Criteria for Re-Irradiation

Background: The treatment options for patients with progressive malignant tumors despite primary radiotherapy are often limited. In selected cases, re-irradiation can be offered. This article concerns the selection criteria and results of re-irradiation for certain types of cancer.

Methods: This review is based on pertinent publications retrieved by a selective search in PubMed, with particular attention to glioblastoma, head and neck tumors, and prostatic carcinoma.

Results: The published studies of re-irradiation are few in number and often of limited methodological quality. For glioblastoma, a randomized controlled trial (RCT) found that adding re-irradiation to treatment with bevacizumab yielded no significant improvement in either median progression-free survival or median overall survival (hazard ratio [HR] 0.73; p = 0.05 and HR 0.98; p = 0.46, respectively). Re-irradiation is a treatment option for locoregional recurrences of head and neck tumors after primary radiotherapy, but it carries a risk of serious side effects. For unresectable recurrences of nasopharyngeal carcinoma, an RCT has shown that hyperfractionated re-irradiation is more effective than normofractionated re-irradiation (overall survival: HR 0.54, p = 0.014). For locally recurrent prostatic carcinoma after radiotherapy, re-irradiation can yield good oncologic outcomes with an acceptable level of urogenital and gastrointestinal side effects (5-year recurrence-free survival: stereotactic body radiation therapy (SBRT), 58%; high dose rate (HDR) brachytherapy, 77%; versus salvage prostatectomy, 72%). RCTs on this topic are lacking.

Conclusion: Re-irradiation is a treatment option for selected cancer patients. As the available scientific evidence is limited, multidisciplinary collaboration and participatory decision-making are particularly important.

Radiotherapy is one of the cornerstones of cancer treatment alongside surgery and systemic therapy. It can be used either alone or in combination with other treatment approaches and plays a crucial role in the curative treatment as well as in the palliative care of cancer patients.

Today, thanks to continuous advances in cancer treatment, there are ever more long-term cancer survivors (1). However, this trend gives rise to new challenges. Following initial radiotherapy, patients may develop locoregional recurrence, metastasis, or a new primary tumor—sometimes in areas of the body that have already undergone radiotherapy. In some cases, new tumors can be treated with curative intent. These secondary treatment approaches are often more complex than the primary interventions, since patients are suffering the effects of previous treatments.

In this context, re-irradiation takes on greater significance (2, 3). Constant advances in radiation treatment planning as well as precise, image-guided radiotherapy make it possible to deliver more targeted and safer radiotherapy—even in regions that have already received high-dose irradiation in the past (4).

The implementation of re-irradiation presents physicians with clinical and technical challenges (5, 6). One of these hurdles is the frequent lack of randomized controlled clinical trials that would help define the role of re-irradiation for the various tumor entities and recurrence scenarios. Trials of this kind are important with regard to determining the criteria for re-irradiation. Important questions in this context include:

• What is the treatment goal: palliation, cure, or local ablation?
• When is re-irradiation the treatment of choice, when can it be considered, and when is it contraindicated?
• How should re-irradiation be ordered and performed?

In order to address these questions, we will focus below on three indications for re-irradiation:

• Head and neck tumors
• Glioblastoma
• Prostatic carcinoma.

Head and neck tumors and prostatic carcinoma were chosen since it is for these entities that the most extensive randomized evidence is available on which to base the definition of criteria for re-irradiation. For prostatic carcinoma, there is no randomized evidence on the efficacy of re-irradiation. The significance of re-irradiation here arises from its relatively frequent use in clinical practice, based on a recent international survey (2) as well as the promising results compared to surgical salvage modalities, based on a recent meta-analysis (7). We also summarize the criteria for re-irradiation in non-small-cell lung cancer (eTable 1) and breast cancer (eTable 2).

eTable 1

Criteria for the re-irradiation of non-small cell lung cancer based on consensus recommendations of the international expert survey conducted by Rulach et al. (e1)

eTable 2

Criteria for the re-irradiation of locally recurrent breast cancer based on the guideline of the German Society of Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) (e2)*

Methods

This review article is based on a selective literature search in PubMed. Prospective, and if available, randomized controlled clinical trials were included; otherwise, recent systematic reviews, meta-analyses, and expert recommendations were drawn upon. Selection criteria included originality, currentness, and relevance of the studies to the broad area of application of the results.

Definition of re-irradiation

To ensure standardized nomenclature, the European Organisation for Research and Treatment of Cancer (EORTC) and the European Society for Radiotherapy and Oncology (ESTRO) proposed a definition of re-irradiation and other forms of retreatment with radiotherapy (8) (Figure 1).

Figure 1

Definition of re-irradiation according to the ESTRO-EORTC consensus as well as of repeat organ irradiation and repeat irradiation with examples of schematic scenarios (8). The figure was created using BioRender.com

Re-irradiation

Re-irradiation type 1 refers to a new course of radiotherapy that overlaps with a previously irradiated volume, irrespective of whether the cumulative dose is expected to increase the risk of side effects. In re-irradiation type 2, there is no overlap with previously irradiated volumes, but an increased risk of side effects is expected due to the cumulative dose.

A distinction needs to be made between re-irradiation and the scenarios of retreatment with radiotherapy described below.

Repeat organ irradiation

This is the repeat irradiation of a previously irradiated organ, but without overlap of the irradiated volumes and without an increased risk of side effects from cumulative doses.

Repeat irradiation

This refers to a new course of radiotherapy of an organ that has not been previously irradiated, with no overlap of irradiated volumes, and no increased risk of side effects from cumulative doses.

The decision tree in Figure 2 can be used in clinical practice to determine whether a case constitutes re-irradiation or a different scenario of retreatment with radiotherapy.

Figure 2

Decision tree for the definition of re-irradiation and differentiation of other scenarios of retreatment with radiotherapy (adapted from [8]).

Re-irradiation of glioblastoma

Glioblastomas, the most aggressive and most frequent type of primary brain tumor, originate from the supporting glial cells in the central nervous system (9). They are characterized by rapid, infiltrative growth and a high rate of recurrence. First-line treatment of glioblastoma is generally intensive multimodal therapy. This usually comprises surgical resection followed by radiotherapy and temozolomide-based chemotherapy (10).

Glioblastoma progression usually occurs near the site of the original tumor. Safe and effective treatment options for these recurrences are limited (11). One can consider either chemotherapy with lomustine (CCNU) or re-exposure to temozolomide. Neurosurgical intervention can be contemplated if the progressive tumor is completely resectable and the patient’s clinical and neurocognitive status is sufficiently stable. In the event that systemic and surgical options have been exhausted and no clinical trials are available, re-irradiation can be considered in an interdisciplinary approach. However, since the surrounding brain tissue has already been exposed to the primary radiotherapy, the risk of developing side effects such as radiation necrosis is higher.

Evidence

On the whole, there is no standardized approach to treating glioblastoma progression, since the therapeutic strategy depends on various factors, such as clinical symptoms, patterns of progression on imaging, or the time interval since first-line therapy. Few studies are devoted to re-irradiation as a potential treatment option. The available randomized controlled studies on re-irradiation of glioblastoma are summarized in Table 1 and eTable 3.

Table 1

Selected randomized controlled clinical studies on re-irradiation of gliomas*

eTable 3

Randomized clinical studies on re-irradiation of gliomas

Of particular note here is the recent randomized controlled, multicenter phase-II trial by Tsien et al., which investigated the use of bevacizumab alone or in combination with re-irradiation (12). Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor (VEGF), is an angiogenesis inhibitor that improves radiological findings in a relevant proportion of recurrent glioblastoma patients (13). The improvements visible only on imaging are mainly attributable to the fact that the blood–retinal barrier is stabilized, which can reduce the tumor-related brain edema and make the contrast-enhancing area smaller. The trial conducted by Tsien et al. included a heterogeneous group of patients with high-grade gliomas confirmed on histopathology and suspected on imaging; isocitrate dehydrogenase (IDH) and promoter methylation (MGMT) status were not known. A Karnofsky index of at least 60% was required, and progression needed to be limited (maximum, 6 cm).

The re-irradiated patients had comparable median, progression-free, and overall survival compared to the group receiving bevacizumab alone. Only progression-free survival at 6 months improved significantly in the re-irradiation arm (54.5 versus 29.1%; p = 0.001). Unfortunately, the trial did not investigate whether there were differences in quality of life and neurocognitive function. Nevertheless, it yielded relevant information on prognostic factors that could be helpful in possible patient selection and discussion on the tumor board. Patients with previous surgery, a better Karnofsky index, longer interval to progression, and fewer previous treatments showed better survival.

A systematic review and meta-analysis by Kazmi et al. investigated the side effects and efficacy of re-irradiation for recurrent glioblastoma (14). The literature included here was heterogeneous and of moderate quality on the whole. The results suggest overall tolerable side effects. However, evidence of clinical efficacy while maintaining quality of life and neurocognitive function is still lacking.

Re-irradiation of head and neck tumors

Head and neck tumors include malignant neoplasms in the region of the oral cavity, pharynx, larynx, and adjacent structures. Incidence varies depending on the specific localization and sex, with risk factors such as tobacco use, alcohol consumption, and infection with certain types of papillomavirus virus (HPV) playing a role. The treatment of head and neck tumors often requires a multidisciplinary approach consisting of surgical resection, radiotherapy, and chemotherapy (15).

Head and neck tumors tend to recur locally or in the regional lymph nodes (16). Patients also have a relevant risk of developing second malignancies (10% within 3 years following radiotherapy, 15% within 5 years, and 23% within 8 years) (17). Locally recurrent and secondary carcinomas in previously irradiated regions are challenging to treat due to the radiation damage that has already taken place. Salvage treatment options include surgical intervention, re-irradiation, chemotherapy, targeted systemic therapy, and immunotherapy. When planning treatment, one must take into consideration the resectability of the recurrence, the side effects of previous treatments, and the patient’s general condition.

Evidence

The definitive and postoperative re-irradiation of head and neck tumors—alone or in combination with chemotherapy—as well as various fractionation regimens have been investigated in randomized controlled trials and can be offered in clinical practice (Table 2, eTable 4).

Table 2

Selected randomized controlled clinical studies on re-irradiation of head and neck tumors* *

eTable 4

Randomized clinical studies on re-irradiation for head and neck tumors

A phase-III trial (GORTEC 98–03) compared methotrexate alone with a combination of re-irradiation and methotrexate in recurrent head and neck cancer and showed no difference in overall survival between the two groups (18). Another phase-III trial investigated postoperative re-irradiation and simultaneous chemotherapy following surgical resection in 130 patients with recurrent head and neck carcinoma (19). Postoperative chemoradiotherapy significantly improved local tumor control (p < 0.0001) without affecting overall survival (p = 0.50). However, toxicity in the chemoradiotherapy group was significantly higher (39% versus 10.5%).

Despite its low incidence in German-speaking countries, the findings on recurrent nasopharyngeal carcinoma are worthy of mention. Two Chinese multicenter randomized controlled trials have yielded important insights in this regard. Liu et al. compared high-dose, normofractionated re-irradiation using intensity-modulated radiotherapy (IMRT) with endoscopic nasopharyngectomy (ENPG) in resectable, locally recurrent nasopharyngeal carcinoma (20). It was shown that overall survival following ENPG was significantly better, which can be attributed to the lower treatment-related side effects (5% compared to 20% fatal radiation-related side effects). These results highlight that in patients with resectable recurrent nasopharyngeal carcinoma, surgery should be preferred over re-radiation.

For patients with non-resectable recurrent nasopharyngeal carcinoma following primary definitive radiotherapy, high-dose re-irradiation is a treatment option. However, the type of delivery is crucial here in order to ensure the best possible tolerability. The randomized controlled trial conducted by You et al. investigated normofractionated and hyperfractionated re-irradiation, both delivered using IMRT, in cases of non-resectable recurrence (21). With hyperfractionation, the total dose is distributed over a higher number of sessions at smaller individual doses, thereby taking advantage of the different repair capacities of tumors and normal tissue and reducing potential late side effects. Indeed, this study showed better overall survival and a significant reduction in fatal side effects in the hyperfractionation group.

Both studies excluded patients that had experienced recurrence within less than 12 months of primary radiotherapy. In these patients, one must assume tumor radioresistance. Persistent higher-grade side effects were also an exclusion criterion in both studies. Persistent side effects of this kind could point to a patient’s intrinsically increased radiosensitivity (for which, unfortunately, there are no established markers available in clinical practice). In addition, the patient’s prognosis should generally be taken into consideration in the decision-making process. Accordingly, patients with distant metastasis were excluded from the studies.

Re-irradiation of prostatic carcinoma

Various therapeutic options are available for the primary treatment of prostatic carcinoma, including radiotherapy, radical prostatectomy, and hormone therapy (22). Despite advances in primary therapy, recurrences can still occur. These often develop in the surrounding lymph nodes, but may also be local to the prostate (between 4 and 15%, depending on the risk group) (23).

In the case of local recurrence in the irradiated volume following primary radiotherapy, a number of salvage treatment options are available. Salvage prostatectomy by an experienced operator can be offered in line with the recommendations in the S3 guideline following biopsy-based confirmation and assuming metastatic spread has been ruled out (24). However, the functional results in terms of potency and continence are significantly worse compared to those with primary surgery. Other treatments can also be considered, such as re-irradiation using stereotactic body radiation therapy (SBRT) or brachytherapy (low-dose rate [LDR] or high-dose rate [HDR]), high-intensity focused ultrasound (HIFU), cryotherapy, continuous or intermittent androgen deprivation therapy (ADT), or combinations of these approaches.

Evidence

For locally recurrent prostatic carcinoma, randomized controlled studies comparing the various salvage treatment options are lacking. However, the available prospective and retrospective studies show that re-irradiation can deliver good oncological results with acceptable side effects.

The recent systematic review and meta-analysis conducted by Valle et al. focused on comparing the efficacy and side effects of the various salvage treatment options for locally recurrent prostate cancer following definitive radiotherapy (7). Interestingly, there were no significant differences in recurrence-free survival at 5 years between the various re-irradiation modalities (SBRT, brachytherapy) and salvage prostatectomy (SBRT: 58% and HDR brachytherapy: 77% versus prostatectomy: 72%). Severe genitourinary side effects were significantly lower across all forms of re-irradiation compared to salvage prostatectomy (SBRT: 5.6% and HDR brachytherapy: 9.6% versus prostatectomy: 21%). Likewise, severe gastrointestinal side effects were significantly lower with re-irradiation using HDR brachytherapy compared to salvage prostatectomy (SBRT: 0.0% and HDR brachytherapy: 0.0% versus prostatectomy: 1.5%).

Since the publication of Valle et al.’s study, further single-arm prospective studies have confirmed the efficacy and acceptable side effects profile of re-irradiation using SBRT or HDR brachytherapy for prostatic carcinoma (Table 3, eTable 5).

Table 3

Selected prospective non-randomized clinical studies on re-irradiation for prostatic carcinoma*

eTable 5

Selected prospective non-randomized clinical studies on re-irradiation for prostatic carcinoma

All the studies exclude patients with severe persistent radiation-induced side effects. Some studies require a recent rectoscopy to rule out higher-grade rectal teleangiectasias consistent with a marked reaction to radiation (25), whereas other studies require recto- and cystoscopy only if severe radiation-induced cystitis or proctitis are suspected. There is no consensus between studies with regard to the need for histological confirmation of recurrence prior to re-irradiation: Whereas the study by Pasquier et al. (25) made histological confirmation of recurrence mandatory, the studies by Cuccia et al. (26), Ryg et al. (27), Lewin et al. (28), and Michalet et al. (29) dispensed with biopsies if there was correspondingly clear suspicion based on multimodal imaging (choline or PSMA PET [PSMA, prostate-specific membrane antigen; PET, positron emission tomography], magnetic resonance imaging [MRI]). All studies described here excluded patients with lymph node and distant metastasis, with the exception of Lewin et al. (28), who permitted patients with a limited number of metastases (referred to as oligometastasis).♥

In addition, a number of international expert groups have issued consensus-based recommendations on patient selection for re-irradiation using brachytherapy and SBRT. The recommendation published by Jereczek-Fossa et al. (30) focusing on SBRT advocates an assessment of metastasis using PET, but metastatic disease is not specifically deemed to be an exclusion criterion. There was also no consensus on the minimum interval, although some experts recommended 2 years. The combination of ADT and re-irradiation is advised against here. In contrast, the expert consensus published by Corkum et al. (31) on brachytherapy permits its combination with ADT. The experts also recommend a minimum interval of 2–3 years from primary radiotherapy as well as a PSA level (PSA, prostate-specific antigen) of below 20 ng/mL at re-irradiation.

Summary

Re-irradiation can represent a treatment option for recurrences following previous radiotherapy, as illustrated using the examples of glioblastoma, head and neck tumors, and prostatic carcinoma. The decision regarding re-irradiation should always be made on a case-by-case basis. The following aspects need to be considered here:

• Alternative treatment options
• Disease spread (particularly distant metastasis)
• The reaction to primary radiotherapy with regard to:
• Efficacy (response, duration of disease control)
• Radiation-induced side effects (type, intensity, persistence).

Multidisciplinary collaboration and participatory decision-making with patients are particularly important. Studies of high methodological quality are needed in order to define the role of re-irradiation.

Conflict of interest statement
NA received study support from ViewRay Inc.

NA and JW are study coordinators of the prospective observational study ReCare on the topic of high-dose re-irradiation.

JEG is President of the German Society for Urology (Deutsche Gesellschaft für Urologie).

GT has received consultancy fees from Bayer, Boehringer Ingelheim, CureVac, Miltenyi Biomedicine, and Novocure. He is a member of the steering committee for non-interventional studies at Bayer and Novocure. He has received lecture fees from Novocure and Servier.

MN has received lecture fees as well as reimbursement of travel expenses and congress fees from Brainlab, AstraZeneca, and Elekta.

JPK declares that no conflict of interest exists.

Manuscript submitted on 3 March 2024, revised version accepted on 18 July 2024.

Translated from the original German by Christine Rye.

Corresponding author
Prof. Dr. med. Dipl.-Phys. Maximilian Niyazi
Universitätsklinik für Radioonkologie, Universitätsklinikum Tübingen
Hoppe-Seyler-Straße 3
72076 Tübingen, Germany

Cite this as:
Willmann J, Andratschke N, Klußmann JP, Gschwend JE, Tabatabai G, Niyazi M: Criteria for re-irradiation. Dtsch Arztebl Int 2024; 121: 725–32. DOI: 10.3238/arztebl.m2024.0156

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