Central-boost Ablative Radiation Therapy for Solid Tumors: Study Protocol of a Single-arm, Phase II Trial (CBART)

Abstract

Background

Though stereotactic body radiation therapy (SBRT) has been widely used in advanced tumors, ablative doses may not be appropriate in the case of large tumors or those abutting to the gastrointestinal tracts, resulting in unfavorable outcomes. Therefore, partial irradiation with high doses to tumors have been investigated. In order to achieve a larger high dose area within the tumor center, we developed a novel radiation modality, which was central-boost ablative radiation therapy (CBART). It was delivered by SBRT, with a central ablative dose in the tumor and a relatively low margin dose. And we tried to assess the efficacy of CBART for patients with large tumors or tumors adjacent to the gastrointestinal tracts.

Methods

It is a prospective, single-arm, phase II trial. Eligible patients would receive CBART. Gross tumor volume (GTV) was defined as a radiographically evident gross disease. The margin of GTV was shrinked to form central core GTV (cGTV). The volume of cGTV should be 50% of GTV volume. A 2-5 mm margin expansion on GTV formed planning target volume (PTV). While no margin expansion was performed on cGTV. The prescription dose of tumor margin was 30-45Gy/5f, determined by the tumor location and pathological features. While the prescription dose of cGTV was 120%-150% of that of tumor margin. Ninety percent of PTV and cGTV should be covered by the prescription dose. After CBART, sequential systemic therapy, including chemotherapy, targeted therapy or immunotherapy would be given according to pathological types and tumor stages. The primary outcome is one-year local control rate.

Discussion

An ablative dose to the hypoxic tumor center while a relatively low dose to the tumor margin may improve local control in the case of large tumors or those abutting the gastrointestinal tracts. Further investigations are required to assess the clinical benefits of CBART.

Introduction

Stereotactic body radiation therapy (SBRT) has been widely used in various malignant tumors, with high local control and potential survival benefits. However, in the case of large tumors or tumors abutting to the gastrointestinal tracts, including pancreatic cancer and retroperitoneal tumors, ablative doses may not be allowed due to increased risks of radiation-induced gastrointestinal toxicities. Therefore, novel radiation paradigms have been adopted to maintain a durable tumor control without increased incidences of severe adverse effects, which were possibly based on the gradual understanding of potential improved anti-tumor immune response after radiotherapy.

Spatially fractionated radiation therapy (SFRT) has been developed to enhance the radiotherapy therapeutic ratio of advanced bulky large tumors, which delivers a single large dose of radiation within the target volume in a heterogeneous pattern with regions of peak dosage and regions of underdosing. This peak and valley distribution of SFRT might induce unique systemic effects due to the varying damage induced by dose or spatial placement of the beams, and it has been suggested that SFRT with different dose and fractionation schedules may create interspersed areas of intratumoral immune cell sparing and vascular access with the potential for better immune system activation when combined with immunotherapy.^1–3

Additionally, another paradigm, SBRT for PArtial Tumor irradiation targeting HYpoxic segment (SBRT-PATHY) was developed. Ablative doses were given to hypoxic areas with a sharp dose fall-off toward the outside of the tumor in order to spare the normoxic portion and the peripheral tumor microenvironment for evoking nontargeted immune radiobiological effects. ⁴ Based on the similar notion of SFRT and SBRT-PATHY, we proposed a novel radiation modality, which is central-boost ablative radiation therapy (CBART). It is delivered by SBRT, with a central ablative dose in the tumor and a relatively low margin dose. Though there were similarities among them, still differences could be found. While scattered high dose areas were delivered in the tumor by SFRT, a whole ablative dose area was given by SBRT-PATHY and CBART. A low dose was given to the tumor margin by CBART while partial tumor was non-irradiated by SBRT-PATHY.

Given the promise of increased therapeutic ratio of SFRT and SBRT-PATHY by immune priming, we hypothesized that CBART may also elicit effects.^3–5 Therefore, we tried to investigate the outcomes of patients with large tumors or tumors adjacent to the gastrointestinal tracts receiving CBART.

Methods

Patient and Public Involvement

Neither patients nor the public have been involved in the design, recruitment and conduct of this study. The results will be disseminated via scientific journals and academic conference.

Hypothesis

We hypothesize that CBART could improve local control of large tumors or tumors adjacent to the gastrointestinal tracts.

Study Design

This is a prospective, single arm, single center phase 2 trial to evaluate the efficacy of CBART delivered to patients with large bulky tumors or tumors abutting to the gastrointestinal tracts. Patients will receive CBART to the candidate lesion, which would be determined by physicians in the case of multiple lesions. After CBART, systemic therapy, including chemotherapy, targeted therapy and immunotherapy, would be delivered to patients according to pathological tumor types, tumor stages and history of treatment.

Ethics

The study was approved by the institutional review board of our center. The trial has also been registered at ClinicalTrials.org. The trial was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Prior to enrolment, the potential candidates would receive information on the study both verbally and in writing. In details, an authorized physician will explain the nature, scope and possible consequences of the trial to the patient. After the patient decide to participate in the study, the written informed consent would be obtained. The investigators will not assume any demands, including publishing or reporting of individual patient's data, especially data required for this clinical trial, until a valid consent has been obtained. Patients’ data would be kept strictly confidential within the study, but their pseudonymous medical records and information would be extracted from the database and reviewed for trial purposes by authorized individuals other than their treating physicians. The reporting of this study conforms to SPIRIT guidelines. ⁶

Procedures of SBRT and Following Treatment

Regarding SBRT, it is performed via Cyberknife, an image-guided frameless stereotactic robotic radiosurgery system (Accuray Corporation, Sunnyvale CA). Gross tumor volume (GTV) was defined as a radiographically evident gross disease. The margin of GTV was shrinked to form central core GTV (cGTV). The volume of cGTV should be 50% of GTV volume. A 2-5 mm margin expansion on GTV formed planning target volume (PTV). While no margin expansion was performed on cGTV. Dose constraints of organs at risk were referred to the American Association of Physicists in Medicine guidelines in TG-101. ⁷ The initial contours were reviewed together by a radiation oncologist and a radiologist for accuracy. The prescription dose of tumor margin was 30-45Gy/5f, determined by the tumor location and pathological features. While the prescription dose of cGTV was 120%-150% of that of tumor margin. Ninety percent of PTV and cGTV should be covered by the prescription dose.

After SBRT, systemic therapy, including chemotherapy, targeted therapy or immunotherapy, should be determined by physicians according to tumor stage and treatment history.

Study Population and Inclusion Criteria

Patients should require a complete workup, including pathological tissue review, complete laboratory tests, medical history review, tumor markers determination and baseline imaging exams based on tumor types.

Participants are eligible to be included if they meet the inclusion criteria and exclusion criteria.

Inclusion criteria:

1. Age >18 and <75 years old.

2. Pathologically confirmed malignant tumors in the lung, liver, pancreas or retroperitoneal space.

3. Oligometastatic lesions if confirmed metastases.

4. The diameter more than 5 cm or the distance between the tumor and gastrointestinal tracts less than 5 mm.

5. ECOG score of 0-1 point.

6. Adequate bone marrow function (white blood cell count of ≥ 4 × 10⁹/L, neutrophil count of ≥ 2 × 10⁹/L, hemoglobin concentration of ≥ 120 g/L, platelet count of ≥ 100 × 10⁹/L), normal liver function (alanine aminotransferase or aspartate aminotransferase is 2.5 times the upper limit of normal or lower and total bilirubin level of < 17.1μmol/L) and kidney function (creatinine level of < 133μmol/L).

7. Be well informed of all procedures and benefits and adverse effects of the study, and providing written informed consent.

Exclusion criteria:

1. History of radiotherapy to the candidate lesion.

2. History of other tumors.

3. ECOG score of ≥ 2 points.

4. History of active inflammatory bowel disease or peptic ulcer and gastrointestinal bleeding or perforation within 6 months in the case of retroperitoneal tumor.

5. Systemic inflammation required antibiotics.

6. Cardiac dysfunction (NYHA grade II-III) or respiratory dysfunction.

7. Participation in other trials.

8. Pregnant or breast-feeding women.

9. Unable to provide written informed consent and comply with study requirements or follow-up schedule.

Follow-up and Assessments

Patients will receive evaluation before treatment for baseline data and during regular follow-up. The examinations include imaging examinations (based on tumor types), tumor markers (CEA, CA199, etc, based on tumor types), complete blood count, blood biochemical examination (aspartate aminotransferase, alanine aminotransferase, Cr, etc).

Quality of life was assessed by Europe Organization for Research and Treatment of Cancer, Quality of Life Questionnaire-C30 (EORTC QLQ-C30), which should be performed before SBRT and one, three, six, nine and twelve months after SBRT. The EORTC QLQ-C30 is a 30-item questionnaire composed of multi-item scales and single items that reflect the multi-dimensionality of the quality-of-life construct. It incorporates five functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and nausea and vomiting), and a global health and quality-of-life scale. ⁸ The remaining single items assess additional symptoms commonly reported by cancer patients (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea), as well as the perceived financial impact of the disease and treatment. Scores were linearly transformed to a 0 to 100 scale. A clinically relevant change was defined as change in health-related quality of life scores of ≥10 points.^9,10 In the case of imaging examinations, contrast-enhanced CT and MRI will be performed before SBRT, and one, three, six, nine and twelve months after SBRT. Furthermore, PET-CT is conducted at the discretion of physicians if disease progressions are suspected. Details were shown in Table 1.

Table 1.

Treatment and Follow-up Schedule.

Time point	Screening	CBART	Follow-up (laboratory tests and imaging examinations will be performed as the below schedule in following months)
	Day −5-0	Day 1-5	Month 1	Month 2	Month 3	Month 4	Month 5	Month 6	Month 7	Month 8	Month 9	Month 10	Month 11	Month 12
Informed consent	X
Characteristics	X
Treatment history	X
ECOG	X		X	X	X	X	X	X	X	X	X	X	X	X
Inclusion and exclusion criteria	X
Blood routine	X		X	X	X	X	X	X	X	X	X	X	X	X
Liver and kidney functions	X		X	X	X	X	X	X	X	X	X	X	X	X
Coagulation tests	X		X	X	X	X	X	X	X	X	X	X	X	X
Tumor biomarkers	X		X	X	X	X	X	X	X	X	X	X	X	X
Urine routine	X		X	X	X	X	X	X	X	X	X	X	X	X
CT/MRI	X			X		X		X		X		X		X
PET-CT	X
QLQ-C30	X			X		X		X		X		X		X
Adverse events	X		X	X	X	X	X	X	X	X	X	X	X	X
Systemic therapy			Chemotherapy, targeted therapy or immunotherapy will be performed at the physician's discretion.

Outcomes

The primary outcome is one-year local control rate, calculated as patients without progressions of the irradiated lesion determined by Response Evaluation Criteria In Solid Tumors (RECIST v1.1) among all enrolled patients. The secondary outcomes are overall survival (OS), progression free survival (PFS) and treatment-related adverse effects. OS is calculated as the time from the enrollment to death. PFS is defined as the time from the enrollment to until documentation of any clinical or radiological disease progression or death, whichever occurred first. PFS is determined by blinded, independent central review. Patients who are still alive and have no progression as of the date of analysis will be recorded as the date of their last evaluation. The severity of adverse effects will be graded using a modified version of The Common Terminology Criteria for adverse effects (CTCAE v5.0), reported and addressed at any time during the course of the study. The relationship between the treatment and adverse effects will be evaluated.

Statistical Analysis

Simon's two-stage design was used to calculate sample size. It was assumed that one-year local control rate of the large tumor or tumor adjacent to the gastrointestinal tracts was 60% after conventional fractionated radiotherapy or relatively low dose SBRT, while the one-year local control rate was 75% after CBART. The power of the test and type I error (two-sided) are 80% and 5%. Therefore, in the first stage, 27 patients should be enrolled, and if no less than 17 patients have no progressions of the irradiated lesion, sequential patients could be enrolled. A total of 67 patients should be enrolled, and CBART would be considered effective given no less than 46 patients with local control of the lesion more than one year.

All efficacy endpoints are assessed in the intention-to-treat population, including patients in the group, whether or not they receive the allocated treatment. Safety is assessed in the as-treated population, which include all enrolled patients who receive one or more courses of trial treatment. Demographic, disease and treatment characteristics are summarized with frequency and percentage for categorical variables, and median and interquartile range (IQR) for continuous variables. OS and PFS associated 95% CIs would be estimated by Kaplan-Meier methods. Additionally, subgroup analyses of OS and PFS will also be performed. An unadjusted Cox regression model for estimation of hazard ratios stratified by subgroup is used. Patients’ scores of QLQ-C30 at different time points will be compared with paired samples t-test. All reported P-values are two-sided and P-values of less than .05 are regarded as significant. Statistical analyses will be performed with IBM SPSS version 22.0 (SPSS Inc., Armonk, NY) and SAS version 9.4 (SAS Institute, Inc., Cary, NC).

Data Collection and Monitoring

Baseline data and follow-up assessment data would be collected by investigators and will be kept in a password-protected database at the Department of Radiation Oncology in our center, which will only be disclosed to authorized individuals. The Ethics Committee of our center will be responsible for data monitoring. In addition, trial conducts will be audited by the committee every 6 months after the recruitment of participants. The accuracy of the data entry into the database will be confirmed by two administrators. The interim results will be accessed to authorized individuals and reported to the Ethics Committee of our center which would make the final decision to terminate the trial if severe adverse effects occur frequently. Unexpected and severe adverse effects would be recorded in case report forms in details and reported to the Ethics Committee immediately.

Discussion

SBRT has been used as a promising avenue for achieving superior tumor local control due to its delivery of a high biological effective dose. Beyond mere DNA double-strand damage, SBRT provides additional biological effects, including immune modulation, vascular disruption, and the elusive abscopal effect albeit rare in clinical practice.^11,12 The immune regulatory elicited by synergy of SBRT and immunotherapy may augment the efficacy of radiotherapy.^13–16 Nevertheless, a thorny problem arises with the radiotherapy to the large aggressive bulky tumor necessitating escalated radiation doses, yet the emergence of a formidable obstacle to administer ablative doses owing to collateral damage to the neighboring organs at risk, which may compromise the local control and patients’ outcomes.

The notion of SFRT was proposed based on the principles of SBRT. Radiation doses of SFRT were delivered in a non-uniform manner across the whole tumor, which may provide potential advantages for the management of large tumors but require further investigations about dosing and fractionation strategies. However, high radiation dose regions in the form of strips and islands were quite small that may result in limited efficacy.

Given the benefits of SFRT targeting the partial tumor and potential bystander effects produced by SBRT to target the hypoxic core of the tumor with escalated doses,^4,17 it may be implied that more central regions of a tumor delivered by ablative doses could increase the likelihood of improved anti-tumor immunity. Therefore, we introduce a novel approach termed as CBART for large bulky tumors or those abutting the gastrointestinal tracts, which employs SBRT to administer a standard dose to the tumor margin with simultaneous boost, usually a high ablative dose, to the central regions of a tumor. As a result, it may increase the central tumor volumes amenable to ablative radiation doses while also minimize the radiation exposure to organs at risk.

Previously, a similar notion as CBART named as Stereotactic Central/Core Ablative Radiation Therapy (SCART), with VMAT as the most utilized approach to deliver ablative doses to the tumor central region and constraints on the dose to surrounding tissues set at 5 Gy per fraction, has shown potential benefits that median OS was 16.3 months and significant tumor shrinkage was observed. ¹⁸ Yet there were differences between CBART and SCART. Firstly, the tumor central volume receiving the ablative dose was determined by the prescription dose. The higher the prescription dose was, the smaller the proportion was. While in CBART, the central volume with a higher dose should be 50% of the whole tumor volume. Secondly, a strict dose fall-off was required in SCART. The tumor margin or gross tumor volume border was prescribed as 5Gy per fraction while the central region received 15-21Gy per fraction with a total two to three fractions. In the case of CBART, standard dose was prescribed to the tumor margin as 30-45Gy/5f, while the dose of cGTV was 120%-150% of that of tumor margin. Furthermore, the distinguish feature of CBART compared with SFRT was dosing regimens and distributions. More tumor central volumes received higher doses in CBART, and relatively low doses were given to the tumor margin while no irradiation in the context of SFRT.

Additionally, CBART may be an optimal option for some patients. Given those who have received radiotherapy previously and subsequently recurrent lesions, re-irradiation may be given based on physicians’ discretion. However, due to previous radiation exposure to the organs at risk, re-irradiation was quite tough especially for the large tumor. Therefore, a decreased risk of radiation adverse effects could be obtained with CBART compared with SBRT with uniform dose distributions. Regarding oligometastatic cancer, direct local treatment to all oligometastases has demonstrated enhanced anti-tumor immunological response and survival benefits. And CBART may be a primary approach for both favorable outcomes and milder radiation toxicity.

However, there are some limitations about the study. First of all, it is an exploratory study to investigate the safety and efficacy of the novel SBRT technique, with a single-arm design and lack of direct comparisons of standard treatment. Therefore, the interpretation of the results should be cautious. Secondly, participants in this study have different solid tumors. Therefore, we could only evaluate the response of the irradiated lesion. Survival outcomes should be accurately assessed as the primary endpoints in our future study where patients with the same tumor and stage receive CBART.

Conclusion

In summary, in this current clinical trial, we try to investigate whether CBART can bring good tumor response, good tolerance and better prognosis for patients with large tumors or tumors adjacent to the gastrointestinal tracts. And further investigations are required for optimizing dosing regimens and distributions of CBART.

Abbreviations

SBRT

stereotactic body radiation therapy

SFRT

spatially fractionated radiation therapy

SBRT-PATHY

stereotactic body radiation therapy for partial tumor irradiation targeting hypoxic segment

CBART

central-boost ablative radiation therapy

GTV

gross tumor volume

cGTV

central core gross tumor volume

PTV

planning target volume

OS

overall survival

PFS

progression free survival

SCART

stereotactic central/core ablative radiation therapy