INTRODUCTION
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.[1] 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%,[2] 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.[5] 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.[6] 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.[7] 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.[8] 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.[10]
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.[11] 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,[5] the United Kingdom,[12] and Australia,[13] 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.
DISCUSSION
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.[14] 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.[6] However, patients with a complete clinical response but with an incomplete pathological response are at increased risk of local regrowth.[15]
Evaluation of response to neoadjuvant treatment is performed clinically (digital rectal examination), through endoscopy and imagistic techniques such as MRI, CT, and PET scan.[16] Following Habr-Gama et al.,[17] 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.[13] 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.[8]
;)
Figure 1: (a and b) The presence of scar tissue (white arrows) 26 months following completion of neoadjuvant treatment for rectal cancer for the first patient
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.[18] 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.[19] 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.[20] 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.[21] 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.[22] The MRI tumor regression grading (mrTRG) system adapted from Mandard classification[23] 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,[25] 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.[26] A good response to neoadjuvant treatment (mRTRG1 and 2) may mean avoiding surgery with increased morbidity and mortality.[27] 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.[28]
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.[29] 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.[31] Furthermore, ESGAR recommends the routine use of DWI MRI for rectal tumor restaging.[28] 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.[31] 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.[32] 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,[33] and the other comprising 63 patients.[34] 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.[37] Similarly, standard CT examinations with low-contrast absorption capacity in tumor tissue showed low accuracy in determining complete pathological response.[38]
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.[39]
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.[40] In terms of tumor size, Habr-Gama et al.[40] 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.[44] 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.[43] 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.[56]
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%).[62]
Local regrowth following the watch and wait approach occurs in about 25%–30% within the first 3 years of attaining complete clinical response.[63]A proportion of these patients can benefit from salvage surgical treatment for local regrowth or systemic dissemination.[64] 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.[15]
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.[67] 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.[70] 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.[71] 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.[72] 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.[73] 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.[74] 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.[63]
CONCLUSION
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.
Authors’ contributions
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
Not applicable.
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
Nil.
Conflicts of interest
There are no conflicts of interest.
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