Hypofractionated stereotactic radiotherapy for brain metastases in lung cancer patients: Dose‒response effect and toxicity

doi:10.21203/rs.3.rs-2853789/v1

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Hypofractionated stereotactic radiotherapy for brain metastases in lung cancer patients: Dose‒response effect and toxicity

https://doi.org/10.21203/rs.3.rs-2853789/v1

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Background

Lung cancer is the main cause of brain metastases, and approximately 40% of lung cancer patients are found to have brain metastasis during the course of the disease. For patients with limited brain metastases, hypofractionated stereotactic radiotherapy (HSRT) has been proven feasible. However, the optimal dose schedule of HSRT remains inconclusive. We aimed to investigate the dose response and toxicity in patients treated with HSRT.

Methods

A retrospective analysis was performed of lung cancer patients treated with 5-fraction HSRT for 1–10 brain metastases at Hangzhou Cancer Hospital from January 1, 2019, to January 1, 2021. All patients were followed up with MRI every 3 months after HSRT. The 1-year intracranial local control rate (iLC) was estimated using the Kaplan‒Meier method. The adverse radiation effects (AREs) were evaluated according to the criteria of the CTCAE 5.0.

Results

Forty patients with 70 brain metastases were reviewed. The median prescription dose was 30 (range, 25–40) Gy. The median maximum diameter of brain metastases was 1.3 (range, 0.6-4.0) cm. The 1-year iLC was 75.6% for patients treated with ≤ 30 Gy vs. 88.8% for patients treated with > 30 Gy (P = 0.09). For patients treated with HSRT combined with targeted therapy, immunotherapy and chemotherapy, the 1-year iLC was 88.9%, 100%, and 45.0%, respectively. No significant associations were observed between maximum diameter, tumour location, pathological type, or number of brain metastases. The rate of all-grade AREs was 32.5%. All AREs were grade 1–2 except for 2 patients with a total dose of 40 Gy who experienced grade 3 headache.

Conclusions

Increasing the prescription dose of HSRT for brain metastases is expected to improve local control, but the occurrence of side effects should also be carefully considered. Systemic therapy can impact the iLC rate, and individualized treatment regimens need to be developed.

brain metastases

hypofractionated stereotactic radiotherapy

lung cancer

For many decades, lung cancer has been the most common cancer and the leading cause of cancer death worldwide [1]. With the rapid development of modern cancer treatment, patients with metastatic disease can have a long survival time. A total of 20–40% of non-small cell lung cancer (NSCLC) patients have brain metastasis during the course of disease, and the incidence is even higher in small cell lung cancer (SCLC) patients [2–3]. The cumulative incidence of brain metastases has increased in these long-term survivors. Currently, brain radiotherapy, including whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS), is still one of the most important treatments for brain metastases [4].

However, patients receiving WBRT often experience cognitive decline, and only one full dose can be delivered safely and efficaciously [5]. For patients with limited brain metastases, hypofractionated stereotactic radiotherapy (HSRT) has been proven feasible. Previous studies have shown that HSRT offers durable local control with limited toxicity [6, 7]. The major advantage of SBRT is the capacity to deliver a higher biologically effective dose (BED) to critically located metastases while reducing the normal tissue irradiated, thus maintaining an acceptable risk of adverse radiation effects (AREs).

Currently, a schedule of 30 Gy in five or six fractions is commonly used in clinical practice. However, a uniform dose might be insufficient for large tumours. Aoyama’s study showed that the 1-year local control rate for lesions > 3 cm³ was 59% compared to 96% for those ≤ 3 cm³ [8]. Marcrom’s study showed that lesions < 3 cm in diameter had a 1-year LC rate of 95% compared to 75% for lesions ≥ 3 cm treated with fractionated stereotactic radiotherapy [9]. Ishihara’s study showed that an increased dose significantly improved the 1-year LC for PTVs ≥ 4 cm³ [10]. Although a few researchers have investigated high doses in patients with brain metastases, the optimal dose and its safety are still unknown in clinical practice.

This study reports the clinical and radiographic outcomes of HSRT for brain metastases with a focus on assessing factors that contribute to treatment response.

Patient selection

A retrospective analysis was performed in patients with 1–10 brain metastases treated with 5-fraction HSRT at Hangzhou Cancer Hospital from January 1, 2019, to January 1, 2021. Patient characteristics, treatment regimens, and dosimetric factors were retrospectively obtained for analyses. The inclusion criteria were as follows: (1) patients with histologically confirmed lung cancer; (2) patients with 1 to 10 brain metastases detected by magnetic resonance imaging (MRI); and (3) patients aged 18–75 years old. The exclusion criteria were (1) prior surgery for brain metastasis and (2) prior brain radiotherapy. All patients were treated using LINAC-based HSRT and received 25–40 Gy in 5 fractions. None of the patients received WBRT before or after HSRT.

Treatment

All patients underwent a noncontrast-CT simulation scan of the entire head region with 1.25–1.5 mm slice thickness using a thermoplastic mask for immobilization. Within two weeks prior to treatment, the patients underwent three-dimensional gadolinium-enhanced axial MRI scans (3D-FLASH) of the head with standard axial and coronal FLAIR and axial T2-weighted and gadolinium contrast-enhanced T1-weighted sequence acquisitions, with a 1.25–1.5 mm slice thickness. The CT simulation and MRI scans were fused semiautomatically, and target and avoidance structures were contoured using Varian Eclipse 13.5/Revision 1.0 treatment planning software.

Gross tumour volume (GTV) included all contrast-enhancing brain metastases on T1-weighted contrast-enhanced MRI. No additional margin was added for the clinical target volume (CTV). The planning target volume (PTV) was created by adding a 3 mm margin to the GTV. HSRT was delivered using Varian True Beam linear accelerators equipped with micro-multileaf collimators using a flattening filter-free beam of 6-MV energy and intensity-modulated radiation therapy (IMRT). Treatment planning guidelines specified coverage of 95% of the PTV by the prescription dose. In cases where PTV coverage cannot be achieved without exceeding organs at risk doses, PTV coverage is to be compromised. All patients were treated on hexapod couches, with a 1-mm tolerance for positional error. Daily cone-beam CT was used for treatment setup verification.

Follow-up and statistics

After treatment, we performed follow-up gadolinium-enhanced axial MRI scans 1 month after SBRT and then every 3 months. Local control of all treated lesions and overall survival, starting with the first day of irradiation, were calculated by the Kaplan‒Meier method. The treatment response of brain metastases was classified as complete response, partial response, stable disease, and progressive disease, according to RANO BM criteria.

ILC was defined as a no more than 20% increase in the longest diameter of the target lesion on follow-up T1-weighted sequence gadolinium contrast-enhanced MRI. Local failure was defined as a 20% increase in the longest diameter of the target lesion with at least one lesion increasing by an absolute value of 5 mm. Subcentimetre brain metastasis response assessment was also reported as per RANO BM suggestions using a minimum 3 mm size increase as the threshold for progression. Intracranial progression free survival (iPFS) was defined as the time between the start of HSRT and intracranial progressive disease. AREs were evaluated according to the criteria of the CTCAE 5.0. Radiation necrosis (RN) was defined as radiographic progression of disease followed by stabilization or regression in the absence of oncologic directed therapies or as suggested by a low relative cerebral blood volume on MR perfusion-weighted imaging.

Subgroups were compared by use of the generalized Wilcoxon test for univariate analysis and the Cox proportional hazard model for multivariate analysis. Variables analysed for local control included age, sex, size of metastasis, histology, number of metastases and use of systemic agents. All P values were 2-sided, with P < 0.05 considered to indicate a statistically significant result.

Patient and lesion characteristics

The characteristics of these patients and tumours are presented in Table 1. Forty lung cancer patients with 70 brain metastases treated with HSRT were reviewed. The median age was 64 years (range 43–87). The median number of target brain metastases was 1 (range 1–4), and 63.8% of patients had a single brain metastasis. The median prescription dose was 30 Gy (range, 25–40 Gy) in 5 fractions. The median follow-up was 10 months. The median maximum diameter and volume of brain metastases were 1.3 cm (range, 0.6-4.0 cm) and 2.4 cm³ (range, 0.2–16.7 cm³), respectively. Among the 70 brain metastases, the most common histology was adenocarcinoma (85.7%). The most common concurrent systemic therapies were targeted therapy (62.9%) and chemotherapy (21.4%).

Table 1 Patient and tumor/treatment characteristics

Intracranial efficacy

We recorded the greatest change from baseline in the longest diameter of treated brain metastases and evaluated treatment efficacy in RANO BM criteria. The 1-year iLC rate of all lesions was 80.3%. For those who developed local failure, the median iPFS was 9 (range, 2–13) months. At the cut-off date, intracranial progression occurred in 12 of the 70 lesions. The 1-year iLC was 75.6% for patients treated with ≤ 30 Gy vs. 88.8% for patients treated with > 30 Gy. The iLC rate was lower in patients with a prescription dose of ≤ 30 Gy (P = 0.09, Fig. 1).

Systemic therapy also had an effect on the local control rate (Fig. 2). For patients treated with HSRT combined with targeted therapy or immunotherapy, the 1-year iLC was 88.9% and 100%, respectively, significantly higher than those receiving HSRT combined with chemotherapy (45.0%).

According to the gene mutation status, we performed further analyses by dividing the pathological type of adenocarcinoma lesions into the sensitive gene mutation group and the no mutation group. In the sensitive gene mutation group, the 1-year iLC was 84.3% for patients treated with ≤ 30 Gy vs. 90.2% for patients treated with > 30 Gy (P = 0.34, Fig. 3A). The effect of the prescription dose on iLC was more obvious in those without a sensitive gene mutation group, and the 1-year iLC was 58.2% for patients treated with ≤ 30 Gy vs. 90.9% for patients treated with > 30 Gy (P = 0.08, Fig. 3B).

Maximal lesion diameter was not found to be a risk factor for 1-year iLC in this model (P = 0.39, Fig. 4). The 1-year iLC was 83.9% for large (> 1.5 cm) lesions compared with 79.8% for small lesions (≤ 1.5 cm). The iLC rate was similar for small lesions and large lesions.

No statistically significant associations were observed on multivariable regression between tumour location, pathological type, and number of brain metastases with risk of failure.

Adverse radiation effects

All-grade AREs are shown in Table 2. The rate of all-grade AREs was 32.5%. Among 13 patients with AREs, 69.2% of AREs occurred within 6 months after HSRT (median 5.8 months). The most common AREs were headache (53.8%), localized oedema (15.4%), nausea (15.4%), hearing loss (7.7%), ataxia (7.7%), and memory impairment (7.7%). All AREs were grade 1–2 except for 2 patients with a total dose of 40 Gy who experienced grade 3 headache.

Table 2 Adverse radiation effects

Brain metastasis usually carries poor prognostic foresight. Radiation therapy is a key component in the management of brain metastases. The challenge for radiation oncologists treating brain metastases is to individualize the treatment approach depending on patient and tumour factors. This study reports favourable outcomes following HSRT for intact brain metastases using 5-fraction schedules. We report a high 1-year local control rate of 84.4% for all lesions, with an acceptable ARE rate of 27%. Delivery of a higher radiation dose was associated with higher rates of local control. These findings may have implications for the implementation of HSRT in the clinic as well as the design of prospective HSRT trials.

HSRT for brain metastases is now common practice. Previously reported 1-year local control estimates of HSRT have ranged from 52%-95% [11–15]. The 1-year local control in our study appears comparable. One important feature of our study was that we excluded patients who had previously undergone brain radiotherapy or surgery, thereby resulting in a more realistic local control rate of HSRT.

Currently, 30 Gy in five fractions is the recommended treatment [16] and is commonly used in clinical practice. However, we observed an improvement in LC when treating with > 30 Gy/5 fractions, with a 1-year cumulative incidence of local failure of 11.2%. Similar results have also been reported [17–19]. Sten Myrehaug’s study showed that local failure at 1 year was 33% for patients treated with < 30 Gy/5 fractions versus 19% for patients treated with ≥ 30 Gy/5 fractions, with a total dose of < 30 Gy as opposed to ≥ 30 Gy (HR, 1.68, P = 0.03) as a significant predictor of local failure [18]. After retrospective analysis of 525 patients with 720 brain metastases treated with HSRT, Baliga Sujith et al. found that the tumour control probability increased with the BED₁₀ with a hazard ratio equal to 0.77 for every 10 Gy₁₀. A 1-year local control rate > 70% seemed to be achieved with a BED₁₀ of 40 to 50 Gy. A BED₁₀ of 50 to 60 Gy seemed to achieve a 1-year local control rate of at least 80% at 12 months [20]. Our study confirmed a 1-year tumour control estimate with dose escalation. Therefore, our results further support the recognition that the radiation dose is dependent on local tumour control.

Our data did not find that the tumour diameter affected the rate of 1-year local control after HSRT (P = 0.39. Figure 4). For small lesions treated with HSRT, the 1-year local control rate was comparable to that for small lesions treated with single-fraction SRS. The high proportion of local control observed in the present study supports the growing employment of HSRT according to the literature, which confirmed small tumour size as a prediction index of improved local tumour control, and HSRT appears to be a reasonable alternative for small brain metastases [21–22]. Studies have shown that SRS in the treatment of large lesions compared with small lesions can significantly reduce the local control rate of large lesions. However, when we set the tumour diameter to ≥ 1.5 cm, we did not find that the local control rate decreased. Due to the high ratio of hypoxic cells in large brain metastases, HSRT may have an advantage with respect to LC versus single-fraction SRS, especially for large metastases. Given that surviving hypoxic tumour cells reoxygenate during fractionation and become more sensitive to subsequent irradiation, reoxygenation between dose fractions is a pivotal phenomenon that should be fully utilized in HSRT [23].

Generally, higher iLC was observed in patients receiving targeted therapy or immunotherapy combined with HSRT than in those receiving chemotherapy combined with HSRT. Common chemotherapies have been evaluated in clinical trials but have failed to demonstrate a significant benefit in patients with brain metastases [24–25]. For targeted therapy combined with HSRT, a good response has recently been reported in non-small cell lung cancer patients with brain metastases treated with tyrosine kinase inhibitors (TKIs). Many targeted therapies, such as EGFR-TKIs or ALK-TKIs, have good central nervous system (CNS) penetration with an intracranial response rate of more than 70% [26]. HSRT can disrupt the BBB, thereby increasing the CNS penetration of TKIs [27]. Therefore, combinatorial HSRT and TKIs may prove to be useful. A retrospective study showed that the local control rate of patients with NSCLC brain metastasis treated with HSRT in combination with TKIs was higher than that of patients treated with HSRT alone [28]. For patients receiving targeted therapy, a lower dose of brain HSRT can also result in a higher local control rate of brain metastases. In patients with negative driver genes, a higher prescription dose may be required to improve intracranial lesion control (Fig. 3).

For immunotherapy combined with HSRT, it has been reported that radiotherapy may be able to counteract the immunosuppressive tumour microenvironment through a variety of mechanisms [29–31]. HSRT is known to increase both innate and adaptive immune responses, making tumour cells more susceptible to T-cell-mediated killing that will boost local effects [32].

Our study showed that none of the patients receiving HSRT had severe CNS toxicity. According to previous reports, the risk of radiation-induced CNS toxicity generally increases with higher doses, prior history of radiation therapy, and larger target volumes [33–35]. HSRT does not damage surrounding tissues to the same extent as it better enables cellular reoxygenation and target volume redistribution, thus better preserving normal tissues than single-fraction SRS [36]. Minniti et al. published a retrospective study that compared the incidence of radionecrosis after single-fraction SRS with multifraction SRS. The results showed that the probability of radionecrosis after treatment with multifraction SRS was significantly lower than that of single-fraction SRS [37]. Due to the small sample size and the difficulty in identifying whether CNS toxicity is caused by brain metastasis or HSRT, we have not found any predictive factors for toxicity.

There are several limitations to this preliminary study. First, the current study was retrospective in design and based on a single institutional experience. There may be a bias in the selection of patients. Second, our sample size was relatively small, and some patients were followed for a shorter time. This led to some numerical differences in the results, but the differences did not reach statistical significance. However, robust data support the safety and efficacy of HSRT in the treatment of metastases.

Hypofractionated stereotactic radiation therapy is an effective and safe treatment option for brain metastases in patients with non-small cell lung cancer. Currently, the dose of HSRT commonly used in clinical practice may not be the optimal dose. When the prescription dose escalation was > 30 Gy in 5 fractions, the local control rate was also improved. The systemic treatment patients receive affects the rate of local control of brain metastases; therefore, it is very important to administer different treatment regimens according to the individual conditions of patients.

HSRT Hypofractionated stereotactic radiotherapy

iLC Intracranial local control

NSCLC Non-small cell lung cancer

SCLC Small cell lung cancer

WBRT Whole-brain radiotherapy

SRS Stereotactic radiosurgery

BED Biologically effective dose

AREs Adverse radiation effects

MRI Magnetic resonance imaging

GTV Gross tumour volume

CTV Clinical target volume

PTV Planning target volume

IMRT Intensity-modulated radiation therapy

iPFS Intracranial progression free survival

RN Radiation necrosis

TKIs Tyrosine kinase inhibitors

CNS Central nervous system

Acknowledgements

Not applicable.

Ethical Approval and Consent to participate

This study had been approved by the Institutional Ethics Review Board of the Hangzhou Cancer Hospital (#73/HZCH-2022).

Consent for publication

All the authors have read and agree to the content of the paper.

Availability of supporting data

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

Competing interests

The authors declare no conflict of interest.

Funding

This work was supported by the Science and Technology Bureau of Hangzhou (No. 20220919Y050) and the Science and Technology Bureau of Hangzhou (No. 202004A19).

Authors' contributions

All authors involved in the article and approved the final manuscript. All authors reviewed the manuscript.

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No competing interests reported.

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Hypofractionated stereotactic radiotherapy for brain metastases in lung cancer patients: Dose‒response effect and toxicity

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Abstract

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Background

Materials and Methods

Patient selection

Treatment

Follow-up and statistics

Results

Patient and lesion characteristics

Intracranial efficacy

Adverse radiation effects

Discussion

Conclusions

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