HEALTH & HUMAN SERVICES - USA \\MENT OF
Published in final edited form as: Cancer J. 2013 ; 19(4): 288-294. doi:10.1097/PPO.0b013e31829e3221.
Role of Radiotherapy in Adrenocortical Carcinoma
Jennifer Ho, MD*, Baris Turkbey, MD+, Maureen Edgerly, MA, RN, Meghna Alimchandani, MD, Kevin Camphausen, MD*, Tito Fojo, MD, PhD+, Aradhana Kaushal, MD*
*Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
+Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Medical Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD. $Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
Abstract
Purpose: Adrenocortical carcinoma (ACC) is a rare and highly malignant tumor usually diagnosed in an advanced stage. Radiation therapy has been a poorly studied and underutilized therapeutic option.
Methods: This retrospective analysis reviewed treatment courses for 14 patients with pathologically confirmed ACC treated between 1997 and 2012. Two patients were treated adjuvantly following surgery, and 12 were treated with palliative intent. Patients presented with stage II (n = 4), stage III (n = 7), and stage IV (n = 3) disease. Patients had a mean age of 51.5 years. Ten patients received chemotherapy before radiotherapy (RT), and 12 patients received surgery before RT, before receiving radiation at a mean of 17.8 months after diagnosis.
Results: In total, 20 sites were treated, 2 of which were in an adjuvant setting, and 18 of which were for palliative indications in 12 patients as follows: (1) pain/neuropathy (n = 10), (2) prophylactic treatment of asymptomatic recurrences (n = 3), and (3) prevention of imminent metastatic complications (n =2), hemoptysis (n = 1), severe mass effect (n =1), and brain metastasis (n = 1). Sites were treated to a median dose of 36.3 Gy (range, 17.5-60 Gy) in a median of 2.5 Gy/fraction (range, 1.8-4 Gy). At a mean follow-up of 22.0 months for the 2 patients given adjuvant RT, 1 patient did not have a local recurrence during a 14.3-month period of follow-up, and the other had a local recurrence 14.5 months after RT. At a mean follow-up of 11.3 months for the 12 patients receiving palliative RT, 10 patients had either a clinical or radiographic response. Of the courses of palliative RT that had adequate radiographic follow-up, 4 treatments (27%) resulted in a partial response. Eleven treatments (73%) that were able to be evaluated resulted in clinical improvement. Acute Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicities observed in 7 patients included 3 grade 1, 4 grade
2, and 1 grade 3. No patient had acute toxicity of grade 4 or greater or any Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer late toxicity of grade 1 or greater.
Discussion: This report is one of the largest to date examining the role of modern radiation techniques in the management of ACC. We conclude that radiation can be effective in the management of metastatic ACC, palliating local symptoms, and preventing complications from large metastases. Radiation should be considered as an option in multimodality management of ACC patients.
Keywords
Radiotherapy; radiation oncology; adrenocortical carcinoma; adrenal gland; palliative; adrenal cortex
Adrenocortical carcinoma (ACC) is a rare yet aggressive disease, affecting 0.5 to 2 per million people per year yet accounting for 0.2% of cancer-related deaths.1-3 Most patients present with large tumors in an advanced stage. Only 5% of patients present with stage I disease (defined as a tumor measuring ≤5 cm), 41% present with stage II disease, 22% present with stage III disease, and 32% present with stage IV disease.4-6 Patient survival by stage ranges from 23 to 84 months for stage I to II disease, 8 to 28 months for stage III disease, and 9 to 15 months for stage IV disease.4 The most common sites of metastases are the liver and lung.3 Unfortunately, even with advances in imaging and thus incidental detection of ACC, there has been no significant improvement or change in presentation, diagnosis, or stage of disease since the 1970s.7
The most consistently reported prognostic factor for improved survival is complete surgical resection.7 Two large analyses of national cancer databases identified increasing age, poorly differentiated tumors, involved margins, and tumor grade as additional prognostic factors.3,7 In 1 large database, those with microscopic and macroscopic positive margins had 5-year survival rates of 21.0% and 9.9%, respectively, compared with 46.1% among those with uninvolved margins. Other potential indicators of survival include tumor morphologic characteristics such as tumor necrosis, mitotic rate, and atypical mitosis, as well as venous, capsular, and adjacent organ invasion.8
Despite treatment, recurrence occurs in up to 84% of patients.8-10 Even among those with complete resections, local recurrence occurs in 19% to 34%, and metastatic recurrence in 28% to 63%.4,11,12 Recurrent or advanced ACC is treated with reresection if possible. One series of 47 patients found that 5-year survival rate for patients with a complete resection for their locally recurrent ACC was 57%.13
Mitotane is an adrenocorticolytic drug that has been used in the treatment of ACC since the 1970s. It is used as primary therapy in those who are unable to receive surgery, as adjuvant therapy, or as treatment for recurrent disease. Mitotane has many adverse effects, and even after adjuvant mitotane use, patients had a recurrence rate of approximately 50%.14,15 Other systemic agents that have failed to demonstrate meaningful responses are erlotinib, gemcitabine, 5-fluorouracil, capecitabine, bevacizumab, and gefitinib.16
In the past, ACC was considered a relatively radioresistant tumor, based on anecdotal case reports.4 Since the publication of these earlier studies, the capability to deliver more effective, precise, and safe radiation treatments has greatly improved. Still, national databases identified only 9.5% to 11.7% of ACC patients as having received radiotherapy (RT) (in any setting).3,7 There has been a limited amount of thorough, RT-specific publications, and many of them are limited by small sample size and/or lack of treatment details. Two recent retrospective studies showed promising results supporting the utilization of adjuvant RT in preventing local recurrence.17,18 In addition to postoperative RT, it is important to provide evidence that RT can be helpful in advanced ACC cases to palliate symptoms or prevent undesirable complications from local or distant tumor. Our study represents one of the largest series to date examining the role of adjuvant and palliative RT in ACC. In this report, we assessed the role of modern RT treatment techniques in patients with ACC, specifically evaluating both the symptomatic responses as well as imaging responses, using the Response Evaluation Criteria in Solid Tumors criteria.
METHODS
This retrospective study reviewed the medical records of 21 patients with pathologically confirmed ACC treated at the National Institutes of Health (NIH) Clinical Research Center between August 1997 and February 2012, who received RT. Seven were excluded because of inadequate radiation records, leaving 14 patients who were included in the final analysis. Seven patients had radiation to more than 1 site of disease. Eight patients received RT at the NIH, 5 patients received RT outside the NIH, and 1 patient received RT both at the NIH and outside the NIH. Patients were selected if they received adjuvant RT, palliative RT, or RT with definitive intent, and if they had adequate records available for review. Patient charts were reviewed for demographic factors, previous treatments including surgery and chemotherapy regimens, pathological characteristics, radiation treatment planning, and relevant toxicity. Patients were staged according to T, N, M guidelines published by the American Joint Committee on Cancer.19
Radiographic responses, local recurrences, and distant recurrences were evaluated by a board-certified radiologist. The Response Evaluation Criteria in Solid Tumors criteria were used to determine response: partial response was defined by target lesion shrinkage of 30% or more, progressive disease was defined by a 20% increase in tumor size, and stable disease was defined as any smaller changes that did not meet these criteria.20 Local recurrences in patients treated with adjuvant RT were defined as any identifiable disease within the treatment field in follow-up imaging. In-field disease progression was defined as any identifiable progressive disease, including lymph nodes or satellite lesions, within the radiation field during subsequent follow-up imaging. Out-of-field progression or new distant disease was defined as progressive disease or presence of new disease outside the treatment field identified in follow-up imaging. Clinical responses were evaluated by a chart review of all physician and provider notes. All available tumor pathology slides were reviewed for histopathologic characteristics by 2 pathologists.
Patient charts were reviewed for documentation of adverse events and were graded according to Radiation Therapy Oncology Group (RTOG) acute and late toxicity assessment
guidelines. Follow-up time was defined as the time from last day of RT to last documented clinic note, imaging, or verified date of death. Overall survival (OS) was measured from date of diagnosis.
RESULTS
Patient Characteristics
Fourteen patients received 20 separate courses of RT: 2 courses were given in an adjuvant setting, and 18 were given in a palliative setting. Patient characteristics are presented in Table 1. The median age of all patients was 51.5 years (range, 19-68 years). Seven of the 14 patients were male. At initial diagnosis, patients presented with stage II disease (n = 4), stage III disease (n = 7), and stage IV disease (n = 3). Treatment characteristics are listed in Table 2. Ten patients received chemotherapy before RT, at a median of 2 different regimens (range, 0-5 regimens). Twelve patients received surgery before RT, at a median of 1 operation (range, 0-3 separate operations).
Information on primary tumor pathology was available for all patients (Table 3). Available slides (one to multiple) were reviewed by 2 pathologists. Tumor pathology was reviewed for characteristics of vascular invasion, capsular invasion, presence of necrosis, and high mitotic index, defined as more than 5 mitoses per 50 high-power fields (modified Weiss criteria). Four specimens did not contain adequate tumor sample to evaluate for the presence of invasion. Tumor specimens demonstrated vascular invasion (n = 7), capsular invasion (n = 8), necrosis (n = 14), and a high mitotic index (n = 11).
Two treatments were given postoperatively: one because of intraoperative tumor spillage and positive margins after a second resection, and one because of positive margins. Eighteen courses of treatment, delivered to 12 patients, were for palliative indications including pain/neuropathy (n = 10), prophylactic treatment of recurrences (n = 3), and prevention of imminent metastatic complications including cord compression (n = 2), hemoptysis (n =1), severe mass effect on surrounding organs (n = 1), and brain metastasis (n = 1).
Details of Radiation
Patients received radiation on average 17.8 months (range,0.3-55.3 months) after diagnosis. Radiation was given at a median dose of 3625 cGy (range, 1750-6000 cGy), in a median of 15 fractions (range, 5-31 fractions), consisting of a median dose of 250 cGy (range, 180-400 cGy). Total RT dose delivered for the 2 adjuvant treatments was a median of 5520 cGy (range, 5040-6000 cGy). One patient received RT as initial definitive treatment for unresectable disease at a total dose of 3500 cGy. Eighteen courses of RT were delivered in a palliative setting to the following treatment sites: abdominal masses (n = 8), bony metastases (n = 6), lymph nodes (n = 3), brain (n = 1), lungs (n=1), and mediastinum (n = 1). The average total RT dose delivered for these different sites was 4264 cGy (range, 3000- 6000 cGy) for abdominal masses, 3083 cGy (range, 2000-4500 cGy) for bony metastases, 3417 cGy (1750-4500 cGy) for lymph nodes, and 3250 cGy (3000-3750 cGy) for other metastases.
All patients received external beam RT, using a linear accelerator with photon energies ranging from 6 to 18 MV. Fifteen instances of RT were delivered with 3-dimensional conformal treatment techniques, and 4 courses were delivered with intensity-modulated RT (IMRT) techniques, and 1 patient had both 3-dimensional conformal and IMRT planning in 1 course (Fig. 1). Of the 7 courses of treatment with gross tumor volumes available, the median was 131.9 cm3 (range 24.4-607.4 cm3).
Details of Chemotherapy
Seven patients received concomitant chemotherapy, including mitotane (n = 4), cisplatin (n =2), and 5-fluorouracil (n = 1). Twelve patients required chemotherapy after RT, receiving a median of 2 regimens (range, 1-4 regimens). Four patients required surgery after RT, receiving a median of 1 operation (range, 1-2 operations). One patient required chemoembolization, and 1 patient required radiofrequency ablation.
Response to Treatment
The median length of follow-up for the entire cohort was 12.3 months (range, 0-39.9 months). In-field progression occurred at a mean of 6.0 months (range, 1.2-16.0 months), and out-of-field progression occurred at a mean of 4.3 months (range, 1.0-18.4 months).
Adjuvant Radiation
At a mean follow-up of 22.0 months (range, 14.3-29.7 months) for the 2 patients given adjuvant RT, one did not have a local recurrence during a 14.3-month period of follow-up, and the other had a local recurrence 14.5 months after RT. These 2 patients had out-of-field disease progression in 2.3 and 4.4 months, respectively.
Palliative Radiation
At a mean follow-up of 11.3 months (range, 0-39.9 months) for the 12 patients receiving palliative RT, 10 patients had either a clinical or radiographic response. Of the 18 courses of palliative RT, 15 could be evaluated clinically (the remaining 3 courses were given for prophylactic aggressive treatment of asymptomatic lesions). Among these 16 courses of treatment, 12 treatments (80%) resulted in a clinical improvement, 3 did not, and one could not be evaluated given limited follow-up. Among these 15 courses of treatment, 11 treatments (73%) resulted in a clinical improvement, 3 did not, and 1 could not be evaluated given limited follow-up. The 4 courses of RT given to prevent cord compression (n = 2), hemoptysis (n = 1), and mass effect from a mediastinal tumor (n = 1) were all successful in preventing these complications for the remainder of a mean follow-up period of 5.1 months (range, 0-9.9 months).
Thirteen of the 18 courses of palliative RT had adequate follow-up imaging to assess a radiographic response. Two patients, representing 3 of the 5 courses of RT without imaging follow-up, died shortly after RT (0.1 and 2.3 months). Of these 13 treatments with available imaging, 4 treatments (27%) resulted in tumor shrinkage of 30% or greater. Seven treated lesions (54%) did not decrease in size at all, but rather proceeded to progress at a mean of 4.8 months (range, 1.2-16.0 months) months after RT. Two treatments (15%) resulted in stable disease for the remainder of follow-up periods of 9.9 and 2.2 months. Out-of-field
progression occurred after 13 treatments (72%) at a mean of 4.4 months (range, 1.0-18.4 months) after RT.
Survival After Treatment
At a median length of follow-up after RT of 12.3 months, 12 of the 14 patients had died. Median OS for all patients was 33.1 months (range, 2.5-50.9 months; Fig. 2). Median survival varied by American Joint Committee on Cancer stage at diagnosis: patients with stage II disease (n = 5) survived a median of 46.8 months, patients with stage III disease (n = 6) survived a median of 36.1 months, and patients with stage IV disease (n = 3) survived a median of 5.6 months, P= 0.0013 (Fig. 2).
Median OS was 33.1 months (range, 2.5-50.8 months) among patients receiving palliative RT, whereas the average OS was 34.9 months (range, 23.8-46.0 months) among patients receiving adjuvant RT.
Median survival after RT was 16.3 months (range, 0.5-36.9 months). Median survival after RT of patients receiving palliative RT was 12.7 months (range, 0.5-36.9 months). Average survival after RT of the 2 patients receiving adjuvant RT was 26.5 months (range, 20.8-32.3 months).
Adverse Events
There were 7 RTOG/European Organization for Research and Treatment of Cancer acute toxicities observed in 6 patients, consisting of 3 grade 1, 3 grade 2, and 1 grade 3 toxicities (Table 4). One of the 3 patients with nausea/vomiting was also taking concurrent cisplatin during RT, which may have contributed to toxicity. No patient had acute toxicity of grade 4 or greater or any RTOG/European Organization for Research and Treatment of Cancer late toxicity of grade 1 or greater.
DISCUSSION
The results of this study suggest that RT can be a useful modality in the management of ACC. Given the rarity of this disease, this modern series is a significant addition to the current management of ACC. Our study is one of the largest to date examining the role of modern radiation techniques in the management of ACC, and to our knowledge, it is the largest study examining the role of RT in a palliative setting evaluating both symptomatic and specific imaging responses. In this cohort, we have shown that RT was effective in palliating symptoms in the majority of patients, including improvement of pain and prevention of metastatic complications.
Interestingly, in vitro experiments suggest that mitotane may be a radiosensitizer. Cerquetti et al21 found that the combination of ionizing radiation with mitotane led to inhibition of cell growth and cell accumulation in the G2/M phase in ACC cell lines, whereas treatment with IR or mitotane alone led only to transient cell cycle arrest and no effect on cell cycle, respectively Four patients in our study received mitotane during RT, as did a number of patients in the studies by Sabolch et al17 and Fassnacht et al.18 However, there have not been any clinical trials studying the specific use of concurrent mitotane and RT.
Although radiation has historically been considered ineffective in the treatment of ACC, our results confirm those of several recent studies supporting the use of RT in ACC. Because of the low prevalence of the disease, evaluation of the role of RT has been limited to small retrospective studies. The historical notion that ACC is radioresistant developed from small studies that omitted important details supporting their conclusions.5,22-24 Percarpio and Knowlton25 refuted these studies as having insufficient evidence and concluded from their series of patients that, in contrast to previous reports, ACC metastases were responsive to irradiation. Since then, there have been published reports supporting the use of RT in various contexts for managing ACC.
Two recent studies using modern radiation techniques examined the effect of adjuvant RT and concluded that RT should be considered after surgery to prevent local recurrence. Fassnacht et al18 examined 14 patients without distant metastases who had received adjuvant RT, at a median dose of 50.4 Gy, and 14 matched patients and found that the probability of remaining free from local recurrence 5 years after surgery was significantly higher in the RT group (79% vs 12%, P< 0.01).18 Sabolch et al17 examined 58 patients with 64 courses of treatment for primary and recurrent disease and found that local failure occurred in 16 of the 38 courses of treatment with surgery alone, 2 of the 10 treatments of surgery followed by RT, and 1 of the 16 courses of definitive RT for unresectable disease. Neither study found any effect of RT on OS. Several other older studies examining adjuvant RT, with patient numbers ranging from 3 to 10, observed local control rates of 0% to 60%.9,25-33 However, these studies, as reviewed by Polat et al,14 provided limited details of patient population, treatment, tumor response, and follow-up time. Because our study included only 2 patients who received adjuvant RT, it is difficult to make a meaningful conclusion from our series. However, it is worth noting that one of these patients did not have a local recurrence (at a follow-up time of 14.3 months), whereas the other one had 14.5 months after RT.
There has also been limited evidence supporting the use of RT in the palliative setting for the management of ACC. Polat et al14 reviewed several retrospective investigations (patient numbers ranging from 2-26) that studied response to palliative RT, as well as data from their own institution, and found that, in total, 52 (57%) of 91 had a response, with response rates ranging from 25% to 100%.9,14,25,26,28-33 These studies were limited in that only 3 of them included information on radiation dose, 14,25,33 and many of them had limited details of indication for RT and/or of symptomatic response.
Our study results show a clinical response was obtained in 11 (92%) of the 12 patients receiving palliative RT. When examining the palliative response of each treatment course more specifically, 11 (73%) of 15 evaluable courses of palliative RT treatment demonstrated a clinical response. Compared with previous studies looking at palliative RT, ours has several advantages. Our patient cohort, treated between 1997 and 2012, received more up-to-date management and care, compared with the patients in previous studies, who were treated as far back as 1944. The patients in our study received more precise and safe RT utilizing more modern techniques, including some patients who received IMRT. To our knowledge, this is also the first series to report on both palliative symptom response and using precise imaging criteria to delineate radiographic response.
This study has limitations. Our patient size was small and included a heterogeneous patient population and treatment regimens; however, this is unfortunately a common problem in studying this disease. There are also the limitations common to any nonrandomized, nonblinded, retrospective study, including bias in patient selection and interpretation of outcome. In addition, not all patients had thorough follow-up because many of them received treatment and management at several different clinics. Prospective studies would be of benefit to understanding the potential effects of RT in the treatment of ACC and, in particular, the use of postoperative RT.
We conclude that RT can be well tolerated and effective in the management of metastatic ACC, palliating local symptoms, and preventing complications from large metastases. Our study supports the evolving notion that ACC is not a radioresistant tumor as it has been viewed previously. Therefore, RT should be considered in the multimodality management of patients with ACC.
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Ho et al.
| Age, y | |
| Median | 51.5 |
| Range | 19-68 |
| Sex, n (%) | |
| Male | 7 (50) |
| Female | 7 (50) |
| Stage, n (%) | |
| I | 0 |
| II | 4 (29) |
| III | 7 (50) |
| IV | 3 (21) |
| Tumor side, n (%) | |
| Left | 7 (50) |
| Right | 7 (50) |
Ho et al.
| Type of surgery, n (%) | |
| Biopsy only | 3 (21) |
| Adrenalectomy | 5 (36) |
| En bloc resection | 6 (43) |
| Lymph node evaluation, n (%) | |
| Dissection | 2 (14) |
| Sampling | 4 (29) |
| None | 8 (57) |
| Time from diagnosis to RT, mo | |
| Median | 15.8 |
| Range | 0.3-42.4 |
| Treatment site, n (%) | |
| Abdominal mass | 8 (40) |
| Bony met | 6 (30) |
| Lymph nodes | 3 (15) |
| Other | 3 (15) |
| RT indication, n (%) | |
| Palliative | 18 (90) |
| Adjuvant | 2 (10) |
| Chemotherapy regimens, median (range) | |
| Before RT | 2 (0-5) |
| After RT | 1.5 (0-4) |
| Surgery, median (range) | |
| Before RT | 1 (0-2) |
| After RT | 0 (0-1) |
| RT dose, cGy | |
| Median | 3625 |
| Range | 1750-6000 |
Type of surgery and lymph node evaluation refer to initial resection.
| ☒ n (%) | |
|---|---|
| Vascular invasion | |
| Present | 6 (43) |
| Absent | 4 (28) |
| Unknown | 4 (28) |
| Capsular invasion | |
| Present | 7 (50) |
| Absent | 2 (14) |
| Unknown | 5 (36) |
| Necrosis | |
| Present | 14 (100) |
| Absent | 0 |
| High mitotic index (>5/50 high-power field) | |
| Present | 11 (79) |
| Absent | 3 (21) |
TABLE 3.
Ho et al.
| Acute RT Toxicity | Adverse Event | Grade |
|---|---|---|
| Upper gastrointestinal | Nausea/vomiting (n = 3) | II |
| Pharynx and esophagus | Dysphagia (n = 1) | I |
| Mucous membrane | Mucositis (n = 1) | I |
| Skin | Erythema (n = 1) | I |
| Hematocrit | Anemia (n = 1) | II |