Half-body irradiation with dose escalation in the era of advanced systemic therapies: unveiling new therapeutic opportunities

Introduction

Bone is a frequent metastatic site for advanced solid tumors, particularly those originating from the prostate, breast, and lung [1]. The presence of bone metastases, particularly those extending to multiple skeletal sites, is typically associated with a poor prognosis [2]. However, recent advances in systemic therapies, along with refinements in local treatment techniques, have contributed to improved survival outcomes [3], [4], [5]. A critical factor influencing prognosis remains the extent of skeletal involvement, as widespread bone metastases markedly increase the risk of severe and life-threatening complications, including pathologic fractures, vertebral collapse, spinal cord compression, hypercalcemia, and debilitating pain [6].

Radiotherapy (RT) typically represents the cornerstone of local treatment for patients with skeletal metastases, aiming primarily at palliation of symptoms and prevention of fractures [7]. It may also be associated with surgery in more severe cases [8].

Despite its well-documented efficacy, RT is often underutilized in cases of extensive painful bone involvement due to concerns about potential side effects, particularly marrow toxicity, associated with irradiation of large anatomic regions [9]. Fitzpatrick et al. addressed this challenge by reporting excellent clinical outcomes with a radiation technique known as half-body irradiation (HBI) [10]. This approach utilized large RT fields to provide symptomatic relief and palliative care to patients with widespread bone metastases.

Initially, HBI was administered as a single high dose of RT. However, due to poor tolerance, often requiring hospitalization or at least premedication, the therapeutic approach was modified and a regimen of 15 Gy in 5 fractions became an attractive alternative [11]. HBI was categorized according to the anatomical region treated into upper (U-HBI), mid (M-HBI), and lower body (L-HBI) irradiation depending on the anatomical region irradiated. Among these, U-HBI was associated with a higher risk of treatment-related toxicity [12].

Despite its demonstrated efficacy in achieving excellent palliative responses, the use of HBI has remained limited, probably due to outdated perceptions arising from its application during the 2D radiotherapy era. At that time, sparing organs at risk (OARs) was not feasible. In contrast, modern techniques, such as intensity-modulated radiotherapy (IMRT), now allow for better dose-sparing of OARs, significantly improving the safety profile of HBI [13]. In this regard, a recent systematic review by Bilski et al. [14] reported grade 3 acute toxicities in only 2.5 % of patients (n=6/240). Notably, gastrointestinal toxicity was observed in only one case, while the remaining five patients experienced hematological toxicity. Beyond its favorable safety profile, the authors confirmed the efficacy of HBI, documenting pain reduction in 75.6–89 % of patients across the analyzed studies. Additionally, a reduction in drug intake was noted, with complete discontinuation in 29.8–46.1 % of patients and a partial reduction in 20.6–30.9 %.

In this study, we aim to evaluate the safety and efficacy of half-body irradiation in improving quality of life, reducing analgesic requirements, alleviating pain intensity, and, secondarily, achieving local disease control. Furthermore, we hypothesized that a higher biological effective dose (BED) could result in an increase in objective response rate (ORR) and analgesic response.

Methods

Data collection

Demographic and treatment-related data collected included the Eastern Cooperative Oncology Group (ECOG) performance status, pain levels, pre- and post-RT complete blood counts, quality of life (QoL) before and after RT, use of analgesics before and after RT, total radiation dose and fractionation, RT treatment site, RT technique, survival status (overall survival, OS), local control (LC), and progression-free survival (PFS) at the last follow-up.

The primary study outcomes include:

1. The pre- and post-RT assessment of pain level using the Numeric Rating Scale (NRS) [19].

2. The pre- and post-RT analgesic-intake.

3. Treatment-related toxicity according to the Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE-5) [20].

We also reported the ORR assessed per PET Response Criteria in Solid Tumors (PERCIST), LC, PFS, and OS.

1. LC was defined as the absence of any in-field recurrence.

2. PFS was defined as the absence of any progression, both in-field and out-of-field.

3. OS was calculated from the end of radiotherapy until death or the last follow-up.

Additionally, we investigated whether there is a correlation between ORR, pain level, analgesic intake, and radiotherapy dose.

Patients were followed with computed tomography (CT) and/or PET/CT, depending on the exam they underwent at the time of their first visit to our radiotherapy department.

Figures 1 and 2 show two treatment approaches (single dose level vs. two dose levels with SIB) in terms of dose distribution and dose to the OARs.

Figure 1:

Dose distribution of treatment with a single dose level. (A) Dose color wash in the axial section and (B) in the coronal section. The displayed dose represents 95 % of the prescribed dose (15 Gy in 5 fractions). (C) shows the DVH. On the x-axis, the dose in Gy is plotted, while the y-axis represents the percentage of volume receiving a specific dose. The prescription is shown in red, the small bowel in green, the bladder in yellow, and the rectum in brown. Note: DVH, dose-volume histogram.

Figure 2:

Dose distribution of treatment with two dose levels using SIB. (A) Dose color wash distribution in the axial section and (B) in the coronal section. The 95 % of the prescribed dose to the CTV (15 Gy in 5 fractions) is highlighted in blue. The areas identified by 18F-FDG PET/CT (BTV) are shown in red, which received a higher dose (27.5 Gy in 5 fractions). (C, D) Dose color wash distribution, in coronal and axial sections, respectively, of the 95 % of the prescribed dose to the BTV. (E) shows the DVH. On the x-axis, the dose in Gy is plotted, while the y-axis represents the percentage of volume receiving a specific dose. The prescribed doses are shown in red, the small bowel in green, the bladder in yellow, and the rectum in brown. Note: DVH, dose-volume histogram; BTV, biological tumor volume; CTV, clinical target volume.

Results

Pain relief and analgesic intake

The median pain score reported before RT was 8 (range: 5–10). Following RT, the median NRS score decreased to 3 at 1 month (range: 0–8) and 1 at 6 months (range: 0–8). Nearly all patients experienced immediate pain relief (i.e., pain relief during RT treatment), with 25 % achieving complete pain response at 1 month. Given that the treatment duration was ≤5 days for 95.65 % of patients, immediate pain relief occurred within this timeframe in 17 out of 23 patients.

In terms of analgesic use, 82.60 % of patients were using pain medication before RT, ranging from acetaminophen to opioids and morphine. Post-RT, 31.57 % of these patients continued their pre-RT analgesic regimen, 21.05 % reduced their dosage or transitioned to less potent analgesics, and 42.10 % discontinued pain medications.

Table 3 shows the pain response based on histology: better responses were achieved in patients with breast cancer, with almost half of them achieving complete pain relief. Two patients affected by urothelial cancer and lung cancer were classified as non-responders, as no benefit from HBI was observed.

Table 3:

Treatment response based on histology.

Histology	NRS pre-RT		NRS post-RT at 1 month		NRS post-RT at 6 months		Analgesic intake pre-RT (% of pts)	Analgesic intake post-RT (% of pts)
	NRS level	N° of pts	NRS level	N° of pts	NRS level	N° of pts
Breast cancer	NRS 5	2	NRS 0	5	NRS 0	4	72.72	9.09
	NRS 6	2	NRS 2	1	NRS 3	2	*NR in 1 pt	*NR in 2 pts
	NRS 7	4	NRS 3	3	NA	5
	NRS 9	2	NRS 4	2
	NRS 10	1
Prostate cancer	NRS 8	1	NRS 0	1	NRS 0	1	100	50
	NRS 9	1	NRS 5	1	NA	1
Lung cancer	NRS 8	3	NRS 2	1	NRS 2	1	66.6	66.6
			NRS 4	1	NA	2	*NR in 1 pt	*NR in 1 pt
			NRS 8	1
Liposarcoma	NRS 7	1	NRS 3	1	NRS 3	1	100	0
Head and neck	NRS 10	2	NRS 2	1	NA	2	100	100
			NRS 6	1
Urothelial carcinoma	NRS 8	1	NRS 8	1	NRS 8	1	100	100
Neuroendocrine	NRS 7	1	NRS 6	1	NRS 3	2	66.66	66.66
	NRS 8	1	NRS 8	2	NRS 4	1	*NR in 1 pt	*NR in 1 pt
	NRS 10	1
Merkel cell carcinoma	NRS 6	1	NRS 3	1	NA	1	100	100

1. NRS, numeric rating scale; NA, not available; NR, not reported; RT, radiation therapy; pt, patient; N°, number.

In addition, we investigated correlations between radiotherapy treatment and the reduction in analgesic use post-RT and/or pain reduction. Regarding analgesic reduction, no correlation was found, regardless of the dose used (p=0.128; Figure 3). As for pain reduction, although not statistically significant, we observed a trend favoring the use of doses greater than 15 Gy in 5 fractions (R=0.36, p=0.084; Figure 4).

Figure 3:

Total RT dose administered to patients stratified by pain treatment modification. Patients who discontinued antalgic therapy received a higher median RT dose, but the overall differences were not statistically significant.

Figure 4:

Scatterplot showing the reduction of pain in association with the administered RT dose. The data indicate a positive, but not statistically significant, trend between the dose and the magnitude of pain symptom reduction.

Adverse events

Despite the absence of systematic premedication, mild nausea, and diarrhea lasting a few days after HBI were the most commonly reported side effects. Three out of 23 patients required blood transfusions within one month after completing RT due to severe anemia, while two patients experienced a significant drop in platelet counts. All these patients were undergoing systemic therapy (two receiving immunotherapy, two on chemotherapy, and one treated with a CDK-i), which had to be delayed due to bone marrow toxicity. However, treatment was resumed in all cases once hematologic parameters had returned to normal, which occurred within 30 days of discontinuation. Ultimately, no additional toxicity was observed in patients treated with SIB (Figure 5).

Figure 5:

Graph illustrating the distribution of acute toxicities (G0, G1, G2, G3, G4) experienced by patients.

ORR, LC, PFS, and OS

The overall response rate to RT was evaluated for 15 treatments, as follow-up imaging was available only for these cases. Of these, six achieved a complete response, and three demonstrated a partial response according to PERCIST criteria. Furthermore, four patients had stable disease.

The actuarial rate of LC at 6 months was 86.67 %. Overall, two patients experienced local relapse or progression, none of whom had received radiotherapy with SIB.

Regarding PFS, the median was 6.5 months (range: 2–36 months).

We also investigated the correlation between PFS and LC with the radiation doses administered. No significant association was observed for PFS (Hazard Ratio, HR=0.93, p>0.05; Figure 6). The threshold dose that maximized differences in PFS curves when used as a stratification criterion was 24 Gy. Regarding LC, although the correlation was not statistically significant, higher doses appeared to be associated with better ORRs. Due to the limited number of local failure events (one after a single fraction of 8 Gy and another following 15 Gy delivered in five fractions, both without SIB), we did not pursue a threshold analysis correlating dose with LC.

Figure 6:

PFS of patients stratified according to total administered RT dose (threshold of 24 Gy used according to ROC analysis).

Similarly, no significant association was found for OS (HR=0.86, p>0.05; Figure 7). The threshold dose that maximized differences in OS curves, when used as a stratification criterion, was 8 Gy.

Figure 7:

OS of patients stratified according to total administered RT dose (threshold of 8 Gy used according to ROC analysis).

Due to the limited number of deaths (n=5) in the overall cohort, it was not possible to calculate the median survival time.

Discussion

In patients with diffuse bone metastases, therapeutic options remain limited due to poor prognosis and significant disease burden, often accompanied by uncontrolled pain. Traditionally, RT has been considered the cornerstone of treatment for bone metastases, serving both palliative purposes and the prevention of potential pathological fractures [25]. Various fractionation schedules have been employed, including 30 Gy in 10 fractions, 20 Gy in 5 fractions, and 8 Gy in a single fraction [8]. The single-fraction approach is typically reserved for patients with a life expectancy of less than 6 months, providing comparable outcomes in terms of pain relief [26].

Recently, attention has been directed toward an RT technique first introduced by Fitzpatrick et al. in the 1970s, known as half-body irradiation (HBI) [10]. This approach enables the simultaneous treatment of multiple skeletal segments, aiming to provide rapid pain relief. However, its application has historically been constrained by concerns regarding the potential side effects associated with large irradiation fields, particularly lung and bone marrow injuries [27]. These earlier cases predominantly utilized 2D or 3D-CRT techniques.

With advancements in RT, particularly the development of volumetric modulated arc therapy (VMAT), IMRT, and tomotherapy it is now possible to deliver highly conformal doses while minimizing exposure to OARs [28]. For example, Bilski et al. [14] reported in a recent systematic review, which included four studies that only 6 out of 240 patients exhibited grade 3 toxicity, predominantly hematological. Notably, with the implementation of advanced techniques, better adherence to dose constraints can be achieved, as demonstrated by Furlan et al. [29], who reported a mean V4Gy value for the intestine of 36 % and a mean intestinal dose of less than 3.8 Gy, resulting in reduced side effects. Consistently, in our study, VMAT or IMRT techniques were employed due to their superior ability to spare OARs. As a result, no grade ≥3 gastrointestinal or genitourinary toxicities were observed in our cohort. Regarding respiratory complications, three patients underwent M-HBI, and none reported acute or late pulmonary side effects.

Hematologic toxicity remains a notable concern, as the bone marrow is directly exposed alongside skeletal lesions. In our cohort, three patients developed severe anemia requiring blood transfusion, while two experienced significant thrombocytopenia. These toxicities are likely to be exacerbated by concurrent systemic therapies, which may further compromise marrow function. In this context, the administration of CDK-i with concurrent radiotherapy has not been shown to increase severe toxicity, particularly bone marrow-related toxicity. As reported by Kubeczko et al., only 1 % of patients experienced severe anemia, and 3 % developed severe thrombocytopenia [30]. However, it is important to note that neutropenia was more frequently observed in patients receiving concurrent radiotherapy and CDK-i. Nevertheless, the rate of CDK-i dose reduction due to side effects was comparable between patients undergoing concurrent treatment and those receiving systemic therapy alone.

Similarly, the combination of radiotherapy and immunotherapy appears to be safe [31]. In contrast, chemotherapy presents a different scenario, as it is well known for its high bone marrow toxicity, often necessitating treatment interruptions and/or dose reductions [32]. For this reason, the timing of radiotherapy treatment should be personalized and ideally administered at a safe interval from the last chemotherapy dose. However, these patients are often highly symptomatic, with a life expectancy of only a few months, making it challenging to maintain a cautious interval from the last chemotherapy administration.

The development of marrow toxicity poses a dual challenge: not only is it a potentially life-threatening condition, but it also necessitates delays in initiating or continuing systemic treatments. In all affected patients, systemic therapies were resumed only after hematologic parameters returned to normal. This underscores bone marrow damage as the principal limitation of this therapeutic approach. Of the five patients who experienced hematologic toxicity, three received 8 Gy in a single fraction, one was treated with an SIB, and one received 15 Gy in five fractions. While no definitive conclusions can be drawn due to the small sample size, our findings suggest that greater caution should be exercised when administering single-fraction treatments.

Interestingly, in our cohort, the use of doses higher than those typically reported and recommended in the literature (e.g., 12–15 Gy in 5 daily fractions, 3.75 Gy BID in two consecutive days to a total of 15 Gy, or 6–8 Gy in a single fraction) [10], 11], 27], 29], 33] was not associated with an increased risk of adverse events. This observation highlights the potential to explore dose escalation strategies to enhance therapeutic responses. Previous studies have demonstrated that achieving a higher BED increases the likelihood of a complete response. For instance, in the study by Arcangeli et al., delivering 40–46 Gy with conventional fractionation resulted in an 81 % pain relief rate compared to 65 % and 46 % for 30–36 Gy and 8–28 Gy, respectively [34]. In our cohort, dose escalation by SIB was decided based on the patient’s clinical condition, tumor histology, and life expectancy.

Despite longer than expected survival times in some cases, these patients remain metastatic with generally poor prognoses, for whom minimizing the frequency of clinical visits is a priority. An SIB approach could achieve a higher BED while minimizing outpatient visits. In our view, increasing the BED could not only improve pain relief but also enhance local response rates, thereby complementing the clinical efficacy of systemic therapies. Indeed, newer systemic treatments have enabled patients to achieve longer survival, suggesting that the exclusive palliative role of HBI may no longer suffice for this population.

In our study, we observed that all patients who received dose escalation per fraction achieved an excellent ORR, suggesting a potential benefit of higher doses. Therefore, this approach could enable increasingly personalized treatment, tailoring the radiotherapy technique to the tumor histology. For instance, more radioresistant histologies, such as melanoma, could be treated with SIB, allowing dose escalation in specific target areas while complying with dose constraints for organs at risk (OARs).

On the other hand, this technique could be particularly beneficial for patients with a more favorable prognosis, such as those with prostate or breast cancer, where achieving a more durable ORR would allow patients to continue their systemic therapy uninterrupted. If the efficacy of SIB in prolonging ORR is confirmed, it could also be considered for patients with more aggressive histologies, such as urothelial or neuroendocrine tumors, in an effort to extend local disease control. However, further studies are needed to validate these therapeutic hypotheses.

Regarding PFS, we did not observe a significant advantage with higher radiation doses. This finding is unsurprising, considering that these patients typically present with nearly ubiquitous disease spread, at least at the bone level.

Moreover, all patients except five were alive at their last follow-up. In contrast, survival rates for similar patients reported in the literature are generally significantly lower [35].

As for the fractionation scheme, single-fraction treatment is often recommended, especially for patients experiencing severe pain. However, in our cohort, all patients completed fractionated regimens without requiring premedication or hospitalization, which are often necessary for single-fraction approaches [36].

In our cohort, HBI demonstrated significant efficacy in pain reduction, with a substantial proportion of patients achieving complete and immediate pain relief. This is not surprising, as literature data suggest that the efficacy of radiotherapy for palliation is observed within one month in up to 96 % of cases [37]. In some cases, pain relief was observed as early as 2–3 weeks after the completion of radiotherapy [34]. Although the underlying mechanisms are not yet fully understood, such rapid responses seem to be linked to the systemic effects of radiotherapy. Indeed, in addition to directly killing tumor cells, radiotherapy also triggers the release of pro-inflammatory molecules and the infiltration of immune cells, which remodel the vascular, stromal, and immunological tumor microenvironment, ultimately impacting tumor growth and angiogenesis [14], 38].

Additionally, the treatment enabled a considerable proportion of patients to reduce or discontinue their use of analgesics. These findings are consistent with those reported in the literature, such as the study by Salazar et al., which reported a pain response rate of nearly 90 % [39]. Almost all of our patients experienced pain relief after treatment, though not all reduced or discontinued their analgesic intake. This may be attributed to the tolerance that many of these drugs can induce. Furthermore, we observed that despite the high levels of pre-treatment pain reported (NRS 7–10), many patients were on inadequate pain management regimens, often using only acetaminophen.

Although we did not use a specific questionnaire to assess QoL, given that most patients presented with significant pain and limited cooperation, we combined the ECOG performance status, the NRS, and analgesic intake before and after radiotherapy to provide an indirect measure of QoL, as suggested by Salazar et al. [39]. From the combination of these factors, it emerged that the treatment led to a significant improvement in QoL at 1 month, especially in patients with metastatic breast and prostate cancer, and this improvement was sustained at 6 months. Thus, the efficacy of the treatment in terms of pain reduction was observed in nearly all patients, regardless of histology, with the best responses seen in those with metastases from breast and prostate cancer, where high rates of complete responses were achieved.

Unfortunately, two patients showed no response to the therapy: one with urothelial carcinoma and another with lung cancer. These findings are consistent with the literature, which reports higher response rates in patients with prostate and/or breast cancer. For instance, in the study by Keen, 70 % of patients with metastatic prostate cancer treated with HBI demonstrated an effective response to treatment [40].

Ultimately, it is important to emphasize that our analysis reveals that the use of higher doses resulted in a greater reduction in pain at 1 month.

The main limitations of this study include its retrospective design and the limited number of patients, which prevented us from performing a robust statistical analysis. Nevertheless, our study is the first to introduce the SIB technique in patients treated with HBI, which warrants attention. Despite the aforementioned limitations, our analysis suggests that dose escalation may correlate with improved ORR and pain response rates. Further studies are needed to better understand the role of dose escalation per fraction in these patients and the impact of this treatment approach based on histology.

Conclusions

HBI appears to be an effective method for palliating symptoms in patients with multiple bone metastases. This technique strikes a balance between clinical efficacy and the convenience of achieving results in a minimal number of fractions, potentially even a single one. In the current era, patients – particularly those with prostate and breast cancer – are experiencing longer survival times due to advances in systemic therapies. Consequently, this technique may require modifications, such as the incorporation of a SIB to PET-avid lesions, in order to increase the BED without extending the number of fractions. Such adjustments could further enhance ORR and pain response rates. Ultimately, HBI is generally well tolerated; however, attention must be given to the risk of bone marrow toxicity. Despite advancements in radiotherapy techniques, the combination of HBI with systemic therapies continues to make marrow toxicity an almost unavoidable concern.