Interval between neoadjuvant treatment and definitive surgery in locally advanced rectal cancer: impact on response and oncologic outcomes

Calvo, Felipe A.; Morillo, V.; Santos, Marcos; Serrano, Javier García; Gómez-Espí, M.; Rodríguez, Marcos; Vale, Emilio del; Gracia-Sabrido, Jose Luis; Ferrer, C.; Sole, Claudio V.

doi:10.1007/s00432-014-1718-z

Cited by 26 publications

(28 citation statements)

References 30 publications

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“…Findings from several retrospective case series have confirmed that a longer chemoradiation-to-surgery interval is associated with higher proportions of patients achieving a pathological complete response. 14,19–24 We chose pathological complete response as our primary endpoint to assess how many patients are potentially eligible for a non-operative approach and to establish whether the proportion of patients achieving a pathological complete response could be increased by lengthening the duration between chemoradiation and surgery. However, at the time that this trial was designed, lengthening the interval between chemoradiation and surgery was thought to be unsafe because it would delay the administration of adjuvant systemic chemotherapy, potentially increasing the risk of metastasis.…”

Section: Discussionmentioning

confidence: 99%

Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial

García-Aguilar¹,

Chow²,

Smith³

et al. 2015

The Lancet Oncology

590

477

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Summary Background Patients with locally advanced rectal cancer who achieve a pathological complete response to neoadjuvant chemoradiation have an improved prognosis. The need for surgery in these patients has been questioned, but the proportion of patients achieving a pathological complete response is small. We aimed to assess whether adding cycles of mFOLFOX6 between chemoradiation and surgery increased the proportion of patients achieving a pathological complete response. Methods We did a phase 2, non-randomised trial consisting of four sequential study groups of patients with stage II–III locally advanced rectal cancer at 17 institutions in the USA and Canada. All patients received chemoradiation (fluorouracil 225 mg/m2 per day by continuous infusion throughout radiotherapy, and 45.0 Gy in 25 fractions, 5 days per week for 5 weeks, followed by a minimum boost of 5.4 Gy). Patients in group 1 had total mesorectal excision 6–8 weeks after chemoradiation. Patients in groups 2–4 received two, four, or six cycles of mFOLFOX6, respectively, between chemoradiation and total mesorectal excision. Each cycle of mFOLFOX6 consisted of racemic leucovorin 200 mg/m2 or 400 mg/m2, according to the discretion of the treating investigator, oxaliplatin 85 mg/m2 in a 2-h infusion, bolus fluorouracil 400 mg/m2 on day 1, and a 46-h infusion of fluorouracil 2400 mg/m2. The primary endpoint was the proportion of patients who achieved a pathological complete response, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00335816. Findings Between March 24, 2004, and Nov 16, 2012, 292 patients were registered, 259 of whom (60 in group 1, 67 in group 2, 67 in group 3, and 65 in group 4) met criteria for analysis. 11 (18%, 95% CI 10–30) of 60 patients in group 1, 17 (25%, 16–37) of 67 in group 2, 20 (30%, 19–42) of 67 in group 3, and 25 (38%, 27–51) of 65 in group 4 achieved a pathological complete response (p=0.0036). Study group was independently associated with pathological complete response (group 4 compared with group 1 odds ratio 3.49, 95% CI 1.39–8.75; p=0.011). In group 2, two (3%) of 67 patients had grade 3 adverse events associated with the neoadjuvant administration of mFOLFOX6 and one (1%) had a grade 4 adverse event; in group 3, 12 (18%) of 67 patients had grade 3 adverse events; in group 4, 18 (28%) of 65 patients had grade 3 adverse events and five (8%) had grade 4 adverse events. The most common grade 3 or higher adverse events associated with the neoadjuvant administration of mFOLFOX6 across groups 2-4 were neutropenia (five in group 3 and six in group 4) and lymphopenia (three in group 3 and four in group 4). Across all study groups, 25 grade 3 or worse surgery-related complications occurred (ten in group 1, five in group 2, three in group 3, and seven in group 4); the most common were pelvic abscesses (seven patients) and anastomotic leaks (seven patients). Interpretation Delivery of mFOLFOX6 after chemoradiation and before total mesorectal excision has the potential to in...

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Section: Discussionmentioning

confidence: 99%

Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial

García-Aguilar¹,

Chow²,

Smith³

et al. 2015

The Lancet Oncology

590

477

View full text Add to dashboard Cite

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“…Only a limited number of studies have demonstrated improved survival for LARC patients with a long treatment interval 15,31. To the best of our knowledge, none of the studies to date that have analyzed the relationship between a prolonged treatment interval and OS have specifically looked into outcomes of ET patients 15,25,28,31–33…”

Section: Discussionmentioning

confidence: 99%

“…Although neoadjuvant CRT has been widely implemented in the treatment of rectal cancer patients, the optimal timing of surgery after neoadjuvant therapy is as yet unclear 15. Surgery was previously performed 6–8 weeks after completion of CRT;16,17 however, recent studies suggest a time-related response of the tumor to CRT.…”

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confidence: 99%

Treatment Interval between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer Patients: A Population-Based Study

et al. 2016

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Background Neoadjuvant chemoradiation therapy (CRT) has been widely implemented in the treatment of rectal cancer patients, but optimal timing of surgery after neoadjuvant therapy is unclear. The purpose of this study was to evaluate the effects of prolonged intervals between long-course CRT and surgery in rectal cancer patients.MethodsData on all rectal cancer patients diagnosed between 2006 and 2011 were retrieved from the population-based Netherlands Cancer Registry; the main outcome parameters were pathologic complete response (pCR) and overall survival (OS). Outcomes were reported separately for patients with early tumors (ETs; N = 217) and locally advanced rectal cancer (LARC; N = 1073). Patients were divided into 2-week interval groups according to treatment interval, ranging from 5–6 to 13–14 weeks. Kaplan–Meier curves, and logistic regression and Cox regression models were used for data analysis.ResultsNo significant difference in pCR rate was observed for ET patients according to treatment interval. Compared with a treatment interval of 7–8 weeks, pCR rates in LARC patients were higher after 9–10 weeks (18.4 %; odds ratio [OR] 1.56, 95 % CI 1.03–2.37) and 11–12 weeks of treatment interval (20.8 %; OR 1.94, 95 % CI 1.15–3.26). Treatment interval did not influence OS in ET or LARC patients.ConclusionsTreatment intervals of 9–12 weeks between surgery and CRT seem to improve the chances of pCR in LARC patients, without an effect on OS. The length of treatment interval did not affect outcomes in patients with ET. The ongoing search for minimally invasive surgery drives the need for exploration of factors that improve pathologic response.Electronic supplementary materialThe online version of this article (doi:10.1245/s10434-016-5294-0) contains supplementary material, which is available to authorized users.

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“…9 This finding was consistent with other retrospective reports that identified higher rates of tumor response with prolonged intervals between CRT and surgery. 10–13 Other groups have reported response rates over 30% by incorporating systemic chemotherapy prior to chemoradiation therapy. 14,15 …”

Section: Introductionmentioning

confidence: 99%

KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy

et al. 2016

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Background The response of rectal cancers to neoadjuvant chemoradiation (CRT) is variable, but tools to predict response remain lacking. We evaluated whether KRAS and TP53 mutations are associated with pathologic complete response (pCR) and lymph node metastasis after adjusting for neoadjuvant regimen. Methods Retrospective analysis of 229 pretreatment biopsies from patients with stage II/III rectal cancer was performed. All patients received CRT. Patients received zero to eight cycles of FOLFOX either before or after CRT, but prior to surgical excision. A subset was analyzed to assess concordance between mutation calls by Sanger sequencing and a next-generation assay. Results 96 (42%) tumors had KRAS mutation, 150 had TP53 mutation (66%), and 59 (26%) had both. 59 patients (26%) achieved pCR following neoadjuvant therapy. 45 of 133 (34%) KRAS wild-type tumors had pCR, compared with 14 of 96 (15%) KRAS mutant tumors (p=0.001). KRAS mutation remained independently associated with a lower pCR rate on multivariable analysis after adjusting for clinical stage, CRT-to-surgery interval, and cycles of FOLFOX (OR 0.34, 95% CI: 0.17-0.66, p < 0.01). Of 29 patients with KRAS G12V or G13D, only 2 (7%) achieved pCR. Tumors with both KRAS and TP53 mutation were associated with lymph node metastasis. The concordance between platforms was high for KRAS (40 of 43, 93%). Conclusions KRAS mutation is independently associated with a lower pCR rate in locally advanced rectal cancer after adjusting for variations in neoadjuvant regimen. Genomic data can potentially be used to select patients for “watch and wait” strategies.

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Interval between neoadjuvant treatment and definitive surgery in locally advanced rectal cancer: impact on response and oncologic outcomes

Cited by 26 publications

References 30 publications

Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial

Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial

Treatment Interval between Neoadjuvant Chemoradiotherapy and Surgery in Rectal Cancer Patients: A Population-Based Study

KRAS and Combined KRAS/TP53 Mutations in Locally Advanced Rectal Cancer are Independently Associated with Decreased Response to Neoadjuvant Therapy

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