Preoperative accelerated hypofractionated radiotherapy (PHYPORT): state of art and potential clinical application

Abstract

Hypofractionation is a radiotherapy regimen that uses fewer fractions with higher doses with respect to conventional regimen. It can reduce overall treatment time and costs.

Preoperative accelerated hypofractionated radiotherapy (PHYPORT) is a new approach in which radiation therapy is delivered in fewer, larger doses over a shorter period of time before surgery and it can be used to shrink tumours before surgical removal in some cancers. The choice of hypofractionated radiotherapy depends on the type of tumour, its localization and total target volume. Also, it is important to assess the potential benefits and risks of higher radiation doses. PHYPORT could be a more convenient and cost-effective option, but its effectiveness is unclear. This review assesses the use of PHYPORT in cancer treatment.

Introduction

The term “hypofractionation: refers to a radiotherapy regimen that uses a reduced number of fractions, with each fraction delivering a higher dose of radiation in respect to conventional radiotherapy. This approach has the potential to reduce overall treatment time (OTT) and cost, while guaranteeing hospital access to a wider range of patients.

Hypofractionation doses range from > 2.0 Gy per fraction (moderate hypofractionation) to ≥ 5.0 Gy for ultra-hypofractionation [1].

Preoperative accelerated hypofractionated radiotherapy (PHYPORT) is a novel treatment approach in which radiation is delivered in fewer but larger doses over a shorter period of time prior to surgery. This approach differs from conventional radiotherapy (which typically uses smaller doses over a longer period of time), and it is often used to shrink tumours prior to surgical removal in some cancers. This approach has the potential to improve both surgical outcomes and local control.

Higher radiation doses per session can target tumour cells more effectively while reducing OTT. Fewer sessions improve patient compliance and reduce healthcare load. Global literature suggests that hypofractionated schedules may result in a significant tumour response, facilitating surgical resection.

The choice of hypofractionated radiotherapy (HFRT) depends on the tumour type, location and total target volume. However, it is important to assess the potential benefits and risks of higher radiation doses.

Basing on this rationale, PHYPORT could be a more convenient and cost-effective option for patients and medical community, but its effectiveness compared to conventional radiotherapy is still unclear.

Advanced intensity modulation and image guidance technologies allow for greater precision and more radiation falloff, reducing exposure of surrounding normal tissues to toxic levels of radiation.

This review, structured as a state-of-the-art overview, assesses the feasibility and safety of PHYPORT in the treatment of various cancers.

Hypofractionation

Classic (or conventional) fractionated radiotherapy (CFRT) uses a dose of 1.8–2 Gy per fraction. This has several implications. Firstly, patients need to visit the radiotherapy centre several times per week. Radiation oncologists must monitor reproducibility, patient positioning and target movement daily due to potential changes during treatment. Regarding cost-effectiveness,, longer OTTs are more expensive, especially if we consider the global increase in cancer prevalence.

The need to keep patients in a radiotherapy unit as little as possible is the main reason why it is important to implement the use of HFRT [2].

Many international scientific groups have recommended the use of hypofractionated regimens in radiation oncology departments during the last COVID-19 pandemic [3].

In addition to radiobiological considerations, hypofractionation represents a more practical approach, allowing for a reduction in treatment time and an increase in the number of patients treated. In accordance with the linear quadratic model, all tissues are characterized by a radiobiological indicator of their radiosensitivity to fraction size, which is called “α/β ratio”. Basically, a low α/β ratio (less than 3 Gy) indicates that the tissue is more capable of resisting radiation damage through DNA repair mechanisms. As the dose per fraction increases, the rate of cell death also rises significantly. Tissues with a high α/β ratio (> 10 Gy), like highly proliferating tissues, demonstrate reduced sensitivity to hypofractionation. The surviving fraction at 2 Gy (SF2) for tissue with a high α/β ratio is therefore lower than for tissue with a low α/β ratio. While this differential effect may appear insignificant, it can result in a considerable difference when multiplied by numerous fractions. Given that tumours (early responding tissues) typically exhibit a high α/β ratio, whereas healthy organs (late-responding tissues) display a low α/β ratio, fractionation can be employed to safeguard electively normal tissue, thereby facilitating a high rate of tumour control without the occurrence of late toxicity [1].

Based on these findings, it could be postulated that hypofractionation may result in less tumour control while simultaneously reducing tissue toxicity. Besides, these observations have been made in the context of two-dimensional radiotherapy, wherein a substantial volume of critical organs is encompassed within the radiation fields. Nevertheless, the advent of new radiation oncology technologies has reduced the incidence of late toxicity, supporting the employment of hypofractionated schemes.

The degree of radiation damage to tissues depends on several factors, including the killing of cells, alterations to the vasculature, and the volume of tissue irradiated [4].

For example, lung toxicity depends on the volume of parenchyma that receives doses above 20 Gy. This volume is related to the development of lung fibrosis [5]. In prostate cancer radiotherapy, proctitis has been associated with rectal volume exposure at doses above 70 Gy [6]. Some studies have shown a similar relationship between radiation exposure and the development of adverse effects in other organs [7].

Preoperative radiotherapy

Preoperative (or neoadjuvant) therapies have several theoretical advantages. They may reduce tumour size, allowing for optimal resectability, although the toxicity profile for healthy surrounding tissues is supposed to be quite higher in PHYPORT compared to CFRT because of radiobiological issues. In soft tissue sarcomas, resection of a large tumour mass may cause incomplete resection (compromising local control) or demolitive resection (compromising post-operative survival and quality of life) [8]. Conversely, post-operative (adjuvant) radiation therapy can have serious adverse effects and outweigh its benefits if it does not offer hope of cure. Late toxicities associated with adjuvant radiotherapy are common. Patients with gastrointestinal cancer often experience anastomotic leakage, bleeding and or dislocation/damage of medical devices. The incidence of these phenomena depends on the dose of radiation delivered [9]. The recovery following initial surgery may be prolonged due to postoperative complications, and patients are at risk of delayed healing if the timing of radiation therapy is not correctly scheduled. The potential timeframe for this is between three and five weeks postoperatively [10, 11].

It is possible that late surgical complications may occur in the irradiated field during the delivery of adjuvant irradiation. These circumstances may result in the interruption of scheduled adjuvant radiation therapy, which could potentially lead to unfavourable outcomes, especially in the case of fast-growing tumours [12]. The objective of preoperative cancer therapy is to reduce the size of the tumour, thereby enhancing the safety and efficacy of surgical procedures.

Thus, long-term benefits of PHYPORT could include local and regional disease failures reduction after surgery. In some cases, it may even obviate the need for supplementary postoperative treatments. Furthermore, it may reduce the contamination of surgical wounds with tumour cells during surgical manipulation [13, 14]. Moreover, the choice of dose delivered and tumour volume delineation before the surgery may offer a greater advantage with PHYPORT because post-operative tumour bed is more difficult to delineate [15].

Neoadjuvant radiotherapy has demonstrated better results in the management of several solid tumours as the rectum, oesophagus and sarcomas, but plays a marginal role in the locally advanced breast cancer management, reserving this treatment for patients enrolled in clinical trials.

Clinical applications and outcomes

Rectal cancer

Rectal cancer is a significant global healthcare challenge. It’s the second most prevalent cancer in general population. Treatment advances have led to improved outcomes. Preoperative radiotherapy is standard for most rectal cancer patients, particularly in Scandinavian populations [16]. The wide spread of preoperative radiotherapy led to new ways of improving these treatments to reduce side effects and treatment duration. So, it is possible to assess a recent increase in interest for hypofractionation for rectal cancer due to potential benefits for patients and centers [17].

Several clinical trials have demonstrated that hypofractionated schedule is both plausible and feasible for the treatment of this disease, particularly when combined with chemotherapy. The available data on preoperative hypofractionated radiotherapy indicate that this approach may result in a higher percentage of R0 (resection without evidence of microscopic residual tumour at histological examination and/or wide free margins) resection rates and a reduction in the size of the primary tumour (18).

Early evidence in favour of the utilization of a brief course of preoperative hypofractionated radiotherapy (e.g. short course radiotherapy; SCRT) followed by surgery was presented in the Swedish [16] and Dutch TME Trials (19). The dose established was 25 Gy, delivered in five consecutive fractions. The surgical procedure was conducted within a seven-day period following the conclusion of the radiation therapy.

The Polish trial firstly demonstrated no-inferiority between SCRT followed by immediate surgery and long-course radiotherapy followed by delayed surgery (within 4–6 weeks) [20]. These findings were supported by the TROG 01.04 trial [21]. The Stockholm III trial demonstrated that there was no statistically significant difference in local recurrence rates between SCRT and immediate surgery, SCRT and delayed surgery, or long-course radio-chemotherapy (LCRT) [22, 23]. Other studies have confirmed these outcomes [24, 25].

The efficacy of SCRT in conjunction with chemotherapy was evaluated in the context of total neoadjuvant therapy (TNT) [26, 27]. The RAPIDO trial compared SCRT followed by six cycles of capecitabine/oxaliplatin (CAPOX) versus nine cycles of folinic acid/fluorouracil/oxaliplatin (FOLFOX) chemotherapy and delayed total mesorectal excision (TME) to LCRT followed by TME and adjuvant chemotherapy [28]. The results demonstrated comparable outcomes with regard to disease-related treatment failure, pathologic complete response (pCR), and distant relapse. In contrast, a long-term analysis (5 yy) of RAPIDO trial revealed that the locoregional failure (LRR) was higher in the experimental TNT SCRT arm [29]. At present, it is not yet possible to establish definitive conclusions regarding the most favourable fractionation scheme in this setting. In the future, genetic patterns could help clinicians to choose the best radiation therapy scheme for patients with rectal cancer. The ongoing clinical trials will be crucial in determining the outcomes. It is recommended that treatment guidelines be followed until further evidence is available.

Soft tissue sarcoma

The optimal treatment for soft tissue sarcoma (STS) is still being researched. In fact, post-operative complications and relapse rates are high, despite the most modern surgical techniques. Recent developments suggest a significant transformation in the STS treatment paradigm. Predictive nomograms and new predictors of overall survival across main STS subtypes highlight the requirement for trials based on more than traditional histology-based criteria [30]. The quality of radiation therapy can be enhanced through the utilisation of sophisticated adaptive techniques, such as intensity-modulated radiotherapy (IMRT) and image-guided radiation therapy (IGRT) [31].

Most centres employ preoperative radiotherapy to reduce the tumour volume and facilitate the surgical procedure [32]. Other potential advantages include clearance of low-grade or dedifferentiated sarcomas at the time of surgery; induction of fibrosis, which makes resection easier and thus reduces morbidity; improved local control by eradicating cells at the margin of the tumour mass; and a possible survival advantage in soft tissue sarcomas of the trunk or extremities. The primary disadvantages of preoperative radiotherapy are the complications associated with wound healing, infection, and fistula. In consideration of the abovementioned factors, surgical intervention is typically undertaken six to eight weeks after the end of radiotherapy.

CFRT is typically administered over a period of five to six weeks, with daily fractions of 1.8–2.0 Gy, resulting in a total dose of 50–50.4 Gy [33].

The potential advantages of PHYPORT include tumour shrinkage, an increase in progression-free survival, a higher rate of limb preservation, and an increase in the feasibility of surgery. Moreover, there is evidence indicating that accelerated radiotherapy regimens may enhance local control [34].

A number of hypofractionated regimens were investigated on the basis that a typical a/b ratio for the control of STS is approximately 3–5 Gy [35]. Guadagnolo et al. [36] conducted a single-institution phase II trial utilising a moderate hypofractionation regimen of 42.75 Gy in 15 fractions of 2.85 Gy over a three-week period. The trial included 120 patients, with a median follow-up period of 24 months and an actuarial 30-month local recurrence-free survival (LRFS) rate of 93%. In 2021, Koseła-Paterczyk et al. [37] published data concerning 311 patients who received a short preoperative course of 5 × 5 (5 Gy daily and consecutively until total dose of 25 Gy). This regimen was associated with lower rates of wound complications (28%) compared to the conventional regimen employed in the SR-2 trial [38].

Kalbasi et al. [39] have applied 6 × 5 (6 Gy daily and consecutively until total dose of 30 Gy) IMRT to two-thirds of patients and IGRT to almost all 50 patients enrolled in a phase 2 trial of a cohort of patients with high-grade sarcoma. A minimum follow-up period of two years was observed, with a total of 5.7% of patients with local recurrence being documented. Leite and colleagues (40) and Kubicek and colleagues [41] evaluated the feasibility of a stereotactic body radiotherapy (SBRT) delivering doses of 8 and 7 Gy for five fractions. The results showed comparable acute wound complications rates to CFRT. Some patients presented vascular occlusion after 8 × 5 (8 Gy daily and consecutively until total dose of 40 Gy), necessitating disarticulation surgery (n = 3) and one case of amputation. In 2021, Spałek et al. investigated the association between chemotherapy and preoperative high-dose-rate brachytherapy in a phase II trial in 46 patients. The primary endpoints were the rates of R0 limb-sparing surgery and the incidence of toxicity in patients with marginally resectable STS. An R0 resection was achieved in 72% of patients, while acute wound complications were observed in 34% of them. The data on late toxicity is still pending. It is important to note that the role of perioperative chemotherapy remains a topic of debate, and it depends on the risk factors [42].

Nevertheless, the evidence supporting the efficacy and safety of neoadjuvant radiotherapy as a standard of care is inadequate in most cases. It is not possible to accurately predict which patient will have outcomes as good as those achieved with primary surgery alone, or which patients may have lower recurrence rates after radiation. The evidence is unreliable due to lack of direct comparisons and contrasting endpoints. Data on acute and late toxicity are conflicting due to heterogeneity of doses and techniques [43].

A group of expert radiation oncologists met at the 2023 Connective Tissue Oncology Society (CTOS) Annual Meeting to discuss hypofractionation for soft tissue sarcomas. A review of the literature on PHYPORT for localized STS of the extremities and trunk was conducted. To be adopted as a standard treatment, hypofractionation must be shown to be as effective as conventional 50 Gy in 25 fractions and have comparable acute and long-term toxicity. Regarding the choice of ultra-hypofractionated radiotherapy schemes, doses ≤ 25 Gy in 5 fractions are insufficient for tumour control, showing an inferior local control (LC) compared to CFRT schemes; 40 Gy in 5 fractions is likely to be an excessive dose, given the unacceptable amputation rate. Better results in terms of local control and toxicities seem to be obtained with 30 Gy in 5 fractions, but consensus of international experts at Connective Tissue Oncology Society (CTOS) is that PHYPORT regimens should not yet be considered the standard of care for STS of the extremities and trunk outside of clinical trials [44].

Breast cancer

Breast cancer treatment requires a multidisciplinary approach. The main treatment is surgery, which can be breast conservative or mastectomy. The main aim of adjuvant radiotherapy is to improve local control and reduce the risk of local or locoregional recurrence. Historical and current evidence reveals a reduction in the incidence of ipsilateral breast tumour recurrence following breast-conservative surgery and a decline in local-regional recurrence following total mastectomy with the use of radiotherapy. Furthermore, the use of adjuvant radiotherapy following breast-conserving surgery improves overall survival (OS). The previous dose/fraction scheme involves the administration of a dose of 50 Gy to 60 Gy in 25–28 daily fractions over a period of 5 to 6 weeks, utilizing megavoltage linear accelerators [45].

Moderate hypofractionated radiotherapy is currently the gold standard of care after breast conservative surgery. The multicentre study, known as Start A, was the first to demonstrate non-inferiority in both efficacy and toxicity compared to the established CFRT [46]. Start B yielded comparable results in terms of local recurrence rate (LRR) when a lower dose was fractionated into 15 fractions (40.05 Gy given in 2.67 Gy/daily fractions) showing superior outcomes in terms of toxicity (47). This approach is currently employed in numerous radiation therapy centres. The FAST trial compared adjuvant CFRT with an ultra-hypofractionated weekly schedule of five fractions delivering a total dose of either 30 Gy or 28.75 Gy in early breast cancer patients. The authors showed similar results in terms of both local control and toxicity (48). In 2020, Brunt et al. conducted a randomised phase III trial that compared a five-fraction schedule delivered in a week with the international standard 15-fraction regimen (START B protocol). The author determined that the experimental arm was non-inferior in terms of local control and toxicity with a follow up of up to five years [49].

The use of preoperative radiotherapy has been largely confined to clinical trials, and reserved for patients with locally advanced, inoperable breast cancer. More recently, a number of clinical trials have been initiated to assess the efficacy of partial breast irradiation (PBI) as a preoperative treatment modality. The feasibility of accelerated partial breast irradiation (APBI) in the postoperative setting for early-stage breast cancer patients was explored through the utilisation of variable dose and fractionation regimens [50]. The limited commitment of this approach has been attributed to concerns regarding an increased risk of local recurrence, poorer cosmetic outcomes and increased dose heterogeneity in the postoperative lumpectomy cavity. This is particularly relevant in patients with larger tumours, where the incidence of fibrosis or tissue necrosis is unacceptable [51]. Limiting the volume of tissue to be treated using advanced imaging-based planning in the preoperative APBI (P-APBI) setting may help to reduce the incidence of toxicities. The use of preoperative radiotherapy bypasses the degree of uncertainty that postoperative one presents in delineating the lumpectomy cavity, particularly when a boost is required. Moreover, oncoplastic reconstruction with cosmetic purpose following tumour resection at the time of lumpectomy may introduce additional complexity to treatment planning, increasing larger treatment volumes and unnecessary toxicity.

Literature reports a variety of doses and fractionations, ranging from one to ten fractions and employing techniques such as IMRT, IGRT, and SBRT. A phase II multi-institutional study using adjuvant three-dimensional conformal radiotherapy (3-DCRT) in 70 early breast cancer patients tested three levels of dose (35, 36 and 38.5 Gy in ten fractions). The authors demonstrated that 100% of patients exhibited good to excellent cosmesis at a three-year follow-up, with minimal treatment-related and postoperative toxicity and only two episodes of local recurrence at a median follow-up period of 23 months [52].

Horton et al. presented the preliminary findings of a Phase I study of single-fraction P-APBI conducted in a single institution. The study cohort comprised 17 patients with T1 disease more than 1 cm away from the skin surface, for whom MRI was used as the imaging modality for planning purposes. The prescribed dose was 15 Gy in single fraction delivered via IMRT. Although the median follow-up period was only 23 months, cosmesis was rated as good or excellent in all patients, with no evidence of early recurrence [53].

The advent of more contemporary studies of P-APBI using sophisticated treatment planning allows the investigation of dose escalation protocols [54–57].

The feasibility of whole breast irradiation (WBI) in conjunction with a simultaneous integrated boost (SIB) in the context of the POPART trial for patients with early-stage breast cancer was investigated by Mulliez et al. The authors reported a favourable locoregional control outcome, although a notable incidence of wound complications was also observed [58]. These outcomes may be attributed to patient and tumour characteristics [59].

The possible benefits of chemotherapy administered concurrently with PHYPORT have been the subject of recent investigation. Bondiau et al. enrolled 26 patients with unifocal early-stage breast cancer in a study that combined SBRT with neoadjuvant chemotherapy, comprising three cycles of taxanes and three cycles of 5-fluorouracil/doxorubicin or epirubicin/cyclophosphamide (FEC). The objective response rate (ORR) was 96%, and the toxicity profile was favourable [60].

Ciervide et al. observed optimal outcomes in terms of both local control and toxicity in early triple negative (TN) and HER2+ breast cancer patients treated with neoadjuvant chemoradiotherapy. The chemotherapy regimens employed were pertuzumab–trastuzumab–paclitaxel followed by anthracyclines in HER2+ patients and carboplatin (CBDCA)-paclitaxel followed by anthracyclines in TN patients. The prescribed radiation dose was 40.5 Gy in 15 fractions of 2.7 Gy to the entire breast and locoregional lymph nodes with a SIB up to 54 Gy in 15 fractions of 3.6 Gy to macroscopic tumour areas highlighted by fluorodeoxyglucose (¹⁸F) positron emission tomography (¹⁸FDG-PET). pCR was observed in 70.8% of TN patients and 53.1% of HER2+ subtype patients [61].

At the 2024 European Society for Medical Oncology (ESMO) annual meeting, preliminary data of the NeoCheckRay trial were presented. The authors investigated the feasibility and safety of combining radioimmunochemotherapy with SBRT to the primary tumour in patients with luminal B breast cancer. Three schemes of neoadjuvant treatment were compared: Arm 1: paclitaxel q1w × 12 with SBRT at week 5 (8 Gy × 3 fractions on primary tumours, avoiding lymph nodes and normal breast tissue) followed by dose-dense epirubicin/cyclophosphamide q2w × 4; Arm 2: Arm 1 + durvalumab 1500 mg q4 w × 5. Arm 3: Arm 2 + oleclumab 300 mg q2w x4. The surgical procedure was conducted from two to six weeks after the end of neoadjuvant treatments. Adjuvant therapy was administered in accordance with the established local guidelines, regarding both endocrine therapy and radiotherapy (boost on tumour bed not allowed). The authors observed superior results in terms of residual cancer burden (RCB 0/1) at the time of surgery in arms 2 and 3 and a higher rate of pCR in patients treated with oleclumab (Arm 3) [62].

This study supports the hypothesis that neoadjuvant radio(chemo)therapy in selected breast cancer patients could offer clinical advantages, including a more precise delineation of the target volumes, an immediate reconstruction after mastectomy, reducing the interval between procedures and potentially leading to improved cosmetic outcomes and minor risk of residual disease in skin-sparing mastectomy techniques. It is further hypothesised that several hypofractionated schemes used in palliative treatments with rapid tumour regression could be adopted with preoperative intent even in locally advanced inoperable breast cancer patients [63].

Pancreatic cancer

The feasibility of both PHYPORT and definitive radiotherapy as SBRT boost in unresectable pancreatic adenocarcinoma (PA) has been investigated and has been associated with high margin negative resection rates [64–66]. This approach is controversial due to concerns about surgical complications. These could be mitigated by modern techniques for dose delivering. Bryant et al. described the clinical experience in a cohort of 26 patients with locally advanced PA who were treated with ablative dose magnetic resonance-guided radiotherapy (A-SMART) prior to potentially curative resection of the local disease. All patients received A-SMART to a median dose of 50 Gy (range, 40–50), delivered in five fractions. The median time to resection was 50 days (range, 37–115 days). The R0 resection rate was 96%. No cases of acute grade 2+ toxicity associated with radiotherapy were observed. A pathological response was observed in 88% of cases. The interval between radiotherapy and surgical resection was found to be associated with tumour regression grade. The derived median progression-free survival from RT was 13.2 months [67].

Conversely, the A021501 is a phase 2 randomised clinical trial in which 126 patients were randomly assigned to receive either chemotherapy alone with eight cycles of mFOLFIRINOX (arm 1) or radiochemiotherapy with seven cycles of mFOLFIRINOX followed by SBRT (33–40 Gy in 5 fractions) or hypofractionated IGRT (25 Gy in 5 fractions) directed to the tumour. The results for arm 1 indicated superior outcomes with regard to both R0 resection and OS, although the incidence of adverse effects associated with neutropenia, leucopenia and weight loss was relatively higher.

It appears that, currently, PHYPORT is not an adequate therapeutic option for the treatment of locally advanced PA, and that chemotherapy is the optimal neoadjuvant treatment for these patients [68].

Other cancers

The available literature on PHYPORT in cancers other than those already described is controversial [69].

The feasibility of administering a moderately fractionated dose of radiotherapy prior to surgery in the treatment of oesophageal cancer has been the subject of only a limited number of studies. Walsh et al. [70] conducted a prospective, randomised trial comparing surgery alone with a combination of HFRT, chemotherapy and surgery. Patients assigned to the multimodal therapy received two courses of chemotherapy and a course of radiotherapy (40 Gy in 15 fractions over three weeks), followed by surgery. It was reported that pCR was achieved in 25% of patients who underwent multimodal therapy. The median OS among patients was 16 months, compared with 11 months for those assigned to surgery alone (p < 0.01). In a retrospective study of 81 patients with esophageal squamous cell carcinoma, Wang et al. [71] observed that those who underwent preoperative hypofractionated radiotherapy exhibited a higher median OS compared to those who underwent surgery alone. Lju et al. [72] have compared the feasibility of a hypofractionated regimen (30 Gy in 10 fractions) of radiotherapy with preoperative CFRT (40 Gy in 20 fractions) in association with chemotherapy with 5-fluorouracil or taxanes followed by surgery 3–8 weeks after completion of chemoradiotherapy. The authors reported comparable results in terms of toxicity, pCR, LRR and OS, although a trend emerged in favour of CFRT.

A clinical study conducted by Prabhu et al. [73] investigated the use of PHYPORT using SBRT in brain metastases patients. The study observed a reduced incidence of leptomeningeal diffusion in the hypofractionated arm when comparing preoperative and postoperative SBRT. Three ongoing trials are comparing the efficacy of preoperative versus postoperative HFRT in the treatment of brain metastases and high-grade gliomas [74–76].

Table 1.

Summary of most used schemes of hypofractionated radiation therapy

Tumour Type	PHYPORT regimens	Main clinical outcomes	Acute toxicity	Late toxicity	Evidence status	References
Rectal Cancer	5 × 5 Gy SCRT, SCRT + Chemo	R0 resection, tumour shrinking	Mild	Moderate	Supported by trials	[28, 29]
Soft tissue sarcoma	5 × 5, 6 × 5, 8 × 5 Gy	LRFS, surgical feasibility	Moderate	Variable	Under investigation	[34, 37]
Breast cancer	5 × 6.1 Gy	pCR in TN/HER2+, ↓treatment time	Low	Low	Experimental	[53, 58]
Pancreatic cancer	5 × 10 Gy (A-SMART)	↑R0 rate, ↑pCR	Mild	Not reported	Investigational	[65, 67, 68]
Others (e.g., brain, oesophageal)	5–10 fractions	Promising but limited	Low	Unknown	Early evidence only	[72, 75]

PHYPORT — preoperative accelerated hypofractionated radiotherapy; SCRT — short course radiotherapy; Chemo — chemotherapy; LRFS — local recurrence-free survival; pCR — pathologic complete response; TN — triple negative

Further considerations and ideas

In the context of the recent pandemic, the use of hypofractionated regimens has been particularly beneficial, as shorter treatment courses have reduced patient and hospital exposure, as well as the risk of infection and interruption of radiotherapy.

Preoperative radiotherapy allows for more precise target delineation than postoperative radiotherapy, which may be obscured by complications such as fibrosis and seroma. Preoperative irradiation may facilitate immediate reconstruction, reduce the interval of delay, and contribute to a better cosmetic result. It may also facilitate organ-sparing reconstruction and reduce the risk of postoperative residual disease.

Hypofractionated regimens have been demonstrated to be more effective in tumours with a low α/β ratio than standard fractionated ones. Furthermore, they can efficiently ablate hypoxic cells in the tumour mass without affecting the microcirculation, thereby reducing the size of the tumour. The probability of tumour shrinkage can be employed to inform the surgical planning process, with the objective of achieving optimal resectability. Moreover, there is evidence to support the hypothesis that tumours develop multiple immune evasion mechanisms as they progress. Also, it has been proposed that radiotherapy applied to a large tumour mass activates a robust antitumour immunity that may contribute to the elimination of the primary tumour and the microscopic locoregional foci, reducing systemic dissemination and leading to a possible abscopal effect from preoperative radiotherapy.

Finally, the concurrent administration of radiotherapy and chemotherapy may also influence the overall duration of the treatment regimen, reducing the interval between the conclusion of radiotherapy and surgical resection and optimising the utilisation of hospital resources. These factors contribute to enhancing the therapeutic adherence, while facilitating a reduction in the overall cost of treatments for the healthcare system.

On the other hand, hypofractionated regimens may be less safe than conventional regimens in some cancers, such as sarcomas, where many studies have demonstrated a higher incidence of surgical wound complications. Other common adverse effects observed in patients treated with PHYPORT approaches and subsequent resection include subcutaneous fibrosis of grade 2, skin necrosis and bone fractures.

The optimal dose to administer in the preoperative setting remains an open question of significant importance. In the context of sarcomas, it has been observed that ultra-hypofractionated schemes, with doses exceeding 6 Gy per fraction, are associated with an elevated risk of postoperative complications. Another important area of investigation is the optimal interval between neoadjuvant treatments and surgery. If surgery is performed too early after neoadjuvant treatment, the tumour may not be optimally downsized. This is due to the fact that tumour regression is a time-related process, with a median volume-halving time of 14 days. Conversely, an excessive delay in surgery could result in the invalidation of both LC and OS. The optimal interval between the preoperative approach and surgery should be 4–6 weeks.

In addition, it would be valuable to determine the optimal timing of surgery and to assess the feasibility and safety of combining this approach with chemotherapy and/or immunotherapy for other tumours.

Conclusion

The preoperative hypofractionated approach allows the delivery of an effective biological dose and limits the necessity for prolonged hospital admission.

Our state-of-the-art review suggests that, with the exception of rectal cancer, PHYPORT should not yet be considered a standard of care for most tumours. We suggest that these approaches should be tested in multi-institutional randomised trials comparing conventional fractionation, moderate hypofractionation and ultra-hypofractionation.