Radiation Therapy for Adjunctive Treatment of Adrenal Cortical Carcinoma
Arnold M. Markoe, M.D., Sc.D., William Serber, M.D., Bizhan Micaily, M.D., and Luther W. Brady, M.D.
Adrenocortical carcinoma is a rare disease which is primarily approached surgically. There have been few reports of the efficacy of radiation therapy and, for the most part, these have been anecdotal. This paper reports on the potential ad- juvant role of radiation therapy after surgical excision of pri- mary adrenal cortical carcinoma and also comments about the efficacy of palliative radiation therapy for metastases. We have identified eight patients treated for adrenal cortical car- cinomas at Hahnemann University Hospital (HUH) from 1962 until the present and have also identified five patients with the same diagnosis at Philadelphia General Hospital (PGH) from 1962 until its close in 1975. These two groups are examined separately. In the PGH group, in which two patients were diagnosed at autopsy and only one patient was treated by radiation therapy, the median survival was between 0 and 1 month for Stage IV disease with the only patient surviving to 6 months being that patient receiving radiation therapy. In the HUH group, five of eight patients were treated adjunctively after diagnosis, one was not and two received palliative therapy. The median survival for treated Stage III patients was between 34 months and 7 years. The suggestion, based on a limited patient series, is that patients treated post- operatively to the tumor bed and nodal areas in Stage III disease may have improved survival over historic series and improved local control.
Key Words: Adrenocortical carcinoma-Radiation therapy.
From the Department of Radiation Oncology, Hahnemann Uni- versity Medical School and Hospital, Philadelphia, Pennsylvania, U.S.A.
Address correspondence and reprint requests to Dr. Arnold M. Markoe at University of Miami School of Medicine, Department of Radiation Oncology (D-31), P.O. Box 016960, Miami, FL 33101, U.S.A.
Adrenal cortical carcinoma is a rare disease with a suggested incidence of 0.2 cases per 105 population per year (1,2) and accounts for 0.2% of deaths per year for all cancers. Median survival over all stages is 2 years (3), although a recent report suggests a lower median survival time of about a year (4), but this may be due to the fact that nearly 70% of patients in that study had Stage IV disease and can be expected to have decreased median survival time.
Surgery is the mainstay of therapy for the primary lesion (2,4) and can be used to treat resectable abdom- inal recurrences or distant metastases (2). Recurrent or metastatic disease or unresectable primary disease can be approached by chemotherapy with ortho,para- DDD (Mitotane; Lysergen; o,p’-DDD) being the drug of choice (4-6).
There is a paucity of literature regarding the efficacy of radiation therapy as an adjunctive modality for treatment of adrenal cortical carcinoma, with most re- ports being anecdotal or omitting the technical details of radiation therapy. Most recently, however, Percarpio and Knowlton (7) have reported on 14 patients of whom 11 received 18 courses of radiation therapy pre or postoperatively. These authors noted good response of metastatic disease to palliative doses of radiation therapy and reported occasional prolonged local con- trol of disease.
Magee et al. (8) later published on 15 patients, nine of whom had postoperative radiation therapy, reporting the potential use of radiation in an adjuvant mode.
This article will discuss the potential adjuvant role of radiation therapy for adrenal cortical carcinoma treated postoperatively.
PATIENT MATERIAL
We have reviewed the tumor registry for cases of adrenal cortical carcinoma presented at Philadelphia
| Pt. # | Age (yr) | Sex | Stage (TMRD) | Mode of diagnosis | Initial XRT |
|---|---|---|---|---|---|
| Philadelphia General Hospital (1962-1975) | |||||
| 1 | 58 | M | IV | Biopsy | No |
| 2 | 67 | M | IV | Biopsy | No |
| 3 | 61 | M | IV | Autopsy | No |
| 4 | 86 | M | IV | Autopsy | No |
| 5 | 47 | M | IV | Biopsy | Palliation |
| Hahnemann University Hospital (1962-1987) | |||||
| 6 | 43 | F | Unknown | Resection | No |
| 7 | 9 | F | III (T3MOD3R0) | Resection | No |
| 8 | 53 | M | III (T3MOD1R2) | Resection | Yes |
| 9 | 25 | M | III (T3MOD1R2) | Resection | Yes |
| 10 | 57 | F | Il! (T3MOD2R2) | Resection | Yes |
| 11 | 66 | F | IV (T3M1D3R2) | Biopsy | Palliation |
| 12 | 63 | F | Il (T3MOD2R0) | Resection | No |
| 13ª | 46 | M | IV (T1M2D3R2) | Autopsy | Palliation |
a Patient treated palliatively to whole brain, then to right supraclavicular area for metastatic disease from unknown primary site. Primary site diagnosis established by post-mortem examination.
General Hospital (PGH) from 1962 until its close in 1975. Such records were under the custodianship of one of us (WS). We have also reviewed the cases seen in the Department of Radiation Oncology at Hahne- mann University Hospital (HUH) from 1962 until the present. We have identified 13 such patients in total.
Table 1 presents the characteristics of the patient population. The PGH population consisted of five males ranging in age from 47 to 86 years, all having biopsy-proven adrenocortical carcinoma. Unfortu- nately, two of five diagnoses were established at au- topsy. All five patients had Stage IV disease by Bradley’s criteria (9) shown in Table 2. Two patients were di- agnosed and not treated. The remaining patient re- ceived cobalt teletherapy for unresectable disease (de- tails unknown).
The HUH series of patients is distinctly different from those patients at PGH. There were 5 of 8 patients who were women. One patient had virilizing symptoms indicative of a functional adrenal cortical carcinoma. The age range was from 9 to 66 years. A single patient presented with distant metastatic disease and was treated with radiation therapy for palliation only and diagnosis was established at autopsy. One patient was seen for recurrent disease and lost to follow-up. It is not known if this patient received any further therapy. One patient was treated palliatively to the abdomen for unresectable disease. The remaining five patients were treated adjuvantly after surgery to the tumor bed and draining lymphatics with wide margins.
In these patients, treatment was by 6-10 mV photon beam therapy. We attempted to deliver 50-60 Gy over
5 to 7 weeks in 1.5-1.8 Gy daily fractions. Fields were usually parallel opposed AP-PA portals that were ini- tially covering the contralateral periaortic nodal chain and, for left-sided primary lesions, were extended up to the diaphragm and down to the iliac crest. The field size was reduced to spare spinal cord after 40 Gy. For
| T Extent of primary tumor | |
|---|---|
| T1 Tumor < 5 cm and confined to adrenal gland T2 5 cm ≤ tumor ≤ 10 cm or adherent to kidney T3 Tumor > 10 cm or invading surrounding structures including renal vein | |
| M Presence and type of metastases | |
| MO No demonstrable metastases | |
| M1 Regional lymphatics involved M2 Distant metastatic disease (e.g., liver, lung) | |
| R Disease residual after resection | |
| RO Tumor completely resected R1 Tumor entered at surgery R2 Tumor tissue remaining after surgery | |
| D Degree of histologic differentiation | |
| D1 Differentiated; no capsular or vascular invasion D2 2 Moderately undifferentiated; either capsular or vascular invasion | |
| D3 Anaplastic; both capsular and vascular invasion | |
| Stage I = score 3 or less (e.g., T1MOROD1) Stage II = score 4 and 5 (e.g., T2MOR1D2) Stage III = score 6 and 7 (e.g., T3M1R1D2) Stage IV = score 8, 10 (e.g., T3M2R2D3) From Bradley, ref. 9. | |
right-sided lesions, the AP-PA fields were used for par- tial treatment after which a multiple field arrangement was employed in an effort to reduce hepatic dose to large areas of liver and homogenize the dose in the more posterior tumor bed area. All therapy was via photon beam throughout. In only one of five of patients so treated did we fail to achieve the desired minimum dose. The treatment course was generally well-tolerated with the expected mild-to-moderate radiation enteritis and nausea with attendant weight loss. Symptoms were easily controlled by antiemetic and antidiarrheal prep- arations.
RESULTS
The outcome of the PGH and the HUH patients is examined in Table 3. Clearly, the PGH patients fared worse than the HUH patients. The two untreated pa- tients diagnosed at autopsy both died within 15 days of admission for diagnostic workup. Of the two patients who were diagnosed antemortem, but not treated, both died within 1 month from diagnosis. The single patient treated palliatively for unresectable abdominal disease by Cobalt teletherapy survived for 6 months, but suc- cumbed to the primary disease.
The HUH patients fared better. The single untreated patient was lost to follow-up after coming for second- opinion consultation after recurrence. The patient treated palliatively for unresectable intra-abdominal disease (patient No. 11) and patient No. 13 treated palliatively for metastatic disease (and diagnosed at
autopsy) both died within 3 months of initiation of therapy. The remaining five patients were treated in a definitive adjuvant manner after surgical resection with known residual disease after surgery. These patients have fared the best. The median survival time is pres- ently 35 months over all HUH patients. Excluding the patient lost to follow-up and the two patients who were initially treated palliatively, the median survival time is 69+ months with two of the patients still alive, one with disease recurrence after 14 years but outside of the irradiated portal and extra-abdominal in nature.
It is interesting to examine several patients in the HUH series more closely. Patient No. 7 was a black girl presenting at age 9 with hirsutism, Cushingoid fea- tures, clitoral enlargement, and a male escutcheon. Biochemical analysis revealed elevated urinary 17-ke- tosteroids and elevated serum cortisol and testosterone levels. An adrenal cortical tumor was suspected. At exploratory surgery in 1976, a tumor of the left adrenal gland was found that grossly involved the left renal vessels and periadrenal fat. Microscopically, the tumor was a poorly differentiated carcinoma with vascular invasion. Postoperatively, she was treated to the left renal fossa tumor bed, receiving 42 Gy in 38 days with a major interruption of therapy due to exploratory sur- gery to rule out hepatic abscess. Treatment was ter- minated prior to the planned minimum tumor dose of 50 Gy. She was begun on o,p’-DDD, but did not tolerate the drug and it was discontinued. She remained well for 2 years until she developed biopsy-proven lo- cally recurrent disease. She was again begun on o,p’-
| Pt. # | Outcome | Survival (mo) | RFS (mo) | Adj XRT | Adj Chemo | Other RX |
|---|---|---|---|---|---|---|
| Philadelphia General Hospital (1962-1975) | ||||||
| 1 | D | 1 | 0 | N | N | N |
| 2 | D | 1 | 0 | N | N | N |
| 3 | D | 0.5 | 0 | N | N | N |
| 4 | D | 0.5 | 0 | N | N | N |
| 5 | D | 6 | 0 | N | N | X (P) |
| Hahnemann University Hospital (1962-1987) | ||||||
| 6 | LFU | 24+ | 24 (?) | N? | N? | N? |
| 7 | D | 35 | 24 (L) | Y (1) | DDD | N |
| 8 | D | 88 | 20 (D) | Y | N | C, X, C |
| 9 | AWD | 205+ | 174 (D) | Y | N | C, X (P) |
| 10 | D | 24 | 18 (L + D) | Y | DDD | X (P) |
| 11 | D | 1.5 | 0 | N | N | X (P) |
| 12 | A (NED) | 75+ | 31 (L) | N | N | C, X (Def) |
| 13 | D | 4 | 0 | N | N | X (P) |
Adj = adjuvant; LFU = lost to follow-up; AWD = alive, with disease; D = dead from disease; A (NED) = alive, no evidence of disease; (L) = locally recurrent; (D) = distant recurrence (extra-abdominal); (1) = adjuvant radiation therapy inadequate and less than prescribed dose; DDD = o,p’-DDD; C = chemotherapy (usually o,p’-DDD) not used adjuvantly to surgery; X = x-ray therapy; (P) = administered for palliation of symptoms; (Def) = administered definitively after surgery for recurrent disease.
DDD, but failed to respond and developed a left upper lobe lung lesion. She then was treated by cis-platinum for 7 months, but slowly deteriorated and succumbed 34 months after diagnosis with diffuse abdominal and pelvic disease and pulmonary metastases.
Patients Nos. 8 and 9 are similar in that they both received postoperative, adjuvant radiation therapy for known residual disease at the primary site. Both pre- sented with nonfunctional Stage III disease and both were treated to 60 Gy over 7 weeks. Patient No. 9 had a well-differentiated carcinoma of the left adrenal gland. This patient underwent a planned “second-look” pro- cedure and an unscheduled “third-look” several years later as a consequence of celiotomy for peptic ulcer disease. Random biopsies within the treated volume failed to reveal demonstrable disease. This patient re- mained well, on no further treatment, for 14.33 years and then developed biopsy-proven bony metastatic rib disease with an associated extrapleural mass for which he was effectively palliated by radiation therapy for bony pain, receiving 45 Gy at 1.5 Gy daily in 30 frac- tions.
He was begun on o,p’-DDD at documentation of metastases at 6 g/day for 1 month, but could not tol- erate the dose longer. He resumed the agent after a 1- month break at 1 g/day with escalation over 2 weeks to 5 g/day. Again, he could not tolerate that dose level and was reduced to 3 g/day along with 7.5 mg of pred- nisone and 0.1 mg flourinef daily and 100 mg testos- terone weekly. He remained at this dose of o,p’-DDD for 11 months, until new bony lesions were docu- mented and then was escalated to 6 g/day. Multiple new bone lesions were shown on bone scan, and biopsy of one of them was positive for adrenal cortical car- cinoma. He was again effectively palliated for bony pain by photon beam radiation therapy and remains alive at present, but with disease, at 205+ months after diagnosis.
Patient No. 8 remained disease-free for 1 year fol- lowing radiation therapy of 60 Gy to the tumor bed at 2 Gy daily fractionation, but then developed pulmo- nary metastases. He was begun on o,p’-DDD with re- sponse for 18 months, but then progressed in the lung. He was irradiated to the right hilum and mediastinum, receiving 49.5 Gy to midplane in 6} weeks at 1.5 Gy daily fractionation. He was continued on o,p’-DDD. His pulmonary disease stabilized for another 18 months, but then began to progress in other lung sites and he was started on a chemotherapeutic regimen consisting of 5-fluorouracil, streptozotocin, cytoxan, halotestin, and cortisone. The pulmonary lesions re- sponded and regressed. However, two years later, this patient presented with a right pleural effusion. Cytology was Class V. Thoracentesis with 32P colloidal chromic
phosphate instillation afforded temporary palliation. However, he ultimately developed progressing right lung disease and new left lung disease. He died in re- spiratory failure 88 months after diagnosis without any clinical or radiographic evidence of recurrence in the irradiated primary intra-abdominal site.
Patient No. 12 is of interest because she had docu- mented radiographic evidence of locally recurrent dis- ease 31 months after initial surgery, which was consid- ered to have left no residual disease. She was then sur- gically partially debulked for this recurrence with gross abdominal residual disease. She has subsequently been treated with o,p’-DDD and had wide field abdominal irradiation to 60 Gy in 8 weeks at 1.5 Gy daily frac- tionation.
Although beginning o,p’-DDD at 10 g/day, she could not tolerate this dose and was decreased to 8 g/day and ultimately to 2.5 g/day, then slowly escalated back to 6 g/day. She proved intolerant to this dose and, because of dehydration secondary to nausea and emesis, was temporarily removed from the agent after 12 months. She was restarted at 3 g/day after recovering from de- hydration, but was stopped again after 4 to 5 months due to small bowel obstruction. At surgery, only adhe- sions and a mass of granulation tissue were found. There was no sign of tumor on any specimen sent to pathology. Subsequent computed tomography (CT) scan of the abdomen and pelvis and bone scan have been stable. She remains alive, with no evidence of disease, at 44 months after debulking surgery and 42 months after completion of radiation therapy. She has been off any chemotherapy for 7 months.
DISCUSSION
Undoubtedly, surgery is the primary and definitive treatment of adrenal cortical carcinoma. The use of o,p’-DDD for recurrent or metastatic disease is widely reported (2,3,5,10-13) with responses ranging from 21 to 100%. A higher response rate is seen for decrease in steroid production by tumor than in actual tumor regression (2,5). Median duration of response, as mea- sured by tumor regression is 6 to 7 months (2,5) and response rates, in terms of tumor regression, varies from 10% (11) to 100% (14). The drug has major gastroin- testinal and neuromuscular toxicity (6) within the therapeutic dose range of 8 to 10 g/day. In a large series of 105 patients (15), 59 of 80 patients who un- derwent surgery for adrenal cortical carcinoma received Mitotane. Fourteen of these 59 patients were treated adjuvantly postoperatively and 13 of 59 received drug both pre and postoperatively. The remaining seven pa- tients only received drug preoperatively. Mitotane controlled hormone secretion in 72% of treated patients
and eight patients had a partial repression of disease. However, the drug therapy did not significantly im- prove survival (15).
The role for radiation therapy as an adjunct to sur- gery or for palliation of metastases from adrenal cortical carcinoma is not well-documented in the literature. Most reports are anecdotal or fail to describe the con- ditions of irradiation. Results of these reports are often conflicting. Several authors consider radiation therapy to be ineffectual for adrenal cortical carcinoma (2,14). Portmann (16) and Murphy (17), however, consider such therapy to have palliative value. Percarpio and Knowlton (7) have reported excellent palliation of os- seous metastases and pain with 30-40 Gy with an oc- casional patient exhibiting prolonged local control of unresectable lesions. Stewart et al. (18) administered 25 Gy whole abdominal irradiation to four children with adrenal cortical carcinoma and reported 3 of 4 surviving disease-free after 1 to 6 years of follow-up without the necessity of chemotherapy.
Magee et al. (8) report on 15 patients seen over 13 years ending in 1981. The age range was from 9 to 65 years and three of the patients were previously reported by Stewart et al. (18) 13 years previously. These results suggest that the important prognostic factors are age, tumor functional activity and ability to completely re- sect the tumor. They suggest that radiotherapy is not likely to control bulky residual disease. Two of the three long-term survivors developed second malignancies; these were the three long-term survivors reported by Stewart et al. (18).
Our experience, also reporting a small population, appears to indicate that postoperative irradiation of the tumor bed with wide margins to doses of 50-60 Gy can provide long-term local control over residual microscopic disease at the primary site. Lower doses failed to prevent local recurrence (patient No. 7). There is a suggestion, based on the small number of patients
in our series, that adjunctive irradiation of the tumor bed may prolong survival. Effective palliation of bone, brain, and nodal metastases can be obtained with sub- stantially lower doses, in the range of 30-45 Gy. ₡
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