Efficacy Analysis of Hypofractionated Radiotherapy for Oligometastatic Tumors: A Retrospective Study

Abstract

Introduction

Metastasis remains a major cause of death among patients with malignant tumors. Radiotherapy is one of the main modalities of cancer treatment. The rapid development of radiotherapy technology has enabled the widespread application of hypofractionated radiotherapy (HFRT) in clinical practice. This study aimed to evaluate the effect of HFRT on the survival and safety of patients with oligometastatic tumors.

Methods

We conducted a retrospective study that involved 65 patients with well-controlled primary tumors and 1–5 metastatic foci treated at the study site between January 2020 and December 2022. Patients were aged >18 years and had a ≥ 6-month life expectancy. The patients received standard treatments plus HFRT for all metastatic foci. The dose fractionation regimen was adjusted according to the location and size of the patient’s metastatic foci. The planning gross tumor volume of HFRT was 82.93 cm³ (range: 10.12-562.80 cm³), and the radiation dose range was 20 Gy/5 F–60 Gy/15 F. Progression-free survival (PFS), overall survival (OS), local control rates, and incidence of adverse events of the patients were observed.

Results

Among the 65 patients, the median follow-up time, PFS, and OS were 26 months (95% CI: 0.80-37.50), 15 months (95% CI: 9.36-20.64), and 28 months (95% CI: 16.71-39.29), respectively. The 1- and 2-year PFS were 53.8% and 40.0%, respectively, while the 1- and 2-year OS rates were 73.8% and 56.9%, respectively. In total, 13.8%, 55.4%, 20.0%, and 13.8% of patients showed complete response, partial response, stable disease, and progressive disease, respectively. Four patients developed grade 3 or worse adverse events, and no treatment-related deaths occurred.

Conclusions

HFRT showed favorable clinical efficacy and safety in patients with oligometastatic tumors, generally achieving a good OS rate. Further randomized trials should be conducted.

Keywords

hypofractionated radiotherapy HFRT oligometastatic tumors safety therapeutic efficacy

Introduction

The causes of treatment failure in malignant tumors mainly include uncontrolled local and distant metastasis. Continuous advancements in treatment methods and technologies have contributed to the decline of local failure as a cause of death. However, metastasis remains a major cause of death among patients with malignant tumors. Traditionally, treatments for metastatic solid tumors were based on systemic therapies, aiming to delay progression and prolong survival rather than achieving a complete cure.¹ However, our understanding is currently evolving to recognize that distant metastasis does not necessarily imply numerous and extensive metastases. Instead, an intermediate transitional state with fewer metastases should be considered, and metastasis should be regarded as a dynamic process of development rather than a definite and fixed state.² The concept of “oligometastasis” was first proposed by the American radiation oncologist Hellman in 1995.² With the development of oligometastatic-related research, the terms oligoprogression³ and oligorecurrence⁴ were derived. Oligoprogression indicates that only a few or limited residual lesions begin to progress following systemic treatment.³ Meanwhile, oligorecurrence refers to a small number of metastases at local or other locations that occur after local treatment of the primary tumor.⁴ Some scholars believed that the concept of oligometastasis emerged from the continual development of anti-tumor drug treatments (eg, targeted therapy, immunotherapy), which significantly prolonged patient survival.^1,2,5 Nonetheless, the question of whether to administer aggressive local treatment to patients with oligometastasis remains controversial. Some researchers believe that the oligometastatic state is distinct from extensive metastasis and represents a potentially curable subset of patients.² Others believe that oligometastasis represents only one part of tumor metastasis, and excessive local treatment may lead to greater toxicity and limited benefits.

Although there is no universally acknowledged definition of oligometastasis in cancer, the oligometastatic state has been accepted by clinicians and widely applied to various tumors, such as lung,⁵ breast,¹ and prostate cancers.⁶ Globally, the number of clinical trials investigating the clinical benefits of local treatment for oligometastasis has been rising steadily. Among them, notable clinical trials include studies on non-small cell lung cancer,⁷ the multi-center SABR-COMET phase II trial,⁸ studies on prostate cancer,^9,10 and prospective clinical studies on breast cancer.¹¹ Presently, most researchers acknowledge the role of local treatment in patients with oligometastasis. Local treatments mainly include surgery, radiotherapy, radiofrequency ablation, and microwave ablation. Surgery is limited by factors such as metastatic site and the patient's general condition. Compared to surgery, radiofrequency ablation, microwave ablation, and other techniques, radiotherapy is the most suitable local treatment method for oligometastatic tumors, given its effective control over the radiation dose, particularly when targeting organs at risk.^7–10

Radiotherapy is one of the main modalities of cancer treatment. In traditional conventional fractionated radiotherapy (CFRT), treatment is generally performed by administering standard doses over the course of several weeks. With the rapid development of radiotherapy techniques, stereotactic body radiation therapy (SBRT) is currently associated with longer overall survival (OS). However, at the beginning of this study, the application of SBRT in less metastatic tumors was mainly in the clinical research stage.⁸ Additionally, SBRT has high requirements for radiotherapy equipment and technology, which many hospitals in developing countries cannot meet. Contrastingly, hypofractionated radiotherapy (HFRT) has slightly lower requirements for radiotherapy equipment and techniques. Therefore, HFRT has been widely used in clinical practice. Compared to CFRT, HFRT involves administering higher radiation doses over fewer sessions.^12,13 Studies have reported that adding HFRT to immunotherapy can enhance anti-tumor immunity and improve prognosis.^14,15 For the clinical treatment of certain tumors, higher physical or biological doses are associated with better local control and better survival.^16,17 Local high-dose radiation appears to be more lethal to tumors than what is predicted by standard radiobiological models.¹⁸ This may be because HFRT not only kills tumor cells directly but also stimulates the body's innate and adaptive immunity to induce tumor cell death and enhance its immune response to cancer.^19,20

Limited evidence on the effect of HFRT on the survival and safety of patients with oligometastatic tumors. This study aimed to evaluate the therapeutic effect of HFRT on patients with well-controlled primary tumors and one to five oligometastatic tumors. Hence, we analyzed the survival rate, local control rate, and safety of patients with oligometastatic tumors who received HFRT.

Methods

Basic Patient Information

A retrospective analysis was carried out on the clinical data of 65 patients with oligometastatic tumors who were treated in the First Affiliated Hospital of Bengbu Medical College from January 2020 to December 2022. Patients were ≥18 years of age, showed an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–1, and had a life expectancy of at least 6 months at the start of treatment. Their primary tumors were well controlled, and imaging tests such as computed tomography (CT), magnetic resonance imaging (MRI), emission CT, and positron emission tomography CT (PET-CT) confirmed the absence of progression at the primary site since receiving treatment. All metastatic foci must be suitable for HFRT, with one to five foci per patient and a maximum of three foci allowed in any one organ. The exclusion criteria were as follows: comorbid brain metastases, severe medical comorbidities, the presence of another malignant tumor that is progressing or requires high-dose systemic chemotherapy, and pregnant or breastfeeding women. Appropriate regulatory approval was obtained for this study. This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of the First Affiliated Hospital of Bengbu Medical College (2020KY109) on December 21, 2020. The reporting of this study conforms to STROBE guidelines.²¹ All the patient data were de-identified. Written informed consent was obtained from all patients.

Radiotherapy

The treatment regimens of the 65 patients enrolled in this study are shown in Table 1. Based on the actual conditions of the primary tumor, 46 (70.8%) patients received surgical treatment, 14 (21.5%) patients received radiotherapy, and 5 (7.7%) patients received other or no treatment. Subsequently, based on the tumor location and indications, patients received the appropriate HFRT regimen for local radiotherapy to control metastasis-induced symptoms, delay symptom onset, or delay disease progression or death. The planning gross tumor volume of HFRT was 82.93 cm³ (range: 10.12-562.80 cm³), the radiation dose range was 20–60 Gy/5–15 fractions, and the median radiation dose was 50 Gy/10 fractions. In the three sites with the highest metastasis, the radiation dose range was 20–60 Gy/5–13 fractions for bone metastasis, 40–60 Gy/5–14 fractions for lung metastasis, and 40–60 Gy/5–14 fractions for liver metastasis. Radiation techniques include intensity-modulated radiation therapy, volumetric modulated arc therapy, and tomoTherapy, using 6MV-X energy. Treatment planning systems include Pinnacle, Monaco, and TomoTherapy. All patients were verified using daily cone beam CT during radiotherapy. Some patients received maintenance chemotherapy after HFRT. Depending on the primary tumor, the combination drug therapy administered included apatinib, bevacizumab, tislelizumab, camrelizumab, sintilimab, cisplatin, and tegafur (with multiple drug combinations).

Table 1.

Treatment Regimens.

Item	n (%)
Treatment modality of primary tumor (%)
Surgery	46 (70.8)
Radiotherapy	14 (21.5)
Others	5 (7.7)
PGTV (volume) –cm³	82.93 (10.12562.80)
Radiation dose (range) –Gy/F	49.32/9.72 (20/5∼60/15)
Post-HFRT maintenance therapy (%)
Apatinib	5 (7.7)
Tegafur	9 (13.8)
Tislelizumab	9 (13.8)
Camrelizumab	8 (12.3)
Bevacizumab	8 (12.3)
Cisplatin	6 (9.2)
Sintilimab	6 (9.2)
Irinotecan	3 (4.6)
Others	24 (36.9)

Abbreviations: PGTV, planning gross tumor volume.

Patient Follow-up and Outcomes

Patients were followed up after the completion of the treatment regimens. During the follow-up, patients received clinical examinations at 4, 8, and 12 weeks. Each follow-up included routine blood tests, biochemical and tumor marker tests, physical examinations, imaging examinations, and other necessary examinations, all performed at the physician's discretion. Follow-up visits were maintained for 24 months. Short-term efficacy evaluation, disease progression status, incidence of adverse events (AEs), and survival status were recorded and evaluated.

Statistical Analysis

Statistical analysis was performed using the SPSS 21.0 package (SPSS Inc., Chicago, IL, USA). The Kaplan–Meier method was employed to estimate progression-free survival (PFS) and OS. Descriptive statistics were calculated for all other data. PFS was calculated based on the date of the first HFRT to the date of progression, death, or final follow-up. OS was calculated from the date of HFRT initiation to the date of death or censored on the date of the final follow-up. Owing to the small sample size, we were unable to perform statistical comparisons with historical controls. Patients with missing data were excluded from the statistical analysis. The significance level was set at 0.05.

Results

Baseline Characteristics of Patients

The basic information and disease characteristics of the patients are shown in Table 2. The patients’ median age was 60 years (range: 19-80 years), with a higher percentage of male (58.5%) than female (41.5%) patients. Additionally, 61.5% of patients had an ECOG score of 1, and 95.4% reported being non-smokers. The most common primary tumor site was the lung (accounting for 20%), followed by the breast (16.9%). The most common pathological type was squamous cell carcinoma (accounting for 30.8%), followed by adenocarcinoma (29.2%). Overall, 63.1% of patients had one metastatic focus, and metastatic foci were found in the lungs for 36.9% of patients.

Table 2.

Baseline Characteristics of Patients.

Characteristic	n (%)
Median age (range) –years	60 (19-80)
Sex
Female	27 (41.5)
Male	38 (58.5)
ECOG score
0	25 (38.5)
1	40 (61.5)
Smoking status
Smoker	3 (4.6)
Non-smoker	62 (95.4)
Primary tumor site
Lung	13 (20.0)
Breast	11 (16.9)
Esophagus	10 (15.4)
Nasopharynx	6 (9.2)
Liver	3 (4.6)
Rectum	9 (13.8)
Others	13 (20.0)
Pathological type
Squamous cell carcinoma	20 (30.8)
Adenocarcinoma	19 (29.2)
Invasive carcinoma	10 (15.4)
Hepatocellular carcinoma	3 (4.6)
Others	13 (20)
No. of metastatic foci
1	41 (63.1)
2	18 (27.7)
3–5	6 (9.2)
Location of metastatic foci
Bone	14 (21.5)
Liver	20 (30.8)
Lung	24 (36.9)
Others	7 (10.8)

Abbreviations: ECOG, eastern cooperative oncology group.

Progression-Free Survival

The data cutoff date was July 30, 2023, and the median follow-up time was 26 months (range: 0.8-37.5). The median PFS was 15 months (95% CI: 9.36-20.64) (Figure 1). Among all 65 patients, the 1-year PFS rate was 53.8%, and the 2-year PFS rate was 40.0%. The 1- and 2-year PFS rates categorized based on the location of metastatic foci are shown in Table 3.

Figure 1.

Progression free survival of the patients treated with HFRT.

Table 3.

1- and 2-Year PFS Rates Grouped Based on Location of Metastatic Foci.

	n	1-year PFS rate	2-year PFS rate
All patients	65	53.8	40.0
Location of metastatic foci
Bone	14	42.9	28.6
Liver	21	52.4	33.3
Lung	23	60.9	52.2
Others	7	57.1	42.9

Overall Survival

The median OS was 28 months (95% CI: 16.71-39.29) (Figure 2). The 1-year OS rate was 73.8%, and the 2-year OS rate was 56.9%. Patients with nasopharynx (83.0%) as the primary tumor site had the highest 2-year OS rate, followed by esophagus (60.0%) and lung (46.2%). The 1- and 2-year OS rates categorized based on the location of metastatic foci are presented in Table 4.

Figure 2.

Overall survival of the patients treated with HFRT.

Table 4.

1- and 2-Year OS Rates Categorized Based on Location of Metastatic Foci.

	n	1-year OS rate	2-year OS rate
All patients	65	73.8	56.9
Location of metastatic foci
Bone	14	64.3	64.3
Liver	21	66.7	38.1
Lung	23	87.0	78.3
Others	7	71.4	28.6

Short-Term Efficacy Evaluation After Treatment

Therapeutic efficacy was evaluated objectively by the evaluators 3 months after treatment based on imaging findings such as CT, MRI, and PET-CT. A few patients who showed partial response on imaging underwent pathological examination. Of the 65 patients with oligometastatic tumors at 3 months post-HFRT, nine (13.8%) showed a complete response (CR), 32 (55.4%) showed a partial response (PR), 13 (20.0%) showed stable disease, and nine showed progressive disease. Additionally, two patients died within 3 months or did not receive imaging examinations and only maintained follow-up visits. The 3-month efficacy grouped based on baseline characteristics is shown in Table 5.

Table 5.

Three-Month Efficacy Grouped Based on Baseline Characteristics.

	n	CR	PR	SD	PD	Death or follow-up
Sex
Female	27	6 (22.2)	14 (51.9)	3 (11.1)	4 (14.8)	0
Male	38	3 (7.9)	18 (47.4)	10 (26.3)	5 (13.2)	2 (5.3)
Age
<60 years	31	4 (12.9)	14 (45.2)	7 (22.6)	4 (12.9)	2 (6.5)
≥60 years	34	5 (14.7)	18 (52.9)	6 (17.6)	5 (14.7)	0
ECOG score
0	25	5 (20.0)	11 (44.0)	6 (24.0)	1 (4.0)	2 (8.0)
1	40	4 (10.0)	21 (52.5)	7 (17.5)	8 (20.0)	0
Pathological type
Squamous cell carcinoma	20	3 (15.0)	9 (45.0)	3 (15.0)	5 (25.0)	0
Adenocarcinoma	19	1 (5.3)	11 (57.9）	4 (21.1)	2 (10.5)	1 (5.3)
Invasive carcinoma	10	2 (20.0)	5 (50.0)	1 (10.0)	2 (20.0)	0
Others	16	3 (18.8)	7 (43.8)	5 (31.3)	0	1 (5.3)
Location of metastatic foci
Bone	14	3 (21.4)	5 (35.7)	4 (28.6)	1 (7.1)	1 (7.1)
Liver	20	0 (0.0)	12 (57.1)	4 (19.0)	5 (23.8)	0
Lung	24	4 (17.4)	11 (47.8)	5 (19.0)	2 (8.7)	1 (7.1)
Others	7	2 (28.6)	4 (57.1)	0	1 (14.3)	0

Safety

The post-treatment AEs experienced by the 65 patients were summarized to evaluate the treatment's safety. Side effects observed in all patients are shown in Table 6. Treatment-related AEs occurred in 58 patients (89.2%); however, most were low-grade AEs, and grade 5 AEs were not reported. Radiation pneumonitis was the most common AE, with 17 (26.2%) patients reporting grade 1–2 radiation pneumonitis and two (3.1%) reporting grade 3–4. The second most common was nausea, with nine (13.8%) patients experiencing grade 1–2 nausea and 1 patient (1.5%) experiencing grade 3 nausea. Six (9.2%) patients experienced diarrhea after treatment, all of which were either grade 1 or 2. One patient had grade 3 myelosuppression.

Table 6.

Summary of Adverse Events.

Adverse events	Grade 1–2 [n (%)]	Grade 3–4 [n (%)]	Total [n(%)]
Nausea	9 (13.8)	1 (1.5)	10 (15.4)
Diarrhea	6 (9.2)	0	6 (9.2)
Radiation pneumonitis	17 (26.2)	2 (3.1)	29 (44.6)
Intestinal mucositis	1 (1.5)	0	1 (1.5)
Myelosuppression	3 (4.6)	1 (1.5)	4 (6.2)

Discussion

Malignant tumors are characterized by systemic metastasis, which not only deteriorates the patient's quality of life but can also shorten their survival time.²² Detection of metastasis in any body part suggests potential occurrence in multiple sites or organs. Previously, local treatment for metastasis was considered to be of limited value in such cases.²³ However, some scholars posit that the oligometastatic state offers a unique therapeutic window for malignant tumors, whereby visible metastatic foci can be ablated to reduce tumor burden, suppress tumor progression to a polymetastatic state, and mitigate any associated or impending morbidity and mortality.^24,25 HFRT involves a special mode of radiotherapy fractionation. Its main advantage is the shorter overall treatment time, which is more convenient for patients and doctors, enhances the patient's treatment compliance, and reduces their financial burden.²⁶ Notably, low toxicity levels were depicted, underscoring the efficacity of HFRT in the treatment of oligometastatic tumors.

In this study, 65 patients with oligometastatic and well-controlled primary tumors, each having one to five metastatic foci, were enrolled. Among them, lung was the most common primary site, and the most common pathological type was squamous cell carcinoma. Most patients had one metastatic focus, with the lung being the most prevalent location, followed by the liver. We evaluated the therapeutic efficacy of HFRT for patients with different types of oligometastatic tumors and analyzed its efficacy and safety.

The radiobiological mechanism in HFRT differs from that of conventional radiotherapy. In conventional radiotherapy, tumor cells are killed directly through irreparable DNA double-strand breaks, leading to mitotic catastrophe and apoptosis, whereas the tumor response to radiotherapy consists of reoxygenation, repopulation, repair, and redistribution.^13,27,28 However, in HFRT, tumor cells may be eliminated via necrosis through single high-dose irradiation.²⁷

Traditional CFRT involves administering a single dose of 1.8–2.2 Gy once daily, five times a week.²⁹ Unlike standard CFRT, HFRT can either increase or decrease the biologically effective dose in the normal tissues of organs at risk, depending on the dose rate administered.³⁰ In this study, the radiation dose range of HFRT was 20–60 Gy/15 F. The lowest radiation dose was administered at the thoracic spine, and the patient's primary tumor was located in the rectum. After surgical treatment, two vertebral metastases were treated with 20 Gy/5 F. The patient reported no AEs during radiotherapy. The highest radiation dose was administered in the lung, and the patient's primary tumor was located in the nasopharynx. After concurrent chemoradiotherapy, one metastatic focus appeared in the lung, and 60 Gy/8 F was administered. No apparent discomfort was reported during radiotherapy, and grade 1 radiation pneumonitis occurred after radiotherapy. For patients with painful bone metastases, numerous trials have been conducted to compare various low-dose radiotherapy regimens, which revealed no difference in pain response and high local failure rates.^31,32 However, a previous study reported that high-dose single-fraction radiotherapy can achieve higher local control rates.³³ Clinical practice has shown that increasing the single dose and total dose can improve the time spent on pain relief while enhancing local control rates.

Among the 65 patients in this study, 13.8% reported grade 1–2 nausea, and 1.5% experienced grade 3–4 nausea during the treatment period. These results are lower compared to the incidence rates of 56% for grade 1–2 nausea and 22% for grade 3–4 nausea reported in other studies.³⁴ Radiation pneumonitis was the most common AE, with 17 patients showing grade 1–2 symptoms and two patients showing grade 3–4 symptoms. Only one patient developed grade 1–2 intestinal mucositis. Similarly, a study on HFRT combined with immunotherapy for extensive-stage small-cell lung cancer also reported one patient developing grade 3 intestinal mucositis.¹⁵ There were no deaths related to the treatment regimen. With the development of radiotherapy technology, MRI-guided radiotherapy can improve the precision of radiotherapy and reduce the side effects of radiotherapy.³⁵

In this study, the median PFS and OS were 15 and 28 months, respectively. A study on HFRT for mediastinal lymph node metastasis after esophageal cancer surgery reported a median OS of 24.2 months.³⁶ Among all 65 patients with oligometastatic tumors, the 1-year and 2-year PFS rates were 53.8% and 40.0%, respectively. The 1-year OS rate was 73.8%, and the 2-year OS rate was 56.9%. By comparing the PFS and OS rates among patients with different locations of metastatic foci, we found that patients with lung metastasis had higher 1-year and 2-year PFS rates of (60.9% and 52.2%, respectively) and higher 1-year- and 2-year OS rates (73.8% and 56.9%, respectively) than those of other patients.

At 3 months after HFRT, among the 65 patients with oligometastatic tumors, 13.8% achieved CR, whereas 55.4% showed tumor shrinkage and achieved PR. The CR rate found in this study is similar to that found in other reports related to oligometastatic tumors.³⁷ Compared to the PR rates of oligometastatic tumors reported by Shen et al and Chiloiro et al, the PR rate of patients in this study is significantly higher.^38,39

Study Limitations

This study has certain limitations. First, our sample size was relatively small. Second, the analysis did not include the 5-year OS rate due to the short follow-up time. Third, we conducted a retrospective analysis, inevitably resulting in some missing data and certain biases, such as selection bias, reporting bias, and confounding effects. Nevertheless, these limitations do not preclude our study from serving as a reference for clinical research on HFRT for oligometastatic tumors.

Conclusions

Performing HFRT on patients with oligometastasis resulted in favorable PFS and OS rates and showed good safety. HFRT may improve the clinical management of oligometastasis. Further randomized trials are needed to verify the benefits of this treatment.

Footnotes

Abbreviations

Acknowledgments

We extend our gratitude to the participants of this study.

Author Contributions

All authors contributed to this work, with responsibilities extending, but not limited to the following: Aili Xuan and Xianming Li designed the study. Qian Sun drafted the manuscript. Hanqing Zhao, Xianwen Zhang, Suli Zhang, and Gengming Wang collected data. Zelai He and Hao Jiang analyzed the data. All authors read and approved the final manuscript.

Consent to Participate

Written informed consent was obtained from all patients.

Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Ethical Considerations

This study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of the First Affiliated Hospital of Bengbu Medical College (2020KY109) on December 21, 2020.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Research Funds of the Joint Research Center for Regional Diseases of IHM [2023bydjk002] and the Special Fund for Key Support and Cultivation of Bengbu Medical University [2023bypy017]. The rapid service fee was funded by the First Affiliated Hospital of Bengbu Medical University.

ORCID iD

Xianming Li

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