BRIEF REPORT
Efficacy of Adjuvant Radiotherapy of the Tumor Bed on Local Recurrence of Adrenocortical Carcinoma
Martin Fassnacht, Stefanie Hahner, Buelent Polat, Ann-Cathrin Koschker, Werner Kenn, Michael Flentje, and Bruno Allolio
University of Wuerzburg, Department of Internal Medicine I, Endocrine and Diabetes Unit (M.Fa., S.H., A .- C.K., B.A.), Department of Radiation Oncology (B.P., M.Fl.), and Department of Radiology (W.K.), 97080 Wuerzburg, Germany
Context: Local tumor recurrence is common in adrenocortical car- cinoma (ACC) and is the most frequent cause for reoperation. Al- though radiotherapy is often considered ineffective in the treatment of ACC, the limited number of available studies does not support this statement.
Objective: The objective of the study was investigation of adjuvant tumor bed irradiation in the treatment of ACC.
Design: We performed a retrospective analysis.
Patients: The German ACC Registry (n = 285) was screened for patients who had received tumor bed radiotherapy in an adjuvant setting (no macroscopic evidence for residual disease after surgery). Fourteen patients without distant metastases (World Health Orga- nization stage I, one patient; stage II, seven; stage III, three; and stage IV, three) were matched with 14 patients for resection status, adju- vant mitotane treatment, stage, and tumor size. Median follow-up of patients still alive (n = 15) was 37 months.
Main Outcome Measure: Survival without local recurrence and disease-free survival was the main outcome measure.
Results: Local recurrence was observed in two of 14 patients in the radiotherapy group and in 11 of 14 control patients. The probability to be free of local recurrence 5 yr after surgery differed significantly [79% (95% confidence interval, 53-100) vs. 12% (0-30); P < 0.01]. However, disease-free and overall survival were not significantly dif- ferent between the two groups. Acute adverse events related to ra- diotherapy were mostly mild. One patient developed a partial Budd- Chiari syndrome.
Conclusion: These data from the largest series of ACC patients treated with adjuvant tumor bed irradiation suggest that radiother- apy is effective in reducing the high rate of local recurrence in ACC. A randomized trial in high-risk patients is needed to further evaluate the efficacy of radiotherapy as an adjuvant treatment option in ACC. (J Clin Endocrinol Metab 91: 4501-4504, 2006)
A DRENOCORTICAL CARCINOMA (ACC) is a rare ma- lignancy with a poor prognosis (1-3). Even after seem- ingly complete surgical resection, most patients develop re- currence within 5 yr (4, 5). Therefore, adjuvant treatment concepts after complete surgical resection are urgently needed. Adjuvant treatment with mitotane is often used, but evidence of its efficacy is still lacking (3, 6, 7). Local recur- rence is particularly frequent in ACC, often leading to re- operation (8, 9).
Radiotherapy has often been considered ineffective for treatment of ACC (9-11). However, several reports with a limited number of patients have described tumor response rates up to 42% (4, 11-17). Although methods and response criteria in these studies do not fulfill modern standards, these reports indicate that ACC is not resistant to radiotherapy. Stewart et al. (18) were the first to use radiotherapy in an adjuvant setting (n = 4). Long-term results of this series showed that three of the four patients treated with radio-
therapy of the tumor bed survived longer than 10 yr without recurrence (14). In addition, King and Lack (12) reported that all patients treated with adjuvant radiotherapy (n = 4) sur- vived more than 5 yr. Based on these observations, we and other colleagues in Germany have in recent years offered postoperative radiotherapy of the tumor bed to patients with ACC and perceived high risk of recurrence. Here, we analyze the outcome of these patients with matched controls derived from the German ACC registry.
Patients and Methods
Patients
We reviewed the German ACC registry (n = 285) for cases who had received tumor bed irradiation (1986-2004). The following inclusion criteria were defined in advance: 1) macroscopically complete tumor resection, 2) no evidence for distant metastases, 3) radiotherapy in an adjuvant setting (no evidence of tumor recurrence) within 6 months after first surgery, 4) a minimum of 12 months follow-up after surgery, and 5) availability of complete follow-up data (up to the death of the patient or follow-up information not older than 3 months at the time of analysis). Fourteen patients met these criteria. Every patient was matched with one control patient for resection (R) status, adjuvant mitotane treatment, tumor stage according the World Health Organization classification 2004 (19), and tumor size. Control patients were selected from a cohort of the German ACC Registry fulfilling the same inclusion criteria but not having received radiotherapy (n = 109). Matching was performed by an
Abbreviations: ACC, Adrenocortical carcinoma; CT, computed to- mography; 3D, three-dimensional; R, resection.
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independent person not involved in the analysis of the data by using clinical information from the time of the primary diagnosis.
Surgery
All tumors were localized at the time of primary diagnosis with no evidence for distant metastases. In all but two patients, conventional open surgery was performed. Surgical removal was macroscopically complete in all patients. In each group, no residual tumor (RO) was detectable in eight patients and microscopic residual tumor (R1) was detectable in two patients. However, in four patients either tumor spill- age occurred or the report by the local pathologist contained no infor- mation indicating whether or not the resection was microscopically complete. These cases were given the resection status RX.
Radiotherapy
All irradiated patients were centrally reviewed, including full treat- ment charts and port films. Seven of the 14 patients were treated in our center. The target volumes included the former tumor bed, and in seven patients additionally the locoregional lymphatic drainage (with bilateral paraaortic lymph nodes) because regional lymph node involvement was either demonstrated by histopathology or was considered very likely (e.g. large tumor size, infiltration of the tumor capsule, lymphangiosis carcinomatosa). Radiotherapy started in most patients within 8 wk after surgery using a linear accelerator with photon energies from 6-18 MV. Twelve of 14 patients had computed tomography (CT)-based three- dimensional (3D) treatment planning. In two patients, conventional simulator planning was performed. Radiation treatment was given in 1.8 to 2.0 Gy fractions daily for 5 d/wk. The median dose was 50.4 Gy (range, 41.4-56 Gy; mean total dose, 49.2 + 4.9 Gy). In eight of 14 patients, boost treatment was given after initial doses of 41.4 to 46.6 Gy to a larger treatment volume.
Documentation of adverse events
Medical records were reviewed for the following adverse events: gastrointestinal (nausea, vomiting, abdominal pain or cramps, diarrhea, constipation, enteritis, ileus), skin (dermatitis, hyperpigmentation, and atrophic skin), general symptoms like fatigue and anorexia, pulmonary (pneumonitis within 3 months after radiotherapy or pulmonary fibro- sis), kidney function (increase of serum creatinine > 0.3 mg/dl or de- crease of creatinine clearance > 20 ml/min), pain (abdominal pain or cramps), hematological (leucopenia, thrombopenia, anemia), and neu- rological (sensory or motoric neuropathy). All adverse events were scored according to the National Cancer Institute-Common Terminol- ogy Criteria-Adverse Events (NCI-CTC-AE) classification (20).
Statistical analysis
Analyses for survival were performed using the Kaplan-Meier method, and differences between the two groups were analyzed by Student’s t test, Wilcoxon test, and log-rank test, respectively. P values < 0.05 were considered as statistically significant.
Results
Characteristics of the patients
A total of 28 patients were included in the radiotherapy group (n = 14) and the control group (n = 14), respectively. Exact matching for R status and adjuvant mitotane treatment was possible. In only eight patients in each group, the re- section of the tumor was classified by the pathologist as RO (no residual tumor), in two cases in each group residual tumor was detected microscopically (R1), and in four cases the resection status was not reported (RX, including two and three cases, respectively, with tumor spillage). Five patients in each group received adjuvant mitotane. The radiotherapy group did not differ significantly from the control group in tumor size (mean, 11.7 ± 3.8 cm vs. 11.0 ± 4.3 cm; P = 0.3), tumor weight (505 g vs. 399 g; P = 0.13), or age (42 ± 15 yr vs. 48 ± 15 yr; P = 0.36) (Table 1). The median Weiss score was 5 (4-8, n = 9) vs. 4 (3-6, n = 8; P = 0.04). The median follow-up of patients still alive (n = 15) was 37 months (range, 13-72 months).
Local recurrence and survival analysis
Local recurrence was observed in 11 of 14 patients in the control group, indicating the high risk of the selected cohort. In contrast, in the radiotherapy group only two of 14 patients developed a local recurrence. More than 70% of local recur- rences occurred within 2 yr. The probability of being free of a local recurrence 5 yr after surgery differed significantly [radiotherapy group, 79% (95% confidence interval, 53-100%) vs. 12% (0-30%) in controls; P < 0.01) (Fig. 1). However, disease-free survival did not differ significantly between the two groups (Fig. 1). Nine patients in the radio- therapy group developed distant metastases (lung, n = 5; liver, n = 6; bone, n = 1) compared with 11 patients in the control group (lung, n = 8; liver, n = 5; bone, n = 1). After recurrence, treatment was similar in the radiotherapy group compared with controls (surgery, n = 6 vs. n = 7; mitotane, n = 9 vs. n = 8; cytotoxic chemotherapy, n = 6 vs. n = 4). Overall survival was also not significantly different (P = 0.9; data not shown). In each group, six patients died as a result of progressive disease.
Adverse events in radiotherapy group
Acute adverse events related to radiotherapy were mostly mild (Table 2). Three of the eight patients with gastrointes-
| Age (yr) | No. of patients with functional ACC | No. of patients with resection status | No. of patients receiving mitotane | No. of patients in tumor stage | Tumor size (cm) | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| R0 | R1 | RX | I II | III | IV | Mean | Median | ||||
| Radiotherapy group | 43 ± 15 | 9ª | 8 | 2 | 4 | 5 | 1 7 | 3 | 3 | 11.7 ± 3.8 | 12.0 (4.5-19) |
| Control group | 48 ± 15 | 96 | 8 | 2 | 4 | 5 | 1 8 | 5 | 11.0 ± 4.3 | 10.3 (3-20) | |
None of the patients received any other adjuvant therapy. R0, No residual tumor; R1, microscopic residual tumor; RX, presence of residual tumor cannot be assessed (tumor spillage or the report by the local pathologist contained no information indicating whether or not the resection was microscopically complete).
” Glucocorticoid excess (n = 3), androgen excess (n = 2), glucocorticoids plus other hormones (n = 4), hormonally inactive (n = 2), not documented (n = 3).
b Glucocorticoid excess (n = 5), androgen excess (n = 2), glucocorticoids plus other hormones (n = 2), hormonally inactive (n = 1), not documented (n = 4).
A
100%
survival without local recurrence
80%
60%
p<0.01
radiotherapy
+ - control
40%
20%
0%
0
1
2
3
4
5
years
B
100%
disease-free survival
80%
radiotherapy
p=0.6
control
60%
40%
20%
0%
0
1
2
3
4
5
years
tinal symptoms were on mitotane, which may also have caused nausea. One patient developed a partial Budd- Chiari syndrome 3 months after radiotherapy but is pres- ently free of hepatic symptoms or specific treatment 5 yr after treatment. In one patient, elevated blood pressure was observed 18 months after radiotherapy together with a decrease in kidney size and an increase of serum creat- inine (CTC grade I).
Discussion
The results of our study indicate that adjuvant radiother- apy may significantly reduce the rate of local recurrence in patients with ACC. These findings are in agreement with two previous reports including a total of eight patients with ACC also suggesting a benefit of adjuvant radiotherapy. However,
| Adverse event | Grade | |
|---|---|---|
| Acute | ||
| Gastrointestinal | Nausea (n = 8) | I-II |
| Skin | Dermatitis (n = 4) | I |
| Hyperpigmentation (n = 1) | I | |
| Others | Anorexia (n = 2) | I |
| Fatigue (n = 3) | I-II | |
| Abdominal pain (n = 2) | I | |
| Long-term | Impaired kidney function, increased serum creatinine (n = 1) Partial Budd-Chiari syndrome (n = 1) | I |
Adverse events were classified according the NCI CTC criteria v3.0 (20). All events that occurred within 3 months of radiotherapy were classified as acute.
our study not only comprises the largest patient group to date but also for the first time for inclusion of a control group matched for tumor status and additional adjuvant therapy with mitotane.
Local tumor recurrence after seemingly curative surgery for ACC is common, and a recent analysis of data from the German ACC registry indicates that 60% of patients develop a local recurrence within 5 yr after complete tumor resection (Fassnacht, M., A. C. Koschker, and B. Allolio, unpublished data). However, this rather high recurrence rate in patients from the German ACC registry is even exceeded by the recurrence rate in our control group. The increased risk of recurrence in this patient cohort is most probably related to the fact that our study also included cases with advanced tumor stage or evidence for tumor spillage during surgery, respectively. In this context, the low rate of local recurrence in the group receiving radiotherapy is even more impressive.
The reduced rate of local tumor recurrence after radio- therapy contradicts the view that ACC is resistant to radio- therapy as it is stated in several publications (9, 10). This view is based on a limited number of studies that are often anec- dotal or omit important technical aspects of radiotherapy. Furthermore, the results of these reports are conflicting. However, there are also reports indicating some efficacy of radiotherapy (4, 11-17). Moreover, the recent consensus con- ference on the management of ACC treatment judged ra- diotherapy in ACC as effective (6). Based on the limited available data, the authors stated that radiotherapy is rec- ommended in the treatment of bone, brain, and other me- tastases as well as in symptomatic local recurrence. In the last few decades, the technique of radiotherapy has been signif- icantly improved and CT-based 3D planning, use of multiple field technique with individual collimation, and high photon energy dosage are now established methods, whereas sev- eral of the older studies were performed without these techniques.
It is well known from radiotherapy in other tumor entities that major adverse events after abdominal radiotherapy are rare when using CT-based 3D planning with calculated tar- get volumes and protection of critical organs like spinal cord, kidney, and liver. In our series, none of the patients devel- oped any grade III or IV adverse events. Of note, three of eight patients who experienced gastrointestinal problems were concomitantly treated with mitotane, which may in-
duce similar symptoms. Therefore, the true rate of side ef- fects might be even lower.
In our study, no significant reduction in disease-free and overall survival was found. This might indicate that disease- free survival and overall survival are more dependent on the development of distant metastases than on local recurrence. However, the sample size of our study population is small and follow-up is still short, limiting the statistical power to detect differences. Moreover, the detailed analysis of the matched pairs reveals that in the radiotherapy group more patients were diagnosed in a more advanced stage (three patients with stage IV vs. no patients in the control group). Thus, a larger trial with a longer follow-up is required to fully assess the efficacy of adjuvant radiotherapy.
Our study has important limitations. Firstly, the analysis was performed retrospectively. Moreover, matching of con- trols was hampered by the still limited number of patients included in the German ACC registry. Accordingly, com- plete matching for all different parameters was not possible in all cases. However, the small remaining differences be- tween the groups would have favored a poorer outcome in the radiotherapy group.
In conclusion, adjuvant radiotherapy should be consid- ered in patients at high risk of local recurrence, and a pro- spective randomized trial of this treatment option is now justified.
Acknowledgments
We thank Uwe Maeder (Tumor Center, University Hospital Wuerz- burg) for his support by establishing the German ACC Registry and for his statistical advice. Seven patients did not receive their radiotherapy at our hospital. We thank Michael J. Eble (University Hospital Aachen), Wolfgang Hinkelbein (University Clinic Charite Berlin), Martin Stus- chke (University Hospital Essen), Jan-Peter Hedde (City Hospital of Merheim, Cologne), Hansjörg Zwicker (Klinikum Konstanz), Hermann Grauthoff (Lukaskrankenhaus Neuss), and Rainer Heyder (Klinikum Weiden) for providing detailed data on the radiotherapy in these patients.
Received May 10, 2006. Accepted July 28, 2006.
Address all correspondence and requests for reprints to: Martin Fassnacht, M.D., Department of Medicine I, Endocrine and Diabetes Unit, University Hospital Wuerzburg, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany. E-mail: fassnacht_m@medizin.uni-wuerzburg.de.
This work was supported by the Deutsche Krebshilfe (Grant 106080 to B.A.) and the European Union (Grant MOIF-7394 to M.Fa.).
Disclosure summary: M.Fa., S.H., B.P., A .- C.K., W.K., and M.Fl. have nothing to disclose. B.A. received lectures fees from Takeda.
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JCEM is published monthly by The Endocrine Society (http://www.endo-society.org), the foremost professional society serving the endocrine community.