Rectal cancer is one of the most common malignant pathologies worldwide. In the European Union, the incidence of rectal cancer is approximately 1,25,000 new cases per year, accounting for 35% of all new cases of colorectal cancer, with mortality rates between 4 and 10/100,000 per year. Currently, the standard treatment of this pathology is represented by radiochemical therapy followed by low anterior resection with total mesorectal excision for stage I distal cancer and stage II or III for superior rectal cancer or proctectomy for stages II and III. For Stage I, surgical treatment may be sufficient, whereas for stages II and III surgery may be associated with postoperative chemotherapy. This therapeutical scheme associates a favorable oncological evolution with a local relapse rate below 10%, and survival at 5 years ranging between 63% and 77.4%.[3,4]
A significant proportion, between 15 and 40% of patients receiving neoadjuvant treatment, developed a complete clinical and pathological response, meaning that no tumor residue is identified on the resection piece. This finding is of great significance because an organ preservation approach, known as the watch and wait strategy, can be considered in selected patients. This involves postponing surgery and clinical, imaging, and endoscopic follow-up of patients who developed a complete clinical response after neoadjuvant therapy. This approach was first proposed following a study published in 2004 by a team in Sao Paulo, Brazil, led by AngelitaHabr-Gama. The study included 265 patients with distal rectal neoplasia who received preoperative radiochemical therapy. Of those included in the study, 71 patients, namely 26.8%, had developed a complete clinical response within 8 weeks after completion of treatment. These patients were the group for which postoperative surgery had been postponed and follow-up was used, with the remaining patients representing the incomplete clinical response group who had received surgery. After a median follow-up of 57.3 months, from the conservative group, two patients had experienced tumor regrowth, whereas three had developed metastatic disease. The 5-year survival rate was 100% in the group treated conservatively, whereas the disease-free survival rate was 92%.
The protocol proposed by the Habr-Gama team requires 54 Gy fractionated radiotherapy in 30 sessions in combination with chemotherapy consisting of 5-fluorouracil and leucovorin, extended over 9 weeks. Ten weeks following radiotherapy, patients are reassessed clinically (digital rectal examination), through colonoscopy and imaging techniques. Patients with complete clinical response are included in a strict follow-up program involving a digital rectal examination, tumor markers, and colonoscopy every 1–2 months in the first year, followed by reevaluation every 3 months in the second year and every 6 months starting with the third year, provided that the clinical response is maintained. During proctoscopy, evaluation biopsies may be taken although the histopathological examination may show false-negative results due to cancerous cells residing deep into the rectal wall. Furthermore, if the first imaging evaluation through magnetic resonance imaging (MRI) is suggestive of complete clinical response, patients are reevaluated every 6 months,[7,9] whereas the positron emission tomography (PET) scans remain reserved for inconclusive cases.
In recent years, centers from different countries have published studies reporting patients included in the watch and wait protocol. In the Netherlands, Maas et al. published a prospective study on a cohort of 21 patients who had complete clinical post-radiochemical therapy response. Of these, 1 patient (5%) had developed local relapse, the remaining 20 maintaining a complete clinical and pathological response at 2 years with the oncologic outcome comparable to those patients who had had surgery, but without the associated complications of radical surgery.
Other retrospective studies in the United States, the United Kingdom, and Australia, showed that global survival at 5 years and 5-year disease-free survival were similar in patients from the watch and wait protocol to those who had benefited from surgery after radiochemotherapy. Despite the favorable oncological results highlighted by the above studies, the greatest challenge resides in identifying the patients who can benefit from this protocol because literature data are rather limited and controversial. In Romania, this approach is not common, with no cases having been reported for the watch and wait protocol.
In this study, we present two patients with low-rectal tumors who developed complete response post neoadjuvant therapy and for whom the watch and wait protocol has been applied over the past 4 years.
CASE REPORT 1
A 63-year-old female patient presented to our service in 2016 for rectal bleeding accompanied by a 5 kg weight loss, which had started 1 month before admission. Digital rectal examination revealed a palpable rectal tumor with minimal bleeding at the touch, located at 5 cm from the anal verge. Proctoscopy examination showed a fragile tumor, 5 cm from the anal verge, that occupied two-thirds of the rectal circumference on a 3 cm length. A biopsy was carried out, and a histopathological examination showed moderately differentiated adenocarcinoma (G2) with the invasion of muscularis mucosae. The thoracoabdominal computed tomography (CT) scan revealed micronodular densification of the perirectal fatty tissue and in the lower rectum, as well as an irregular concentric thickening of the intestinal wall with the reduction of the digestive lumen, without the CT individualization of a tumor formation and no suggestive changes for the thoracoabdominal metastases.
Approximately 2 months later, an elective diverting colostomy was performed, followed by radiotherapy. The patient received a total dose of 54 Gy fractionated in 30 sessions. The patient also underwent chemotherapy with oxaliplatin and capecitabine. This double chemotherapy association was used because imagistic findings showed no individualization of a tumor, so based on TNM (T=tumor, N = nodes, M = metastasis), it was staged as a Tx locally extended tumor (TxN0M0).
Reassessment at 10 weeks post-radiotherapy revealed a complete clinical response: rectal digital examination did not flush the tumor and proctoscopy revealed areas of neovascularization without the presence of a tumor. Endosonography revealed a rectal wall thickening from 5 cm of the anal orifice (AO) to 9 cm from AO, from which bioptic material was taken, without visualization of tumor cells at the histopathological examination (complete pathologic response). Upon MRI examination, no definite endoluminal tumor formation or signal abnormalities in perirectal fat suggestive of tumor infiltration were identified in the recto-sigmoid region. Due to the patient’s complete clinical response following neoadjuvant therapy, a watch and wait approach was used with clinical, biological, and imaging follow-up. The subsequent re-evaluations carried out every 2 months in the first year, then at 6 months, showed tumor markers within normal limits, whereas echo-endoscopy and colonoscopy evaluations did not detect any tumor lesions. After 25 months of complete clinical and pathological response, we intervened for the restoration of the digestive tract, and the patient was discharged 6 days after surgery. The MRI examination performed a year later did not reveal any suggestive signs of a tumor in the rectum and perirectal fat, whereas colonoscopy only revealed a scar area in the rectal wall, with no signs of local regrowth.
CASE REPORT 2
A 52-year-old female patient presented to our service in early 2016 for rectal bleeding occurring 24 h before admission. Digital rectal examination revealed a semi-circumferential fragile tumor growth located approximately 2 cm from the anal verge on a 4 cm length. Laboratory tests showed no signs of anemia, with hemoglobin measuring 14.2 g/dL. Ultrasound endoscopy staged the tumor as a T3N0, whereas initial liver imaging was inconclusive for metastases. Subsequent imagistic studies showed liver cysts without signs of metastatic disease. An incisional biopsy was taken from the tumoral growth, and the histopathological examination revealed moderately differentiated tubular adenocarcinoma (G2) with the invasion of the rectal musculature. The following month, the patient received neoadjuvant radiotherapy, with a 54 Gy total dose divided into 30 fractions, and 6 sessions of chemotherapy with oxaliplatin (130 mg/m2) and capecitabine (2000 mg/m2 per day from day 1 to day 14), one session every 21 days. Clinical and imaging reassessment, 10 weeks following neoadjuvant treatment completion, revealed a complete clinical response. At the digital rectal examination, the tumoral formation could not be felt, whereas the colonoscopy identified suggestive lesions of radiation proctitis without individualization of a tumoral growth. Therefore, it was decided to delay the surgical intervention and perform clinical, biological, and colonoscopy follow-ups every 2 months in the first 12 months and MRI every 6 months. The last echoendoscopy re-assessment carried out 5 months after the initial presentation revealed a thickening of the mucosa and submucosa at the level of the middle and lower rectum, with integral muscularis mucosa and no locoregional adenopathies. At the same time, the last colonoscopy with biopsy examination showed inferior rectal mucosal edema but no signs of tumor regrowth. The MRI reassessment performed more than 3 years after diagnosis suggested 38 months of complete clinical response, revealing a diffuse thickening of the rectal wall, with no changes in the mesorectum and with no pelvic adenopathies, a result comparable to previous examinations.
The examinations and protocols depicted in this paper were performed for medical purposes and the patients’ personal information has not been disclosed to the public. We have obtained informed consent from both patients before submitting these cases along with the accompanying photographs.
At present, the biggest challenge is to identify patients who can benefit from the watch and wait protocol. The main literature data come from retrospective studies and show differences in patient selection criteria, such as staging or tumor size. Essential for the application of the watch and wait protocol is the appearance of complete clinical response following radiochemical therapy. The main purpose is to identify those patients who, following surgical treatment, may present a complete pathological response on the resection piece. Interestingly, a complete clinical response does not always correlate with a complete pathological response. In the initial study published by Habr-Gama, 8.3% of patients had an incomplete clinical response and were surgically treated; however, no tumor cells were identified on the resection pieces. However, patients with a complete clinical response but with an incomplete pathological response are at increased risk of local regrowth.
Evaluation of response to neoadjuvant treatment is performed clinically (digital rectal examination), through endoscopy and imagistic techniques such as MRI, CT, and PET scan. Following Habr-Gama et al., tumor absence in the digital rectal examination and the presence of scar tissue or telangiectasias as seen in the rectal mucosa during proctoscopy are considered suggestive signs of complete clinical response [Figure 1a and 1b], whereas digital palpation of a tumor or the presence of mucosal ulceration with or without areas of necrosis or rectal stenosis suggests an incomplete response, in which case surgical treatment is indicated. Some studies recommend biopsies as part of the follow-up protocol. However, in a study carried out in 2013, a significant percent of biopsy results (25–40%) were false negative, due to cancer cell distribution in the deep layers of the rectal wall, with no tumoral lesion on the surface. This particular study recommended full-thickness biopsies instead of mucosal biopsies.
Endoscopy alone in assessing tumor response and its predictive value in identifying complete response has been less studied. However, a retrospective study comprising 161 patients from a single center in the Netherlands who were evaluated at a median of 9 weeks following neoadjuvant therapy, showed that over 70% of the patients had a luminal complete response, with up to 77% of cases presenting a typical flat scar. Moreover, a pilot study that analyzed 25 patients with locally advanced rectal cancer, from another center in the Netherlands used an innovative endoscopic technique that can fluorescently visualize and quantify tumor tissue. This technique, known as quantitative fluorescence endoscopy (QEA), targets vascular endothelial growth factor A (VEGA), which is significantly higher in tumoral tissue, thus detecting residual tumors after completion of neoadjuvant treatment. This study reported an improved prediction of complete response, compared to endoscopy and MRI alone. Although this technique needs more validation trials, it could prove a useful tool in assessing complete response in rectal cancer.
Radiological assessment of the neoadjuvant treatment response has an important role in selecting patients who can benefit from the watch and wait approach. The main imaging modalities for evaluating the clinical response are MRI (T2 and diffusion sequence pattern, DWI), PET/CT scan, and echo-endoscopy. MRI examination is the preferred imaging modality of tumor regression assessment. The presence of a low-intensity signal characteristic of fibrosis on the T2 module and the absence of a suggestive signal for the residual tumor indicate a complete radiological response. There should also be no sign of perirectal or lymphatic invasion, such as irregular margins and the presence of a non-homogeneous signal on the T2 module. One of the limitations of the T2 signal MRI is the low capacity of differentiation between fibrosis and residual tumor tissue. Instead, the diffusion-weighted MRI (DWI MRI) has the advantage of delimiting fibrous tissue from residual tumor tissue. Examination of MRI should be of high quality to visualize tumor extension and tumor response to neoadjuvant treatment.
In recent years, MRI has begun to be used to assess tumor response to neoadjuvant treatment and to classify patients according to tumor regression in responsive, poorly responsive, and nonresponsive. The MRI tumor regression grading (mrTRG) system adapted from Mandard classification divides patients into five categories according to tumor-specific changes, specifically fibrous-residual tumor ratio after completion of neoadjuvant treatment[22,24]: mrTRG1: fibrosis, no tumor signs, complete radiological response; mrTRG2: low-intensity signal suggestive for fibrosis with minimal residual tumor signal; mrTRG3: low-intensity signal for fibrosis and a medium intensity signal representing the residual tumor; mrTRG4: minimal fibrosis, predominantly medium signal intensity suggestive for the presence of tumor tissue; mRTRG5: residual tumor/tumor recurrence. Moreover, although mrTRG proved to be a good predictor of the response to neoadjuvant treatment, being 10 times more sensitive in identifying patients with a complete clinical and pathological response who could benefit from the watch and wait approach, there are not enough data in the literature to support the modification of the current treatment protocol, depending on this imaging marker for the evaluation of tumor regression. A prospective randomized controlled trial (TRIGGER) is currently taking place, analyzing mrTRG and its efficacy in identifying patients with complete clinical response. A good response to neoadjuvant treatment (mRTRG1 and 2) may mean avoiding surgery with increased morbidity and mortality. Consensus meetings of the European Society of Gastrointestinal Abdominal Radiology (ESGAR) have proposed another grading system, which involves a three-stage classification: 1) normalized wall, 2) fibrotic thickening of the wall, and 3) residual mass. Moreover, they have suggested that, apart from tumor grading, following neoadjuvant treatment, MRI reassessment should include local tumor status, mesorectal fascia invasion, lymph node involvement, and establishing if there is any extramural venous invasion.
One of the biggest issues in using MRI for rectal tumor staging following neoadjuvant treatment is the assessment of regional lymph nodes, with nodal size remaining one of the main criteria for malignant invasion, although morphological features such as border irregularities or round shape, a heterogeneous signal can also suggest malignant transformation. In patients treated with radiotherapy, lymph node size has been shown to decrease in up to 84% of cases, with nodes measuring less than 5 mm in the short axis being considered benign.[28,30]
MRI has been proven an important tool in assessing tumor response following radiotherapy for rectal cancer, with growing evidence showing that DWI sequences have better results in assessing tumor response compared to conventional morphological sequences. Furthermore, ESGAR recommends the routine use of DWI MRI for rectal tumor restaging. Moreover, recent studies have highlighted a shift from the qualitative assessment of treatment response to quantitative DWI assessment, with studies on the use of apparent diffuse coefficient (ADC) as the main quantitative predictive marker of complete pathological response. ADC assesses the water diffusion throughout the tissue, having a negative correlation with tissue cellularity, thus meaning that increased cellularity and structural modification of tumor cells are associated with reduced ADC values. Therefore, ADC has been studied as a biomarker to assess and predict tumor response following neoadjuvant treatment for rectal cancer. To this extent, two recent retrospective studies have evaluated the role of DWI imaging based on readout-segmented echo-planar imaging (rs-EPI) in assessing tumor response after neoadjuvant therapy in locally advanced rectal cancer, one comprising 76 patients, and the other comprising 63 patients. Both studies have found that quantitative ADC values of rs-EPI DWI, which are higher in patients with a complete pathological response after neoadjuvant treatment for locally advanced rectal cancer, could help differentiate these patients from non-responders, although their findings were consistent with prior data from the literature.[35,36]
Other imaging modalities for assessing the response to neoadjuvant treatment are endorectal ultrasound (ERUS) and CT examination. Although echo-endoscopy is useful in initial rectal tumor assessment, it has low accuracy in differentiating the tumor from fibrous tissue in patients receiving neoadjuvant treatment. Similarly, standard CT examinations with low-contrast absorption capacity in tumor tissue showed low accuracy in determining complete pathological response.
Watch and wait studies have used different modalities and protocols to evaluate complete clinical response after neoadjuvant treatment. Also, several clinical, biological, and radiological markers associated with the appearance of complete clinical response have been identified and analyzed. The question has arisen regarding the predictive factors of the complete clinical response after neoadjuvant treatment and which patients would benefit most from the watch and wait approach. To this extent, a study published in 2015 by Bitterman et al. revealed five predictive factors for complete clinical response, namely, a low level of carcinoembryonic antigen (CEA) at the time of diagnosis, reduced tumor size, small distance to the anal orifice, tumor staging, a longer interval between neoadjuvant treatment, and surgery.
There is currently no standardized guide to selecting patients with complete neoadjuvant clinical responses who can benefit from non-surgical treatment. Recent studies have established several selection criteria for patients who can be managed non-surgically.
First, the tumor should be located up to 7 cm from the anal orifice and should be palpable to a digital rectal examination. In terms of tumor size, Habr-Gama et al. reported that tumors measuring less than 7 cm could be treated non-surgically, whereas other studies reported that sizes of less than 5 cm correlated with complete clinical and pathological responses.[41–43] Another criterion related to the size of the tumor can be considered the occupation of the rectal lumen, with tumors occupying less than 50% of the rectal wall circumference being correlated with the appearance of complete clinical and pathological response. Other studies have shown that the degree of tumor differentiation and tumor staging correlated with the appearance of complete clinical response. The results of two studies involving over 20,000 patients each demonstrated that well-differentiated tumors with lower TNM stages were associated with the occurrence of complete clinical and pathological responses[45,46] with the difference that in the second study, a higher dose of radiotherapy was associated with a higher frequency of complete clinical response. Furthermore, Garland et al. identified the absence of lymph node invasion as a predictive factor for a complete clinical response.
Another important criterion is the interval from the end of neoadjuvant treatment and the assessment of tumor response to evaluate the need for surgical treatment. In most studies, patients are re-evaluated at 6–8 weeks after treatment; however, an optimal re-evaluation time has not been established yet. Several studies have demonstrated that longer intervals, over 8 weeks, are a predictive factor in the occurrence of complete clinical and pathological responses.[45–48] However, some studies suggested that extending the interval between completing neoadjuvant treatment and surgery in case of incomplete response does not benefit patients in this category because it only associates higher morbidity and mortality in the later evaluated group.[49,50]
In recent years, several biological markers have been identified as predictors of response to neoadjuvant treatment, with the carcinoembryonic antigen (CEA) tumor marker probably being the most studied. CEA is mostly used to assess tumor response to radio- and chemotherapy treatment and to track patients over time, an increase in serum is suggestive of tumor recurrence. Low CEA levels at diagnosis are more frequently associated with favorable responses to neoadjuvant therapy. Retrospective studies have indicated that CEA values of less than 5 ng/mL before the initiation of neoadjuvant therapy are correlated with the occurrence of complete clinical response.[51–53] Other studies suggested that CEA values of less than 2.6 ng/mL evaluated following radio-chemotherapy are predictive factors for the development of complete clinical response.[54,55] Peripheral blood leukocyte count is another biological marker associated with the appearance of complete clinical response, its elevation before initiating neoadjuvant treatment followed by its decrease after completion of treatment is associated with complete clinical response.
Obtaining a complete clinical response after neoadjuvant treatment may, in selected patients, mean avoiding radical surgery and associated complications. Although the standard for neoadjuvant treatment is chemoradiotherapy (CRT), in recent years an alternative known as total neoadjuvant therapy (TNT) has emerged, and it started shifting the classical approach. The TNT approach consists of the administration of CRT plus neoadjuvant chemotherapy before surgery. Literature data have shown that using this regimen has better results in increasing complete pathological and clinical response rates, especially in locally advanced rectal cancer.[57,58] Because there is currently no definite protocol for TNT, various options combine radiotherapy with either induction or consolidation chemotherapy, with good results. Recently two high-quality prospective randomized control trials (RAPIDO and PRODIGE23) comparing standard CRT with TNT published their results.[59,60] The main differences between the two trials were the type of neoadjuvant chemotherapy, namely induction (PRODIGE23) vs. consolidation (RAPIDO), duration of radiotherapy (short vs. long course), and chemotherapy. In the PRODIGE23 study, which enrolled 461 patients, the TNT arm consisted of 12 weeks of induction triple therapy (a modified FOLFIRIOX) followed by CHT, surgery, and 12 weeks of adjuvant therapy, whereas for the RAPIDO study, which enrolled 912 patients, the TNT arm consisted of upfront short-course radiation therapy (SCRT) followed by double oxaliplatine-based chemotherapy (6 cycles of CAPOX or 9 cycles of FOLFOX).[59–61] Both studies reported a better outcome in achieving a complete pathological response on the TNT arm (27.8% vs. 12.1% for the PRODIGE23 study and 28.4% vs 14.3% for the RAPIDO study). They also reported lower distant metastases rates on the TNT arm, and, whereas local regrowth was higher on the TNT arm for the RAPIDO study, the overall survival was better for the TNT approach.
Another study comparing the induction versus consolidation therapy for the total neoadjuvant therapy reported that although there was not a significant difference between the induction and consolidation therapy pertaining to 3-year disease-free survival and 3-year distant metastases-free survival for the two groups, patients included in the consolidation group had better organ preservation rates (58% vs. 43%).
Local regrowth following the watch and wait approach occurs in about 25%–30% within the first 3 years of attaining complete clinical response.A proportion of these patients can benefit from salvage surgical treatment for local regrowth or systemic dissemination. The use of the watch and wait strategy for patients with complete pathological responses seems a feasible option if a strict clinical, biological, and imaging follow-up protocol is applied.
The success of this approach consists in maintaining a complete clinical response. A group of five studies presenting a rigorous follow-up protocol for non-operative treated patients established that complete clinical response can be considered maintained only after 12 months.[6,11,12,65,66] Also, according to literature data, in most cases where non-operative treatment was chosen, local regrowth occurred mostly in the first 12 months, the majority of them associated with an endoluminal component. For extraluminal local recurrences, MRI proved to be a useful tool. Upon MRI examination, the detection of wall thickening without mucosal lesions and the detection of a tumoral mass into the mesorectum were considered signs of tumor regrowth. For this reason, rigorous monitoring protocols for these patients allow the detection of these recurrences, followed by surgical treatment with long-term favorable outcomes in 80–90% of cases.[68,69] In their meta-analysis, Dossa et al. have compared local recurrences and the survival rates of conservative vs. surgically treated patients. Their analysis comprised 23 studies, including 867 patients. Of the total patients analyzed, 15.7% had tumor regrowth, 95.4% of whom received salvage surgery with a sphincter preservation rate of 49.8%. As for the overall survival rate, there was no significant difference between conservative and surgically treated patients. In a more recent meta-analysis, Zhao et al. reported similar outcomes to Dossa. Their analysis included nine studies with 1,131 patients divided into three groups (watch and wait, rectal surgery, and local excision). 12.6% of the watch and wait group had tumor regrowth, whereas the rectal surgery group had a 3.3% local recurrence rate, and the local excision group had a 28.6% local recurrence rate. The local regrowth and local recurrence patients underwent salvage surgery and chemotherapy with better results for the watch and wait patients. The overall survival and disease-free survival rates were similar between the watch and wait and surgery groups. These findings are also supported by cohort studies.
Wang et al. published a retrospective study that included two matching cohorts of 94 patients each, comparing the watch and wait approach with radical surgery, and reported a higher local regrowth following the conservative approach, but lower distant metastases. Most local regrowths were reported within the first 2 years and 85.7% of those patients received salvage surgery with a good outcome. Moreover, the watch and wait group had higher sphincter preservation rates (92.6%) vs. the radical surgery group (66%). In a smaller retrospective study, Cotti et al. reported 29.9% local regrowth for the watch and wait approach. All those patients received salvage surgery, a sphincter sparing procedure in most cases (75%). The overall survival was 91.1% for the sustained clinical response and 71.1% in patients with recurrent tumors.
In 2014, an International Watch and Wait Database were set up to collect and analyze data on this strategy, presenting its first report in January 2017. This included the analysis of 775 patients who benefited from the watch and wait strategy, followed for an average of 2.6 years. In this group, the rate of local regrowth was 25%, the majority of which (84%) had occurred within the first 2 years of completing neoadjuvant treatment. Ninety-four percent of recurrences were endoluminal and 4% had a locoregional extension. Seven percent of the patients analyzed developed distant metastases. Overall, the 5-year survival rate was 91%.
A more recent multicenter retrospective study using a dataset from the International Watch and Wait Database, which includes data from 47 clinics in 15 countries, analyzed 793 patients followed for an average of 4.7 years, with complete clinical response, who had benefited from the watch and wait strategy. The probability of remaining free from tumor regrowth for another 2 years was 88.1% for patients with sustained complete clinical response in the first year, and 98.6% for those with 5 years of recurrence-free survival. Furthermore, this study showed that after the first year of complete clinical response, the probability of developing distant metastasis in the subsequent 2 years was quite low, thus implying that the intensity of patient surveillance after 3 years of complete clinical response could be reduced.
Although the watch and wait protocol appears to be a feasible option in the management of patients with a complete clinical and pathological response, more prospective studies and randomized trials comparing this approach with standard surgical treatment are required before establishing it as the standard of care for distal rectal cancer. Most data accumulated so far comes from retrospective studies and comprise a small number of patients. Another dilemma is the heterogeneity of the patients included in the studies, the differences in their selection criteria, and the lack of a standard follow-up protocol for these patients. Therefore, establishing universal criteria for the selection and assessment of the patients with the complete clinical response following neoadjuvant treatment is required.
Availability of data and materials
All data generated or analyzed during this study are included in this published study.
Conceptualization: D.A.D., A.R.S. Case identification and management: D.A.D., A.R.S., V.A.P., O.I.D. Investigation: S.B., A.N.C., A.H. Writing-original draft preparation: S.B., A.N.C., A.H. Writing - review, and editing: D.C., C.E.C. Supervision: O.I.D., V.T.G. All authors contributed to the article and approved the submitted version.
Ethics approval and consent to participate
Patient consent for publication
We have obtained informed consent from both patients before submitting these cases along with the accompanying photographs.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
1. Glynne-Jones R, Wyrwicz L, Tiret E, Brown G, Rödel C, Cervantes A, et al. Rectal cancer
:ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28 (Suppl 4):22–40.
2. Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. 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 2012;30:1926–33.
3. Marks JH, Huang R, McKeever D, Greenfield M. Outcomes in 132 patients following laparoscopic total mesorectal excision (TME) for rectal cancer
with greater than 5-year follow-up. Surg Endosc 2016;30:307–14.
4. Fischer J, Hellmich G, Jackisch T, Puffer E, Zimmer J, Bleyl D, et al. Outcome for stage II and III rectal and colon cancer equally good after treatment improvement over three decades. Int J Colorectal Dis 2015;30:797–806.
5. Smith JD, Ruby JA, Goodman KA, Saltz LB, Guillem JG, Weiser MR, et al. Nonoperative management of rectal cancer
with complete clinical response after neoadjuvant therapy. Ann Surg 2012;256:965–72.
6. Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U Jr, Silva e Sousa AH Jr, et al. Operative versus nonoperative treatment for stage 0 distal rectal cancer
following chemoradiation therapy:Long-term results. Ann Surg 2004;240:711–7; discussion 717-8, Oct.
7. Habr-Gama A. Assessment and management of the complete clinical response of rectal cancer
to chemoradiotherapy. Color Dis 2006;8:21–4.
8. Duldulao MP, et al. Distribution of Residual Cancer Cells in the Bowel Wall After Neoadjuvant Chemoradiation in Patients With Rectal Cancer
. Dis Colon Rectum 2013;56:142–9.
9. Habr-Gama A, São Julião GP, Perez RO. Nonoperative management of rectal cancer
. Hematol Oncol Clin North Am 2015;29:135–51.
10. Habr-Gama A, Fernandez LM, São Julião GP, Vailati BB, Perez RO. Alternative treatment to surgery for rectal cancer
. Ann Laparosc Endosc Surg 2018;3. doi:10.21037/ales.2018.05.05.
11. Maas M, Beets-Tan RG, Lambregts DM, Lammering G, Nelemans PJ, Engelen SM, et al. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer
. J Clin Oncol 2011;29:4633–40.
12. Dalton RS, Velineni R, Osborne ME, Thomas R, Harries S, Gee AS, et al. A single-centre experience of chemoradiotherapy for rectal cancer
:Is there potential for nonoperative management?. Color Dis 2012;14:567–571.
13. Sposato LA, et al. Observation of 'complete clinical response'in rectal cancer
after neoadjuvant chemoradiation:The flinders experience. Asia Pac J Clin Oncol 2018;14:439–45.
14. Bernier L, Balyasnikova S, Tait D, Brown G. Watch-and-wait as a therapeutic strategy in rectal cancer
. Curr Colorectal Cancer Rep 2018;14:37–55.
15. Li J, Li L, Yang L, Yuan J, Lv B, Yao Y, et al. Wait-and-see treatment strategies for rectal cancer
patients with clinical complete response after neoadjuvant chemoradiotherapy:A systematic review and meta-analysis. Oncotarget 2016;7:44857–70.
16. Pozo ME, Fang SH. Watch and wait
approach to rectal cancer
:A review. World J Gastrointest Surg 2015;7:306–12.
17. Habr-Gama A, Perez R, Proscurshim I, Gama-Rodrigues J. Complete clinical response after neoadjuvant chemoradiation for distal rectal cancer
. Surg Oncol Clin N Am 2010;19:829–45.
18. van der Sande ME, Maas M, Melenhorst J, Breukink SO, van Leerdam ME, Beets GL. Predictive value of endoscopic features for a complete response after chemoradiotherapy for rectal cancer
. Ann Surg 2021;274:e541–7.
19. Tjalma JJ, Koller M, Linssen MD, Hartmans E, de Jongh SJ, Jorritsma-Smit A, et al. Quantitative fluorescence endoscopy:An innovative endoscopy approach to evaluate neoadjuvant treatment response in locally advanced rectal cancer
. Gut 2020;69:406–10.
20. Nahas SC, RizkallahNahas CS, Sparapan Marques CF, Ribeiro U Jr, Cotti GC, Imperiale AR, et al. Pathologic complete response in rectal cancer
:Can we detect it?Lessons learned from a proposed randomized trial of watch-and-wait treatment of rectal cancer
. Dis Colon Rectum 2016;59:255–63.
21. Timmerman C, Taveras LR, Huerta S. Clinical and molecular diagnosis of pathologic complete response in rectal cancer
:An update. Expert Rev Mol Diagn 2018;18:887–96.
22. Patel UB, Blomqvist LK, Taylor F, George C, Guthrie A, Bees N, et al. MRI after treatment of locally advanced rectal cancer
:How to report tumor response—The MERCURY experience. Am J Roentgenol 2012;199:W486–95.
23. Mandard AM, Dalibard F, Mandard JC, Marnay J, Henry-Amar M, Petiot JF, et al. Pathologic assessment of tumor regression after preoperative chemoradiotherapy of esophageal carcinoma. Clinicopathologic correlations. Cancer 1994;73:2680–6.
24. Battersby NJ, Moran B, Yu S, Tekkis P, Brown G. MR imaging for rectal cancer
:The role in staging the primary and response to neoadjuvant therapy. Expert Rev Gastroenterol Hepatol 2014;8:703–19.
25. Bhoday J, Smith F, Siddiqui MR, Balyasnikova S, Swift RI, Perez R, et al. Magnetic resonance tumor regression grade and residual mucosal abnormality as predictors for pathological complete response in rectal cancer
postneoadjuvant chemoradiotherapy. Dis Colon Rectum 2016;59:925–33.
26. Battersby NJ, Dattani M, Rao S, Cunningham D, Tait D, Adams R, et al. A rectal cancer
feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER):Study protocol for a randomised controlled trial. Trials 2017;18:394.
27. Renehan AG, Malcomson L, Emsley R, Gollins S, Maw A, Myint AS, et al. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer
(the OnCoRe project):A propensity-score matched cohort analysis. Lancet Oncol 2016;17:174–83.
28. Beets-Tan RG, Lambregts DM, Maas M, Bipat S, Barbaro B, Curvo-Semedo L, et al. Magnetic resonance imaging for clinical management of rectal cancer
:Updated recommendations from the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus meeting. Eur Radiol 2018;28:1465–75.
29. Lambregts DM, Boellaard TN, Beets-Tan RG. Response evaluation after neoadjuvant treatment for rectal cancer
using modern MR imaging: A pictorial review. Insights Imaging 2019;10:15. doi: 10.1186/s13244-019-0706-x.
30. López-Campos F, Martín-Martín M, Fornell-Pérez R, García-Pérez JC, Die-Trill J, Fuentes-Mateos R, et al. Watch and wait
approach in rectal cancer
:Current controversies and future directions. World J Gastroenterol 2020;26:4218–39.
31. Schurink NW, Lambregts DM, Beets-Tan RG. Diffusion-weighted imaging in rectal cancer
:Current applications and future perspectives. Br J Radiol 2019;92. doi:10.1259/bjr. 20180655.
32. Pham TT, Liney GP, K Wong, Barton MB. Functional MRI for quantitative treatment response prediction in locally advanced rectal cancer
. Br J Radiol 2017;90:20151078. doi: 10.1259/bjr. 20151078.
33. Yang L, Qiu M, Xia C, Li Z, Wang Z, Zhou X, et al. Value of high-resolution DWI in combination with texture analysis for the evaluation of tumor response after preoperative chemoradiotherapy for locally advanced rectal cancer
. Am J Roentgenol 2019;212:1279–86.
34. Yang L, Xia C, Liu D, Fang X, Pan X, Ma L, et al. The role of readout-segmented echo-planar imaging-based diffusion-weighted imaging in evaluating tumor response of locally advanced rectal cancer
after neoadjuvant chemoradiotherapy. Acta Radiol 2020;61:1155–64.
35. Monguzzi L, Ippolito D, Bernasconi DP, Trattenero C, Galimberti S, Sironi S. Locally advanced rectal cancer
:Value of ADC mapping in prediction of tumor response to radiochemotherapy. Eur J Radiol 2013;82:234–40.
36. Birlik B, Obuz F, Elibol FD, Celik AO, Sokmen S, Terzi C, et al. Diffusion-weighted MRI and MR- volumetry-in the evaluation of tumor response after preoperative chemoradiotherapy in patients with locally advanced rectal cancer
. Magn Reson Imaging 2015;33:201–12.
37. Memon S, Lynch AC, Bressel M, Wise AG, Heriot AG. Systematic review and meta-analysis of the accuracy of MRI and endorectal ultrasound in the restaging and response assessment of rectal cancer
following neoadjuvant therapy. Color Dis 2015;17:748–61.
38. Ryan JE, Warrier SK, Lynch AC, Heriot AG. Assessing pathological complete response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer
:A systematic review. Color Dis 2015;17:849–61.
39. Bitterman DS, Resende Salgado L, Moore HG, Sanfilippo NJ, Gu P, Hatzaras I, et al. Predictors of complete response and disease recurrence following chemoradiation for rectal cancer
. Front Oncol 2018;5:286. doi: 10.3389/fonc. 2015.00286.
40. Habr-Gama A, Perez RO, Wynn G, Marks J, Kessler H, Gama-Rodrigues J. Complete clinical response after neoadjuvant chemoradiation therapy for distal rectal cancer
:Characterization of clinical and endoscopic findings for standardization. Dis Colon Rectum 2010;53:1692–8.
41. De Felice F, Izzo L, Musio D, Magnante AL, Bulzonetti N, Pugliese F, et al. Clinical predictive factors of pathologic complete response in locally advanced rectal cancer
. Oncotarget 2016;7:33374–80.
42. Das P, Skibber JM, Rodriguez-Bigas MA, Feig BW, Chang GJ, Wolff RA, et al. Predictors of tumor response and downstaging in patients who receive preoperative chemoradiation for rectal cancer
. Cancer 2007;109:1750–5.
43. Garland ML, Vather R, Bunkley N, Pearse M, Bissett IP. Clinical tumour size and nodal status predict pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer
. Int J Colorectal Dis 2014;29:301–7.
44. Song JH, Park YH, Seo SH, Lee A, Kim KH, An MS, Song JH, et al. Difference in tumor area as a predictor of a pathological complete response for patients with locally advanced rectal cancer
. Ann Coloproctol 2017;33:219–26.
45. Lorimer PD, Kirks RC, Boselli D, Crimaldi AJ, Hill JS, Salo JC. Pathologic complete response rates after neoadjuvant treatment in rectal cancer
:An analysis of the NCDB. J Clin Oncol 2016;34:713. doi:10.1200/jco.2016.34.4_suppl. 713.
46. E Al-Sukhni, Attwood K, Mattson DM, Gabriel E, Nurkin SJ. Predictors of pathologic complete response following neoadjuvant chemoradiotherapy for rectal cancer
. Ann Surg Oncol 2016;23:1177–86.
47. Probst CP, Becerra AZ, Aquina CT, Tejani MA, Wexner SD, Garcia-Aguilar J, et al. Extended intervals after neoadjuvant therapy in locally advanced rectal cancer
:The key to improved tumor response and potential organ preservation. J Am Coll Surg 2015;221:430–40.
48. Petrelli F, Sgroi G, Sarti E, Barni S. Increasing the interval between neoadjuvant chemoradiotherapy and surgery in rectal cancer
. Ann Surg 2016;263:458–64.
49. Sloothaak DA, Geijsen DE, van Leersum NJ, Punt CJ, Buskens CJ, Bemelman WA, et al. Optimal time interval between neoadjuvant chemoradiotherapy and surgery for rectal cancer
. Br J Surg 2013;100:933–9.
50. Lefevre JH, Mineur L, Kotti S, Rullier E, Rouanet P, de Chaisemartin C, et al. Effect of interval (7 or 11 weeks) between neoadjuvant radiochemotherapy and surgery on complete pathologic response in rectal cancer
:A multicenter, randomized, controlled trial (GRECCAR-6). J Clin Oncol 2016;34:3773–80.
51. Moureau-Zabotto L, Farnault B, de Chaisemartin C, Esterni B, Lelong B, Viret F, et al. Predictive factors of tumor response after neoadjuvant chemoradiation for locally advanced rectal cancer
. Int J Radiat Oncol 2011;80:483–91.
52. Restivo A, Zorcolo L, Cocco IM, Manunza R, Margiani C, Marongiu L, et al. Elevated CEA levels and low distance of the tumor from the anal verge are predictors of incomplete response to chemoradiation in patients with rectal cancer
. Ann Surg Oncol 2013;20:864–71.
53. Probst CP, Becerra AZ, Aquina CT, Tejani MA, Hensley BJ, González MG, et al. Watch and wait
?—Elevated pretreatment CEA is associated with decreased pathological complete response in rectal cancer
. J Gastrointest Surg 2016;20:43–52.
54. Russo AL, Ryan DP, Borger DR, Wo JY, Szymonifka J, Liang WY, et al. Mutational and clinical predictors of pathologic complete response in the treatment of locally advanced rectal cancer
. J Gastrointest Cancer 2014;45:34–9.
55. Patel PM, Harris K, Huerta S. Clinical and molecular diagnosis of pathologic complete response in rectal cancer
. Expert Rev Mol Diagn 2015;15:1505–16.
56. Kitayama J, Yasuda K, Kawai K, Sunami E, Nagawa H. Circulating lymphocyte is an important determinant of the effectiveness of preoperative radiotherapy in advanced rectal cancer
. BMC Cancer 2011;11:64. doi:10.1186/1471-2407-11-64.
57. Kasi A, Abbasi S, Handa S, Al-Rajabi R, Saeed A, Baranda J, et al. Total neoadjuvant therapy vs standard therapy in locally advanced rectal cancer
:A systematic review and meta-analysis. JAMA NetwOpen 2020:e2030097. 10.1001/jamanetworkopen.2020.30097.
58. Gilshtein H, Ghuman A, Dawoud M, Yellinek S, Kent I, Sharp SP, et al. Total neoadjuvant treatment for rectal cancer
:Preliminary experience. Am Surg 2021;87:708–13.
59. Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CA, Putter H, Kranenbarg EM, et al. 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. Lancet Oncol 2021;22:29–42.
60. Conroy T, Bosset JF, Etienne PL, Rio E, François É, Mesgouez-Nebout N, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer
(UNICANCER-PRODIGE 23):A multicentre, randomised, open-label, phase 3 trial. Lancet Oncol 2021;22:702–15.
61. Giunta EF, Bregni G, Pretta A, Deleporte A, Liberale G, Bali AM, et al. Total neoadjuvant therapy for rectal cancer
:Making sense of the results from the RAPIDO and PRODIGE 23 trials. Cancer Treat Rev 2021;96:102177. 10.1016/j.ctrv. 2021.102177.
62. Garcia-Aguilar J, Patil S, Kim JK, Yuval JB, Thompson H, Verheij F, et al. Preliminary results of the organ preservation of rectal adenocarcinoma (OPRA) trial. J ClinOncol 2020;38:4008. doi:10.1200/JCO.2020.38.15_suppl. 4008.
63. Fernandez LM, São Julião GP, Figueiredo NL, Beets GL, van der Valk MJ, Bahadoer RR, et al. Conditional recurrence-free survival of clinical complete responders managed by watch and wait
after neoadjuvant chemoradiotherapy for rectal cancer
in the international watch &wait database:A retrospective, international, multicentre registry study. Lancet Oncol 2021;22:43–50.
64. Glynne-Jones R, Hughes R. Critical appraisal of the 'wait and see'approach in rectal cancer
for clinical complete responders after chemoradiation. Br J Surg 2012;99:897–909.
65. Araujo RO, Valadão M, Borges D, Linhares E, de Jesus JP, Ferreira CG, et al. Nonoperative management of rectal cancer
after chemoradiation opposed to resection after complete clinical response. A comparative study. Eur J Surg Oncol 2015;41:1456–63.
66. Li J, Liu H, Yin J, Liu S, Hu J, Du F, et al. Wait-and-see or radical surgery for rectal cancer
patients with a clinical complete response after neoadjuvant chemoradiotherapy:A cohort study. Oncotarget 2015;6:42354–61.
67. Smith JJ, Strombom P, Chow OS, Roxburgh CS, Lynn P, Eaton A, et al. Assessment of a watch-and-wait strategy for rectal cancer
in patients with a complete response after neoadjuvant therapy. JAMA Oncol 2019;5:e185896. doi: 10.1001/jamaoncol. 2018.5896.
68. Habr-Gama A, Gama-Rodrigues J, São Julião GP, Proscurshim I, Sabbagh C, Lynn PB, 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 2014;88:822–8.
69. Kong JC, Guerra GR, Warrier SK, Ramsay RG, Heriot AG. Outcome and salvage surgery following “watch and wait
”for rectal cancer
after neoadjuvant therapy:A systematic review. Dis Colon Rectum 2017;60:335–45.
70. Dossa F, Chesney TR, Acuna SA, Baxter NN. A watch-and-wait approach for locally advanced rectal cancer
after a clinical complete response following neoadjuvant chemoradiation:A systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2017;2:501–13.
71. Zhao GH, Deng L, Ye DM, Wang WH, Yan Y, Yu T. Efficacy and safety of wait and see strategy versus radical surgery and local excision for rectal cancer
with cCR response after neoadjuvant chemoradiotherapy:A meta-analysis. World J Surg Oncol 2020;18:232: doi:10.1186/s12957-020-02003-6.
72. Wang QX, Zhang R, Xiao WW, Zhang S, Wei MB, Li YH, et al. The watch-and-wait strategy versus surgical resection for rectal cancer
patients with a clinical complete response after neoadjuvant chemoradiotherapy. Radiat Oncol 2021;16:16. doi:10.1186/s13014-021-01746-0.
73. Cotti GC, Pandini RV, Braghiroli OF, Nahas CS, Bustamante-Lopez LA, Marques CFS, et al. Outcomes of patients with local regrowth after nonoperative management of rectal cancer
after neoadjuvant chemoradiotherapy. Dis Colon Rectum 2022;65:333–9.
74. van der Valk M. The international watch &wait database (IWWD) for rectal cancer
:An update. J Clin Oncol 2017;35:521.