Assessment of a Watch-and-Wait Strategy for Rectal Cancer in Patients With a Complete Response After Neoadjuvant Therapy

Smith, J. Joshua; Strombom, Paul; Chow, Oliver; Roxburgh, Campbell S.D.; Lynn, Patricio B.; Eaton, Anne; Widmar, Maria; Ganesh, Karuna; Yaeger, Rona; Cercek, Andrea; Weiser, Martin R.; Nash, Garrett M.; Guillem, José G.; Temple, Larissa K.; Chalasani, Sree B.; Fuqua, James L.; Petkovska, Iva; Wu, Abraham J.; Reyngold, Marsha; Vakiani, Efsevia; Shia, Jinru; Segal, Neil H.; Smith, James D.; Crane, Christopher H.; Gollub, Marc J.; Gönen, Mithat; Saltz, Leonard; García-Aguilar, Julio; Paty, Philip B.

doi:10.1001/jamaoncol.2018.5896

Cited by 410 publications

(352 citation statements)

References 21 publications

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“…At present, only approximately 30% of neoadjuvant patients will achieve clinical or pathologic complete responses to nCR therapy and are candidates for organ preservation. Moreover, these patients have better outcomes in terms of disease-free and overall survival (49). However, success of this approach is hindered by lack of molecular and/or functional assays that predict response to therapy, emphasizing the need for development of personalized models that can predict treatment response.…”

Section: Discussionmentioning

confidence: 99%

Organoids Reveal That Inherent Radiosensitivity of Small and Large Intestinal Stem Cells Determines Organ Sensitivity

et al. 2020

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Tissue survival responses to ionizing radiation are nonlinear with dose, rather yielding tissue-specific descending curves that impede straightforward analysis of biologic effects. Apoptotic cell death often occurs at low doses, while at clinically relevant intermediate doses, double-strand break misrepair yields mitotic death that determines outcome. As researchers frequently use a single low dose for experimentation, such strategies may inaccurately depict inherent tissue responses. Cutting edge radiobiology has adopted full dose survival profiling and devised mathematical algorithms to fit curves to observed data to generate highly reproducible numerical data that accurately define clinically relevant inherent radiosensitivities. Here, we established a protocol for irradiating organoids that delivers radiation profiles simulating the organ of origin. This technique yielded highly similar dose-survival curves of small and large intestinal crypts in vivo and their cognate organoids analyzed by the singlehit multi-target (SHMT) algorithm, outcomes reflecting the inherent radiation profile of their respective Lgr5 þ stem cell populations. As this technological advance is quantitative, it will be useful for accurate evaluation of intestinal (patho)physiology and drug screening. Significance: These findings establish standards for irradiating organoids that deliver radiation profiles that phenocopy the organ of origin. See related commentary by Muschel et al., p. 927

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Section: Discussionmentioning

confidence: 99%

Organoids Reveal That Inherent Radiosensitivity of Small and Large Intestinal Stem Cells Determines Organ Sensitivity

et al. 2020

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“…Up to 40% of patients may show a complete pathologic response following neoadjuvant chemoradiation 31,32 . Some studies have shown that local recurrence and survival in patients not undergoing surgery with complete clinical response compared to patients undergoing surgery with a pathologic complete response are similar, 32,33 while others have shown decreased survival 34 . An unintended consequence of this neoadjuvant chemoradiation is that some patients may refuse subsequent treatment with surgery.…”

Section: Discussionmentioning

confidence: 99%

Treatment of stage I‐III rectal cancer: Who is refusing surgery?

Fields

Yoo

et al. 2020

Journal of Surgical Oncology

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Background and Objectives Surgical resection is a cornerstone in the management of patients with rectal cancer. Patients may refuse surgical treatment for several reasons although the rate of refusal is currently unknown. Methods The National Cancer Database was utilized to identify patients with stage I‐III rectal cancer. Patients who refused surgical resection were compared to patients who underwent curative resection. Results A total of 509 (2.6%) patients with stage I and 2082 (3.5%) patients with stage II/III rectal cancer refused surgery. In multivariable analysis for stage I disease, older age, Black race, and Medicaid/no insurance were independent predictors of surgery refusal. Patients were less likely to refuse surgery if they had a higher income or lived further distances from the treatment facility. In multivariable analysis for stage II/III disease, older age, Black race, insurance other than private, and rural county were independent predictors of surgery refusal. Patients were less likely to refuse surgery if they had higher Charlson comorbidity scores, lived further distances from the treatment facility, or underwent chemoradiation. There was a significant decrease in survival for patients refusing surgery compared to patients undergoing recommended surgery. Conclusions A small proportion of patients refuse surgery for rectal cancer, and this treatment decision significantly affects survival.

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“…The unsalvageable local disease rate is 0.2-1% [2,3]. Recently, Smith et al [4] observed distant metastases (DM) in 36% of patients with LR compared with only 1% in patients without LR (p = 0.001). These findings incited a debate about the safety of the omission of immediate surgery in terms of the increased risk of DM.…”

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The risk of distant metastases in rectal cancer managed by a watch-and-wait strategy – A systematic review and meta-analysis

Socha

Kępka

Michalski

et al. 2020

Radiotherapy and Oncology

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Background: The watch-and-wait (w&w) strategy is associated with frequent local regrowth (LR). Distant metastases (DM) occur more often in the patients with LR than in those without. However, it is unknown whether omitting immediate surgery results in the additional risk of DM. Materials/methods: A systematic review and meta-analysis were performed to determine the maximum risk of additional DM. To estimate this, we used data showing the proportions of DM in patients with and without LR, assuming that the excess DM in patients with LR may develop in two ways: from subclinical DM already present at baseline and due to seeding from the uncontrolled primary tumor, and that the incidence of subclinical DM at baseline in the LR subgroup is at least not lower than in the non-LR subgroup. Based on the calculated rate of excess DM in the LR subgroup we have obtained the rate for the whole group of patients undergoing w&w. Results: The maximum estimated risk of additional DM was 3.0% (95% CI: 1.2-4.9%) in the total group. After correction for short follow-up, the maximum risk at 5 years was 6.5%. Thus, the risk of excess DM is between 0% and 6.5%. Other evidence from a systematic review and the conservative assumptions taken for the calculation of the correction suggest that this maximum risk may be overestimated. Conclusions: The additional risk of DM seems to be low. However, the high probability of bias, heterogeneity of the patients' population and low quality of evidence make our estimation uncertain.

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Assessment of a Watch-and-Wait Strategy for Rectal Cancer in Patients With a Complete Response After Neoadjuvant Therapy

Abstract: The watch-and-wait (WW) strategy aims to spare patients with rectal cancer unnecessary resection. OBJECTIVE To analyze the outcomes of WW among patients with rectal cancer who had a clinical complete response to neoadjuvant therapy.

Cited by 410 publications

References 21 publications

Organoids Reveal That Inherent Radiosensitivity of Small and Large Intestinal Stem Cells Determines Organ Sensitivity

Organoids Reveal That Inherent Radiosensitivity of Small and Large Intestinal Stem Cells Determines Organ Sensitivity

Treatment of stage I‐III rectal cancer: Who is refusing surgery?

The risk of distant metastases in rectal cancer managed by a watch-and-wait strategy – A systematic review and meta-analysis

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