Keywords

18.1 Role of Radiotherapy in Adrenocortical Carcinoma

18.1.1 Radiobiology of Adrenocortical Carcinoma

Classically, adrenocortical carcinoma (ACC) was considered a radioresistant disease. This assumption was based on results from very small series in which radiotherapy (RT) was used for palliation. More recent studies report improved tumor control being achieved by delivering higher doses using more accurate techniques. Such data suggest that ACC could be sensitive to higher doses and high doses per fraction. Thus, RT may have a role beyond palliation in adjuvant, advanced and recurrent disease. This chapter discusses the current role of RT in the management of ACC. A focus on the technique will help clinicians to familiarize with the lexicon of the radiation oncologist.

18.1.2 Adjuvant Radiotherapy

18.1.2.1 Aim of Radiotherapy

RT after curative-intent surgery uses high-energy ionizing radiation delivered to the tumor bed to prevent disease relapse by killing microscopically persistent cancer cells. The aim of adjuvant RT in ACC is therefore to reduce the risk of local relapse. Data on efficacy are mainly based on retrospective reports that show a benefit in local control for high-risk patients [1,2,3].

18.1.2.2 Patient Selection

RT is indicated for patients with high-risk features such as:

  • non-curative R2 resection, at any stage of disease;

  • margin positive R1/Rx resection, at any stage of disease;

  • intraoperative violation of tumor capsule, tumor spillage or necrotic tumoral fluid dissemination, at any stage of disease;

  • stage ≥III;

  • R0 resection of tumors with adverse features such as: diameter >8 cm, lympho-vascular invasion, Ki67 >10% and high-grade tumor with >20 mitotic figures per 50 HPF.

18.1.2.3 Efficacy and Timing

RT effectiveness in preventing local relapse is supported by small retrospective series with inhomogeneous results, reporting relapse rates ranging from 5% to 31.3%. RT is recommended to start no later than 12 weeks after surgery.

18.1.2.4 Acute and Late Toxicity

Expected adverse events depend on the laterality of the target, extension of the radiation volume to the para-aortic nodes, the RT technique and schedule. Concerning acute toxicity, G1–2 nausea, anorexia, abdominal pain and dyspepsia are frequent, with symptoms resolving a few days after the end of treatment owing to the close relationship with the stomach and duodenum. G1–2 fatigue is frequent and resolves after treatment. Late toxicity is rare, but G1–2 impaired kidney function with increased serum creatinine has been described. Radiation-induced liver disease and biliary tract disease have also been reported. Thanks to radiobiologic and technical advances, modern RT minimizes exposure of healthy tissues, making hepatic and biliary toxicities anecdotal [4].

18.1.2.5 Radiotherapy Technique, Dose and Volumes

The major body of evidence supporting the role of RT in the adjuvant scenario refers to 3D conformal RT (3DcRT) with X-ray photons. Briefly, 3DcRT delivers the dose to the target using multileaf collimators and multiportal fields which guarantee better dose conformity than older 2D techniques, potentially reducing the dose to healthy tissues close to the target. Nevertheless, contemporary RT uses intensity-modulated RT (IMRT) in its various declinations, such as: step-and-shoot IMRT, dynamic IMRT, helical IMRT, and volumetric-modulated arc therapy (V-MAT) (Fig. 18.1). Of note, stereotactic RT (SRT-SBRT) is a treatment modality were IMRT in its various declinations is used to precisely deliver a high radiation dose to a relatively small target, allowing high conformity to the target and steep dose fall-off outside, therefore maximizing efficacy to the target and minimizing the dose to critical organs at risk.

Fig. 18.1
Two C T scans depict a 3-dimensional view of the adrenal cortex, highlighting the outer region of adrenal gland cancer and the tumor's spread to adjacent tissues surrounding the adrenal cortex.

Comparison between 3D conformal radiotherapy (3DcRT, left) and volumetric-modulated arc therapy (V-MAT, right) for the same dose prescription: 45 Gy in 6 fractions for an unresectable adrenocortical carcinoma. The solid blue area encompassed by the thin red line is the adrenal target volume, accounting for set-up errors (planning target volume, PTV); the thin sky blue line is the gross tumor volume, accounting for its motion during breathing (internal target volume, ITV); the yellow bold line represents 32 Gy isodose in 6 fractions, a dose potentially related to stomach damage; the orange bold line is the isodose prescription of 45 Gy in 6 fractions (a potentially therapeutic dose); the red bold line is 50 Gy isodose in 6 fractions. Note the higher conformity of the 32 and 45 Gy isodoses in the V-MAT plan (orange and yellow bold lines), the superior sparing of the stomach and the presence of 50 Gy isodose in the V-MAT plan that is absent in the 3DcRT plan. Therefore, careful V-MAT planning increases the doses to the target while minimizing doses to the stomach and other organs at risk

Full size image

Modern techniques are important but not sufficient for performing high quality therapy on adrenal targets. In fact, respiratory motion management through tumor gating, tumor tracking, or breath holding is essential to maximize treatment accuracy. These techniques have a critical role in further reducing the exposure of critical organs at risk; as a consequence, the toxicity profile of published series might be even better with the use of IMRT in its various declinations (including the SRT technique) without compromising the dose to the target.

18.1.2.6 Concurrent Systemic Therapy to Radiotherapy

There are limited data to guide decisions concerning the administration of mitotane concurrently to RT. Concurrent therapy is feasible without exceeding a mitotane dose of 3 g/day. An increase in abdominal RT-induced toxicity is expected when mitotane is administered during RT. Careful weekly monitoring of liver and kidney function is warranted, especially in right-sided irradiation.

18.1.3 Definitive Radiotherapy for Unresectable Disease or Local Recurrence

Use of RT to manage unresectable local disease is limited to very small single-center series. The literature up to 2022 reports on patients with an unresectable adrenal mass or local relapse in the tumor bed receiving RT with doses ranging between 39.2–73.5 Gy in 22–40-day schedules. The treatment techniques used 2D and 3DcRT. Despite these limitations, the responses achieved were encouraging and deserve some biological and technical considerations. From the biological point of view, ACC in the metastatic and palliative setting demonstrates a higher-than-expected radiosensitivity. From the technical point of view, contemporary techniques achieve a dose reduction to critical organs at risk while potentially increasing dose conformity to the target. Interestingly, several reports have described the feasibility, safety and effectiveness of high dose treatments of large adrenal masses using cutting-edge RT techniques, such as IMRT and proton therapy. A very large multi-institutional series published in 2023 confirmed those results: 132 target lesions in 80 patients were treated with modern techniques between 2010 and 2020. In 22 cases the target was a local recurrence and in 110 a metastasis. The RT schedules included normally fractionated RT (i.e., 2 Gy per fraction) with total doses ranging from 20 to 60 Gy and SRT. Considering the 22 patients treated for local recurrence, a complete response was observed in 13.6% of cases, a partial response in 36.4%, stable disease in 40.9%, while local progression occurred in 9.1% of cases. Median time to progression was 9.8 months. Such promising results form the backbone for a possible future role of RT in the multimodal management of unresectable/recurrent ACC [4].

18.1.4 Radiotherapy for Metastatic Disease and Palliation

RT is an option for the palliation of symptoms from locally advanced or distant metastatic disease, including metastatic bone pain.

The available literature supports the moderate benefit of palliative RT for symptom relief. In an old series of patients treated with moderate-low doses, a benefit in reduction of pain and other symptoms was achieved in 57% of patients, while more recent series describe better results with the use of higher doses, also in the palliative context [5, 6]. Such results support the hypothesis of the relative radiosensitivity of ACC to hypofractionated regimens and underline the importance of using contemporary techniques.

18.2 Role of Radiotherapy in Pheochromocytoma

18.2.1 Radiobiology of Pheochromocytoma

Pheochromocytoma (PHEO) was also considered a radioresistant disease. Despite the paucity and heterogeneity of published data, which also include paragangliomas in the analysis, it is now clear that a dose response to RT does exist and that doses >40 Gy (physical dose) seem associated with better local disease control in the context of metastatic disease [5].

Nevertheless, there are several other important issues that hampered the use of RT in this context. First, the early reports that identified a dose-response relationship also showed high toxicity to organs at risk. Such an observation is mainly explained by the attempt to reach dose escalation with outdated techniques (such as 2D techniques). Another important point is the unique biologic nature of PHEO. The production of catecholamines/metanephrines has raised concerns about the safety of RT, owing to the risk of a hypertensive crisis consequent to amine release after tumor cell death. Importantly, a possible exacerbation of hypertensive crisis few hours after the fifth day of palliative RT (20 Gy in 5 fractions) was described in only one case report. To date, no other hypertensive crisis triggered by tissue irradiation have been reported. On the other hand, no study has been designed to consistently test catecholamine/metanephrine changes before and after RT. Despite encouraging outcomes in modern series and the lack of G3 or worse side effects, this topic is still an open issue, and we suggest testing metanephrines and chromogranin-A before and shortly after RT.

Finally, as reported for other diseases, interpreting response to RT is challenging. PHEOs are characterized by slow response to RT and anatomical imaging may usually show residual masses also in the event of successfully treated lesions. An explanation for this behavior can be found in the heterogeneous tumor microenvironment, where tumor cells in active replication represent a minority of the tumor bulk. Magnetic resonance imaging, functional imaging together with biochemical response are useful in the differential diagnosis between disease persistence and tumor response [6].

18.2.2 Radiotherapy for Metastatic Disease and Palliation

In the past, the use of high-dose RT was associated with significant morbidity, which limited its utilization in malignant PHEO. More recently, reports of cases in which contemporary techniques (e.g., IMRT and SRT/SBRT) were employed described high dose delivery without significant toxicity to normal tissue resulting in a high rate of symptomatic and radiographic local disease control. However, most of these reports are biased by the limited number of patients and their selection. In fact, the available series analyzed together both PHEO and paraganglioma with different sites of metastatic spread, and delivered RT concurrently to radiometabolic therapy. As a consequence, there is wide heterogeneity in RT series for metastatic PHEO that limits the interpretation and applicability of results. Nevertheless, Vogel et al. treated 24 patients (13 with metastatic PHEO) on 36 metastatic sites (bone, pelvis, brain, upper abdomen) and found an overall symptomatic improvement in 81.1% of patients after RT regardless of site or radiation technique. Overall local control was equal to 86.7% in patients treated with mean doses of 31.8 Gy in 3.3-Gy fractions by 3DcRT and 21.9 Gy in 10.4-Gy fractions by SBRT/SRT. One case of G3 acute neuropathy emerged. No other acute or late ≥G3 toxicity was recorded [5]. Breen et al. in 2017 reported the outcomes of 41 patients (15 treated for PHEO on 37 lesions), confirming the fairly good results in terms of local control (81% at 5 years) and a dose-response relationship favoring patients treated with higher doses. Two patients developed grade ≥3 late adverse events thought to be related to RT (one case of iatrogenic menopause and one of sciatic neuropathy). Interestingly, seven patients were offered comprehensive treatment on all metastatic sites; a biochemical response was appreciated in all of the five patients who underwent blood/urine catecholamine/metanephrine assays before and after radiation [6].

Taken together, the limited available literature shows that RT is an effective treatment modality to control metastatic foci of PHEO, with most patients experiencing radiographic local tumor control and/or improvement of tumor-related symptoms. RT is also well tolerated, with few severe treatment-related adverse events and without hypertensive crises in modern series. Higher doses may guarantee improved local tumor control in selected patients.

18.2.3 Adjuvant Radiotherapy and Definitive Radiotherapy (Unresectable Disease)

There are no data concerning the use of RT as adjuvant treatment after resection or in the context of unresectable disease. Therefore, the authors of this chapter consider such an approach investigational and suggest that RT may be employed only within a clinical trial.