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Risk and location of distant metastases in patients with locally advanced rectal cancer after total neoadjuvant treatment or chemoradiotherapy in the RAPIDO trial
Correspondence to: Department of Medical Oncology, University Medical Center Groningen, Hanzeplein 1, Postbus 30.001, 9700 RB Groningen, the Netherlands.
Footnotes
2 Principal investigators of the RAPIDO trial.
Affiliations
University Medical Center Groningen, Department of Medical Oncology, Hanzeplein 1, Postbus 30.001, 9700 RB Groningen, the Netherlands
1 Editorial correspondence: Department of Surgery, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, the Netherlands.
Corrie A.M. Marijnen
Footnotes
1 Editorial correspondence: Department of Surgery, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, the Netherlands.
Affiliations
Netherlands Cancer Institute, Department of Radiation Oncology, Plesmanlaan 121, 1066 CX Amsterdam, the NetherlandsLeiden University Medical Center, Department of Radiation Oncology, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, the Netherlands
1 Editorial correspondence: Department of Surgery, Leiden University Medical Center, Albinusdreef 2, Postbus 9600, 2300 RC Leiden, the Netherlands. 2 Principal investigators of the RAPIDO trial. 3 Appendix.
With the experimental treatment, the risk of distant metastases is reduced.
•
The metastatic pattern of LARC changed after the RAPIDO total neoadjuvant schedule.
•
The experimental treatment caused a decrease in liver metastases.
•
This treatment did not change the timing of the diagnosis of DM.
•
Survival after DM was poorer in the experimental group.
Abstract
Introduction
Although optimising rectal cancer treatment has reduced local recurrence rates, many patients develop distant metastases (DM). The current study investigated whether a total neoadjuvant treatment strategy influences the development, location, and timing of metastases in patients diagnosed with high-risk locally advanced rectal cancer included in the Rectal cancer And Pre-operative Induction therapy followed by Dedicated Operation (RAPIDO) trial.
Material and methods
Patients were randomly assigned to short-course radiotherapy followed by 18 weeks of CAPOX or FOLFOX4 before surgery (EXP), or long-course chemoradiotherapy with optional postoperative chemotherapy (SC-G). Assessments for metastatic disease were performed pre- and post-treatment, during surgery, and 6, 12, 24, 36, and 60 months postoperatively. From randomisation, differences in the occurrence of DM and first site of metastasis were evaluated.
Results
In total, 462 patients were evaluated in the EXP and 450 patients in the SC-G groups. The cumulative probability of DM at 5 years after randomisation was 23% [95% CI 19–27] and 30% [95% CI 26–35] (HR 0.72 [95% CI 0.56–0.93]; P = 0.011) in the EXP and SC-G, respectively. The median time to DM was 1.4 (EXP) and 1.3 years (SC-G). After diagnosis of DM, median survival was 2.6 years [95% CI 2.0–3.1] in the EXP and 3.2 years [95% CI 2.3–4.1] in the SC-G groups (HR 1.39 [95% CI 1.01–1.92]; P = 0.04). First occurrence of DM was most often in the lungs (60/462 [13%] EXP and 55/450 [12%] SC-G) or the liver (40/462 [9%] EXP and 69/450 [15%] SC-G). A hospital policy of postoperative chemotherapy did not influence the development of DM.
Conclusions
Compared to long-course chemoradiotherapy, total neoadjuvant treatment with short-course radiotherapy and chemotherapy significantly decreased the occurrence of metastases, particularly liver metastases.
Treatment of locally advanced rectal cancer (LARC) has evolved during the past decades. Irradiation has shifted from postoperative to preoperative, leading to fewer local recurrences [
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.
Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial.
]. Moreover, the addition of chemotherapy to radiotherapy has proven to be effective in further reducing local recurrence rates in more advanced tumours but it has not improved survival except possibly in most LARCs [
]. Improved preoperative imaging has contributed in selecting patients for neoadjuvant treatment. Moreover, due to improvements in surgical technique, local recurrence is no longer a major problem after the treatment of LARC. In contrast, up to 30–40% of the patients still develop distant metastases (DM) [
The RAPIDO trial enrolled patients diagnosed with LARC including at least one high-risk criterion. A decrease in the probability of disease-related treatment failure at 3 years from 30% to 24% after treatment with preoperative short-course radiotherapy followed by chemotherapy compared to preoperative long-course chemoradiotherapy and optional postoperative chemotherapy was demonstrated [
Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.
]. Although this difference could mainly be attributed to fewer DM in the experimental group, no improvement in overall survival was observed after a median follow-up of 4.6 years.
The current study aims to investigate whether a total neoadjuvant treatment strategy influences the development, location and timing of DM and the prognosis thereafter in patients diagnosed with high-risk LARC included in the RAPIDO trial after a median follow-up of 5.6 years.
2. Materials and methods
2.1 Study population and design
The RAPIDO trial is an investigator-driven, international, open-label, phase III, randomised trial. The design, inclusion and exclusion criteria and results of the primary endpoint were published previously [
Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.
]. Eligible patients had non-metastasised LARC fulfilling at least one high-risk criteria on pelvic MRI (clinical tumour stage T4, clinical nodal stage N2, extramural vascular invasion [EMVI+], involved mesorectal fascia [MRF+], or enlarged lateral lymph nodes) indicating high risk of failing locally and/or systemically. Between 21 June 2011 and 2 June 2016, 920 patients were assigned to either short-course radiotherapy (5 × 5 Gy), followed by six cycles of CAPOX or nine cycles of FOLFOX4 and surgery after a recovery period of 2–4 weeks (n = 462, experimental group) or long-course radiotherapy (28–25 × 1.8–2.0 Gy) with concurrent capecitabine, followed by surgery after 8 ± 2 weeks (n = 450, standard-care group). Administration of postoperative chemotherapy in the standard-care group was allowed when recommended by the hospitals’ local policy. The RAPIDO trial was carried out in accordance with the Good Clinical Practice guidelines and the Declaration of Helsinki. After central evaluation and approval by the medical ethics committee of University Medical Center Groningen, the boards of directors or local ethics committees of all participating centres approved the protocol. The RAPIDO trial is registered with EudraCT (2010-023957-12) and ClinicalTrials.gov (NCT01558921).
2.2 Evaluation of the primary tumour and during follow-up
Pre-treatment screening included CEA, CT thorax-abdomen-pelvis and an MRI of the pelvis. Re-staging before surgery was mandatory (in the experimental group 1–2 weeks after the last chemotherapy cycle; in the standard-care group 2–3 weeks prior to planned surgery). After surgery, a standardised, minimal follow-up schedule was defined, with clinical assessments at 6, 12, 24, 36, and 60 months postoperatively, including CEA measurement. A chest X-ray and liver ultrasound or CT of thorax and abdomen were required at least at 12 and 36 months. Evidence of recurrent disease was accepted in case of positive histology or cytology, or with metastases on ultrasound, X-ray, (PET)CT, bone-scintigraphy and/or pelvic pathology on PET. Distant metastases were defined as relapse of the tumour outside the pelvic region. Analyses were based on information from the case report forms and corresponding copies of imaging and/or pathology reports in which the first occurrence of DM was documented. Type of imaging modality used all involved subsites at that assessment, and treatment of the metastases were recorded.
2.3 Statistical analyses
The reverse Kaplan-Meier method was used for the calculation of median follow-up. Proportions were compared with chi-square tests. Survival analyses were performed on an intention-to-treat basis. For calculation of the cumulative incidence of DM, competing risks analyses were performed with death as competing risk. For calculation of the cumulative incidence of different sites of DM competing risks analyses were also performed, with time as the time of the first occurrence of distant metastasis, death or last follow-up, and the different sites of DM (liver-only, lung-only, liver + lung, other), and death as competing risks. Patients alive and DM-free at last follow-up were censored. A Cox proportional hazards regression, with the time-interval of DM after randomisation as a continuous variable (in years), was performed to investigate the influence of time of first occurrence of DM on subsequent survival. Patients with locoregional failure prior to the diagnosis of DM were excluded when calculating the risk of developing locoregional failure after the diagnosis of DM. Locoregional failure and DM diagnosed within 90 days of each other were considered to occur synchronously. HRs and 95% confidence intervals (CI) were computed using Cox regression (for competing risks analyses based on the cause-specific hazards). Violation of the proportional hazards assumption was checked by visual inspection. P-values were calculated based on (cause-specific) log-rank tests [
. Univariate Cox regressions were performed to investigate the influence of baseline characteristics on the development of DM. Variables with a P-value< 0.10 were included in a multivariate Cox regression, with the exception of ‘number of high-risk criteria’ as the high-risk criteria were already included in the multivariate analyses. Subgroup analyses of the effect of treatment on associations between prognostic factors of DM and the development thereof were performed and presented in a forest plot. The significance threshold for all P-values was 0.05. All analyses were performed using IBM SPSS Statistics version 25.0 or ‘R′ version 4.0.1.
3. Results
Clinical characteristics of eligible patients are demonstrated in Table 1. At the time of analyses (data lock: 11 March 2022), the median follow-up was 5.6 years (IQR 5.4–7.5).
At 5 years after randomization, the cumulative probability of DM was 23% [95% CI 19–27] and 30% [95% CI 26–35] in the experimental and standard-care groups, respectively (HR 0.72 [95% CI 0.56–0.93]; P = 0.011, Fig. 1A). Median time from randomisation to the diagnosis of DM was 1.4 years (IQR 0.9–2.5) in the experimental group and 1.3 years (IQR 0.5–2.2) in the standard-care group. The moment of diagnosis of the first appearance of DM is described in Table 2. From diagnosis of DM, patients in the experimental group had a worse prognosis than those in the standard-care group (HR 1.39 [95% CI 1.01–1.92]; P = 0.04) with a median survival of 2.6 years [95% CI 2.0–3.1] and 3.2 years [95% CI 2.3–4.1], respectively, Fig. 1B. A hospital policy of postoperative chemotherapy in the standard-care group did not influence the development of DM (Supplementary Fig. A). Table 3 describes the occurrence of DM and locoregional failure in relation to each other. Supplementary Fig. B contains additional information on the timing of the development of DM and/or locoregional failure. At 5 years, the cumulative probability of developing locoregional failure synchronously or after being diagnosed with DM was 25% [95% CI 15–35] in the experimental group and 13% [95% CI 7–19] in the standard-care group (HR 2.02 [95% CI 1.07–3.81]; P = 0.03). The cumulative probability of disease-related treatment failure at 5 years was 28% [95% CI 24–32] in the experimental group and 34% [95% CI 30–38) in the standard-care group (HR 0.79 [95% CI 0.63–1.00]; P = 0.048. Overall survival of all eligible patients in the RAPIDO trial at 5 years was 82% [95% CI 78–85] for the experimental group and 80% [95% CI 77–84] for the standard-care group (HR 0.91 [95% CI 0.70–1.19]; P = 0.50). For all analyses, visual inspection showed no evidence of a violation of the proportional hazards assumption.
Fig. 1The risk of distant metastases (A) and survival after diagnosis of metastases (B).
In the experimental and standard-care groups, 73% (81/111) and 78% (109/139) of patients were initially diagnosed with DM in 1 organ-site, 22% (24/111) and 17% (23/139) had DM in 2 organ-sites, and 5% (6/111) and 5% (7/139) in 3–6 organ-sites, respectively (P = 0.58).
Distant metastases were most often located in the liver or the lungs ( Figs. 2 and 3). In the experimental group, 9% (40/462) of patients were diagnosed with liver metastases compared to 15% (69/450) of patients in the standard-care group (P = 0.002). Lung metastases were equally common in both groups, 13% (60/462) in the experimental group and 12% (55/450) in the standard-care group (P = 0.73). Survival after lung-only versus liver-only metastases was not statistically significantly different, stratified for the treatment group or for the treatment groups combined (Supplementary Fig. C). Tumour level did not influence first metastatic organ-site (Supplementary Table A).
Fig. 2First metastasised organ-site. *Other includes bone, brain, peritoneum, distant lymph nodes, and pleura.
Fig. 3First diagnosis of distant metastases over time, based on cumulative probabilities according to the first metastasised organ-site. Other includes liver and another organ-site, lung, and another organ-site, chiefly bone, brain, peritoneum, lymph nodes.
Of the patients with DM, 46% (51/111) and 52% (72/139) underwent surgery for metastatic disease (P = 0.36), 14% (15/111) and 16% (22/139) received radiotherapy (P = 0.61), 45% (50/111) and 58% (81/139) received chemotherapy (P = 0.037), and 6% (7/111) and 9% (12/139) received other or no treatment (P = 0.49) in the experimental and standard-care groups, respectively. Treatment according to the location of DM is displayed in Table 4 (in more detail, Supplementary Table B).
Table 4Treatment according to the location of distant metastases.
Treatment group, all high-risk criteria except cT4, and the total number of high-risk criteria were associated with the development of DM. In the multivariate analyses, the treatment group, EMVI+, cN2 and MRF+ were statistically significant (Table 5). No interaction between risk factors and treatment groups could be demonstrated (Fig. 4).
Table 5Univariate and multivariate cox regression analyses for distant metastases.
The RAPIDO trial demonstrates that short-course radiotherapy followed by chemotherapy before surgery decreases the cumulative probability of DM at 5 years to 23% compared to 30% after chemoradiotherapy before surgery and optional postoperative chemotherapy in patients with LARC who are considered to have a high risk of systemic recurrence. Median time for the appearance of DM was the same and median survival after DM was 6 months longer in the standard-care group than in the experimental group (3.1 versus 2.6 years, P = 0.04). The decrease in DM is mainly caused by a reduction in liver-only metastases.
4.1 The appearance of DM
As reported earlier from the RAPIDO trial, compliance with systemic chemotherapy was increased when this was delivered pre-operatively [
Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer – results of the international randomized RAPIDO-trial.
]. With the TNT approach, the intended dose of chemotherapy could be given to more patients resulting in a lower DM rate. In colon cancer, an early start of adjuvant chemotherapy is more effective than starting more than 10 weeks after surgery, the latter negatively impacts disease-free survival [
]. By bringing forward chemotherapy as part of a TNT in rectal cancer, micrometastases, when susceptible to chemotherapy, can be combatted earlier in the treatment process, preventing the development of detectable metastases. This is supported by our finding that DM was more often diagnosed during re-staging in the standard-care group than in the experimental group, where restaging was after a longer interval. The follow-up schedule after surgery was standardised leading to clear increases in DM at set times. Merely postponement of DM does not seem to be the case as the median time to DM is comparable between treatment groups.
4.2 Decrease in liver metastases
It is unknown why neoadjuvant chemotherapy appears more effective in decreasing liver metastases than lung metastases in the RAPIDO trial. The literature is not unequivocal regarding the most common metastasised organ in rectal cancer. Some studies have reported the liver as the most common metastasised organ [
]. Tumour height did not influence first-metastasised organ-site in the RAPIDO trial as distance from the anal verge was equal between the treatment groups (Supplementary Table A).
4.3 Prognosis after DM
In the experimental group, 84% (387 of 462) of patients received at least 75% of the prescribed courses of systemic chemotherapy before the diagnosis of DM compared to 24% (108 of 450) of patients in the standard-care group [
Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer – results of the international randomized RAPIDO-trial.
]. As a consequence, patients in the experimental group with metastatic disease who progressed after this systemic treatment had already received a nearly cumulative maximum dose of oxaliplatin, hampering the administration of oxaliplatin-containing chemotherapy in the metastatic setting. These patients often received second-line chemotherapy, known to be less effective in the palliative setting, as tumour cells that cause relapse after treatment with systemic chemotherapy can have a worse biological profile and could therefore be partly responsible for a poorer prognosis [
]. In contrast, patients developing the metastatic disease in the standard-care group who had not received adjuvant chemotherapy could be treated with first-line oxaliplatin-containing chemotherapy. The gain in fewer DM from preoperative chemotherapy may be counterbalanced by shortening of survival after recurrence, as recently stressed in a systematic review [
Does the gain of total neoadjuvant therapy outweigh the harm in rectal cancer? Importance of the ATRESS (neoAdjuvant Therapy-RElated Shortening of Survival) phenomenon: a systematic review.
Also, a more aggressive treatment with multiple interventions creates survival advantages for chemo-resistant tumour cells after each successful intervention. A combined treatment such as the RAPIDO schedule (radiotherapy and chemotherapy) is more effective than only one local intervention (chemoradiotherapy in the standard-care group) resulting in a higher pCR rate [
Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.
]. This selection effect was observed in the experimental group with worse survival and a higher probability of developing locoregional failure synchronously or after the diagnosis of DM.
The experimental treatment possibly prevented the DM with very little tumour burden, which was still present in the standard-care group. These patients may be the ones cured by the local treatment being another reason for better survival after DM in the standard-care group. Metastases with the worst prognosis (non-resectable, non-responsive to chemotherapy etc) were the ones remaining in both treatment groups influencing overall survival. Possibly explaining why the overall survival of the whole group is comparable at 5 years. However, another possible explanation is that the RAPIDO trial was not powered to address overall survival. The gain in DM rate (7%-unites) may be too small to detect a difference in overall survival with the number of patients included.
4.4 Strengths and limitations
To our knowledge, this study is the first to compare the first metastatic organ-site in LARC while comparing TNT to conventional chemoradiotherapy and to report a changed metastatic pattern with the different treatment regimens. A limitation of the current study is that further diagnostics of the occurrence of DM were not always fully performed after an LRF had been established and vice versa. This has not been checked and corrected for in the analyses as this differs per hospital and country. In addition, comparisons with regard to systemic chemotherapy were more challenging as the standard-care group was not evenly distributed because adjuvant chemotherapy was allowed according to the hospital protocol. Although the results of the RAPIDO trial are promising with respect to a decrease in DM, a higher pCR rate, and therewith a possible organ-saving strategy, an important clinical dilemma still concerns the selection of LARC patients who will most likely benefit from this new treatment schedule. Recently our study group published that enlarged lateral lymph nodes, a positive circumferential resection margin, tumour deposits, node positivity at pathology and experimental treatment were significant predictors for developing locoregional recurrence. No statistically significant association was found in the multivariate analysis regarding distance from the anal verge [
Locoregional failure during and after short-course radiotherapy followed by chemotherapy and surgery compared to long-course chemoradiotherapy and surgery – a five-year follow-up of the RAPIDO trial.
]. In the current manuscript, we demonstrated that EMVI, cN2, MRF and standard-care treatment are prognostic factors for the development of DM, yet, the identification of patients who would benefit the most from the RAPIDO schedule or other TNT schedules is not yet possible. Although health-related quality of life and bowel function was not compromised and no increase in grade ≥ 3 toxicity was observed [
Quality of life and late toxicity after short-course radiotherapy followed by chemotherapy or chemoradiotherapy for locally advanced rectal cancer – the RAPIDO trial.
], the benefits and harms of a total neoadjuvant treatment should be carefully balanced, as some patients are overtreated.
Further research is needed to predict clinical response, for example, via biomarkers and to define the optimal selection criteria for total neoadjuvant treatment. In addition, standardised follow-up schedules should be applied to future studies to provide comparable results.
5. Conclusion
In summary, compared to standard care with long-course chemoradiotherapy, short-course radiotherapy in combination with systemic chemotherapy effectively decreases liver metastases in patients with high-risk LARC without influencing the time of diagnosis of DM. With the experimental TNT, an effective dose of chemotherapy can be given to eliminate more micrometastases, when susceptible to chemotherapy, early in the treatment process, preventing development into detectable metastases. Why this effect mainly occurs in liver metastases cannot be fully explained based on the current data.
Disclosure
Per Nilsson reports honoraria from Ethicon and Johnson & Johnson. Bengt Glimelius reports research support from the Swedish Cancer Society. Geke Hospers reports consulting fees from Roche, MSD, Amgen and Novartis; consulting fee and research support to their institution from Bristol-Myers Squibb; and research support to their institution from Seerave Foundation. All other authors have declared no conflicts of interest. The corresponding author had full access to all data and had final responsibility for the decision to submit for publication.
Funding
This work was supported by the Dutch Cancer Foundation (CKS-2011-4997); the Swedish Cancer Society; the Swedish Research Council (Project number K2014-99X-22481-01-3); the Spanish Ministry of Economy and Competitiveness through the Carlos III Health Institute (EC11-423) and by the Spanish Clinical Research Network (SCReN-PT13/0002/0031; PT17/0017/0003; co-financed by European Regional Development Fund 'A way to make Europe'). The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
CRediT authorship contribution statement
Conceptualisation: RB, GH, CM, KP, HP, ED, EM, AR, BE, PN, BG, CV. Methodology: RB, GH, KP, CV. Software: HP. Validation: HP. Formal analysis: RB, HP. Investigation: RB. Resources: EM, AR. Data curation: EM, AR. Writing—original draft: RB. Writing—review & editing: RB, GH, CM, KP, HP, ED, EM, AR, BE, PN, BG, CV. Visualisation: RB, GH, KP. Supervision: GP, CM, KP, BE, PN, BG, CV. Project administration: EM, AR. Funding acquisition: GP, CM, BE, PN, BG, CV.
Conflict of interest statement
The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Per Nilsson reports honoraria from Ethicon and Johnson & Johnson. Bengt Glimelius reports research support from the Swedish Cancer Society. Geke Hospers reports consulting fees from Roche, MSD, Amgen and Novartis; consulting fee and research support to their institution from Bristol-Myers Squibb; and research support to their institution from Seerave Foundation. All other authors have declared no conflicts of interest.
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.
Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial.
Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.
Compliance and tolerability of short-course radiotherapy followed by preoperative chemotherapy and surgery for high-risk rectal cancer – results of the international randomized RAPIDO-trial.
Does the gain of total neoadjuvant therapy outweigh the harm in rectal cancer? Importance of the ATRESS (neoAdjuvant Therapy-RElated Shortening of Survival) phenomenon: a systematic review.
Locoregional failure during and after short-course radiotherapy followed by chemotherapy and surgery compared to long-course chemoradiotherapy and surgery – a five-year follow-up of the RAPIDO trial.
Quality of life and late toxicity after short-course radiotherapy followed by chemotherapy or chemoradiotherapy for locally advanced rectal cancer – the RAPIDO trial.
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