though the benefit of postoperative radiation therapy (RT) has not been es- tablished. In this study of grossly resected ACC, we compare local control of patients treated with surgery followed by adjuvant RT to a matched cohort treated with surgery alone. Methods and Materials: We retrospectively identified patients with localized disease who underwent R0 or R1 resection followed by adjuvant RT. Only patients treated with RTat our institution were included. Matching to surgical controls was on the basis of stage, surgical margin status, tumor grade, and adjuvant mitotane.
Results: From 1991 to 2011, 360 ACC patients were evaluated for ACC at the University of Michigan (Ann Arbor, MI). Twenty patients with localized disease received postoperative adjuvant RT. These were matched to 20 controls. There were no statistically significant dif- ferences between the groups with regard to stage, margins, grade, or mitotane. Median RT dose was 55 Gy (range, 45-60 Gy). Median follow-up was 34 months. Local recurrence occurred in 1 patient treated with RT, compared with 12 patients not treated with RT (P =. 0005; hazard ratio [HR] 12.59; 95% confidence interval [CI] 1.62-97.88). However,
Reprint requests to: Shruti Jolly, MD, Department of Radiation Oncology, University Hospital Floor B2, Room C447, 1500 E. Medical Center Dr, SPC 5010, Ann Arbor, MI 48109. Tel: (734) 936-4300; E-mail: shrutij@med.umich.edu
Conflict of interest: G.D.H. serves as a consultant or on the advisory boards of Isis Pharmaceuticals, Orphagen Pharmaceuticals, OSI, HRA
Int J Radiation Oncol Biol Phys, Vol. 92, No. 2, pp. 252-259, 2015 0360-3016/$ - see front matter @ 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ijrobp.2015.01.007
Pharma, Embera NeuroTherapeutics, Atterocor, and Corcept Therapeutics; receives grant/research support from OSI, Corcept Therapeutics, and Atterocor; and has equity ownership/stock options with Atterocor, Orphagen Pharmaceuticals, and Embera NeuroTherapeutics.
Supplementary material for this article can be found at www.redjournal.org.
recurrence occurred in 1 pa- tient treated with radiation therapy, compared with 12 patients with surgery alone (P =. 0005).
recurrence-free survival was no different between the groups (P =. 17; HR 1.52; 95% CI 0.67-3.45). Overall survival was also not significantly different (P =. 13; HR 1.97; 95% CI 0.57-6.77), with 4 deaths in the RT group compared with 9 in the control group.
Conclusions: Postoperative RT significantly improved local control compared with the use of surgery alone in this case-matched cohort analysis of grossly resected ACC patients. Although this retrospective series represents the largest study to date on adjuvant RT for ACC, its findings need to be prospectively confirmed. @ 2015 Elsevier Inc. All rights reserved.
Introduction
Adrenocortical carcinoma (ACC) is rare, with an estimated incidence of 0.7 per million in the United States (1). Owing to this low incidence, prospective randomized data have been scarce. Indeed, only 2 randomized phase 3 studies have been completed, both in patients with advanced disease. The first addressed optimal systemic chemotherapy management de- cisions, and the second explored the effect of an anti-insulin- like growth factor 1 receptor agent (2, 3). For localized disease, surgery remains the only curative approach (4-6), although survival and recurrence rates after resection remain poor (7-11). In fact, as many as one-third of patients who have undergone a complete surgical resection with negative mar- gins may still experience a local recurrence of their disease, despite the use of adjuvant mitotane or chemotherapy (7, 8, 12). Indeed, local recurrences are common, accounting for two-thirds of all failures in a recent surgical series (13). Though this highlights the need to achieve better local control, there remains a paucity of compelling data regarding adjuvant treatments. As a result, there is controversy regarding the use of adjuvant radiation therapy after surgical resection (14-25).
While there have been older anecdotal reports involving from 2 to 5 patients each that have concluded radiotherapy is ineffective for ACC (26-28), these series used outmoded radiation techniques and provided scant clinical and treat- ment details. The majority of recent studies, using modern treatment approaches, have suggested that adjuvant radia- tion therapy can significantly reduce local recurrences (10, 11, 15, 22, 23); however, this conclusion remains contro- versial (14). To further investigate whether radiation ther- apy does in fact improve rates of local recurrence, we present the largest series to date on adjuvant radiation for ACC resected with curative intent. In this matched-pair, cohort study, all radiation therapy was delivered at the University of Michigan in the context of recommendations from its multidisciplinary Endocrine Oncology Program, which has served as a longstanding tertiary referral center for patients with ACC for more than 20 years.
Methods and Materials
A retrospective review was undertaken of the University of Michigan experience with ACC. We identified patients with localized disease (stage I-III according to the European
Network for the Study of Adrenal Tumors staging system; Table 1) (29), who underwent total surgical resection fol- lowed by adjuvant radiation therapy. Only patients treated with radiation therapy at the University of Michigan were included in this analysis, to limit variations in radiation therapy techniques. These patients were then matched to controls who received surgery with curative intent but without adjuvant radiation therapy. Matching was performed in a blinded fashion-without knowledge of eventual treat- ment outcomes-on the basis of stage, surgical margin sta- tus, tumor grade, and adjuvant mitotane use. If there was more than 1 patient without radiation therapy who met the matching criteria for a given radiation therapy patient, the control patient was randomly chosen from among them. Because of the rarity of ACC as well as the retrospective nature of this study, matching was not performed on the basis of date of surgery or surgical center. Characteristics were compared between matched groups using paired t tests and McNemar test of paired proportions. Local recurrence was defined as tumor recurrence within the adrenal fossa or the radiation field. This was assessed using written reports of computed tomography, all of which were reviewed by ra- diologists from the University of Michigan. Kaplan-Meier estimates were generated for local recurrence-free sur- vival, recurrence-free survival, and overall survival.
Results
From 1991 to 2011, 360 ACC patients were evaluated for ACC at the University of Michigan. Of these, 20 patients
| Stage | TMN |
|---|---|
| I | T1, N0, M0 |
| II | T2, N0, M0 |
| III | T1-2, N1, M0 |
| IV | T3-4, N0-1, M0 Any M1 |
See reference 29. T1 indicates tumors ≤5 cm in greatest dimension, T2 indicates tumors >5 cm, T3 denotes infiltration of surrounding tissues, and T4 is reserved for tumors invading adjacent organs or with the presence of a tumor thrombus in the vena cava or renal vein. N0 denotes the absences of involved lymph nodes, whereas N1 indicates their positivity. M0 indicates no distant metastases, whereas M1 in- dicates their presence.
with localized disease received postoperative adjuvant ra- diation therapy at the University of Michigan. These were matched to 20 controls per the criteria described above. Of the 40 patients included in this study, 5 were previously included in a retrospective review of this topic from our institution (23). Patient and treatment characteristics for both groups are presented in Table 2. Furthermore, the in- dividual patient, disease, and treatment characteristics for each matched pair are shown in Table E1 (available online at www.redjournal.org). All patients had localized disease and underwent surgery with curative intent. Five patients in the radiation therapy group had their adjuvant therapy after resection with curative intent of an isolated local recurrence that followed a prior surgery. For such patients, treatment characteristics and follow-up were calculated from the time of second surgery. Median follow-up was 34 months (range, 6-168 months) for the entire group. For those who
| Characteristic | Radiation therapy | No radiation therapy | P |
|---|---|---|---|
| Sex | .20* | ||
| Female | 10 (50) | 15 (75) | |
| Male | 10 (50) | 5 (25) | |
| Age at | 49.5 (12.0), | 42.3 (10.3), | .57+ |
| diagnosis (y) | 23.8-70.1 | 22.2-61.9 | |
| Disease stage | Matched | ||
| by design | |||
| II | 13 (65) | 13 (65) | |
| III | 7 (35) | 7 (35) | |
| Mitotane | Matched | ||
| by design | |||
| Yes | 15 (75) | 15 (75) | |
| No | 5(25) | 5 (25) | |
| Grade | Matched by design | ||
| 1 | 10 (50) | 10 (50) | |
| 2 | 9 (45) | 10 (50) | |
| Missing | 1 (5) | ||
| Size (cm) | 10.6 (4.0), | 12.6 (6.0), | .72+ |
| 5.5-21.0 | 5.1-28.0 | ||
| Hormones | .39* | ||
| Yes | 11 (55) | 13 (65) | |
| No | 9 (45) | 7 (35) | |
| Cortisol | .99* | ||
| Yes | 9 (45) | 11 (55) | |
| No | 11 (55) | 9 (45) | |
| Surgical margins | Matched by design | ||
| Negative | 11 (55) | 14 (70) | |
| Positive | 4 (20) | 3 (15) | |
| Missing | 5 (25) | 3 (15) | |
| Radiation therapy | 55 (45-60) | ||
| dose (Gy) | |||
| Values are number (percentage) or mean (SD), range. * McNemar test of dependent proportions. + Paired Student t test. | |||
received radiation therapy, the median time from surgery to the initiation of radiation therapy was 51 days (mean, 62 days; range, 33-140 days). Though patients were not matched on the basis of date of surgery, those who received radiation therapy underwent resection in the period be- tween 1999 and 2011, whereas those in the surgery alone group were treated between 1999 and 2010. Intensity modulated radiation therapy was used in 15 patients and 3-dimensional conformal therapy in 5 patients. Two- dimensional techniques were not used.
While there were slightly more female patients in the group that did not receive radiation therapy compared with the group that did, there were no differences between the 2 groups with regard to stage at diagnosis, tumor grade, surgical margin status, or adjuvant mitotane use. With re- gard to patient factors that were not included in the matching algorithm, 11 of 20 patients in the radiation therapy group had hormone-producing tumors, compared with 13 patients in the group that did not undergo radiation therapy. The majority of such tumors involved the pro- duction of cortisol, and there was no difference between the 2 groups in this regard (9 tumors in the radiation therapy group and 11 in the surgery-alone group). Most patients underwent open surgical resection, and only 3 patients in the radiation therapy group and 2 in the surgery-alone group had a laparoscopic procedure. Five patients in the control group had surgery performed at the University of Michigan, compared with 12 patients in the radiation therapy group. Finally, there was no significant difference between the 2 groups with regard to tumor size.
All radiation therapy was delivered at the University of Michigan. Treatment was preceded by simulation using computed tomography. Beginning in 2008, 4-dimensional motion assessment of the tumor bed-consisting of computed tomography performed throughout the entirety of the breathing cycle-was used in all patients. If tumor bed motion of >1 cm was observed, patients were treated with a breath-hold technique. The primary clinical target volume was defined as the surgical fossa, and this was constructed using a combination of presurgical imaging, operative re- ports, and surgical clips placed at the time of resection and subsequently imaged at simulation. The adjacent, bilateral para-aortic lymph node basin was contoured as a secondary clinical target volume. Treatment planning used either 3- dimensional conformal or intensity modulated techniques. Dose to the primary target ranged from 45 to 60 Gy, with a median of 55 Gy, which was delivered in half of all radi- ation therapy patients.
Three-quarters of all patients received adjuvant mito- tane, which was typically started concurrently with radia- tion therapy. Doses were steadily increased, aiming for a therapeutic plasma concentration of 14 to 20 µg/mL. Dur- ing radiation therapy, patients typically did not reach a dose of mitotane that would be expected if mitotane were being used as monotherapy. Because of incomplete documenta- tion and interindividual differences in tolerance, we were unable to estimate average blood levels. Only 1 patient had
a dose-limiting reaction to therapy, and the majority un- derwent the regimen described above.
Local recurrence occurred in only 1 of 20 patients treated with radiation therapy, as compared with 12 of 20 patients not treated with radiation therapy (P =. 0005; hazard ratio [HR], 12.59; 95% confidence interval [CI], 1.62-97.88). Kaplan-Meier curves for local recurrence-free survival are shown in Figure 1. Of note, with only a single event for recurrence in the radiation therapy group, it was not statistically possible to construct a multivariable Cox proportional hazards model.
Despite this benefit in local control, recurrence-free sur- vival was no different between the groups (P =. 17; HR, 1.52; 95% CI, 0.67-3.45). Kaplan-Meier curves for recurrence-free survival are shown in Figure 2. Likewise, overall survival was not significantly different between the 2 groups (P =. 13; HR, 1.97; 95% CI, 0.57-6.77), with 4 deaths in the radiation therapy group compared with 9 in the control group. Kaplan- Meier curves for overall survival are shown in Figure 3.
Among patients who underwent radiation therapy, 16 of 20 experienced an adverse event during the period of radi- ation. However, the vast majority of such events were Common Terminology Criteria for Adverse Events grade 1 or 2 nausea (16 patients). Only a single patient, who received 55 Gy without concurrent mitotane, experienced a grade 3 toxicity. This patient experienced significant nausea requiring brief hospitalization with intravenous antiemetics and hydration. No renal toxicity was observed, as it is our practice to limit radiation dose to the contralateral kidney, such that only 10% of the organ receives 18 Gy or more. Overall rates of toxicity were not different between the ra- diation therapy group that received concurrent mitotane versus those who did not (2-tailed Fisher exact test: P= . 59).
Discussion
In this retrospective cohort series, which is the largest study to date analyzing radiation therapy as an adjuvant therapy
1.0
Local Recurrence-free Survival
0.8
+ Censored P =. 0005
0.6
0.4
0.2
With Radiotherapy
Without Radiotherapy
0.0
0.0
2.0
4.0
6.0
8.0
10.0
Years
Recurrence-free Survival Probability
1.0
+ Censored
P =. 1684
0.8
0.6
0.4
0.2-
With Radiotherapy
Without Radiotherapy
0.0
0.0
2.0
4.0
6.0
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for ACC (10, 14, 15, 19-23), we found that radiation following resection of all gross disease dramatically im- proves the rate of local control compared with patients not treated with radiation therapy but matched for stage, tumor grade, surgical margin status, and adjuvant mitotane use. This improvement is clinically meaningful given that, in our institutional experience, recurrence within the adrenal fossa often represents the largest lesion in patients with metastatic disease. As such, these recurrences significantly contribute to both morbidity and potentially increased hormone levels.
That radiation therapy might very well improve rates of local recurrence is particularly notable given that rates of local recurrence are extremely high even in those patients who undergo R0 resection (7-10). In such patients, local recurrence is not uncommon (7-9). Additionally, a large proportion of patients do not undergo a R0 resection: a recent analysis of the National Cancer Data Base showed 19% of surgical patients had only an R1 or R2 resection (4), further suggestive of a possible role for radiation therapy. While refinements of surgical technique may yield im- provements (24, 30, 31), recurrence rates remain high. This
1.0
+ Censored
P =. 1313
Survival Probability
0.8
0.6-
0.4-
0.2-
With Radiotherapy Without Radiotherapy
0.0
0.0
2.5
5.0
7.5
10.0
12.5
Years
is true even when resection is combined with systemic therapy, as demonstrated in the seminal series reported by Terzolo et al (32), which found that even in those patients who receive surgery as well as adjuvant mitotane, the rate of relapse was 49%, indicating that additional methods of tumor control are likely necessary.
Despite this, studies of the Surveillance, Epidemiology, and End Results program and the National Cancer Data Base have found that radiation therapy is only used in 9% to 12% of ACC treatment plans (1, 4). Such a slim rate of utilization likely owes much to ACC’s reputation for radioresistance, which was derived from several small, historical series that showed limited rates of success with outmoded radiation therapy techniques in a handful of heterogeneous cases (16-18, 33). Given the rapid advancement in radiation therapy technology, which has allowed for delivery of increased dosages with higher margins of safety, it seems premature to dismiss the modality’s efficacy on the basis of early studies that involved techniques not relevant to modern practice.
Rather, it is more instructive to examine more recent studies on the use of adjuvant radiation, the results of which are presented in Table 3. The strength and applicability of these studies are constrained by several significant limita- tions, and as a result, it is not surprising that they show a wide spread of local control rates, ranging from 0% to 100% (10, 14, 15, 20, 21, 23, 28). These limitations include the fact that radiation therapy was often delivered outside a tertiary center for ACC, and in some series it was provided entirely in the community setting (14). This is especially notable given that multidisciplinary care at expert referral-based centers has been shown to improve outcomes when compared with results from less specialized centers (34, 35).
A recent series that did not confirm a benefit of radiation therapy in the adjuvant setting was the study by Habra et al (14). However, this study included a fairly large number of patients with R1 or R2 resections. This makes it more an analysis of radiation therapy as an adjunct initial therapy rather than a true adjuvant therapy (14). Though the authors concluded that radiation therapy did not significantly improve local control, an alternative interpretation is that such a lack of improvement might have been a function of suboptimal surgery, for which radiation therapy could not compensate.
An additional limitation of prior studies is that mitotane or chemotherapeutic agents were either infrequently used - as they were used in 25% to 40% of cases (10, 14, 20) - or their use was not reported at all (15, 21, 28). Given that mitotane has been shown to improve outcomes in the adju- vant setting (32), its relative lack of use in these series is concerning. This contrasts with the approach at our institu- tion, where radiation is typically delivered concomitantly with initiation of mitotane therapy. Such an approach is supported by preclinical evidence that these 2 modalities may behave synergistically rather than additively for disease control (36). The results of the present study suggest that such a concurrent regimen results in no significant increase in toxicity, and it does not increase the rate of adverse events.
In contrast to prior studies, the strengths of our study lie in its large number of radiation therapy patients, the uni- formity of radiation therapy treatment delivered at a single tertiary center, the high rate of mitotane utilization, the absence of R1 and R2 resections, and the use of non- radiation therapy controls matched on the basis of disease and treatment characteristics that would otherwise serve to confound causes of local recurrence.
Limitations include the retrospective nature of our study, and it is subject to the inherent drawbacks of such an approach. For instance, although the recommendation as to whether a patient should receive radiation therapy was made after discussion in the University of Michigan’s Multidis- ciplinary Endocrine Oncology Tumor Board, the precise rationale used in individual cases could not be reconstructed from the medical record. An additional limitation is that several patients within the radiation therapy group had a primary surgery, followed thereafter by an isolated local recurrence, a secondary resection, and adjuvant radiation therapy. Given the rare nature of this disease, subjects could not be matched on the basis of primary versus secondary resection. Nonetheless, if any bias were introduced by the inclusion of these patients within the radiation therapy group, it would be in favor of the surgery-alone cohort, given that the tumors in question have already demonstrated an aggressive phenotype and proclivity for local recurrence.
Further, it is of note that tumor sizes in the control group (median, 12.6 cm) were larger than those in the radiation therapy group (median, 10.6 cm), though not in a statistically significant fashion (Table 2; P =. 72). Though larger size
| Table 3 Prior studies of adjuvant radiation therapy for the treatment of adrenocortical carcinoma | |||||
|---|---|---|---|---|---|
| Study | Year | No. of cases | Radiation therapy dose (Gy) | Chemotherapy or mitotane, n (%) | Local control, n (%) |
| Percarpio (21) | 1976 | 4 | 28-40 | NR | 1/4 (25) |
| Markoe (20) | 1991 | 5 | 42-60 | 2/5 (40) | 3/5 (60) |
| Pommier (28) | 1992 | 3 | 39-45 | NR | 0/3 |
| Fassnacht (10) | 2006 | 14 | 40-54 | 5/14 (36) | 12/14 (86) |
| Hermsen (15) | 2010 | 3 | NR | NR | 3/3 (100) |
| Habra (14) | 2012 | 16 | 36-59.4 | 4/16 (25) | 9/16 (56) |
| Sabolch | Present study | 20 | 45-60 | 15/20 (75) | 19/20 (95) |
Abbreviation: NR = not reported.
A
B
C
D
E
F
might have made achieving a complete resection more difficult, nonetheless there were fewer positive margins in those treated with surgery alone compared with those who received radiation. Regardless, the impact of tumor size may have introduced a bias in favor of improved outcomes in the radiation therapy group. The impact of this bias could not be estimated, owing to the limited events for either recurrence or survival in the radiation therapy group, which made it impossible to construct a multiple variable Cox proportional hazards model to account for any potential disparities in characteristics not matched for in the study design.
An additional limitation is that 5 patients in the control group underwent surgery at the University of Michigan, compared with 12 patients in the radiation therapy group. Because this might bias outcomes in favor of the radiation therapy group, a Kaplan-Meier analysis was performed, comparing recurrence- free survival in those who received surgery at the University of Michigan versus those who did not. This demonstrated that there were no significant differences between these 2 groups (P =. 88; Fig. E1, available online at www.redjournal.org).
Finally, though our study showed a significant decrease in local recurrence with the use of radiation therapy, no recurrence-free survival or overall survival benefits were observed. This could be because local control does not improve rates of metastatic recurrence or survival in patients with ACC, but it might also be that a small study of an aggressive disease is insufficiently powered to detect subtle differences in these endpoints. Nevertheless, we must pre- pare for a time when a better chemotherapeutic option will be available to control distant metastatic disease because at that time optimal local control will be necessary. Additionally, more alternative therapies are being used to control distant metastases, and reoperations to control minimal metastatic disease in highly selected patients are being pursued more often and have been found to improve survival (37, 38).
Regardless, the benefits of achieving local control should not be underestimated, especially since local recurrence rates remain high even after R0 resection and adjuvant mitotane or chemotherapy (8, 9, 12). In fact, one surgical series found that local recurrence represented the
single most common site of treatment failure (13). Such recurrences are often unresectable and potentially morbid in terms of pain, nausea, and hormone excess (for func- tional tumors). In our attempts to improve local control, we have routinely targeted the adjacent para-aortic lymph node basin. Treating this area is of particular importance given that approximately 15% to 27% of patients have lymph node metastases at the time of diagnosis (4, 29). Despite this, lymph nodes are infrequently examined at surgery, as demonstrated by one study that found they were evaluated in only 18% of patients at the time of resection (4), and the extent of lymphadenectomy is a matter of ongoing dis- cussion in the surgical community (39, 40). Given the substantial rate of lymph node metastases present in the aforementioned historical series, it is our current practice to cover the nodal basin to 45 Gy at 1.8 Gy per fraction with a simultaneous integrated boost, whereas the primary post- operative bed receives to 50 Gy at 2.0 Gy per fractions after an R0 resection or 55 Gy at 2.2 Gy per fraction after an R1 resection. However, it should be noted that our study has not addressed the optimal dosage, and given the excellent local control rate achieved, it may be that lower doses might also be effective.
The tumor bed clinical target volume (CTV) is con- toured to entirely encompass the preoperative gross tumor volume, as well as any postoperative surgical clips. The para-aortic lymph node CTV should be contoured to include the aorta with the addition of a 1-cm radial margin into the surrounding tissue. The lateral aspect of the lymph node CTV should ideally extend such that it is contiguous with the adjacent tumor bed CTV. Of note, the CTVs do not enter the vertebral bodies. The cranio-caudal extent of the lymph node CTV is constructed to match that of the tumor bed CTV. If the patient will be treated with a breath-hold technique, each CTV is expanded 0.5 cm in all directions to create a planning target volume. If a breath-hold technique will not be used, the CTVs are expanded 0.5 cm radially and then a cranial-caudal expansion is created, based on the extent of tumor bed and surgical clip motion observed on 4- dimensional computed tomography.
In terms of normal tissue constraints, we limit the volume of the duodenum receiving 50 Gy (V50 Gy) to <33 cm3, V51 Gy is limited to <5 cm3, and V54 to <1 cm3. A maximum of 0.5 cm3 of the duodenum is allowed to reach the prescription dose. The rest of the small intestine is limited to V51 Gy <1 cm3. The colon is limited to a V60 Gy of <1 cm3. Our parameters for the stomach are V51 Gy <5 cm3 and V54 Gy <0.5 cm3. If the patient has a single kidney, V18 Gy is limited to ≤10% of its volume. If both kidneys are intact, V18 Gy is limited to ≤30% of their combined volume. The spinal cord is allowed to reach a maximum of 45 Gy, and dosage to the liver is limited to as low as is reasonably achievable. In our planning process, meeting normal tissue constraints takes priority over reaching planning target vol- ume dosage goals. Figure 4 demonstrates representative clinical target volumes of both the adrenal fossa and the adjacent para-aortic lymph node basin.
In conclusion, our study demonstrates that adjuvant radi- ation therapy significantly lowers the risk of local recurrence for patients with ACC treated with resection of all gross dis- ease. Nonetheless, these findings await confirmation from prospective, randomized trials. Until such data are available, we recommend adjuvant radiation therapy after resection in patients with stage II or III disease. Regardless of the presence of other identifiable risk factors, radiation therapy should at least be considered, and expert consensus guidelines have indicated it might be especially appropriate for those thought to be at higher risk of local recurrence, whether due to involved surgical margins, operative approach, high grade, large tumor size, or tumor capsule rupture (6, 41).
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