Re-re-irradiation for palliation: knowns, unknowns, and next steps

Introduction

Due to improvements in cancer care, life expectancy has increased which has led to paradigm shifts in the feasibility and willingness to deliver re-irradiation. Both animal and retrospective human data exist which have eased concerns regarding the tolerability of second course irradiation to many critical organs at risk (OARs) such as the spinal cord, brain, lung, etc. (1-4). Using these data, many radiation oncologists are now cautiously inclined to offer re-irradiation using evidence-based OARs dose constraints, usually separated by six months or more from prior radiation to the site (5).

However, there remains a gap in evidence regarding the feasibility and tolerability of re-re-irradiation (i.e., third course irradiation); thus, the safety and efficacy of third course irradiation remains largely anecdotal. As patients continue to live longer, the need for third course irradiation for metastatic disease or primary site—as well as increased peer-reviewed literature on this topic—is imperative to continue to deliver high-quality palliative care. Currently, modern data on third course, extra-cranial irradiation are limited to a few small, retrospective studies with palliative intent (6,7).

Available modern data

Literature review revealed four modern peer-reviewed studies investigating palliative, extra-cranial third course irradiation with external beam radiation (Table 1) (8-11). These studies were retrospective, had small sample sizes (n=10–25 patients), and limited follow-up (7–12 months), often due to limited survival. The primary disease sites, treatment sites, re-re-irradiation dose and fractionation schemes, cumulative dose, and time intervals between treatments were either heterogenous among these studies or not reported.

Three of these studies reported the efficacy of third course palliative radiotherapy with pain reduction occurring in 71–80% (8,9,11). This is comparable to the rates of pain reduction following first course radiation. All studies reported acute and long-term toxicity. Rates of acute grade 3 toxicity were low and occurred within two of the four studies: Abusaris et al. reported grade 3 dysuria (7%) and pain (4%); Katsoulakis et al. reported grade 3 fatigue (10%) and dermatitis (10%). Late toxicity grade 3 toxicity was more uncommon and occurred in only one patient: Abusaris et al. reported this late grade 3 skin toxicity (4%). The next most severe toxicity was reported by Katsoulakis et al. where one patient (10%) experienced late grade 2 neuropathy after receiving an equivalent dose in 2 Gy fractions (EQD2) of 101.7 Gy to the L3 cauda equina. Caution must be taken when interpreting these results: While acute grade 3 toxicities occurred in only half of these studies and were limited to ≤10% of the cohorts, cumulative EQD2s and intervals between treatments were not consistently available or reported. Clearly, this confounds interpretation of these results. Additionally, with short median survivals (range, 1.8–13 months) after third course irradiation, one must consider whether more late toxicities would have occurred if more time was allowed.

In summary, few data exist regarding the safety and efficacy of third course, extra-cranial irradiation. These data are retrospective, small, have limited follow-up, and contain heterogenous or un-reported cumulative EQD2s and intervals between treatments. Therefore, caution should be used when interpreting these data. Given current data, re-re-irradiation appears to have rates of pain palliation comparable with first time irradiation (71–80% success), limited acute grade 3 toxicities (≤10% of patients), and even fewer late grade 3 toxicities (8-11).

General principals when considering third-course irradiation

With such limited data available, it is critical to remember the general principals of palliative radiotherapy (5). The first and most important rule is to do no harm: significant toxicity is not acceptable in the palliative setting. Attention must be paid to how the patient tolerated radiation initially and his/her initial responses should be assessed. Small volumes far from critical OARs are preferred. Patients should be assessed in a multi-disciplinary environment to ensure there are no other alternative methods of palliation such as optimization of long-acting and short-acting opioids, neuropathic agents, steroid pulses, and nerve blocks (12-14).

The prognosis of the patient and their goals should be evaluated prior to offering third course irradiation. The most feared radiation-induced toxicities such as cord myelopathy often occur late (Table 2) (15-18). If a patient has a limited predicted life expectancy—as demonstrated in the aforementioned trials with survival ranging from 1.8–13 months following extra-cranial re-re-irradiation—the risk of late toxicity such as cord myelopathy may not be as concerning (8-11).

Caution should be used when proceeding with re-re-irradiation: patient selection is paramount, and physicians should be candid with patients about expectations and unknowns. The decision to perform third course palliative radiation is ultimately highly individualized and should be a joint decision between the radiation oncologist, the patient, and his/her multidisciplinary team.

As there exist no data to drive cumulative doses or time intervals between treatments in the third course irradiation setting, the available data and guidelines for second course irradiation should be used (19,20). If proceeding with third course irradiation, consider more conformal techniques such as 3D or intensity modulated radiotherapy. Strict immobilization and daily image guidance should be used when applicable to avoid dose to OARs. In those with expected longer survivals, twice a day (BID) fractionation can be employed in efforts to limit late toxicity, and proton therapy may help achieve lower doses to OARs (21-23).

Lastly, we encourage the long-term follow-up of these patients so toxicities can be appropriately identified and addressed, clinicians can gain experience with this unique setting, and more data can be contributed to the field to help standardize recommendations. As patients with metastatic disease continue to live longer, there continues to be a need for more published data on third course irradiation to ensure safe and efficacious care is delivered to our patients. The biggest challenge remains that the ceiling for biologically equivalent dose (BED) tolerances remains unknown for OARs following varied intervals of radiation delivery which will require much more robust analyses. Until these values are better classified, the investigation of prophylactic use of radioprotectants and radiation necrosis modifying agents, such as vascular endothelial growth factor (VEGF) inhibitors, may provide interesting avenues of toxicity reduction in the setting of clinical trials.

Conclusions

While data for re-re-irradiation is scarce, available retrospective series have demonstrated that pain palliation from third course irradiation can be as effective as first course irradiation with response rates ranging from 71–80%. Re-re-irradiation appears well-tolerated in these studies with rates of acute and late toxicity being ≤10%. Notably, these trials had limited follow-up due to short survival, possibly resulting in lesser than expected rates of late toxicity. For this reason, it is important to consider estimated patient prognosis when weighing risks of third course irradiation. In the absence of robust data, we must rely on many principals of re-irradiation. Ultimately, decisions for third course irradiation should be highly individualized, based on patient goals, estimated prognosis, available alternative treatments, and honest communication regarding possible toxicities under the care of a multidisciplinary team.

Acknowledgments

The data of this article were presented in part during a joint session of the American Society for Radiation Oncology (ASTRO) and the Society for Palliative Radiation Oncology (SPRO) at the 65^th ASTRO Annual Meeting in San Diego, CA on Oct. 2^nd 2023.

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editors (Candice Johnstone and Michael Shing Fung Lee) for the series “Palliative Radiotherapy Column”, published in Annals of Palliative Medicine. The article has undergone external peer review.

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-24-18/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-24-18/coif). The series “Palliative Radiotherapy Column” was commissioned by the editorial office without any funding sponsorship. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ang KK, Jiang GL, Feng Y, et al. Extent and kinetics of recovery of occult spinal cord injury. Int J Radiat Oncol Biol Phys 2001;50:1013-20. [Crossref] [PubMed]
2. Doi H, Tamari K, Oh RJ, et al. New clinical data on human spinal cord re-irradiation tolerance. Strahlenther Onkol 2021;197:463-73. [Crossref] [PubMed]
3. Rulach R, Hanna GG, Franks K, et al. Re-irradiation for Locally Recurrent Lung Cancer: Evidence, Risks and Benefits. Clin Oncol (R Coll Radiol) 2018;30:101-9. [Crossref] [PubMed]
4. Schaub SK, Tseng YD, Chang EL, et al. Strategies to Mitigate Toxicities From Stereotactic Body Radiation Therapy for Spine Metastases. Neurosurgery 2019;85:729-40. [Crossref] [PubMed]
5. Dörr W, Gabryś D. The Principles and Practice of Re-irradiation in Clinical Oncology: An Overview. Clin Oncol (R Coll Radiol) 2018;30:67-72. [Crossref] [PubMed]
6. Nieder C. Second re-irradiation: A delicate balance between safety and efficacy. Phys Med 2019;58:155-8. [Crossref] [PubMed]
7. Nieder C, Langendijk JA, Guckenberger M, et al. Second re-irradiation: a narrative review of the available clinical data. Acta Oncol 2018;57:305-10. [Crossref] [PubMed]
8. Abusaris H, Storchi PR, Brandwijk RP, et al. Second re-irradiation: efficacy, dose and toxicity in patients who received three courses of radiotherapy with overlapping fields. Radiother Oncol 2011;99:235-9. [Crossref] [PubMed]
9. Jeremic B, Shibamoto Y, Igrutinovic I. Second single 4 Gy reirradiation for painful bone metastasis. J Pain Symptom Manage 2002;23:26-30. [Crossref] [PubMed]
10. Katsoulakis E, Riaz N, Cox B, et al. Delivering a third course of radiation to spine metastases using image-guided, intensity-modulated radiation therapy. J Neurosurg Spine 2013;18:63-8. [Crossref] [PubMed]
11. Thibault I, Campbell M, Tseng CL, et al. Salvage Stereotactic Body Radiotherapy (SBRT) Following In-Field Failure of Initial SBRT for Spinal Metastases. Int J Radiat Oncol Biol Phys 2015;93:353-60. [Crossref] [PubMed]
12. Anekar AA, Hendrix JM, Cascella M. WHO analgesic ladder. 2020. Available online: https://www.ncbi.nlm.nih.gov/books/NBK554435/
13. Habib MH, Schlögl M, Raza S, et al. Interventional pain management in cancer patients-a scoping review. Ann Palliat Med 2023;12:1198-214. [Crossref] [PubMed]
14. Kettyle G. Multidisciplinary Approach to Cancer Pain Management. Ulster Med J 2023;92:55-8. [PubMed]
15. Khan M, Ambady P, Kimbrough D, et al. Radiation-Induced Myelitis: Initial and Follow-Up MRI and Clinical Features in Patients at a Single Tertiary Care Institution during 20 Years. AJNR Am J Neuroradiol 2018;39:1576-81. [Crossref] [PubMed]
16. Munier S, Ginalis EE, Patel NV, et al. Radiation Necrosis in Intracranial Lesions. Cureus 2020;12:e7603. [PubMed]
17. Zelga P, Tchórzewski M, Zelga M, et al. Radiation-induced rectovaginal fistulas in locally advanced gynaecological malignancies-new patients, old problem? Langenbecks Arch Surg 2017;402:1079-88. [Crossref] [PubMed]
18. Voruganti IS, Donovan E, Walker-Dilks C, et al. Chest wall toxicity after stereotactic radiation in early lung cancer: a systematic review. Curr Oncol 2020;27:179-89. [Crossref] [PubMed]
19. Andratschke N, Willmann J, Appelt AL, et al. European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus on re-irradiation: definition, reporting, and clinical decision making. Lancet Oncol 2022;23:e469-78. [Crossref] [PubMed]
20. Armstrong S, Hoskin P. Complex Clinical Decision-Making Process of Re-Irradiation. Clin Oncol (R Coll Radiol) 2020;32:688-703. [Crossref] [PubMed]
21. Ahmed KA, Correa CR, Dilling TJ, et al. Altered fractionation schedules in radiation treatment: a review. Semin Oncol 2014;41:730-50. [Crossref] [PubMed]
22. Withers HR. Biologic basis for altered fractionation schemes. Cancer 1985;55:2086-95. [Crossref] [PubMed]
23. Lo Greco MC, Milazzotto R, Liardo RLE, et al. The Role of Reirradiation in Childhood Progressive Diffuse Intrinsic Pontine Glioma (DIPG): An Ongoing Challenge beyond Radiobiology. Brain Sci 2023;13:1449. [Crossref] [PubMed]