Single-arm Multicenter Phase II Study on Aggressive Local Consolidative Therapy in Combination With Systemic Chemotherapy for Stage IV Non- small Cell Lung Carcinoma With Oligometastases: CURE-OLIGO (TORG1529)

doi:10.21203/rs.3.rs-4910366/v1

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Single-arm Multicenter Phase II Study on Aggressive Local Consolidative Therapy in Combination With Systemic Chemotherapy for Stage IV Non- small Cell Lung Carcinoma With Oligometastases: CURE-OLIGO (TORG1529)

https://doi.org/10.21203/rs.3.rs-4910366/v1

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Introduction: Stage IV non-small cell lung carcinoma (NSCLC) with oligometastases is potentially curable by radical treatment. This study aimed to evaluate the efficacy and safety of chemoradiotherapy (CRT) for thoracic disease, including the primary lesion and lymph node metastases, combined with local consolidative therapy (LCT) for oligometastases.

Methods: This was a multicenter Phase II trial for patients with Stage IV NSCLC with oligometastases for whom CRT for thoracic disease was feasible. The treatment procedures included CRT containing platinum-doublet for thoracic disease and LCT for oligometastases within 8 weeks of starting or completing CRT. The primary endpoint was the 2-year survival rate.

Results: We enrolled 19 patients between June 2016 and May 2020. The median age was 68 (range: 51–74) years. Twelve patients had adenocarcinoma, and 6 had squamous cell carcinoma. The metastasis sites included the brain, bone, adrenal gland, lung, and cervical lymph node (n = 9, 7, 2, 1, and 1, respectively). All patients completed CRT concurrently with LCT for all oligometastases. There were 11 partial responses, resulting in a response rate of 58% (95% confidence interval [CI]: 33.5–79.7%). Median progression-free survival and overall survival were 8.6 (95% CI: 7.0–10.2) and 42.1 (80% CI: 13.6–not reached) months, respectively. The 2-year survival rate was 68.4% (80% CI: 52.6–79.9%). Fourteen patients (74%) showed progression with newly observed lesions. There were no severe adverse events, and toxicities were tolerable.

Conclusion: Chemotherapy in combination with aggressive LCT for NSCLC with oligometastases might extend survival and achieve local control.

Clinical trial registration: University Hospital Medical Information Network, Japan (protocol identification number: UMIN000022431, first registration date: 01/JUN/2016)

oligometastasis

local consolidative therapy

non-small cell lung cancer

Some preclinical and translational analyses have suggested that Stage IV disease that is limited to only a small number of sites (oligometastatic disease) represents an indolent phenotype that could benefit from local consolidative therapy (LCT; e.g., surgery or radiotherapy).^1–4 The clinical practice guidelines of the European Society for Medical Oncology recommend imaging for oligometastases.⁵ Although uncertainty remains regarding the exact definition of limited metastases, current trial design and clinical practice are fairly consistent in limiting oligometastatic disease to a maximum of three to five sites.⁶

A single extrathoracic metastasis was newly categorized as M1b by the eighth edition of the American Joint Committee on Cancer (AJCC) TNM Staging of Lung Cancer. Several single-arm prospective studies and a meta-analysis of many retrospective studies revealed that patients with non-small cell lung carcinoma (NSCLC) with solitary and synchronous oligometastasis who received LCT and/or systemic chemotherapy showed a trend toward prolonged survival in subgroup analyses.^7–10 However, no prospective data have been available on this patient population.

Thus, we launched a multicenter, single-arm Phase II study of aggressive LCT in combination with systemic chemotherapy for Stage IV NSCLC with solitary and synchronous oligometastasis: CURE-OLIGO (TORG1529). Here we report the final analysis results, including efficacy and safety data.

Study Design

This was an open-label, multicenter, single-arm Phase II study. The primary endpoint was the 2-year survival rate. Secondary endpoints were progression-free survival (PFS) as assessed by the investigator, overall survival (OS), and safety.

Eligibility and Exclusion Criteria

Eligible patients were pathologically confirmed as having NSCLC with solitary oligometastasis. As an exception, brain metastases that could be controlled by stereotactic radiosurgery (SRS) were eligible even if there were two more. Additionally, eligible patients had to be treatment-naive with Stage IV disease (as per the seventh edition of the AJCC TNM Staging of Lung Cancer) regardless of whether the target lesions were assessable using the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 criteria. Those patients with pleural effusion, pleural dissemination, ascites, peritoneal dissemination, bilateral adrenal gland metastases, and activating EGFR mutations or ALK rearrangement were excluded. Other inclusion criteria were an Eastern Cooperative Oncology Group (ECOG) performance status of 0–1 and adequate organ function. Before treatment initiation, mandatory chest and abdomen computed tomography (CT) scans, brain magnetic resonance imaging (MRI) or CT scans, and positron emission tomography (PET) scans or bone scans were performed.

Owing to the slow accrual of participants, we amended the protocol twice. First, the locoregional lymph node range was increased from N0–1 to N0–3. Second, the upper age limit was changed from ≤ 75 years to no limit, and the number of metastases was changed from only 1 to ≤ 3 within 2 organs, except for brain metastases, where ≥ 4 were allowed if it was possible to treat all lesions with SRS.

Study Treatment

All patients were administered platinum-doublet chemotherapy and radiotherapy for thoracic disease and LCT for distant disease within 8 weeks of starting or completing thoracic radiotherapy. Treatment was composed of concurrent chemoradiotherapy (CCRT) and subsequent consolidation chemotherapy and LCT. Investigators could choose the regimen of systemic chemotherapy: either cisplatin plus vinorelbine or cisplatin plus docetaxel.

Thoracic radiotherapy was started on day 1 and delivered 5 days per week in 2-Gy fractions for a total dose of 60 Gy. Three-dimensional CT planning was mandatory, and involved-field radiotherapy was used. Gross tumor volume included the primary tumor and clinically positive lymph nodes observed during CT planning (> 1 cm short-axis diameter) or pretreatment PET. The clinical target volume included gross tumor volume plus a total margin of ≥ 0.5 cm. The total planning target volume included the clinical target volume plus a total margin of ≥ 0.5 cm. The dose was prescribed at a reference point. The optimal planned target volume coverage was 95–107% of the prescribed dose. All radiation doses were calculated using heterogeneity corrections (superposition/convolution dose calculation algorithms). The maximum spinal cord dose was limited to 52 Gy, and 1 cm³ of the spinal cord could not exceed 48 Gy. The volume of both lungs that received ≥ 20 Gy (V20) did not exceed 35% of the total. Brachial plexus doses were maintained at < 66 Gy.

The LCT protocol for oligometastases was administered within 8 weeks of starting or completing systemic treatment. Patients with brain metastases were treated with either resection or SRS, depending on the volume and the location of the brain metastases. Resection for brain metastases followed by whole-brain radiotherapy was not mandatory. When surgery was considered in cases of extracranial metastases, a radical resection was envisaged. The type of LCT was determined in consultation with radiologists. The treating radiotherapist was responsible for the choice of dose-fractionation regimen, with curative intent when possible. Stereotactic body radiotherapy (SBRT) and conventional radiotherapy were allowed.

Efficacy and Safety Evaluations

Before treatment initiation, all patients underwent mandatory chest and abdomen CT scans, brain MRI or CT scans, and PET scans or bone scans. Tumor assessments were performed at baseline and every 8–12 weeks for a 2-year follow-up period. The tumor response was evaluated according to RECIST version 1.1. Adverse events (AEs) were recorded using Common Terminology Criteria for Adverse Events version 4.0.

Statistical Analysis

The primary endpoint was the 2-year survival rate. The key secondary endpoints were PFS, OS, and safety. A single-arm Phase II study for NSCLC with oligometastases showed a 2-year survival rate of 16.4–23.3%.^7,10 The 2-year survival rate of Phase III studies for advanced NSCLC treated with chemotherapy without immune checkpoint inhibitors (ICIs) is typically approximately 30%.^{11, 12} Thus, we set the threshold at 30% because we used aggressive LCT for Stage IV patients, so we expected a greater therapeutic effect. In contrast, the 2-year survival rate of stage III NSCLC treated with CCRT without ICI was reported as 60%.^13–15 Assuming a clinically meaningful 20% increase and setting the expected value at 50%, 51 patients were required in this study according to the exact binomial test (one-sided α = 0.05, 1 − β = 0.9). Considering patient ineligibility, a sample size of 55 patients was set. In 2018, owing to the slow accrual of participants, we amended the one-sided α-error to 0.10 and the statistical power to 0.70. As a result, the number of required patients was reduced to 20.

Patients’ Characteristics

We enrolled 19 patients between June 2016 and May 2020. The trial was terminated before completing full enrollment (n = 20) due to slow accrual, and the baseline characteristics of the 19 enrolled patients are summarized in Table 1. The median age was 68 years, 13 patients (68.4%) were male, 17 patients (89.5%) had a smoking history, and all patients had an ECOG performance status of 0 or 1. Adenocarcinoma and squamous cell carcinoma were present in 12 (63.2%) and 6 (31.6%) patients, respectively. The primary tumor size was as follows: <3 cm for T1a/T1b (n = 7, 36.8%), < 5 cm for T2a (n = 4, 21.1%), < 7 cm for T2b (n = 1, 5.3%), and > 7 cm for T3/T4 (n = 7, 36.8%). There were 7 (36.8%) patients without regional lymph node metastasis, 5 (26.3%) with N2, and 4 (21%) with N3 disease. The metastasis sites included the brain, bone, adrenal gland, lung, and cervical lymph node (n = 9, 7, 2, 1, and 1, respectively).

Table 1

Patient characteristics.
Characteristic		N = 19
Age (years)
	Median	68
	Range	51–74
Sex
	Male	13
	Female	6
Smoking status
	Never-smoker	17
	Smoker	2
Performance status
	0–1	19
Histology
	Adenocarcinoma	12
	Squamous	6
	NOS	1
T*
T1a/T1b		2/5
T2a/T2b		4/1
T3/T4		4/3
N
	0/1/2/3	7/3/5/4
M
M1a/M1b (ver7)		0/19
M1a/M1b/M1c (ver8)		0/17/2
Number metastasis
1/2		17/2
Metastatic site
	Brain	9
	Bone	7
	Adrenal grand	2
	Lung	1
	Cervical lymph node	1
*TNM version 7

Treatment Delivery

All patients received platinum-containing chemotherapy, such as cisplatin plus vinorelbine (n = 18) or cisplatin plus docetaxel (n = 1). Overall, 17 (89.5%) patients completed 4 cycles, and 2 (10.5%) patients terminated treatment after 3 cycles because of disease progression. All patients completed chemoradiotherapy (CRT) during the concurrent phase and LCT for all oligometastases (Table 2). Surgery for oligometastases was performed for 6 (31.5%) cases, including brain, adrenal gland, and cervical lymph node operations in 4,1, and 1 patient, respectively. Among them, radiotherapy was added to 3 cases of brain and the single case of cervical lymph node oligometastases. The remaining 13 (68.4%) patients with oligometastases (brain, 5; bone, 7; and adrenal gland, 1) were treated with radiotherapy only.

Table 2

Treatment delivery
Chemotherapy	N = 19
Cisplatin + Vinorelbine 3 cycles 4 cycles Cisplatin + Docetaxel 4cycles	18 (94.7%) 2 16 1 (5.3%) 1
Thoracic radiotherapy	N = 19
60Gy completed without discontinuation with discontinuation	19 (100%) 10 9*
Local consolidative therapy	N = 19
Brain Surgery Surgery + whole-brain radiotherapy Stereotactic irradiation	9 (47.4%) 1 3 5
Bone Radiotherapy	7 (36.8%) 7
Adrenal grand Surgery Radiotherapy	2 (10.5%) 1 1
Cervical lymph node Surgery + radiotherapy	1 (5.3%) 1
*Neutrophil count decreased: 6, Febrile neutropenia: 1, other: 2

Efficacy

The data cutoff date was May 31, 2022. The median follow-up time was 42.1 months (95% confidence interval [CI]; 13.6–not reached). The primary endpoint of the study was the 2-year survival rate, which was 68.4% (80% CI: 52.6–79.9%), and the median OS was 42.1 months (95% CI: 13.6–not reached) (Fig. 1A). The median PFS was 8.6 months (95% CI: 7.0–10.2) (Fig. 1B). Eleven patients (57.9%) showed partial response, 8 (42.1%) had stable disease, and there were no patients with progressive disease (see Fig. 2).

Patterns of Recurrence

At the data cutoff date, 2 patients (10.5%) had maintained their status of no disease progression (Fig. 3A, Case No. 08 and 16). Of the 17 patients with disease progression, 14 (73.7%) showed the emergence of new lesions (Fig. 3B). There were 10 (58.8%) who received LCT at the time of progression. The other 3 patients had disease progression such as only LCT lesion (n = 2, brain), and no LCT lesion (contralateral lung metastasis that disappeared following chemotherapy) and a newly observed lesion (n = 1). ICIs were administered to 8 patients as subsequent therapy after progression of the study protocol treatment. There was no statistically significant difference between the patients who did and did not receive subsequent ICIs (see Fig. 4).

Adverse Events

Table 3 shows the AEs that occurred during the trial. The most common AEs ≥ grade 3 were a decreased white blood cell count (68%) and decreased neutrophil count (74%). However, febrile neutropenia occurred in 16% of patients (all grade 3). The AEs were generally mild (grades 1–2), and there were no treatment-related deaths. Regarding radiotherapy, common AEs included esophagitis (73.7%), followed by radiation dermatitis (68.4%), and pneumonitis (10.5%). No AE related to LCT for oligometastases occurred.

Table 3

Adverse Events
Adverse Event	Grade				N = 19
Adverse Event	1	2	3	4	≧G3	%
WBC decreased	0	6	8	5	13	68%
Neutrophil count decreased	1	3	4	10	14	74%
Platelet count decreased	12	1	0	0	0	0%
Anemia	7	11	1	0	1	5%
Increased ALT	3	1	0	0	0	0%
Increased AST	7	1	0	0	0	0%
Decrease albumin	12	6	0	0	0	0%
Hyponatremia	10	0	1	1	2	11%
Hypokalemia	4	0	0	0	0	0%
Hyperkalemia	9	0	0	0	0	0%
Fever	6	0	0	0	0	0%
Fatigue	2	1	1	0	1	5%
Malaise	8	3	1	0	1	5%
Alopecia	5	3	0	0	0	0%
Constipation	7	5	0	0	0	0%
Diarrhea	4	0	0	0	0	0%
Nausea	5	5	1	0	1	5%
Vomiting	2	0	1	0	1	5%
Anorexia	8	4	1	0	1	5%
Febrile neutropenia	0	0	3	0	3	16%
Dysgeusia	2	2	0	0	0	0%
Esophagitis	10	4	0	0	0	0%
Dermatitis radiation	13	0	0	0	0	0%
Pneumonitis	2	0	0	0	0	0%
Vasculitis	3	2	0	0	0	0%
AST; aspartate aminotransferase, ALT; alanine aminotransferase

The aim of our study was to evaluate the prolongation of survival, including cure following aggressive LCT for both primary lesions with lymph node metastases and all oligometastases combined with systemic chemotherapy for Stage IV NSCLC. Our treatment protocol resulted in a 2-year survival rate of 68.4%, and 2 (10.7%) patients maintained PFS at the end of the 2-year follow-up period. There were 10 (52.6%) patients who developed oligometastatic progression, and all patients received additional LCT. Two of them have maintained a status of no disease progression without systemic treatment after LCT against an oligometastatic progression lesion. Our treatment strategy induced a cure in 10% of patients with advanced NSCLC and 10% of patients with true oligometastases. Notably, although our study did not use ICIs to treat advanced NSCLC, systemic chemotherapy combined with LCT potentiated a promising survival benefit in NSCLC patients with oligometastases, in contrast to data from previous prospective trials using ICIs in NSCLC.^{16, 17} However, we could only identify oligometastatic disease using radiological findings in our current study. Only a limited number of studies have addressed the unique biology of oligometastases, and few address potential prognostic or predictive biomarkers that could guide patient selection for specific therapeutic strategies. Thus, further study is warranted to specify an oligometastatic state, including biological findings.

The European Organization for Research and Treatment of Cancer and the European Society for Radiotherapy and Oncology proposed an oligometastatic state model in 2020.¹⁸ Two randomized Phase II trials have reported that LCT with or without maintenance therapy for patients with ≤ 3 oligometastases from NSCLC that did not progress after initial systemic therapy improved PFS and OS compared with maintenance therapy alone.^{19, 20} Patients with induced oligometastatic disease were enrolled in these studies. Induced oligometastatic disease is defined as a diagnosis of polymetastatic disease followed by systemic treatment with or without local treatment, and the primary tumor is assumed to be controlled by ongoing or previous treatment. Our study aimed to target de novo oligometastatic disease with synchronous oligometastatic disease without postoperative recurrence. Both treatment goals and treatment strategies have changed with the introduction of the concept of oligometastatic disease. Whereas local treatment aims to eradicate all oligometastases and the potentially uncontrolled primary tumor, the choice of the optimal combination strategy with systemic treatment depends on the oligometastatic disease state and the specific treatment goal.

The general contemporary definition of oligometastatic disease is a malignancy with a limited number of metastases and a limited tumor burden.²¹ In our study, 17 (89.5%) patients had solitary metastasis equivalent to M1b in TNM edition 8. However, 12 (63.2%) patients with a tumor ≥ 3 cm (other than T1 in TNM edition 7) were enrolled, including 7 (36.8%) patients with a tumor ≥ 7 cm (T3/T4 in TNM edition 7) and 9 (47.4%) patients with N2/N3 disease. CCRT for unresectable stage III NSCLC patients has been the standard of care for the past decade, with the induction of cure in approximately 20%. Although the response rate has been reported as 60–70%, approximately 50% of patients experienced locoregional recurrence. Our study achieved a good response against thoracic disease treated with CRT, and only 1 patient developed locoregional progression at first recurrence. In other words, 14 (73.7%) patients developed progressive disease in newly observed lesions. Durvalumab maintenance therapy after CCRT for stage III NSCLC has been shown to reduce distant metastases.²² Furthermore, ICIs in combination with chemotherapy against metastatic NSCLC have been confirmed to confer a better survival benefit than chemotherapy. Moreover, the use of pembrolizumab after SBRT for oligometastatic NSCLC recently showed promising results, with a median PFS of 19.1 months and a 2-year survival rate of 77.5%.²³ Although no clear difference in OS was observed with or without ICI after disease progression in our study, we speculate that ICIs may be a more effective treatment before disease progression, even in cases of oligometastatic disease. Since several studies are currently investigating the use of ICIs in combination with LCT, once these results have been released, we will discuss their implications.

It is necessary to determine whether LCT is tolerable for patients with advanced-stage cancer in addition to systemic treatment. Recently, a single-arm Phase II clinical trial found that the incidence of SBRT toxic effects ≥ grade 3 was < 5%, and the rate of AEs ≥ grade 2 was 18.6%.²⁴ On the other hand, the rate of AEs ≥ grade 2 was 29% and treatment-related death was 4.5% in a randomized Phase III trial.²⁵ In our study, the main AEs related to CRT were myelosuppression and gastrointestinal symptoms, and the incidence rates of each AE were similar to CRT against stage III NSCLC. In other words, treatment with CRT for thoracic disease combined with LCT was safely performed in 6 patients (31.5%) who underwent surgery for oligometastases.

The limitation of this study is that it was a single-arm Phase II trial with a small number of patients and was prematurely terminated. Therefore, we were unable to draw definitive conclusions about both the safety and efficacy of our treatment protocol from the results of this study alone. Thus, more studies involving a larger number of patients are necessary.

In conclusion, aggressive LCT in combination with systemic chemotherapy for Stage IV NSCLC with solitary and synchronous oligometastasis revealed tolerability and possible efficacy. Further studies incorporating ICIs for treating oligometastatic disease are warranted and could lead to further outcome improvements. Additionally, exploring the optimal administration is also important for the results to be generalizable to clinical practice.

Ethics Approval and Consent to Participate

This study was conducted in accordance with the Declaration of Helsinki and Japan’s Clinical Trials Act. The protocol was registered with the University Hospital Medical Information Network, Japan (protocol identification number: UMIN000022431). All patients provided written informed consent.

Consent for Publication

All patients provided consent for publication.

Availability of Data and Material

All data generated or analyzed during this study are included in this published article.

Competing interests

T Tokito reports personal fees from AstraZeneca, MSD, Boehringer Ingelheim, Chugai, Ono Pharmaceutical, Bristol Myers Squibb, and Nippon Kayaku outside the submitted work. K Yamada reports consulting fees from Healios, Boehringer Ingelheim, Chugai, and Bristol Myers Squibb outside the submitted work. H Ishii reports personal fees from AstraZeneca, MSD, Ono Pharmaceutical, Chugai, Bristol Myers Squibb, and AMCO outside the submitted work. Y Takiguchi reports research contact and personal fees from AstraZeneca and Ono Pharmaceutical; research contact from MSD; research grant and personal fees from Chugai; and research grant from Eli Lilly outside the submitted work. G Saito reports personal fees from AstraZeneca, MSD, Novartis Pharma, Daiichi Sankyo, Chugai, Ono Pharmaceutical, and Taiho Pharmaceutical outside the submitted work. H Tanaka reports personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Chugai, Ono Pharmaceutical, Bristol Myers Squibb, and Merck outside the submitted work. S Miura reports personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Chugai, Ono Pharmaceutical, Bristol Myers Squibb, Merck, Novartis Pharma, Daiichi Sankyo, Taiho Pharmaceutical, Pfizer, MSD, Kyowa Hakko Kirin, AbbVie, Nippon Kayaku, AMGEN, and Takeda Pharmaceutical outside the submitted work. K Watanabe reports personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Ono Pharmaceutical, Bristol Myers Squibb, Merck, MSD, AMGEN, and Takeda Pharmaceutical outside the submitted work. A Ono reports research funding and personal fees from AstraZeneca; research funding from Janssen Research & Development; and personal fees from Chugai, Ono Pharmaceutical, and Bristol Myers Squibb outside the submitted work. N Furuya reports personal fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Chugai, Bristol Myers Squibb, Novartis Pharma, Taiho Pharmaceutical, and Pfizer outside the submitted work. T Misumi reports personal fees from AstraZeneca and Chugai outside the submitted work. H Okamoto reports grants and personal fees from MSD, Chugai, and Bristol Myers Squibb; personal fees from AstraZeneca, Kyorin, Boehringer Ingelheim, and Novartis; and grants from Merck, Taiho, Eli Lilly, and Astellas outside the submitted work. The remaining authors declare no conflict of interest.

Funding:

This study did not receive any funding.

Authors’contributions

Takaaki Tokito: Conceptualization, Methodology, Investigation, Visualization, Project administration, Funding acquisition, Writing - original draft.

Kazuhiko Yamada: Conceptualization, Methodology, Project administration, Writing - reviewing and editing.

Hidenobu Ishii: Investigation, Writing - reviewing and editing.

Yuichi Takiguchi: Investigation, Writing - reviewing and editing.

Go Saito: Investigation, Writing - reviewing and editing.

Koichi Minato: Investigation, Writing - reviewing and editing.

Hisao Imai: Investigation, Writing - reviewing and editing.

Hiroshi Tanaka: Investigation, Writing - reviewing and editing.

Satoru Miura: Investigation, Writing - reviewing and editing.

Kageaki Watanabe: Investigation, Writing - reviewing and editing.

YoshifusaKoreeda: Investigation, Writing - reviewing and editing.

Akira Ono: Investigation, Writing - reviewing and editing.

Naoki Furuya: Investigation, Writing - reviewing and editing.

Toshihiro Misumi: Methodology, Formal analysis, Writing - reviewing and editing.

Kazushige Hayakawa: Conceptualization, Methodology, Project administration, Writing - reviewing and editing.

Etsuyo Ogo: Conceptualization, Methodology, Project administration, Writing - reviewing and editing.

Hiroaki Okamoto: Methodology, Supervision, Project administration, Writing - reviewing and editing.

Acknowledgments

We thank the patients, their families, Thoracic Oncology Research Group data center staff, and all the investigators who participated in the TORG1529 study.

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No competing interests reported.

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Single-arm Multicenter Phase II Study on Aggressive Local Consolidative Therapy in Combination With Systemic Chemotherapy for Stage IV Non- small Cell Lung Carcinoma With Oligometastases: CURE-OLIGO (TORG1529)

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Abstract

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Introduction

Materials and Methods

Study Design

Eligibility and Exclusion Criteria

Study Treatment

Efficacy and Safety Evaluations

Statistical Analysis

Results

Patients’ Characteristics

Treatment Delivery

Efficacy

Patterns of Recurrence

Adverse Events

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1