The importance of measuring baseline tumour volume (or alternatively tumour length along with its rectal circumferential extent) in the watch-and-wait strategy in rectal cancer: a review

Figures & data

Figure 1. PRISMA flow chart.

Table 1. The design and outcomes of the studies evaluating the association of baseline tumour volume or size with clinical complete response.

	Number of patients	% of patients with cCR	Eligibility criteria and design	Results of univariable analysis	Significant variables in the multivariable analysis
Jankowski [4]	490	15	Pooled two prospective multi-institutional observational studies evaluating the effectiveness of w&w in consecutive patients receiving routine preoperative radio(chemo)therapy (short-course with delayed surgery, short-course with 6 weeks of consolidation chemotherapy or chemoradiation). The secondary aim in both trials was to evaluate predictive factors for cCR. The time interval between the start of radiation and tumour response assessment was 10–13 weeks.	All tumour-related evaluated variables were significantly associated with initial cCR, namely: tumour length, % of circumferential rectal extent, tumour volume, cT category, cN category, distance between the tumour and the anal verge, mesorectal fascia threatening, tumour mobility (movable vs. fixed).	Tumour length: OR = 0.24 (95% CI 0.07–0.80), for tumours 1–3 cm vs. ≥7 cm, p = 0.033; Proportion of circumferential extent: OR = 0.13 (95% CI 0.04–0.50) for tumours with ≤ 40% extent vs. circular tumour, p = 0.004; Tumour volume (available in 85% of patients, the tumour length and circumferential extent were excluded to avoid collinearity): OR = 0.10 (95% CI 0.03–0.30) for tumour < 20 cc vs. >65 cc, p < 0.001. cN category: OR = 0.46 (95% CI 0.26–0.84) for cN0 vs. cN+, p = 0.011.
Benezery [3]	60	68	Retrospective single-institution observational study evaluating the effectiveness of w&w in consecutive elderly patients with small tumours (≤5 cm in the largest dimension and ≤ 50% of rectal circumferential extent) receiving chemoradiation and contact X-ray brachytherapy boost. The time interval between the start of radiation and tumour response assessment was 13–15 weeks.	The following variables were significantly associated with initial cCR or near-cCR combined: the treatment chronology (external beam radiation first vs. brachytherapy first), the cT category, the clinical aspect (polypoid vs. fungating) and the circumferential rectal extent. Tumour volume reached borderline significance (p = 0.075).	The treatment chronology: OR = 7.53 (95% CI 1.72–32.81) for external beam radiation first vs. brachytherapy first.
Rijkmans [9]	33	61	Prospective single-institution observational study evaluating the effectiveness of w&w in medically inoperable patients with small tumours treated with external beam radiation followed by high-dose-rate iridium brachytherapy boost. The time interval between the start of radiation and tumour response assessment was about 30 weeks.	The tumour volume was the only significant (p-value <0.01) predictor of initial cCR: OR = 1.15 (cc), p = 0.005. Tumour thickness, circumferential rectal extent and the cN category showed a trend (p-value between 0.01 and 0.1). Both the cT category and the tumour length were not associated with initial cCR. For sustained cCR a trend was observed for baseline tumour volume (HR = 1.05, 95% CI 1.01–1.09, p = 0.02), circumferential involvement (HR = 1.33 (95% CI 1.04–1.68, p = 0.02) and thickness (HR = 1.08 95% CI 1.01–1.16, p = 0.03).	Not performed
Yuval [15] abstract	289	Not given	Randomised phase II OPRA study evaluating whether the organ preservation rate would differ between patients who underwent induction chemotherapy for 16 weeks followed by chemoradiation and patients who underwent chemoradiation followed by consolidation chemotherapy for 16 weeks. The time interval between the start of treatment and tumour response assessment was about 34 weeks.	Not given	The following variables were significantly associated with organ preservation (defined as the time from randomisation to the clinical decision of total mesorectal excision or last follow up) with sustained cCR: Mesorectal fascia: HR = 1.55 (95% CI 1.05–2.28) involved vs. clear, p = 0.028 cN category: HR = 1.89 (95% CI 1.23–2.90) N + vs. N0, p = 0.004 EMVI: HR = 1.63 (95% CI 1.02–2.59) present vs. absent/intermediate, p = 0.041 Tumour length (continuous variable) reached borderline significance HR = 1.10 (95% CI 0.99–1.23), p = 0.066. The association with cT category was not significant.
Jimenez-Rodriguez [16]	88	36	Retrospective observational study evaluating the effectiveness of induction chemotherapy for 16 weeks and chemoradiation in w&w in patients with advanced cancer treated by a single surgeon. The time interval between the start of chemotherapy and tumour response assessment was 23–28 weeks.	Tumour length was the only parameter significantly associated with initial cCR (p = 0.003). Both the cT category and stage of disease (II vs. III) were not associated with cCR. The association with circumferential rectal extent was not investigated.	Not performed
Gerard [8]	201	16	ACCORD 12 randomised trial comparing preoperative chemoradiation either with or without oxaliplatin in patients with advanced cancer. Of the total 598 patients, 201 (34%) had clinical tumour response evaluation before surgery, 3–5 weeks after chemoradiation. They form the basis of this analysis. The time interval between the start of radiation and tumour response assessment was 9–11 weeks.	Three parameters were significantly associated with initial cCR: the cT category (p = 0.025) tumour diameter (p = 0.175) and its circumferential extent within the rectal wall (p = 0.04).	Not performed
Habr-Gama [5]	183	49	Retrospective single-institution observational study evaluating the effectiveness of w&w in consecutive patients receiving chemoradiation. The time interval between the start of radiation and tumour response assessment was 13 weeks.	None of the analysed cancer variables (the cT category, N0 vs. N + and the tumour size) were significantly associated with initial cCR.	Not performed
Chin et al. [11]	86	50	Retrospective single-institution observational study evaluating the effectiveness of w&w in patients receiving short-course radiation and 16 weeks of consolidation chemotherapy. The time interval between the start of radiation and tumour response assessment was 23–28 weeks.	Tumour size (p = 0.002), mesorectal fascia involvement (0.009) and cT category (p = 0.045) were significantly associated with initial cCR. The cN category showed a trend (p = 0.05). The association with circumferential rectal extent was not investigated.	Not performed
Mbanu [17]	322	161	Retrospective propensity-score matched study from two institutions evaluating baseline predictors of cCR in patients receiving chemoradiation. The time interval between the start of radiation and tumour response assessment was 13–15 weeks.	Of tumour related factors, tumour length (p < 0.001), T-category (p < 0.001) were significantly associated with cCR. N-category was insignificant. The association with circumferential rectal extent was not investigated.	Tumour length: OR = 0.75 (95% CI 0.62–0.91), p = 0.004; cT-category: cT3 vs. cT2 OR = 0.26 (95% CI 0.09–0.70), p = 0.008, cT4 vs cT2 OR = 0.28 (95% CI 0.07–1.04), p = 0.058

Abbreviations used: cCR: clinical complete response; w&w: watch-and-wait strategy; OR: odds ratio; HR: hazard ratio; CI: confidence interval; EMVI: extramural vascular invasion.

Figure 2. Tumour volume in relation to the cT category in 360 patients. This previously unpublished analysis was performed for the purpose of the present study using the database from a previous publication [4] co-authored by two of the current authors. The box indicates the interquartile range. The thick horizontal line within the box indicates the median value. The vertical bar indicates the location of 95% measurements.

Figure 3. Regression curve showing the association between tumour volume and the probability of clinical complete response (cCR) achieved after routine doses of preoperative radiotherapy (5 × 5 Gy with delayed surgery or 5 × 5 Gy + 6 weeks of consolidation chemotherapy or chemoradiation using 50 Gy, 2 Gy per fraction) in 360 patients. Reproduced from [4] with permission from Elsevier.

Jankowski M, Pietrzak L, Rupiński M, Polish Colorectal Study Group, et al. Watch-and-wait strategy in rectal cancer: is there a tumour size limit? Results from two pooled prospective studies. Radiother Oncol. 2021;160:229–235.

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Benezery K, Montagne L, Evesque L, et al. Clinical response assessment after contact X-Ray brachytherapy and chemoradiotherapy for organ preservation in rectal cancer T2-T3 M0: the time/dose factor influence. Clin Transl Radiat Oncol. 2020;24:92–98.

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Rijkmans EC, Marijnen CAM, van Triest B, et al. Predictive factors for response and toxicity after brachytherapy for rectal cancer; results from the HERBERT study. Radiother Oncol. 2019;133:176–182.

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Yuval JB, Verheij FS, Lin ST, On behalf of the OPRA consortium, et al. Clinical and radiological predictors of organ preservation in patients with rectal cancer treated with total neoadjuvant therapy. J Clin Oncol. 2022;40(16_suppl):3619–3619.

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Jimenez-Rodriguez RM, Quezada-Diaz F, Hameed I, et al. Organ preservation in patients with rectal cancer treated with total neoadjuvant therapy. Dis Colon Rectum. 2021;64(12):1463–1470.

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Gérard JP, Chamorey E, Gourgou-Bourgade S, et al. Clinical complete response (cCR) after neoadjuvant chemoradiotherapy and conservative treatment in rectal cancer. Findings from the ACCORD 12/PRODIGE 2 randomized trial. Radiother Oncol. 2015;115(2):246–252.

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Habr-Gama A, Gama-Rodrigues J, São Julião GP, et al. Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. Int J Radiat Oncol Biol Phys. 2014;88(4):822–828.

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Chin RI, Roy A, Pedersen KS, et al. Clinical complete response in patients with rectal adenocarcinoma treated with short-course radiation therapy and nonoperative management. Int J Radiat Oncol Biol Phys. 2022;112(3):715–725.

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Data availability statement

The database has been deposited in a repository and is available upon request from the corresponding author [KB].