Organ preservation in rectal cancer: have all questions been answered?

doi:10.1016/S1470-2045(14)70398-5

The Lancet Oncology

Volume 16, Issue 1, January 2015, Pages e13-e22

https://doi.org/10.1016/S1470-2045(14)70398-5 Get rights and content

Summary

Improved treatment strategies have eliminated local control as the major problem in rectal cancer. With increasing awareness of long-term toxic effects in survivors of rectal cancer, organ-preservation strategies are becoming more popular. After chemoradiotherapy, both watchful waiting and local excision are used as possible alternatives for radical surgery. Although these seem attractive strategies, many issues about the safety of organ preservation remain. Additionally, radiotherapy strategies are mainly aimed at intermediate and high-risk rectal tumours, and adaptation of this standard practice for a completely new treatment indication has yet to start. This Review will discuss the options and problems of organ preservation, and address the research questions that need to be answered in the coming years, with a specific focus on radiotherapy.

Introduction

Different viewpoints exist about the optimal (neo)-adjuvant treatment for rectal cancer. Preoperative radiotherapy provides significantly better local control than postoperative radiotherapy.1, 2 However, there is no international consensus about the radiation schedule or patient selection for radiotherapy for rectal cancer. Results from two studies3, 4 with total mesorectal excision have shown a significant reduction in local recurrences after short-course preoperative radiotherapy (5 × 5 Gy, followed by immediate surgery). In many countries patients are treated with preoperative radiotherapy (45–50 Gy) in combination with chemotherapy based on the results of the FFCD 9203⁵ and EORTC 22921⁶ studies. Results from two studies7, 8 comparing the efficacy of short-course radiotherapy with chemoradiation showed no significant difference in local recurrences.

Surgery is the mainstay of cure for rectal cancer, but is, unfortunately, associated with serious adverse events1, 9, 10 both for patients with and without a permanent colostomy.¹¹ In the past few years, the awareness of the delicate balance between cure and quality of life has risen, and the role of radical surgery for all patients with rectal cancer is increasingly questioned.

The introduction of population screening has led to improved survival and to a shift towards more early detection of rectal cancers, with 35% of tumours detected by screening being Dukes stage A versus 14% in a non-screened population.¹² If this finding is taken into account, together with the negative effects of rectal cancer treatment on quality of life for cancer survivors, treatment initiatives aimed at organ preservation are very timely.

Section snippets

Organ preservation

Local excision is increasingly used instead of total mesorectal excision in early rectal cancers (figure 1). Findings from two studies13, 14 showed good outcomes in selected T1 tumours, but not in high-risk T1 or T2–3 tumours. Although different techniques are used for local excision (varying from a simple mucosectomy to an extensive local excision, which can occasionally include regional lymph nodes), transanal endoscopic microscosurgery is thought to be the standard of care because improved

Radiotherapy target volume

One of the most challenging factors in radiation therapy is delineation of treatment volumes. Despite all discussions about tailor-made treatment, treatment volumes in radiotherapy are not always adapted to the primary tumour status or the aim of the treatment. Target volumes for early or locally advanced tumours are often very similar, and generally contain the primary tumour, the mesorectal fat, and the presacral and internal iliac nodes (figure 2A and C).⁴⁹ For early rectal tumours, the

New neoadjuvant treatment strategies

To overcome the risk of disease progression during the interval between radiotherapy and surgery, the addition of neoadjuvant chemotherapy is an attractive option in locally advanced tumours for several reasons. Apart from addressing possible distant (micro)metastases, the additional chemotherapy might result in an increase of primary tumour downstaging. However, some studies with treatment escalation showed increased T downstaging, but no difference in N stage after chemoradiotherapy for

Conclusion

So far, little evidence from randomly controlled trials supports general acceptance of organ preserving strategies in rectal cancer and several radiotherapy issues for early tumours are unsolved. There is no consensus about target volumes, timing of response assessment, or the optimum treatment schedule. Attempts to improve the proportions of patients achieving pathological complete responses or tumour downstaging have been disappointing so far, although there is some evidence that radiotherapy

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Organ Preservation in Rectal Cancer: An Overview of the Dutch Perspective and Recent Developments
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Although current guidelines on rectal cancer treatment often recommend rectal resection with or without neoadjuvant (chemo)radiotherapy, there is growing interest in organ-preserving treatment approaches among patients and clinicians in the Netherlands. Currently, multiple ongoing studies are investigating the value of different non-operative treatment modalities to improve tumour response rates and increase the chance of successful organ preservation. Papillon contact X-ray brachytherapy is a promising treatment modality to improve the chance of organ preservation, which seems especially relevant for elderly and frail patients unable or refusing to undergo total mesorectal excision surgery. The elderly and frail patient with rectal cancer poses a significant challenge and warrants a thorough multidisciplinary approach to provide the most optimal organ-preserving treatment. In this overview, an insight into the Dutch perspectives and developments within the field of organ preservation and the set-up of a Papillon facility to complete the spectrum of organ-preserving treatment options in a tertiary referral centre for rectal cancer treatment has been provided.
MRI-based delta-radiomics are predictive of pathological complete response after neoadjuvant chemoradiotherapy in locally advanced rectal cancer
2021, Academic Radiology
Citation Excerpt :
Approximately 10%–30% of patients achieve pathological complete response (pCR) after nCRT (1–5); these patients show a better oncologic outcome with excellent overall and disease-free survival than do patients with residual tumor (4,6). A conservative therapeutic strategy ("watch-and-wait") is recommended for patients with pCR to avoid the morbidity and mortality associated with surgical resection (7). However, while confirmation of pCR is essential for clinical decision making, it is not feasible before surgery because it is traditionally achieved by histopathologic evaluation after surgery.
To investigate the capability of delta-radiomics to predict pathological complete response (pCR) after neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC).
This retrospective study enrolled 165 consecutive patients with LARC (training set, n = 116; test set, n = 49) who received nCRT before surgery. All patients underwent pre- and post-nCRT MRI examination from which radiomics features were extracted. A delta-radiomics feature was defined as the percentage change in a radiomics feature from pre- to post-nCRT MRI. A data reduction and feature selection process including the least absolute shrinkage and selection operator algorithm was performed for building T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) delta-radiomics signature. Logistic regression was used to build a T2WI and DWI combined radiomics model. Receiver operating characteristic analysis was performed to assess diagnostic performance. Delong method was used to compare the performance of delta-radiomics model with that of magnetic resonance tumor regression grade (mrTRG).
Twenty-seven of 165 patients (16.4%) achieved pCR. T2WI and DWI delta-radiomics signature, and the combined model showed good predictive performance for pCR. The combined model achieved the highest areas under the receiver operating characteristic curves of 0.91 (95% confidence interval: 0.85–0.98) and 0.91 (95% confidence interval: 0.83–0.99) in the training and test sets, respectively (significantly greater than those for mrTRG; training set, p < 0.001; test set, p = 0.04).
MRI-based delta-radiomics can help predict pCR after nCRT in patients with LARC with better performance than mrTRG.
Image-based deep learning model for predicting pathological response in rectal cancer using post-chemoradiotherapy magnetic resonance imaging
2021, Radiotherapy and Oncology
To develop an image-based deep learning model for predicting pathological response in rectal cancer using post-chemoradiotherapy magnetic resonance (MR) imaging.
A total of 466 patients with locally advanced rectal cancer who received preoperative chemoradiotherapy followed by surgical resection were collected from single center, among whom 113 (24.3%) were allocated to the holdout testing set. Complete response (pCR) was defined as Dworak tumor regression grade (TRG) 4, while good response (GR) was defined as TRG 3 or 4. Based on post-chemoradiotherapy T2-weighted axial MR images, two deep learning models were developed to predict pCR and GR, respectively. The prediction performance of the deep learning models was evaluated in the testing set and was compared to that of a senior radiologist and a radiation oncologist.
The deep learning model showed an area under the receiver operating characteristic curve, sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of 0.76, 0.30, 0.96, 0.67, 0.87, and 85.0% for predicting pCR and 0.72, 0.54, 0.81, 0.60, 0.77, and 71.7% for predicting GR, respectively. The deep learning model had a superior predictive performance than the observers. Fair agreement between the ground truth and the model was shown for pCR prediction (kappa = 0.34) and GR prediction (kappa = 0.36).
The post-chemoradiotherapy T2-weighted axial MR image-based deep learning model showed acceptable performance in predicting pCR or GR in patients with rectal cancer, compared with human observers.
Watch-and-Wait Compared to Operation for Patients with Complete Response to Neoadjuvant Therapy for Rectal Cancer
2020, Journal of the American College of Surgeons
Trimodality therapy with neoadjuvant chemoradiation (nCRT), surgery, and adjuvant chemotherapy is the standard treatment for locally advanced rectal cancer. There is evidence that surgery can be deferred in patients with complete response (CR) to nCRT, a strategy termed “watch-and-wait” (WW). We compare WW to surgery in patients with CR to nCRT.
We reviewed records of patients treated with nCRT for nonmetastatic rectal cancer at our institution. Complete endoscopic response (CER) was defined as negative digital rectal exam and negative endoscopy at the end of neoadjuvant therapy (NAT). Clinical complete response (cCR) was defined as CER with negative rectal MRI. Patients with CER refusing surgery were offered WW, which included strict surveillance with digital rectal exam and endoscopy.
From January 2015 through February 2019, 465 patients completed nCRT; 406 patients had response assessment, of which 95 (23%) had CER. Of these patients, 53 patients underwent WW and 42 patients had surgery. Median follow-up was 35 months. In the WW group, 3-year freedom from local regrowth was 85%. In the surgical and WW groups, 3-year overall survival, rectal cancer-specific survival, and freedom from nonregrowth recurrence were 100% vs 88% (p = 0.03), 100% vs 95% (p = 0.16), and 92% vs 85% (p = 0.36), respectively. Of the 6 WW patients with local regrowth, 5 (83%) eventually developed distant recurrence.
WW in lieu of surgery appears to be a safe and feasible treatment approach for patients achieving CR to nCRT. Careful evaluation to confirm cCR after nCRT is valuable in selecting patients for WW.
RHBDD2 overexpression promotes a chemoresistant and invasive phenotype to rectal cancer tumors via modulating UPR and focal adhesion genes
2020, Biochimica et Biophysica Acta - Molecular Basis of Disease
The current standard of care for locally advanced rectal cancer (RC) is neoadjuvant radio-chemotherapy (NRC) with 5-fluorouracil (5Fu) as the main drug, followed by surgery and adjuvant chemotherapy. While a group of patients will achieve a pathological complete response, a significant percentage will not respond to the treatment. The Unfolding Protein Response (UPR) pathway is generally activated in tumors and results in resistance to radio-chemotherapy. We previously showed that RHBDD2 gene is overexpressed in the advanced stages of colorectal cancer (CRC) and that it could modulate the UPR pathway. Moreover, RHBDD2 expression is induced by 5Fu. In this study, we demonstrate that the overexpression of RHBDD2 in CACO2 cell line confers resistance to 5Fu, favors cell migration, adhesion and proliferation and has a profound impact on the expression of both, the UPR genes BiP, PERK and CHOP, and on the cell adhesion genes FAK and PXN. We also determined that RHBDD2 binds to BiP protein, the master UPR regulator. Finally, we confirmed that a high expression of RHBDD2 in RC tumors after NRC treatment is associated with the development of local or distant metastases. The collected evidence positions RHBDD2 as a promising prognostic biomarker to predict the response to neoadjuvant therapy in patients with RC.
Mesorectal radiotherapy for early stage rectal cancer: A novel target volume
2020, Clinical and Translational Radiation Oncology
With the introduction of population-based bowel cancer screening, rectal cancer is diagnosed at earlier stages, yet standard treatment still requires the same extensive surgery that is used for more advanced stages. Organ preserving treatment is rapidly developing and is subject of investigation in numerous clinical trials. The STAR-TREC trial is an international, multi-centre randomised trial investigating organ preservation using (chemo)radiotherapy. Patients with small mrT1-3bN0V0M0 tumours are randomized between three arms: standard TME, organ preservation with SCRT or with CRT. In this trial, the clinical target volume has been tailored to the early staged disease of the included patients. This mesorectal irradiation volume includes the mesorectum and pre-sacral lymph nodes at the level of the tumour, two centimetres below and cranially up to the S2-3 interspace level. In contrast to conventional irradiation volumes, the lateral lymph nodes and the nodes along the superior rectal artery are excluded. As a result, the dose to the bowel, bladder, anal sphincter and the neurovascular plexus in the lower pelvis is substantially decreased, especially when combined with modern irradiation techniques, such as dynamic arc therapy. These lower doses are expected to lead to decreasing acute and late toxicity and beneficial functional outcomes. The implementation of this novel target volume will be accompanied by an extensive quality assurance program in the STAR-TREC trial. We describe the rationale behind the novel, mesorectal only radiotherapy treatment used in the STAR-TREC trial specifically tailored for early stage disease, with the goal of organ preservation.

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ReviewOrgan preservation in rectal cancer: have all questions been answered?

Summary

Introduction

Section snippets

Organ preservation

Radiotherapy target volume

New neoadjuvant treatment strategies

Conclusion

Lancet

Lancet Oncol

Lancet Oncol

Eur J Cancer

Int J Radiat Oncol Biol Phys

Lancet Oncol

Eur J Surg Oncol

Clin Oncol (R Coll Radiol)

Radiother Oncol

Eur J Surg Oncol

Eur J Surg Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Lancet Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Lancet Oncol

Lancet Oncol

Ann Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Preoperative or postoperative irradiation in adenocarcinoma of the rectum: final treatment results of a randomized trial and an evaluation of late secondary effects

Dis Colon Rectum

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

Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203

J Clin Oncol

Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer

Br J Surg

Randomized trial of short-course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group trial 01.04

J Clin Oncol

Adverse effects of preoperative radiation therapy for rectal cancer: long-term follow-up of the Swedish Rectal Cancer Trial

J Clin Oncol

Quality of life after rectal resection for cancer, with or without permanent colostomy

Cochrane Database Syst Rev

A retrospective observational study examining the characteristics and outcomes of tumours diagnosed within and without of the English NHS Bowel Cancer Screening Programme

Br J Cancer

The influence of histopathologic criteria on the long-term prognosis of locally excised pT1 rectal carcinomas: results of local excision (transanal endoscopic microsurgery) and immediate reoperation

Dis Colon Rectum

A predictive model for local recurrence after transanal endoscopic microsurgery for rectal cancer

Br J Surg

Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results

Ann Surg

Critical appraisal of the ‘wait and see’ approach in rectal cancer for clinical complete responders after chemoradiation

Br J Surg

Survival outcome of local excision versus radical resection of colon or rectal carcinoma: a Surveillance, Epidemiology, and End Results (SEER) population-based study

Ann Surg

Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer

J Clin Oncol

Long-term outcomes of patients with localized rectal cancer treated with chemoradiation or radiotherapy alone because of medical inoperability or patient refusal

Dis Colon Rectum

Could a wait and see policy be justified in T3/4 rectal cancers after chemo-radiotherapy?

Acta Oncol

A single-centre experience of chemoradiotherapy for rectal cancer: is there potential for nonoperative management?

Colorectal Dis

Complete clinical response after neoadjuvant chemoradiation therapy for distal rectal cancer: characterization of clinical and endoscopic findings for standardization

Dis Colon Rectum

Complete clinical response after preoperative chemoradiation in rectal cancer: is a “wait and see” policy justified?

Dis Colon Rectum

Review
Organ preservation in rectal cancer: have all questions been answered?