Circulating Tumor DNA Predicts Early Recurrence Following Locoregional Therapy for Oligometastatic Colorectal Cancer.

(1) Background: Local therapies offer a potentially curative approach for patients with oligometastatic colorectal cancer (CRC). An evidence-based consensus recommendation for systemic therapy following definitive locoregional therapy is lacking. Tumor-informed circulating tumor DNA (ctDNA) might provide information to help guide management in this setting. (2) Methods: A multi-institutional retrospective study was conducted, including patients with CRC that underwent curative-intent locoregional therapy to an isolated site of metastatic disease, followed by tumor-informed ctDNA assessment. The Kaplan-Meier method and log-rank tests were used to compare disease-free survival based on ctDNA results. ctDNA test performance was compared to carcinoembryonic antigen (CEA) test results using McNemar's test. (3) Results: Our study cohort consisted of 87 patients treated with locoregional interventions who underwent ctDNA testing. The initial ctDNA test post-intervention was positive in 28 patients and negative in 59 patients. The median follow-up time was 14.0 months. Detectable ctDNA post-intervention was significantly associated with early disease recurrence, with a median disease-free survival (DFS) of 6.63 months compared to 21.30 months in ctDNA-negative patients (p < 0.001). ctDNA detected a numerically higher proportion of recurrences than CEA (p < 0.097). Post-intervention systemic therapy was not associated with improved DFS (p = 0.745). (4) Conclusions: ctDNA results are prognostically important in oligometastatic CRC, and further prospective studies are urgently needed to define its role in guiding clinical decisions.

Executive Summary of the American Radium Society® (ARS) Appropriate Use Criteria (AUC) for Non-Operative Management (NOM) for Rectal Adenocarcinoma: Systematic Review and Guidelines.

PURPOSE: For rectal cancer patients, the standard approach of chemotherapy, radiation therapy (RT), and surgery (Trimodality Therapy, TMT) is associated with significant long-term toxicity and/or colostomy for most patients. Patient options focused on quality-of-life (QOL) have dramatically improved, but there remains limited guidance regarding comparative effectiveness. This systematic review and associated guidelines evaluate how various treatment strategies compare to each other in terms of oncologic outcomes and QOL. MATERIALS AND METHODS: Cochrane and PRISMA methodology were used to search for prospective and retrospective trials and meta-analyses of adequate quality within the Ovid Medline database between 1/1/2012-6/15/2023. These studies informed the expert panel, which rated the appropriateness of various treatments in 6 clinical scenarios through a well-established consensus methodology (modified Delphi). RESULTS: The search process yielded 197 articles that advised voting. Increasing data show non-operative management (NOM) and primary surgery result in QOL benefits noted over TMT without detriment to oncologic outcomes. For rectal cancer patients for whom TME would result in permanent colostomy or inadequate bowel continence, NOM was strongly recommended as usually appropriate. Restaging with tumor response assessment 8-12 weeks following completion of RT/CRT was deemed a necessary component of NOM. The panel recommended active surveillance in the setting of a near complete or complete response. In the setting of NOM, 54-56 Gy in 27-33 fractions concurrent with chemotherapy and followed by consolidation chemotherapy was recommended. The panel strongly recommends primary surgery as usually appropriate for a T3N0 high rectal tumor for whom LAR and adequate bowel function is possible, with adjuvant chemotherapy considered if N+. CONCLUSIONS: Recent data supports NOM and primary surgery as important options that should be offered to eligible patients. Considering the complexity of multi-disciplinary management, patients should be discussed in a multi-disciplinary setting and therapy should be tailored to individual patient goals/values.

Combinatorial Approaches for Chemotherapies and Targeted Therapies With Radiation: United Efforts to Innovate in Patient Care.

Combinatorial therapies consisting of radiation therapy (RT) with systemic therapies, particularly chemotherapy and targeted therapies, have moved the needle to augment disease control across nearly all disease sites for locally advanced disease. Evaluating these important combinations to incorporate more potent therapies with RT will aid our understanding of toxicity and efficacy for patients. This article discusses multiple disease sites and includes a compilation of contributions from expert Red Journal editors from each disease site. Leveraging improved systemic control with novel agents, we must continue efforts to study novel treatment combinations with RT.

Executive Summary of the American Radium Society Appropriate Use Criteria for Neoadjuvant Therapy for Nonmetastatic Pancreatic Adenocarcinoma: Systematic Review and Guidelines.

For patients with locoregionally confined pancreatic ductal adenocarcinoma (PDAC), margin-negative surgical resection is the only known curative treatment; however, the majority of patients are not operable candidates at initial diagnosis. Among patients with resectable disease who undergo surgery alone, the 5-year survival remains poor. Adjuvant therapies, including systemic therapy or chemoradiation, are utilized as they improve locoregional control and overall survival. There has been increasing interest in the use of neoadjuvant therapy to obtain early control of occult metastatic disease, allow local tumor response to facilitate margin-negative resection, and provide a test of time and biology to assist with the selection of candidates most likely to benefit from radical surgical resection. However, limited guidance exists regarding the relative effectiveness of treatment options. In this systematic review, the American Radium Society multidisciplinary gastrointestinal expert panel convened to develop Appropriate Use Criteria evaluating the evidence regarding neoadjuvant treatment for patients with PDAC, including surgery, systemic therapy, and radiotherapy, in terms of oncologic outcomes and quality of life. The evidence was assessed using the Population, Intervention, Comparator, Outcome, and Study (PICOS) design framework and "Preferred Reporting Items for Systematic Reviews and Meta-analyses" 2020 methodology. Eligible studies included phases 2 to 3 trials, meta-analyses, and retrospective analyses published between January 1, 2012 and December 30, 2022 in the Ovid Medline database. A summary of recommendations based on the available literature is outlined to guide practitioners in the management of patients with PDAC.

Pre-operative chemoradiotherapy with or without induction chemotherapy for operable locally-advanced esophageal cancer.

Background: For patients with operable locally advanced esophageal carcinoma (LA-EC), we hypothesized that pre-operative induction chemotherapy followed by chemoradiotherapy (IC-CRT) would improve progression-free survival (PFS) and overall survival (OS) when compared to chemoradiotherapy (CRT). Methods: This was a single institution retrospective cohort study including patients with LA-EC who received preoperative-intent IC-CRT vs. CRT between 2013-2019. The Kaplan-Meier method was used to estimate OS and PFS. Cox proportional hazards regression was used to assess for variables associated with survival. The impact of treatment group on pathologic response was assessed by chi-square. Results: Ninty-five patients were included for analysis (IC-CRT n=59; CRT n=36) and the median follow-up was 37.7 months (IQR: 16.8-56.1). There was no difference in median PFS or OS for IC-CRT or CRT, 22 months (95% CI: 12-59) vs. 32 months (95% CI: 10-57) (P=0.64) and 39 months (95% CI: 23-not reached) vs. 56.5 months (95% CI: 38-not reached) (P=0.36), respectively. Amongst the subset of patients with adenocarcinoma histology, there was no difference in median PFS or OS, nor was there when analyses were further restricted to those who received ≥3 cycles of induction 5-fluorouracil and platinum, or for those who underwent esophagectomy. Pathologic complete response occurred in 45% vs. 29% (P=0.24) and N-stage regression occurred in 72% vs. 58% (P=0.28) of patients in the IC-CRT and CRT cohorts, respectively. Distant metastasis occurred in 44% of patients in each treatment cohort. Conclusions: For patients with LA-EC, preoperative-intent IC-CRT was not associated with improved PFS or OS when compared with CRT.

American Radium Society Appropriate Use Criteria for the use of liver-directed therapies for nonsurgical management of liver metastases: Systematic review and guidelines.

The liver is a common site of cancer metastases. Systemic therapy is widely accepted as the standard treatment for liver metastases (LM), although select patients with liver oligometastases may be candidates for potentially curative liver resection. Recent data support the role of nonsurgical local therapies such as ablation, external beam radiotherapy, embolization, and hepatic artery infusion therapy for management of LM. Additionally, for patients with advanced, symptomatic LM, local therapies may provide palliative benefit. The American Radium Society gastrointestinal expert panel, including members representing radiation oncology, interventional radiology, surgical oncology, and medical oncology, performed a systemic review and developed Appropriate Use Criteria for the use of nonsurgical local therapies for LM. Preferred Reporting Items for Systematic reviews and Meta-Analyses methodology was used. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in seven representative clinical scenarios through a well-established consensus methodology (modified Delphi). A summary of recommendations is outlined to guide practitioners on the use of nonsurgical local therapies for patients with LM.

Comparing Oncologic Outcomes and Toxicity for Combined Modality Therapy vs. Carbon-Ion Radiotherapy for Previously Irradiated Locally Recurrent Rectal Cancer.

No standard treatment paradigm exists for previously irradiated locally recurrent rectal cancer (PILRRC). Carbon-ion radiotherapy (CIRT) may improve oncologic outcomes and reduce toxicity compared with combined modality therapy (CMT). Eighty-five patients treated at Institution A with CIRT alone (70.4 Gy/16 fx) and eighty-six at Institution B with CMT (30 Gy/15 fx chemoradiation, resection, intraoperative electron radiotherapy (IOERT)) between 2006 and 2019 were retrospectively compared. Overall survival (OS), pelvic re-recurrence (PR), distant metastasis (DM), or any disease progression (DP) were analyzed with the Kaplan-Meier model, with outcomes compared using the Cox proportional hazards model. Acute and late toxicities were compared, as was the 2-year cost. The median time to follow-up or death was 6.5 years. Median OS in the CIRT and CMT cohorts were 4.5 and 2.6 years, respectively (p ≤ 0.01). No difference was seen in the cumulative incidence of PR (p = 0.17), DM (p = 0.39), or DP (p = 0.19). Lower acute grade ≥ 2 skin and GI/GU toxicity and lower late grade ≥ 2 GU toxicities were associated with CIRT. Higher 2-year cumulative costs were associated with CMT. Oncologic outcomes were similar for patients treated with CIRT or CMT, although patient morbidity and cost were lower with CIRT, and CIRT was associated with longer OS. Prospective comparative studies are needed.

American Radium Society (ARS) Appropriate Use Criteria (AUC) for Extrahepatic Cholangiocarcinoma.

Although uncommon, extrahepatic cholangiocarcinoma (EHCC) is a deadly malignancy, and the treatment approaches remain controversial. While surgery remains the only cure, few patients are candidates for resection up front, and there are high rates of both local and distant failure following resection. Herein, we systematically review the available evidence regarding treatment approaches for patients with EHCC, including surgery, radiation, and chemotherapy. The evidence regarding treatment outcomes was assessed using the Population, Intervention, Comparator, Outcome, and Study design (PICOS) framework. A summary of recommendations based on the available literature is outlined for specific clinical scenarios encountered by providers in the clinic to guide the management of these patients.

Multiagent Chemotherapy Followed by Stereotactic Body Radiotherapy Versus Conventional Radiotherapy for Resected Pancreas Cancer.

BACKGROUND AND PURPOSE: Chemotherapy followed by margin-negative resection (R0) is the treatment of choice for patients with localized pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant multiagent chemotherapy (MAC) or MAC then radiotherapy (RT) may optimize surgical candidacy. The purpose of this study was to compare pathologic outcomes of MAC followed by conventionally fractionated radiotherapy (CRT) versus stereotactic body radiotherapy (SBRT) for patients with resected PDAC. METHODS: Patients diagnosed with nonmetastatic PDAC between 2012 and 2017 and who received preoperative MAC or MAC+RT were identified in the National Cancer Database. Variables associated with R0 and overall survival were identified with logistic regression and Cox analysis (P<0.05). RESULTS: A total of 5273 patients were identified (MAC: 3900, MAC+CRT: 955, MAC+SBRT: 418). The median RT dose/fraction (fx) in the MAC+CRT and MAC+SBRT cohorts was 50.4 Gy/28 fx and 33 Gy/5 fx. Patients receiving MAC+CRT versus MAC+SBRT had similar rates of ypT3-T4 disease (54% vs. 58%, P=0.187), R0 (87% vs. 84%, P=0.168), and pathologic complete response (pathologic complete response; 6% vs. 4%, P=0.052), however, MAC+CRT was associated with less regional lymphatic disease (ypN+: 28% vs. 41%, P<0.001). The median overall survival of patients receiving MAC+CRT versus MAC+SBRT was 24.6 versus 29.5 months (P=0.045). CONCLUSIONS: For patients with resected PDAC, MAC+CRT, and MAC+SBRT had similar rates of R0 and pathologic complete response, although MAC+CRT was associated with lower ypN+. Prospective evaluation of neoadjuvant RT regimens with attention to radiation therapy design is warranted.

A Critical Review of the Role of Local Therapy for Oligometastatic Gastrointestinal Cancer.

PURPOSE: The purpose of this critical review is to provide an overview of the role and outcomes associated with the use of local therapy for patients with oligometastatic gastrointestinal cancers. METHODS AND MATERIALS: A review of clinical data was performed to describe outcomes associated with the use of systemic therapy and/or locoregional therapies for patients with oligometastatic gastrointestinal cancers including esophagus, gastric, liver, biliary, pancreas, colorectal, and anal canal. RESULTS: This review describes outcomes associated with current first line systemic therapy and oligometastasis directed locoregional therapy for patients with gastrointestinal cancers. Available data suggest that for well-selected patients among each gastrointestinal disease subsite, the use of local therapy is associated with favorable disease control and possible survival benefit. CONCLUSIONS: These data emphasize the importance of multidisciplinary collaboration and consideration of radiation therapy for patients with oligometastatic gastrointestinal cancers to improve locoregional control and progression-free survival. Multiple trials are ongoing to determine whether metastasis-directed radiation therapy improves overall survival.

Patterns of Recurrence After Primary Local Therapy for Pancreatic Ductal Adenocarcinoma - A Critical Review of Rationale and Target Delineation for (Neo)Adjuvant Radiation Therapy.

PURPOSE: The purpose of this work was to describe pancreatic ductal adenocarcinoma (PDAC) patterns of locoregional spread and recurrence to help guide clinicians on (neo)adjuvant radiation therapy (RT) planning strategies and target volume delineation. METHODS AND MATERIALS: A comprehensive review of clinical data was performed to describe PDAC patterns of locoregional spread, including extrapancreatic tumor extension, perineural invasion, regional lymph node involvement, and patterns of disease recurrence as influenced by (neo)adjuvant treatment strategy. RESULTS: This review describes PDAC patterns of spread, disease progression, and evolving treatment techniques. Based upon this data, we advocate for inclusion of elective at-risk regions of extrapancreatic extension, perineural invasion, and lymphatic spread for patients receiving neoadjuvant RT. CONCLUSIONS: This review provides a nuanced description of PDAC patterns of spread and recurrence to guide clinicians on target volume delineation and planning strategies to maximize the effectiveness of neo(adjuvant) RT delivery for patients with PDAC. Further prospective studies are needed to better define the optimal RT dose, fractionation regimens, and target volumes to be used in the (neo)adjuvant setting.

Practice Patterns Related to Mitigation of Neurocognitive Decline in Patients Receiving Whole Brain Radiation Therapy.

Purpose: Whole brain radiation therapy (WBRT) is often used as an effective treatment for patients with brain metastasis, although it is also known to have deleterious cognitive effects. Multiple trials have identified strategies to help mitigate neurocognitive decline after WBRT, although there may be barriers to integrating these techniques into routine clinical practice. The aim of this study was to characterize national practice patterns related to neurocognitive preservation strategies used during WBRT. Methods and Materials: We conducted an online survey of all American Society for Radiation Oncology-registered radiation oncologists (ROs), excluding trainees, regarding their practice patterns and attitudes toward employing memantine and hippocampal avoidance whole brain radiation therapy (HA-WBRT). Pearson χ2 tests for categorical variables or Student t tests for continuous variables were used to assess associations between provider characteristics and prescribing of either memantine or HA. All statistical tests were 2-sided and a P value <.05 was considered statistically significant. Results: Among 4408 ROs invited to participate, 417 (9.5%) completed the survey. Among respondents, 79.6% reported having offered memantine, 72.7% HA-WBRT, and 63.1% both for any of their patients undergoing WBRT. Common reasons for not offering memantine included limitations of current evidence (35.3%) and concerns about adverse effects (22.4%). Common reasons for not offering HA-WBRT included resource-intensive treatment planning and treatment delay (43.9%) and concern about obtaining prior authorization (38.6%). ROs with fewer years in practice (mean 15.7 vs 23.4 years) were more likely to prescribe memantine (P < .001), whereas HA was more likely prescribed by central nervous system specialists (P < .001) and ROs in academic settings (P = .04). Conclusions: Our survey suggests that the majority of respondents offer approaches for neurocognitive preservation during WBRT for their patients. Further efforts are needed to broaden education and reduce barriers among ROs to improve implementation of neurocognitive-sparing techniques in patients undergoing WBRT.

Detectable Postoperative Circulating Tumor Human Papillomavirus DNA and Association with Recurrence in Patients With HPV-Associated Oropharyngeal Squamous Cell Carcinoma.

PURPOSE: The purpose of our study is to determine the rate of detectability of ctHPVDNA after surgery but before adjuvant therapy in patients with human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (HPV[+]OPSCC) and to investigate whether detectable ctHPVDNA at this time point may be associated with risk of recurrence. METHODS AND MATERIALS: We examined prospectively collected samples from patients with OPSCC in a blinded fashion using a multianalyte polymerase chain reaction assay. We collected 45 samples from patients with HPV(+)OPSCC preop (before any treatment) and 159 samples postop (before or at the start of adjuvant radiation therapy). We identified samples via the radiation oncology biobank or via participation in a clinical trial. Radiation therapy consisted of 60 Gy ± cisplatin or de-escalation (30 Gy to 36 Gy in 20 bid fractions + docetaxel). For our preliminary analysis, 32 patients had paired samples available pre- and postop. We performed additional exploratory analyses including associations of patient and tumor characteristics with recurrence using Cox proportional hazards models for all 159 postop samples. We compared detectability of ctHPVDNA across groups using logistic regression. We used Kaplan-Meier to estimate recurrence-free survival. RESULTS: In a paired analysis of 32 pre- and postop timepoints, 94% of patients had detectable ctHPVDNA preop and 41% did postop. Recurrence-free survival at 18 months was 83% (95% confidence interval, 47%-95%) for patients with detectable postop ctHPVDNA compared with 100% for patients with undetectable postop ctHPVDNA (P = .094). In an exploratory analysis of nonpaired postop samples, ctHPVDNA was detectable in 26% of patients (41 of 159) (median of 22 days postop). Age (odds ratio,1.06, P = .025), lymphovascular space invasion (odds ratio, 3.17, P = .011) and extranodal extension (odds ratio = 5.67, P = .001) were associated with detectable ctHPVDNA after surgery. Detectable postop ctHPVDNA was significantly associated with recurrence-free survival (P < .001). CONCLUSION: Among patients with detectable preop ctHPVDNA, a significant proportion have detectable postop ctHPVDNA in paired postop samples collected before the initiation of adjuvant radiation therapy. Future prospective study is warranted to investigate the association of detectable postop ctHPVDNA with recurrence, including in comparison to established clinical and pathologic risk factors.

Multi-institutional Comparison of Intensity Modulated Photon Versus Proton Radiation Therapy in the Management of Squamous Cell Carcinoma of the Anus.

PURPOSE: Concurrent chemoradiation therapy is a curative treatment for squamous cell carcinoma of the anus, but patients can suffer from significant treatment-related toxicities. This study was undertaken to determine whether intensity modulated proton therapy (IMPT) is associated with less acute toxicity than intensity modulated radiation therapy (IMRT) using photons. MATERIALS AND METHODS: We performed a multi-institutional retrospective study comparing toxicity and oncologic outcomes of IMRT versus IMPT. Patients with stage I-IV (for positive infrarenal para-aortic or common iliac nodes only) squamous cell carcinoma of the anus, as defined by the American Joint Committee on Cancer's AJCC Staging Manual, eighth edition, were included. Patients with nonsquamous histology or mixed IMPT and IMRT treatment courses were excluded. Acute nonhematologic toxicities, per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 4, were recorded prospectively at all sites. Acute and late toxicities, dose metrics, and oncologic outcomes were compared between IMRT and IMPT using univariable and multivariable statistical methods. To improve the robustness of our analysis, we also analyzed the data using propensity score weighting methods. RESULTS: A total of 208 patients were treated with either IMPT (58 patients) or IMRT (150 patients). Of the 208 total patients, 13% had stage I disease, 36% stage II, 50% stage III, and 1% stage IV. IMPT reduced the volume of normal tissue receiving low-dose radiation but not high-dose radiation to bladder and bowel. There was no significant difference between treatment groups in overall grade 3 or greater acute toxicity (IMRT, 68%; IMPT, 67%; P = .96) or 2-year overall grade 3 or greater late toxicity (IMRT, 3.5%; IMPT, 1.8%; P = .88). There was no significant difference in 2-year progression-free survival (hazard ratio, 0.8; 95% CI, 0.3-2.0). CONCLUSIONS: Despite reducing the volume of normal tissue receiving low-dose radiation, IMPT was not associated with decreased grade 3 or greater acute toxicity as measured by CTCAE. Additional follow-up is needed to assess whether important differences arise in late toxicities and if further prospective evaluation is warranted.

Malignancies diagnosed before and after anal squamous cell carcinomas: A SEER registry analysis.

BACKGROUND: Increased risk of a second primary malignancy (SPM) before or after diagnosis of anal squamous cell carcinoma (ASCC) has been reported in a previous single-institution study. We hypothesize that patients diagnosed with ASCC are at increased risk for developing SPMs before or after the diagnosis of ASCC. The primary objective of this study was to identify the diagnoses of cancer most likely to occur as SPMs before or after ASCC. METHODS: This work employs the Surveillance, Epidemiology, and End Results (SEER) Program registry data to conduct a US-population-based study of patients diagnosed with ASCC between 1975 and 2016. In patients diagnosed with ASCC, we evaluated the risk of SPMs and the risk of developing ASCC as an SPM after another cancer using standardized incidence ratios (SIR) for all SPMs by calculating the ratio of observed events in the ASCC cohort compared to expected (O/E) events in a matched reference cohort of the general population. RESULTS: A total of 7,594 patients with primary ASCC were included. Patients with ASCC were at increased risk of the diagnosis of an SPM (SIR = 1.45), particularly cancers of the lung, vulva, oropharynx, or colon. Patients with ASCC had an increased rate of previous malignancy (SIR = 1.23), especially Kaposi sarcoma or vulvar cancer. Overall elevated incidence of SPMs was unrelated to prior radiation treatment. Radiation treatment was associated with increased risk for SPMs in the female genital system but appeared protective against prostate cancer as SPMs. CONCLUSIONS: Our findings support increased surveillance and screening for second malignancies in patients with these diagnoses, as patients with ASCC are often either survivors of a prior cancer diagnosis or are at increased risk of developing later malignancies.

Does the dural resection bed need to be irradiated? Patterns of recurrence and implications for postoperative radiotherapy for temporal lobe gliomas.

BACKGROUND: Patterns of recurrence and survival with different surgical and radiotherapy (RT) techniques were evaluated to guide RT target volumes for patients with temporal lobe glioma. METHODS AND MATERIALS: This retrospective cohort study included patients with World Health Organization grades II to IV temporal lobe glioma treated with either partial (PTL) or complete temporal lobectomy (CTL) followed by RT covering both the parenchymal and dural resection bed (whole-cavity radiotherapy [WCRT]) or the parenchymal resection bed only (partial-cavity radiotherapy [PCRT]). Patterns of recurrence, progression-free survival (PFS) and overall survival (OS) were evaluated. RESULTS: Fifty-one patients were included and 84.3% of patients had high-grade glioma (HGG). CTL and PTL were performed for 11 (21.6%) and 40 (78.4%) patients, respectively. Median RT dose was 60 Gy (range, 40-76 Gy). There were 82.4% and 17.6% of patients who received WCRT and PCRT, respectively. Median follow-up time was 18.4 months (range, 4-161 months). Forty-six patients (90.2%) experienced disease recurrence, most commonly at the parenchymal resection bed (76.5%). No patients experienced an isolated dural recurrence. The median PFS and OS for the PCRT and WCRT cohorts were 8.6 vs 10.8 months (P = .979) and 19.9 vs 18.6 months (P = .859), respectively. PCRT was associated with a lower RT dose to the brainstem, optic, and ocular structures, hippocampus, and pituitary. CONCLUSION: We identified no isolated dural recurrence and similar PFS and OS regardless of postoperative RT volume, whereas PCRT was associated with dose reduction to critical structures. Omission of dural RT may be considered a reasonable alternative approach. Further validation with larger comparative studies is warranted.