Abstract

Background: Neoadjuvant chemoradiotherapy is regarded as the standard of treatment for locally advanced lower rectal cancer although some of these cases are systemic, and local control may be inadequate. We aimed to stratify patients into prognostic groups based on preoperative factors, including response to neoadjuvant chemotherapy. 

Methods: We retrospectively analyzed patients with locally advanced lower rectal adenocarcinoma (clinical stage II/III with high-risk features of distant metastasis) who were treated with neoadjuvant chemotherapy followed by curative resection between 2010 and 2017 and those, who did not receive neoadjuvant chemoradiotherapy. Reduction in tumor volume (before vs. after neoadjuvant chemotherapy) was measured using magnetic resonance imaging. Recurrence and overall survival were also evaluated.

Results: The cohort was composed of 105 patients. Good response to neoadjuvant chemotherapy was associated with better 5-year recurrence-free survival (good responders: 83.3%, poor responders: 50.9%; p=0.001) and 5-year overall survival (good responders: 95.8%, poor responders: 82.5%; p=0.04). In a multivariate analysis, extramural venous invasion on magnetic resonance imaging before neoadjuvant chemotherapy was significantly and independently associated with worse recurrence-free survival (hazard ratio: 2.57, 95% confidence interval: 1.32–5.03, p=0.006). Good responders without extramural venous invasion had the best 5-year recurrence-free and overall survival (89.7% and 94.9%, respectively). Poor responders with extramural venous invasion had the worst 5-year recurrence-free and overall survival (26.7% and 60.0%, respectively).

Conclusions: Reductions in tumor volume after neoadjuvant chemotherapy were associated with better prognosis in patients with locally advanced lower rectal cancer. Extramural venous invasion was a preoperative prognostic factor. 

Background

The prognosis of locally advanced lower rectal cancer (LALRC) might be improved by individualizing treatment. There are two fundamental aspects to the treatment of rectal cancer: interventions to control local disease, such as surgery and radiotherapy, and interventions to control systemic disease, such as chemotherapy and immunotherapy. The standard treatment for LALRC is neoadjuvant chemoradiotherapy (NACRT) followed by total mesorectal excision (TME) [1, 2]. This combination is generally thought to be essential and is performed for almost all patients. Systemic adjuvant chemotherapy is provided after tumor resection, and neoadjuvant chemotherapy (NAC) is optional.

Although fluorouracil-based adjuvant chemotherapy significantly improves overall survival (OS) and recurrence-free survival (RFS), nearly 30% of eligible patients do not receive adjuvant chemotherapy because of their postoperative status [1, 2]. Moreover, in standard treatment, NACRT and surgery delay the start of systemic therapy for approximately 6 months. Approximately 30% of LALRCs are systemic diseases at high risk for distant metastasis, and more distant metastases may occur in patients suspected of having extraluminal lesions, including patients with lymph node metastasis and/or very low tumor location [3–6]. NAC could compensate for such shortcomings, potentially yielding better survival outcomes. However, only few studies have reported the efficacy of NAC for LALRC without NACRT [7, 8].

NACRT strongly improves local control in patients with LALRC progression [6, 9, 10]. The essential role of NACRT derives from its ability to boost local control. However, some cases of LALRC require systemic therapy like NAC, rather than local treatments like NACRT or even surgery. NAC may control distant metastasis and should therefore be considered equally important. However, it is difficult to accurately identify the malignancy grade of LALRC before the start of local treatment.

We considered that the response of LALRC to NAC might predict the emergence of distant recurrence postoperatively. Therefore, we analyzed patients who underwent NAC for LALRC without receiving NACRT to investigate the associations between the effects of NAC and long-term postoperative outcomes. This study aimed to stratify patients with LALRC into prognostic groups based on preoperative information, including response to NAC. Prognosis was compared between patients who showed good and poor responses after chemotherapy. Further, we aimed to identify preoperative prognostic factors that could be obtained before chemotherapy.

Methods

Patients and study design

We retrospectively analyzed all patients with locally advanced lower rectal adenocarcinoma (clinical stage II/III with high-risk features of distant metastasis) who received NAC followed by curative resection at the National Cancer Center Hospital East, Japan between January 2010 and February 2017. During this period, we selected therapeutic strategies involving NAC (instead of NACRT) for patients with LALRC who were thought to be at high risk of distant recurrence. The selection criteria were as follows: (1) high risk of distant metastasis and (2) resectable primary lesion. All patients gave informed consent for strategies that were not a standard treatment. From this initial population, all of the patients with primary elective surgery were identified. Those with no magnetic resonance imaging (MRI) data or intolerance to NAC were excluded.

Data on the following clinicodemographic characteristics were extracted from medical and operation reports: age, sex, body mass index, anal verge (AV) distance, carcinoembryonic antigen level, clinical TNM classifications, clinical circumferential resection margin (CRM), extramural venous invasion based on MRI (mrEMVI), surgical procedure, operation type, pathological TNM classifications, histological type, pathological CRM, distal margin, and adjuvant chemotherapy. The patients were followed until September 2018. This study was approved by our institutional review board (National Cancer Center Hospital Approval no. 2017–349).

Clinical TNM classifications, clinical CRM, mrEMVI, and TVRR

Pretreatment clinical TNM classifications were assessed based on computed tomography (CT) and MRI findings. The tumor location was determined via endoscopy and barium enema. Clinical CRM was measured via MRI pre-NAC, and clinical CRM-positive was defined as a ≤2-mm margin between adjacent organs or nerve tissue, muscles, and the deepest part of the primary lesion. mrEMVI status was evaluated according to the 5-scale EMVI scoring system [5] and recorded as positive (scores 3 and 4) (Fig. 1) or negative (scores 0, 1, and 2). The tumor volume reduction rate (TVRR) was also calculated as described previously [11]. The length and width of the tumor were measured on the axial slice of the maximum dimension, and the maximum height was measured on a sagittal slice. Tumor volume was estimated by multiplying tumor length, width, and height. The TVRR was defined as 100×[(Volume baseline − Volume post NAC)/Volume baseline]. We classified the patients into two groups according to previously established criteria: good responders (those having a TVRR ≥60) and poor responders (those having a TVRR <60) [12, 13]. The sizes of primary lesions and the presence of mrEMVI were evaluated by two experienced colorectal surgeons and incongruent results were reviewed and finalized by consensus.

Preoperative chemotherapy, surgery, and postoperative chemotherapy

Patients were generally treated with FOLFOX (folinic acid, fluorouracil, and oxaliplatin), although CAPOX (capecitabine and oxaliplatin) was also administered. All NAC regimens were based on fluorouracil and oxaliplatin, and a few patients received combined chemotherapy with molecular targeted drugs in their former hospitals. Each physician determined the regimen that the patient received. In general, FOLFOX and CAPOX were administered as 6- and 4-cycle regimens, respectively.

The surgical procedures consisted of low anterior resection, intersphincteric resection (ISR), and abdominoperineal resection, which were performed via the conventional open method or laparoscopic surgery. Laparoscopic procedures began to be used for LALRC in 2012 and gradually became more common thereafter. All of the procedures included lymphadenectomy using the standard TME technique. All patients underwent lateral pelvic lymph node dissection (LPLND). LPLNDs for internal iliac and obturator lesions were performed as described previously [14].

Postoperative adjuvant chemotherapy was generally administered for 3 or more months.

Statistical analysis

Categorical variables are reported as the number (percent) and were analyzed using the Chi-square test or Fisher’s exact test. Quantitative variables are reported as the median (range). RFS and OS were estimated using the Kaplan-Meier method. RFS was defined as the period from the date of operation to any recurrence. OS was defined as the time between surgery and death from any cause. Survival differences were assessed using the log-rank test. Variables with p<0.05 in univariate survival analyses were included in multivariate survival analyses, which were performed using the Cox proportional hazards model. Multivariate analyses were used to identify independent predictors of RFS and OS before preoperative chemotherapy. Results of the multivariate analyses are reported as hazard ratios (HRs) and 95% confidence intervals (95% CIs). All statistical analyses were performed using SPSS 22.0 (SPSS Inc., Chicago, IL, USA), and p<0.05 was considered statistically significant.

Results

Patient characteristics

We treated 450 patients with primary LALRC located below the peritoneal reflection. Of these patients, 120 received NAC without NACRT. We excluded 13 patients who did not undergo MRI and 2 patients who underwent only one course of NAC. The final study population consisted of 105 patients who underwent curative surgery after NAC.

The characteristics of the 105 patients are summarized in Table 1. Neoadjuvant regimens included FOLFOX (95 patients), CAPOX (7 patients), FOLFOX + bevacizumab (1 patient), FOLFOX + panitumumab (1 patient), and FOLFOX + cetuximab (1 patient). Of the 11 patients who did not receive adjuvant chemotherapy, treatment could not be initiated in two patients because of surgical complications. Of the 94 patients who received adjuvant chemotherapy, treatment was discontinued in four patients because of adverse effects and in 1 patient because of recurrence during treatment.

Forty-eight and 57 patients were classified as good and poor responders, respectively. The median timing of restaging MRI was 2 weeks (range: 0–8 weeks) after the administration of the last round of chemotherapy. The differences between good and poor responders are summarized in Tables 2 and 3. No statistically significant difference was observed in any of the demographic or clinical characteristics. With respect to the pathological and postoperative characteristics, only ypT stage differed significantly between good and poor responders (p = 0.004).

Prognosis according to response

The overall 5-year RFS and OS were 65.7% and 88.6%, respectively. Fig. 2 shows the Kaplan-Meier curves for RFS and OS in the good and poor responders. The 5-year RFS was 50.9% for poor responders and 83.3% for good responders (p = 0.001). The 5-year OS was 82.5% for poor responders and 95.8% for good responders (p = 0.04).

Independent prognostic factors obtainable before preoperative chemotherapy

Table 4 shows the results of the univariate and multivariate Cox proportional hazards analyses. In the univariate analyses of RFS, cT stage (p = 0.007), clinical CRM (p = 0.005), and mrEMVI (p = 0.002) were significant prognostic factors. In the multivariate analysis of RFS, mrEMVI (HR: 2.57, 95% CI: 1.32–5.03, p = 0.006) was the only significant independent prognostic factor. In the univariate analyses of OS, clinical CRM (p = 0.04) and mrEMVI (p = 0.004) were significant prognostic factors. There was no significant independent prognostic factor for OS.

Fig. 3 shows the Kaplan-Meier curves for RFS (p<0.001) and OS (p = 0.002) stratified by response to NAC and mrEMVI status. Good responders without mrEMVI had the best 5-year RFS and OS (89.7% and 94.9%, respectively). Poor responders with mrEMVI had the worst 5-year RFS and OS (26.7% and 60.0%, respectively). Good responders with mrEMVI (5-year RFS, 59.5%; 5-year OS, 90.5%) and poor responders without mrEMVI (5-year RFS, 55.6%; 5-year OS, 100.0%) had similar survival outcomes.

Recurrence rate and pattern

Thirty-six patients (34.3%) experienced recurrence. Twenty patients (19.0%) had local recurrence, including 5 (10.4%) good responders and 15 (26.3%) poor responders. Twenty-two patients (21.0%) had distant metastasis, including 3 (6.3%) good responders and 19 (33.3%) poor responders. Eleven patients (10.5%) had lung metastasis, including 2 (4.2%) good responders and 9 (15.8%) poor responders. Nine patients (8.6%) had distant lymph node metastasis, all of whom were poor responders (9/57, 15.8%). Three patients (2.9%) had liver metastasis, including 1 (2.1%) good responder and 2 (3.5%) poor responders.

Discussion

We found that tumor volume reduction after NAC was associated with a better prognosis in patients with LALRC, even in patients with features that suggest a very high risk of recurrence. Patients with good responses to NAC had better outcomes (5-year RFS, 83.3%; 5-year OS, 95.8%) than patients with poor responses to NAC (5-year RFS, 50.9%; 5-year OS, 82.5%). The best responders had better survival outcomes than the poorest responders. Particularly, all 7 patients with TVRR >90% experienced cancer-free survival with only one case of resectable lung recurrence. However, of the seven patients with TVRR <0%, six developed unresectable recurrences. Extreme response to NAC could be a useful factor for predicting prognosis and selecting individualized treatment strategies. Additionally, we found that preoperative mrEMVI was associated with a worse prognosis. In poor responders with mrEMVI, the 5-year RFS and OS were 26.7% and 60.0%, respectively. However, in good responders without mrEMVI, the 5-year RFS and OS were 89.7% and 94.9%, respectively. mrEMVI was associated with significantly poorer survival outcomes, even when TME and LPLND were performed after NAC.

Survival outcomes can be predicted from tumor volume reductions after preoperative CRT [12, 16, 17]. MRI-based assessments of response to CRT are associated with survival outcomes, including RFS and OS. Response to preoperative chemotherapy is reportedly associated with tumor regression grade and downstaging; however, associations with prognosis have not been reported [18]. Our study revealed that the TVRR was associated with RFS and OS, and that response to preoperative chemotherapy was predictive of survival, consistent with the findings of prior studies on CRT. Poor response to NAC was associated with worse survival outcomes. There are several potential reasons for this finding, including the biological malignancy of the tumor, sensitivity to the administered drugs, and host immunity. Very good responders may not need NACRT to achieve local disease control. Several randomized controlled trials are currently investigating this topic. Conversely, it may be difficult for very poor responders to obtain good prognosis even when they receive multidisciplinary treatments, such as total neoadjuvant therapy.

mrEMVI was a significant preoperative prognostic factor in this study. EMVI is defined as the presence of tumor cells within blood vessels beyond the extramural area near the primary tumor. The incidence of mrEMVI in LALRC is approximately 9%–61% [19]. Histological EMVI is a poor prognostic factor [20, 21], and mrEMVI is an independent risk factor for poor survival outcomes [5, 22, 23]. Therefore, the European Society for Medical Oncology guidelines suggest that mrEMVI indicates high risk; CRT followed by TME is recommended in such cases [24]. Our study also revealed that mrEMVI was associated with poor survival outcomes, even in good responders. Indeed, the survival outcomes of good responders with mrEMVI were similar to those of poor responders. Our results suggest that mrEMVI is a strong prognostic factor for LALRC. Therefore, the presence of mrEMVI might require separate treatment strategies.

The local recurrence rate for the whole cohort was high (19%). We selected NAC followed by surgery for patients with high-risk features for distant metastasis, which was regarded as the key factor for survival. In the end, our strategy caused a high rate of local recurrence that might have had a negative effect on patient survival. Further, the results show that NACRT is essential for local control even in patients at high risk of distant recurrence if the aim is to cure the disease. Good response to NAC without mrEMVI was strongly associated with good prognosis. Patient who showed very good responses to NAC did not necessarily require NACRT. However, lymph node metastasis, EMVI, and very low location of the tumor were high-risk features for both local and distant recurrence; therefore, not only NAC but also NACRT should be considered for disease control. In our facilities, there has been a tendency to omit radiation therapy and to choose anal-sparing surgery. As the number of patients who undergo NACRT increases, there will be reductions in the rate of anal-sparing surgery, which is strongly affected by CRT in terms of anal function. Although ISR cannot be expected to increase the CRM-positive rate for the surrounding organs and neural tissues, except for the levator ani muscles, the rate of anal-sparing surgery might also affect the rate of local recurrence.

The present study had several limitations. First, it used a retrospective, single-institution study design and had a small sample size. Several prospective trials of preoperative chemotherapy for LALRC are ongoing, and their results are expected to lead to tailored treatments. Second, the patients received different NAC regimens. However, almost all regimens were FOLFOX or CAPOX, and the differences between these regimens would not have had a substantial effect on the prognosis in each group. Third, the methods of evaluating tumor volume reduction and mrEMVI might not be universally applicable. However, despite these limitations, our results suggest that the tumor volume reduction after NAC was an important prognostic factor for patients with LALRC and might be used to identify patients who will have good or poor prognoses.

Conclusion

The findings of this retrospective study suggest that tumor volume reduction after NAC is associated with the prognosis of LALRC. Patients with good responses to NAC have better survival outcomes. Further, mrEMVI is a significant and independent preoperative prognostic factor for RFS. mrEMVI was also associated with significantly worse survival outcomes in stratified analyses.

Abbreviations

LALRClocally advanced lower rectal cancer

NACRTneoadjuvant chemoradiotherapy

TMEtotal mesorectal excision

NACneoadjuvant chemotherapy

OSoverall survival

RFSrecurrence-free survival

MRImagnetic resonance imaging

AVanal verge

CRMcircumferential resection margin

mrEMVIextramural venous invasion based on magnetic resonance imaging

CTcomputed tomography

TVRRtumor volume reduction rate

FOLFOXfolinic acid, fluorouracil, and oxaliplatin

CAPOX capecitabine and oxaliplatin

ISRintersphincteric resection

LPLNDlateral pelvic lymph node dissection

HRshazard ratios

95% CIs 95% confidence intervals

Declarations

Ethics approval and consent to participate: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (National Cancer Center Hospital Approval no. 2017–349) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All patients gave informed consent for strategies that were not a standard treatment, and the consent was obtained in writing.

Consent for publication: Not applicable

Availability of data and material: Not applicable

Competing interests: The authors declare that they have no conflict of interest for this study.

Funding: The authors claim no conflict of interest regarding this manuscript for this study.

Authors’ contributions: All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Takuya Shiraishi and Takeshi Sasaki. The first draft of the manuscript was written by Takuya Shiraishi and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Acknowledgements: Not applicable

References

1 Franke AJ, Parekh H, Starr JS, et al (2018) Total neoadjuvant therapy: a shifting paradigm in locally advanced rectal cancer management. Clin Colorectal Cancer 17:1–12

2 Rana N, Chakravarthy AB, Kachnic LA (2017) Neoadjuvant treatment for locally advanced rectal cancer: new concepts in clinical trial design. Curr Treat Options Oncol 18:13

3. Kuo LJ, Liu MC, Jian JJ, et al (2007) Is final TNM staging a predictor for survival in locally advanced rectal cancer after preoperative chemoradiation therapy? Ann Surg Oncol 14:2766–2772

4 Betge J, Pollheimer MJ, Lindtner RA, et al (2012) Intramural and extramural vascular invasion in colorectal cancer: prognostic significance and quality of pathology reporting. Cancer 118:628–638

5 Smith NJ, Barbachano Y, Norman AR, et al (2008) Prognostic significance of magnetic resonance imaging-detected extramural vascular invasion in rectal cancer. Br J Surg 95:229–236.

6 Sauer R, Liersch T, Merkel S, et al. (2012) Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO–94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30:1926–1933

7 Schrag D, Weiser MR, Goodman KA, et al (2014) Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol 32: 513–518

8 Glynne-Jones R, Hall MR, Lopes A, et al. (2012) BACCHUS: A randomised non-comparative phase II study of neoadjuvant chemotherapy (NACT) in patients with locally advanced rectal cancer (LARC). Heliyon 4:e00804.

9 Sauer R, Becker H, Hohenberger W, et al. (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740

10 Sebag-Montefiore D, Stephens RJ, Steele R, et al (2009) Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 373:811–820

11 Patel UB, Brown G, Rutten H, et al (2012) Comparison of magnetic resonance imaging and histopathological response to chemoradiotherapy in locally advanced rectal cancer. Ann Surg Oncol 19:2842–2852

12 Han YB, Oh SN, Choi MH, et al (2016) Clinical impact of tumor volume reduction in rectal cancer following preoperative chemoradiation. Diagn Interv Imaging 97:843–850

13 Yeo SG, Kim DY, Kim TH, et al (2010) Tumor volume reduction rate measured by magnetic resonance volumetry correlated with pathologic tumor response of preoperative chemoradiotherapy for rectal cancer. Int J Radiat Oncol Biol Phys78:164–171

14 Fujita S, Akasu T, Mizusawa J, et al (2012) Postoperative morbidity and mortality after mesorectal excision with and without lateral lymph node dissection for clinical stage II or stage III lower rectal cancer (JCOG0212): results from a multicentre, randomised controlled, non-inferiority trial. Lancet Oncol 13:616–621

15 Kobayashi H, Mochizuki H, Kato T et al (2009) Outcomes of surgery alone for lower rectal cancer with and without pelvic sidewall dissection. Dis Colon Rectum 52:567–576

16 Patel UB, Taylor F, Blomqvist L et al (2011) Magnetic resonance imaging-detected tumor response for locally advanced rectal cancer predicts survival outcomes: MERCURY experience.J Clin Oncol 29:3753–3760

17 Yeo SG, Kim DY, Park JW, et al (2012) Tumor volume reduction rate after preoperative chemoradiotherapy as a prognostic factor in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 82:e193–e199

18 Xiao J, Cai Z, Li W, et al (2015) Tumor volume reduction rate predicts pathologic tumor response of locally advanced rectal cancer treated with neoadjuvant chemotherapy alone: results from a prospective trial. J Cancer 6:636–642

19 Chand M, Siddiqui MR, Swift I, et al (2016) Systematic review of prognostic importance of extramural venous invasion in rectal cancer. World J Gastroenterol 22:1721–1726

20 Freedman LS, Macaskill P, Smith AN (1984) Multivariate analysis of prognostic factors for operable rectal cancer. Lancet 2:733–736

21 Krasna MJ, Flancbaum L, Cody RP, et al (1988) Vascular and neural invasion in colorectal carcinoma. Incidence and prognostic significance. Cancer 61:1018–1023

22 Messenger DE, Driman DK, Kirsch R (2012) Developments in the assessment of venous invasion in colorectal cancer: implications for future practice and patient outcome. Hum Pathol 43:965–973

23 Chand M, Evans J, Swift RI, et al (2015) The prognostic significance of postchemoradiotherapy high-resolution MRI and histopathology detected extramural venous invasion in rectal cancer. Ann Surg 261:473–479

24 Glynne-Jones R, Wyrwicz L, Tiret E, et al (2017) Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 28: iv22–40

Tables

Table 1 Clinical characteristics of the patient cohort

BMI, body mass index; AV, anal verge; CEA, carcinoembryonic antigen; LPLN, lateral pelvic lymph node; CRM, circumferential resection margin; mrEMVI, extramural venous invasion based on magnetic resonance imaging

Table 2 Comparison of the clinical characteristics of good responders and poor responders

AV, anal verge; CEA, carcinoembryonic antigen; LPLN, lateral pelvic lymph node; CRM, circumferential resection margin; mrEMVI, extramural venous invasion based on magnetic resonance imaging

Table 3 Comparison of the pathological and postoperative characteristics of good responders and poor responders

LPLN, lateral pelvic lymph node; CRM, circumferential resection margin

Table 4 Univariate and multivariate analyses of preoperative prognostic factors for recurrence-free survival and overall survival

HR, hazard ratio; CI, confidence interval; AV, anal verge; CEA, carcinoembryonic antigen; LPLN, lateral pelvic lymph node; CRM, circumferential resection margin; mrEMVI, extramural venous invasion based on magnetic resonance imaging