Skip to main content

Alliance for clinical trials in Oncology (Alliance) trial A022101/NRG-GI009: a pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur)

Abstract

Background

For patients with liver-confined metastatic colorectal cancer (mCRC), local therapy of isolated metastases has been associated with long-term progression-free and overall survival (OS). However, for patients with more advanced mCRC, including those with extrahepatic disease, the efficacy of local therapy is less clear although increasingly being used in clinical practice. Prospective studies to clarify the role of metastatic-directed therapies in patients with mCRC are needed.

Methods

The Evaluating Radiation, Ablation, and Surgery (ERASur) A022101/NRG-GI009 trial is a randomized, National Cancer Institute-sponsored phase III study evaluating if the addition of metastatic-directed therapy to standard of care systemic therapy improves OS in patients with newly diagnosed limited mCRC. Eligible patients require a pathologic diagnosis of CRC, have BRAF wild-type and microsatellite stable disease, and have 4 or fewer sites of metastatic disease identified on baseline imaging. Liver-only metastatic disease is not permitted. All metastatic lesions must be amenable to total ablative therapy (TAT), which includes surgical resection, microwave ablation, and/or stereotactic ablative body radiotherapy (SABR) with SABR required for at least one lesion. Patients without overt disease progression after 16–26 weeks of first-line systemic therapy will be randomized 1:1 to continuation of systemic therapy with or without TAT. The trial activated through the Cancer Trials Support Unit on January 10, 2023. The primary endpoint is OS. Secondary endpoints include event-free survival, adverse events profile, and time to local recurrence with exploratory biomarker analyses. This study requires a total of 346 evaluable patients to provide 80% power with a one-sided alpha of 0.05 to detect an improvement in OS from a median of 26 months in the control arm to 37 months in the experimental arm with a hazard ratio of 0.7. The trial uses a group sequential design with two interim analyses for futility.

Discussion

The ERASur trial employs a pragmatic interventional design to test the efficacy and safety of adding multimodality TAT to standard of care systemic therapy in patients with limited mCRC.

Trial registration

ClinicalTrials.gov: NCT05673148, registered December 21, 2022.

Peer Review reports

Background

For patients with metastatic colorectal cancer (mCRC), surgical resection, when possible, has been associated with long-term progression-free survival (PFS) and overall survival (OS). Several large retrospective series have demonstrated 5-year OS rates of 40–70% in patients with isolated liver metastasis following liver metastasectomy [1,2,3,4,5]. Indeed, improvements in OS in patients with newly diagnosed mCRC over the last several decades have been attributed, in part, to an increase in hepatic resection [6]. For patients with limited extrahepatic disease, complete surgical resection has also been associated with prolonged PFS and OS, although the data are more limited [7,8,9]. While prospective evidence is lacking, these retrospective studies have demonstrated excellent long-term survival for patients with resectable mCRC and have defined the current standard of care (SOC).

In patients with multiorgan oligo-mCRC (e.g., low burden but liver inoperable disease or minimal extra-hepatic and/ or extra-thoracic disease), it is less clear whether local ablative therapies, including thermal ablation and stereotactic ablative radiation therapy (SABR), can provide clinical benefit such as durable control of disease or improve survival. Limited prospective data exist on the benefit of thermal ablation to all areas of inoperable hepatic disease. The CLOCC phase II randomized trial (EORTC-40,004) demonstrated that the addition of radiofrequency ablation to systemic therapy improved OS in patients with mCRC with inoperable liver disease (hazard ratio [HR] 0.58, 95% confidence interval [CI] 0.38–0.88, p = 0.01) [10, 11]. Multiple mature retrospective series have also reported high rates of local control and favorable long-term survival following the use of thermal ablation for CRC liver metastases [12,13,14,15].

SABR appears to be a safe and effective way to treat multiple metastatic sites in the lung, abdomen/pelvis, bone, and spine [16]. The use of SABR for the treatment of CRC lung and liver metastases has demonstrated local control rates of 80–90% with minimal toxicity [17, 18]. Additionally, there is emerging evidence that SABR to all sites of radiographic disease may improve PFS and OS [17, 18]. SABR-COMET was a randomized, phase II trial that demonstrated improved OS with SABR compared to the standard of care arm (median OS 41 vs. 28 months, HR 0.57, 95% CI 0.30–1.10, p = 0.090), although having 4.5% grade 5 treatment-related adverse events in the SABR arm. While SABR-COMET was designed as a tumor-agnostic trial in 99 patients with up to 5 metastatic lesions, 27% (n = 9) of the patients in the control group and 14% (n = 9) in the SABR group had a CRC primary [19, 20]. In addition to SABR-COMET, multiple other trials have shown the benefit of SABR in the oligometastatic setting including non-small cell lung cancer, prostate, and renal cell carcinoma [21,22,23,24,25]. These studies demonstrate that SABR is a safe and highly effective locoregional therapy that improves oncologic outcomes in a variety of disease settings, including in some settings where an oligometastatic paradigm has not been well established, in contrast to CRC. In fact, to date there are no completed randomized clinical trials investigating the benefit of SABR in patients with mCRC.

High quality data on the utilization of multimodality metastatic-directed therapy, including the combination of surgical resection, thermal ablation, and SABR, for patients with mCRC is limited despite increased use in clinical practice. A recent prospective Finnish interventional study (RAXO study) highlights the potential for multimodality directed therapy in patients with metastatic CRC [26]. The 5-year OS for patients treated with systemic therapy alone was 6% compared to 40% for patients treated with local ablative therapies and/ or surgical debulking (i.e., R2 resection) [26]. A 5-year survival of 40% with multimodality metastatic-directed therapy is quite notable, as for context the 5-year survival for patients who underwent metastasectomy (R0/R1 resection) was in comparison 66%. These data suggest that local metastatic-directed therapy with SABR, thermal ablation, and surgery may significantly enhance cancer control and enhance overall survival in patients with mCRC rather than continuing with systemic therapy alone.

ERASur was jointly developed by the National Cancer Institute (NCI)’s Alliance for Clinical Trials in Oncology and NRG Oncology to evaluate multimodality metastases-directed therapy in patients with mCRC. Despite the long history of treating oligometastatic CRC, questions remain regarding the benefit of extending local metastatic-directed therapies to patients with more extensive metastatic disease including in patients with extrahepatic disease. The ERASur trial seeks to fill this gap by testing if total ablative therapy (TAT) to all sites of metastatic disease improves survival using a pragmatic design that integrates the current spectrum of multimodality local therapies. If the addition of TAT to SOC systemic therapy improves OS, it will be established as a new standard of care for patients with limited mCRC. If TAT is associated with increased toxicity without improving OS, then future treatment paradigms can avoid unnecessary toxicity associated with TAT.

Methods/design

Study objectives

The primary objective of ERASur is to compare the outcome of using TAT in addition to SOC systemic therapy versus SOC systemic therapy alone in terms of OS, measured from the time of randomization, in patients with newly diagnosed limited mCRC. The secondary objectives include evaluating event-free survival, adverse events, and time to local recurrence for patients treated with TAT, defined as the time from the end of TAT to the date of first documented recurrence at any disease site treated with TAT.

Study setting

ERASur is co-led by the Alliance for Clinical Trials in Oncology and NRG Oncology through the NCI National Clinical Trials Network (NCTN) and supported by the Southwest Oncology Group (SWOG) and the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) Cancer Research Group. Patients will be accrued from member institutions of these NCTN cooperative groups which includes community and academic sites. NCI Central Institutional Review Board (CIRB) approved the study, with participating institutions relying on the CIRB. All patients must provide written informed consent.

Study design

ERASur is a two-arm, multi-institutional, randomized phase III study investigating the effect of the addition of TAT to SOC systemic therapy in patients with limited mCRC. The study schema is illustrated in Fig. 1.

Fig. 1
figure 1

ERASur trial schema

Patient selection and eligibility criteria

Patients 18 years of age or older with histologically confirmed mCRC with 4 or fewer sites of metastatic disease are eligible. Metastatic sites must be radiographically evident, but pathologic confirmation is not required. Single sites include: each hemi-liver (right and left), each lobe of the lungs, each adrenal gland, lymph nodes amenable to a single resection or treatment in a single SABR field, and bone metastases amenable to treatment in a single SABR field. Patients with liver-only metastatic disease are not eligible, nor are patients whose tumors are known to have BRAF V600E mutations or microsatellite unstable. Metastatic lesions must be amenable to any combination of surgical resection, microwave ablation (MWA), and/or SABR. SABR is required to at least one site. Detailed eligibility criteria are shown in Table 1. Patients will have the option of pre-registering for the study within 16 weeks of starting first-line SOC systemic therapy with regimens including 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6), capecitabine and oxaliplatin (CAPOX), 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI), and 5-fluorouracil, leucovorin, oxaliplatin, and irinotecan (mFOLFOXIRI) with or without anti-VEGF or EGFR therapies. For registration, a minimum of 16 weeks and a maximum of 26 weeks of first-line systemic therapy is required. Patients with overt disease progression after 16–26 weeks of first-line systemic therapy are not eligible for the study and if pre-registered will be removed. The study calendar is shown in Table 2.

Table 1 Eligibility Criteria
Table 2 Study calendar. pre-study testing to be completed ≤ 28 DAYS before registration: scan of any type which is used for tumor measurement per protocol, all laboratory studies and history and physical

Treatment plan

Upon registration, which occurs after completing a minimum of 16 weeks or a maximum of 26 weeks of first-line systemic therapy, patients will be randomized to one of two treatment arms. Patients in arm 1 will undergo TAT followed by SOC chemotherapy per institutional practice. For patients in arm 1, the overall treatment plan will be discussed in a multidisciplinary setting, and the patient will be evaluated by physicians from all planned treatment modalities as early as possible for treatment planning. TAT will consist of surgical resection, MWA, and/or SABR to all sites of disease and must be completed within 90 days from randomization. At least one measurable site of metastatic disease needs to be present after completion of induction systemic therapy for treatment, and patients with a complete response to systemic therapy at time of randomization will be removed from the trial. At least one metastatic site must be treated with SABR. The remaining sites can be treated by either SABR with or without surgery and/or MWA. For treatment with SABR, the goal is to deliver a radiation dose that maximizes local control at the treatment site within the confines of anatomic and normal tissue constraints. However, sites must be credentialed for the treatment modality that they intend to use on all patients. All radiation therapy plans will be reviewed in real-time for quality assurance.

Resection of each planned metastatic lesion will be approached with the intent of an R0 resection. If surgical resection of a given metastasis is incomplete with gross or microscopic residual margins, the treatment team should strongly consider using an alternative ablative treatment modality such as MWA or SABR to any residual gross or microscopic disease. When addressing liver metastases, non-anatomic resection will be considered when feasible, and MWA will be considered to allow for a parenchymal-sparing approach for deep lesions less than 3 cm in size. For all patients who undergo surgery during protocol treatment, the preoperative imaging, operative note, surgical pathology report, and adverse events with 30 days of surgery will be reviewed by the study team for quality assurance.

MWA can be delivered either intra-operatively or using a percutaneous approach. Multiple electrodes and overlapping ablations will be permitted to ensure adequate coverage of the target. A minimum margin of 5.0 mm will be required for lesions treated with MWA on this study. Initial assessment of the ablation zone will be verified immediately intra-procedurally using ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). If a margin of < 5.0 mm is observed at initial assessment, additional ablation will be attempted to extend the ablation zone, expand the area of insufficient coverage and provide for at least 5.0 mm minimal margin around the target tumor. If at the first imaging timepoint the tumor is deemed to be incompletely covered, the tumor can undergo repeat treatment without penalization. As quality assurance, the study team will review pre-treatment imaging, the procedure notes, and adverse events within 30 days of treatment associated with MWA. Imaging from the first assessment timepoint at 14–18 weeks post-randomization will also be reviewed to ensure completion of planned ablation.

Lesions that are too small to be treated with any of the modalities included in TAT will be monitored and treated if they progress to a size that is amenable to treatment, and they will not be considered as Response Evaluation Criteria in Solid Tumors (RECIST) progression. Following completion of TAT, the treating healthcare team will consider re-starting systemic therapy within 2 weeks if no surgery is performed or within 4 weeks if surgery is included as part of TAT. Use of maintenance systemic therapy or systemic therapy breaks is permitted at the discretion of the treatment team. Patients randomized to arm 1 with the primary tumor intact will have the primary tumor removed within 6 months of randomization. Resection of the primary tumor may be performed at the same time as metastasectomy or may be staged per discretion of the healthcare team. For patients with primary rectal cancers, the use of pre-operative radiation or chemoradiation will be left to the discretion of the healthcare team.

Patients randomized to arm 2 will continue with systemic therapy with use of maintenance chemotherapy per institutional practice. Local metastatic-directed therapy will not be permitted except for palliation as per institutional standard practices. Palliative radiation therapy will be permitted for lesions causing symptoms that are not controlled by medical therapy with acceptable regimens including 30 Gy in 10 fractions, 24 Gy in 6 fractions, 20 Gy in 5 fractions, 8 Gy in 1 fraction, or an equivalent regimen. Systemic therapy breaks are permitted at any time at the discretion of the treatment team.

Assessment and follow-up

Radiologic response will be evaluated using the RECIST version 1.1 guidelines [27]. A local recurrence will be defined differently based on the modality of treatment. For patients treated with SABR, a recurrence will be deemed local if located in or directly adjacent to the planning target volume. For a site treated using MWA, a recurrence will be deemed local if it is within 1 cm of the treatment site. For patients who undergo surgery, a recurrence will be considered local if it is located at the margin of resection.

Adverse events (AEs) will be graded using the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. Solicited AEs will be collected at baseline prior to treatment until off treatment. Routine AEs will be collected starting after registration until the end of survival follow-up. The first treatment response assessment timepoint will be at 14–18 weeks post-randomization, and then every 3 months until disease progression or at the start of off-protocol anticancer therapy. Off-protocol anticancer therapies consists of any investigational agent, systemic therapy regimen(s) not included in the protocol; for patients randomized to arm 2, this includes any local metastatic-directed therapy other than therapy delivered with palliative intent. All visits will include a history and physical examination, laboratory studies, AE assessment, and imaging with CT of the chest along with CT or MRI of the abdomen and pelvis or, alternatively, a positron emission tomography/computed tomography (PET/CT). All patients, irrespective of whether continuing on study, or who are receiving off protocol therapy, will be followed for OS (except patients who withdraw consent).

Correlative studies

Patients may elect to consent to collection of blood and archival formalin-fixed paraffin-embedded tissue for future genomic analyses. Three 10 mL blood samples will be collected at several time points including within 14 days of pre-registration for those who enroll prior to initiating systemic therapy, at randomization, at 4 months, 8 months, and 1 year after randomization, and at disease progression.

Statistics

Sample size

Per study design, a total of 346 patients (173 per arm) are needed to evaluate the primary endpoint. An additional 18 patients (5% inflation) will be accrued to allow for withdrawal after randomization and major violations. Thus, the total planned target accrual will be 364 patients. Approximately 405 patients will be pre-registered to reach this target accrual, allowing for a 10% drop out during the initial 16 to 26 weeks of SOC systemic therapy due to complete response status, progressive disease, unacceptable toxicity, patient withdrawing consent, treating physician’s decision, etc. With an anticipated accrual of 6.5 patients per month, we estimate the accrual period to be 4.7 years.

Power analysis

Eligible patients will be stratified by the number of metastatic organ sites (1–2 vs. 3–4), timing of metastatic disease diagnosis (synchronous metastatic disease vs. metachronous metastatic disease diagnosed ≥ 12 months following completion of definitive treatment for initial diagnosis), and presence of at least one metastatic site outside the liver and lungs (yes vs. no). Participants will be assigned to one of two treatment arms in a 1:1 ratio, using a dynamic allocation algorithm [28]. This study will utilize a group sequential design with two interim analyses for futility after observing 25% (52 events) and 50% (104 events) of events, adopting the Rho family (Rho = 1.5) beta spending function for controlling the type II error rate. Based on historical data, the median OS is assumed to be 26 months (following 16–26 weeks of initial SOC systemic therapy) for newly diagnosed mCRC patients treated with SOC systemic therapy. We assume an accrual rate of 6.5 patients per month, minimum follow-up on all patients of 60 months, exponential survival, and a one-sided log-rank test for superiority conducted at a one-sided significance level of 0.05. Based on these assumptions, a total number of 208 events will provide 80% power to detect an HR of 0.7 at a one-sided significance level of 0.05 requiring randomization of at least 346 evaluable patients (173 per arm).

Discussion

ERASur is a multicenter randomized phase III clinical trial currently accruing through the U.S. NCI NCTN, which is designed to evaluate the benefit of adding metastatic-directed therapy to SOC systemic therapy in patients with limited mCRC. As imaging and treatment technology and techniques improve, the ability to detect and safely treat metastatic disease with local therapy has improved. However, carefully designed prospective randomized trials are necessitated to fully inform the value of this strategy with regard to efficacy, safety, costs and other consideration. The results of ERASur will help to define the clinical utility of TAT in patients with limited mCRC with extrahepatic disease. The trial activated in January 2023 through the NCI Cancer Trials Support Unit and is currently enrolling.

The conceptualization and design of ERASur was co-led by the Alliance for Clinical Trials in Oncology and NRG Oncology. The study incorporated input from a multidisciplinary team, comprised of experts in surgical, medical, radiation, interventional radiology, imaging and other disciplines, including patient advocacy, which was particularly important given the varied therapeutic modalities under investigation. The final study design was forged with critical input from the NCI Colon Task Force, alongside the guidance of the NCTN including the NCI Gastrointestinal steering committee and Cancer Therapy Evaluation Program. Patient advocates provided input early in the trial design in collaboration with COLONTOWN, a large online community of patients who have had or currently have CRC. Patient engagement and input was sought through multiple online polls run independently by COLONTOWN leadership in order to assist with key study design questions and to gauge patient interest for the trial within the COLONTOWN community [29]. The COLONTOWN community showed exceptionally strong support for ERASur with 90% of patients (N = 127) stating an interest in participating on the trial if they were eligible.

While inception of the trial required multidisciplinary input, successful completion of the trial will also require a concerted effort of the treatment teams at participating sites. For patients randomized to the TAT experimental arm, the selection and sequencing of metastatic-directed therapy will largely be left to the individual healthcare teams within the protocol’s guidance, including use of SABR for at least one site and surgery reserved for lung, liver, and portocaval lymph nodes. This design is by intent, both to maintain the pragmatic nature of this study and to reflect ‘real world’ clinical practice. Rigorous quality assurance mechanisms are in place in addition to two interim analyses to ensure that patients are treated safely with sufficient thresholds for stopping the study for futility.

ERASur is a study that could only be designed and conducted in a cooperative group setting with federal support. Specifically, the primary study hypothesis does not involve an investigational therapeutic or a new device, lending itself relatively unsuitable to pharmaceutical or device manufacture sponsorship. This trial has the potential to significantly impact practice with a positive result providing the much-needed high level evidence to support the practice of integration of TAT in mCRC, and a negative or neutral outcome of this strategy suggesting that SOC systemic therapy is a preferred approach for most patients.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

AEs:

Adverse events

CAPOX:

Capecitabine and oxaliplatin

CIRB:

Central Institutional Review Board

CRC:

Colorectal cancer

CT:

Computed tomography

CTCAE:

Common Terminology Criteria for Adverse Events

ECOG-ACRIN:

Eastern Cooperative Oncology Group-American College of Radiology Imaging Network

ERASur:

Evaluating Radiation, Ablation, and Surgery

FOLFIRI:

5-fluorouracil, leucovorin, and irinotecan

HAIP:

Hepatic artery infusion pump

mCRC:

Metastatic colorectal cancer

mFOLFOX6:

5-fluorouracil, leucovorin, and oxaliplatin

mFOLFOXIRI:

Fluorouracil, leucovorin, oxaliplatin, and irinotecan

MRI:

Magnetic resonance imaging

MSI:

Microsatellite instable

MWA:

Microwave ablation

NCI:

National Cancer Institute

NCTN:

National Clinical Trials Network

OS:

Overall survival

PET/CT:

Positron emission tomography/computed tomography

PFS:

Progression-free survival

RECIST:

Response Evaluation Criteria in Solid Tumors

SABR:

Stereotactic ablative body radiotherapy

SOC:

Standard of care

SWOG:

Southwest Oncology Group

TAT:

Total ablative therapy

ULN:

Upper limit of normal

References

  1. Choti MA, Sitzmann JV, Tiburi MF, Sumetchotimetha W, Rangsin R, Schulick RD, et al. Trends in long-term survival following liver resection for hepatic colorectal metastases. Ann Surg. 2002;235(6):759–66.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Fong Y, Fortner J, Sun RL, Brennan MF, Blumgart LH. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230(3):309–18. discussion 18–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kanemitsu Y, Shimizu Y, Mizusawa J, Inaba Y, Hamaguchi T, Shida D, et al. Hepatectomy followed by mFOLFOX6 Versus Hepatectomy alone for liver-only metastatic colorectal Cancer (JCOG0603): a phase II or III randomized controlled trial. J Clin Oncol. 2021;39(34):3789–99.

    Article  CAS  PubMed  Google Scholar 

  4. Morris EJ, Forman D, Thomas JD, Quirke P, Taylor EF, Fairley L, et al. Surgical management and outcomes of colorectal cancer liver metastases. Br J Surg. 2010;97(7):1110–8.

    Article  CAS  PubMed  Google Scholar 

  5. Nordlinger B, Sorbye H, Glimelius B, Poston GJ, Schlag PM, Rougier P, et al. Perioperative FOLFOX4 chemotherapy and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC 40983): long-term results of a randomised, controlled, phase 3 trial. Lancet Oncol. 2013;14(12):1208–15.

    Article  CAS  PubMed  Google Scholar 

  6. Kopetz S, Chang GJ, Overman MJ, Eng C, Sargent DJ, Larson DW, et al. Improved survival in metastatic colorectal cancer is associated with adoption of hepatic resection and improved chemotherapy. J Clin Oncol. 2009;27(22):3677–83.

    Article  PubMed  PubMed Central  Google Scholar 

  7. McCormack PM, Burt ME, Bains MS, Martini N, Rusch VW, Ginsberg RJ. Lung resection for colorectal metastases. 10-year results. Arch Surg. 1992;127(12):1403–6.

    Article  CAS  PubMed  Google Scholar 

  8. Shah SA, Haddad R, Al-Sukhni W, Kim RD, Greig PD, Grant DR, et al. Surgical resection of hepatic and pulmonary metastases from colorectal carcinoma. J Am Coll Surg. 2006;202(3):468–75.

    Article  PubMed  Google Scholar 

  9. Leung U, Gonen M, Allen PJ, Kingham TP, DeMatteo RP, Jarnagin WR, et al. Colorectal Cancer Liver metastases and Concurrent Extrahepatic Disease treated with resection. Ann Surg. 2017;265(1):158–65.

    Article  PubMed  Google Scholar 

  10. Ruers T, Punt C, Van Coevorden F, Pierie JPEN, Borel-Rinkes I, Ledermann JA, et al. Radiofrequency ablation combined with systemic treatment versus systemic treatment alone in patients with non-resectable colorectal liver metastases: a randomized EORTC Intergroup phase II study (EORTC 40004). Ann Oncol. 2012;23(10):2619–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ruers T, Van Coevorden F, Punt CJA, Pierie J-PEN, Borel-Rinkes I, Ledermann JA et al. Local treatment of Unresectable Colorectal Liver metastases: results of a Randomized Phase II Trial. J Natl Cancer Inst. 2017;109(9).

  12. Shady W, Petre EN, Gonen M, Erinjeri JP, Brown KT, Covey AM, et al. Percutaneous Radiofrequency ablation of Colorectal Cancer Liver metastases: factors affecting Outcomes–A 10-year experience at a single Center. Radiology. 2016;278(2):601–11.

    Article  PubMed  Google Scholar 

  13. Solbiati L, Ahmed M, Cova L, Ierace T, Brioschi M, Goldberg SN. Small liver colorectal metastases treated with percutaneous radiofrequency ablation: local response rate and long-term survival with up to 10-year follow-up. Radiology. 2012;265(3):958–68.

    Article  PubMed  Google Scholar 

  14. Knott EA, Ziemlewicz TJ, Lubner SJ, Swietlik JF, Weber SM, Zlevor AM, et al. Microwave ablation for colorectal cancer metastasis to the liver: a single-center retrospective analysis. J Gastrointest Oncol. 2021;12(4):1454–69.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Puijk RS, Dijkstra M, van den Bemd BAT, Ruarus AH, Nieuwenhuizen S, Geboers B, et al. Improved outcomes of thermal ablation for Colorectal Liver metastases: a 10-Year analysis from the prospective Amsterdam CORE Registry (AmCORE). Cardiovasc Intervent Radiol. 2022;45(8):1074–89.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Chmura S, Winter KA, Robinson C, Pisansky TM, Borges V, Al-Hallaq H, et al. Evaluation of safety of stereotactic body radiotherapy for the treatment of patients with multiple metastases: findings from the NRG-BR001 phase 1 trial. JAMA Oncol. 2021;7(6):845–52.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Miller ED, Hitchcock KE, Romesser PB. Oligometastatic colorectal Cancer: a review of definitions and patient selection for local therapies. J Gastrointest Cancer. 2023.

  18. Hitchcock KE, Romesser PB, Miller ED. Local therapies in Advanced Colorectal Cancer. Hematol Oncol Clin North Am. 2022;36(3):553–67.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051–8.

    Article  PubMed  Google Scholar 

  20. Palma DA, Olson R, Harrow S, Gaede S, Louie AV, Haasbeek C, et al. Stereotactic ablative radiotherapy for the Comprehensive Treatment of Oligometastatic Cancers: long-term results of the SABR-COMET phase II randomized trial. J Clin Oncol. 2020;38(25):2830–8.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Phillips R, Shi WY, Deek M, Radwan N, Lim SJ, Antonarakis ES, et al. Outcomes of Observation vs Stereotactic Ablative Radiation for oligometastatic prostate Cancer: the ORIOLE phase 2 Randomized Clinical Trial. JAMA Oncol. 2020;6(5):650–9.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gomez DR, Tang C, Zhang J, Blumenschein GR Jr., Hernandez M, Lee JJ, et al. Local consolidative therapy Vs. maintenance Therapy or Observation for patients with Oligometastatic Non-small-cell Lung Cancer: long-term results of a multi-institutional, phase II, Randomized Study. J Clin Oncol. 2019;37(18):1558–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Iyengar P, Wardak Z, Gerber DE, Tumati V, Ahn C, Hughes RS, et al. Consolidative Radiotherapy for Limited Metastatic Non-small-cell Lung Cancer: a phase 2 Randomized Clinical Trial. JAMA Oncol. 2018;4(1):e173501.

    Article  PubMed  Google Scholar 

  24. Siva S, Bressel M, Wood ST, Shaw MG, Loi S, Sandhu SK, et al. Stereotactic radiotherapy and short-course Pembrolizumab for Oligometastatic Renal Cell Carcinoma-the RAPPORT Trial. Eur Urol. 2022;81(4):364–72.

    Article  CAS  PubMed  Google Scholar 

  25. Tang C, Msaouel P, Hara K, Choi H, Le V, Shah AY, et al. Definitive radiotherapy in lieu of systemic therapy for oligometastatic renal cell carcinoma: a single-arm, single-centre, feasibility, phase 2 trial. Lancet Oncol. 2021;22(12):1732–9.

    Article  PubMed  Google Scholar 

  26. Osterlund P, Salminen T, Soveri LM, Kallio R, Kellokumpu I, Lamminmaki A, et al. Repeated centralized multidisciplinary team assessment of resectability, clinical behavior, and outcomes in 1086 Finnish metastatic colorectal cancer patients (RAXO): a nationwide prospective intervention study. Lancet Reg Health Eur. 2021;3:100049.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.

    Article  CAS  PubMed  Google Scholar 

  28. Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial. Biometrics. 1975;31(1):103–15.

    Article  CAS  PubMed  Google Scholar 

  29. George M, Smith JJ, Miller ED, Romesser PB, Seybold N. Impact and utility of COLONTOWN, an online CRC patient and caregiver support group in clinical trial design. J Clin Oncol. 2021;39(3).

Download references

Acknowledgements

We acknowledge Jennifer Huber for editorial assistance.

Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG). No funding agency was involved in the design of the study, or the collection, analysis, and interpretation of data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Support: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), UG1CA189850, UG1CA232760, UG1CA233180, UG1CA233277, UG1CA233290, UG1CA233331; U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); and U10CA180888 (SWOG). https://acknowledgments.alliancefound.org. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Contributions

KEH, EDM, and PBR contributed equally to this manuscript. KEH, EDM, TJG, EMO, JAM, and PBR conceived of the clinical trial. KEH, EDM, QS, JGD, SG, SBW, CW, CCG, MG, KJ, CJW, RY, AS, TSH, TJG, EMO, JAM, and PBR developed the protocol. QS and JGD designed the statistical analyses. KEH, EDM, and PBR wrote the main manuscript. All authors reviewed and edited the manuscript.

Corresponding author

Correspondence to Paul B. Romesser.

Ethics declarations

Ethics approval and consent to participate

The study has been reviewed and approved by the National Cancer Institute Adult Central IRB. All patients must provide written informed consent on the CIRB approved consent form.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hitchcock, K.E., Miller, E.D., Shi, Q. et al. Alliance for clinical trials in Oncology (Alliance) trial A022101/NRG-GI009: a pragmatic randomized phase III trial evaluating total ablative therapy for patients with limited metastatic colorectal cancer: evaluating radiation, ablation, and surgery (ERASur). BMC Cancer 24, 201 (2024). https://doi.org/10.1186/s12885-024-11899-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12885-024-11899-2

Keywords