JAMA Oncol. The association and resection of adjuvant chemotherapy with survival in patients with pCR is unclear. We selected patients with nonmetastatic invasive rectal cancer who achieved pCR after neoadjuvant chemoradiation therapy and resection. We separately matched subgroups of patients with node-positive disease before treatment and node-negative disease before treatment to investigate for effect modification by pretreatment nodal status. We matched patients with pCR who received adjuvant chemotherapy and at least 8 weeks of follow-up after surgery to patients with pCR who did not receive adjuvant treatment.
Consent for publication Not applicable Competing interests The authors declare that Adjuvant chemo rectal cancer have no competing interests. Given the paucity of randomized trials appertaining to pCR status, the present pooled analysis provides clinical insights into the role of ACT in patients who achieved remarkable tumor eradication following CRT. J Cancer Res Clin Oncol— New York, NY: Raven, We generated Kaplan-Meier survival curves to compare overall survival between the propensity score—matched groups. Polanco PM et al.
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Patients were divided into two groups depending on whether adjuvant chemotherapy was administered or not. Overall survival, distant metastases, and local recurrence were compared between both groups. Fifty-four patients with adjuvant ACT and 50 patients without adjuvant chemotherapy NACT after neoadjuvant chemoradiation followed by radical resection for rectal cancer were included in the analysis. One patient without adjuvant chemotherapy and none in the ACT group developed a local recurrence.
Median disease-free survival for all patients was Multivariate analysis showed adjuvant chemotherapy to be the most relevant factor for disease-free and overall survival. Patients staged ypT2 ypN0 showed a significantly better disease-free survival after application of adjuvant chemotherapy.
Disease-free survival in ypT0—1 ypN0 patients showed no correlation to the administration of adjuvant chemotherapy. Administration of adjuvant chemotherapy after neoadjuvant chemoradiation and radical resection in rectal cancer improved disease-free and overall survival of patients with ypT0—2 ypN0 tumor stages in our study. In particular, ypT2 ypN0 patients seem to profit from adjuvant treatment.
Neoadjuvant chemoradiation is a considered standard treatment for locally advanced rectal cancer [ 1 ]. Current guidelines for the treatment of colorectal cancer in Germany recommend the administration of adjuvant chemotherapy for all rectal cancer patients after neoadjuvant chemoradiation and total mesorectal excision TME , regardless of the postoperative pathologic staging result [ 2 ].
However, hard evidence is lacking, especially for patients staged ypT0—2 ypN0. While an exploratory analysis suggested that particular patients with good response ypT0—2 benefit from adjuvant chemotherapy [ 4 ] randomized controlled trials addressing the same question showed no benefit for adjuvant chemotherapy [ 5 , 6 ].
However, these trials have relevant methodological restrictions. While a recent pooled analysis showed positive effects for adjuvant chemotherapy, another recent meta-analysis failed to do so [ 7 , 8 ].
In adherence to the German national guidelines from before , ypT0—2 ypN0 patients were then not treated with postoperative chemotherapy NACT at our institution. After the introduction of the amended guidelines in , adjuvant treatment was routinely administered to the same group of patients ACT. On the basis of a prospectively maintained database, the oncologic outcomes of these patients were analyzed.
The institutional review board reviewed and approved the protocol; the study was conducted in accordance with the Declaration of Helsinki. All surgically treated colorectal carcinomas at the Department of Surgery, University Hospital Mannheim, Germany, between and were retrospectively analyzed on the basis of prospective databases.
Patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiation and subsequent TME in curative intent were eligible for the study when diagnosed ypT0—2 ypN0 in postoperative pathological staging.
Exclusion criteria were postoperative death in-hospital mortality , UICC stage IV and recurrent disease, or missing information on whether adjuvant chemotherapy was administered. Primary outcome measure was disease-free survival DFS. The presence of adenocarcinoma was confirmed by pathological examination in all cases.
Clinical staging was performed using rigid rectoscopy, endorectal ultrasound, radiographic imaging of the chest, and abdominal ultrasound. Routine performance of magnetic resonance imaging MRI of the pelvis was introduced in Radiation therapy was applied as external-beam radiation with a target dose of Resected specimens were fixated in formalin and pathological work-up was done according to published standards [ 9 ]. If no residual tumor was apparent, the initial tumor-bearing area was sliced and embedded.
According to national colorectal cancer guidelines before the year , patients were not offered postoperative chemotherapy when diagnosed ypT0—2 ypN0 in final pathological staging.
After , adjuvant chemotherapy became the treatment of choice for those patients when no contraindications were present. Baseline characteristics of all patients together were evaluated with respect to their influence on outcome.
The characteristics were then compared between patients who received adjuvant chemotherapy and those who did not. Differences of non-parametric quantitative data were analyzed using the Mann-Whitney U test. Kaplan-Meier estimates were computed for recurrence and survival and were compared between the two treatment groups using the log-rank test. All calculations were made with the SPSS version Initial screening of the database returned patients staged ypT0—2 ypN0 rectal cancer between and out of patients who had received neoadjuvant treatment.
Twenty-seven patients were excluded due to the above mentioned exclusion criteria. A total of patients met the inclusion criteria, 28 females Low rectal cancer was present in 48 patients Median dose of delivered radiation was Sphincter-preserving operation was performed in Postoperative chemotherapy was given to 54 patients Ten of the patients A total of 46 patients Patients with ypT0—1 versus ypT2 showed no difference between the treatment groups.
Neither the distribution of tumor regression grading nor the number of retrieved lymph nodes showed differences between both groups. Mean follow-up was Mean disease-free survival was Overall recurrence of the disease was seen in nine patients 8.
Metachronous metastasis occurred in eight cases 7. In the univariate analysis, age, sex, tumor height, and extirpation had no influence on disease-free survival.
Completeness of chemotherapy had no influence on the outcome. Introduction of neoadjuvant chemoradiation for rectal adenocarcinoma has in combination with TME surgery led to reduce rates of locoregional recurrence [ 1 ]. This improvement of local control, however, did not result in prolonged overall survival [ 11 ]. Our data show a significant benefit from adjuvant treatment for disease-free and overall survival but no benefits with respect to recurrence.
Adjuvant chemotherapy after neoadjuvant treatment and TME surgery is administered with the intention of reducing the incidence of distant metastasis and thereby improving survival.
Although this has been prospectively investigated in several trials, controversy remains [ 5 , 6 ]. In the just recently published study by Breugom et al. A meta-analysis identified this subgroup to profit the most from adjuvant chemotherapy [ 14 ].
Maas et al. Our analysis found the most pronounced effect of adjuvant chemotherapy in ypT2 patients. Another restriction in the analysis of Breugom et al. However, an explanatory phase III trial showed better disease-free survival after perioperative treatment with capecitabine than with 5-FU [ 15 ]. In our analysis, only two patients received 5-FU postoperatively; therefore, a comparison of the effect of the two agents cannot be undertaken.
Meta-analyses presented inherently contradictory results with respect to the positive effects of adjuvant chemotherapy on disease-free and overall survival [ 7 , 8 , 17 , 18 ]. However, it is difficult to draw conclusions from these meta-analyses as the included studies have relevant shortcomings. Low adherence to planned postoperative chemotherapy is one of the major problems of the available randomized trials, and it is a serious problem for interpretation of non-significant results as a proof for ineffectiveness of adjuvant chemotherapy [ 6 , 8 , 19 ].
Anastomotic leakage is a major problem for patients who actually would have been eligible for adjuvant therapy. This is well in accord with general clinical experience that anastomotic leakage often prevents application of chemotherapy.
In this study, no benefit from adjuvant chemotherapy could be detected. However, again, there are limitations in this study. The trial had to be closed earlier due to poor patient recruitment and survival was better than expected suggesting that the trial was probably underpowered. The question if the number of lymph nodes retrieved during surgery would influence long-term outcome respectively the application of chemotherapy and thereby the outcome has to be addressed.
Most guidelines recommend investigation of at least 12 lymph nodes for determining final pathologic tumor stage [ 21 ]. In several studies, the number of detected locoregional lymph nodes was decreased after neoadjuvant chemoradiation [ 22 , 23 ].
As performance of adjuvant treatment is stage-dependent also patients that would need therapy are then excluded. While some studies indicate an association between the number of harvested lymph nodes and oncologic outcome [ 24 ], the same authors could not reproduce these results when neoadjuvant chemoradiation was administered [ 25 ]. Recent studies on this topic continue to give conflicting results; therefore, the significance of retrieving more than 12 lymph nodes remains unclear [ 26 , 27 ].
In the present study, retrieval of less than 12 lymph nodes showed no influence of adjuvant chemotherapy with respect to disease-free survival, while more than 12 lymph nodes and adjuvant chemotherapy were correlated to a better disease-free survival. There are several limitations to our study. First, this is a retrospective study. Patients were not prospectively randomized and selection bias cannot be excluded, even though the groups were well matched in size, age, gender, and tumor-specific parameters.
As the indication for adjuvant therapy changed in in Germany, the comparison could be described as historical. Second, follow-up time was significantly longer in the NACT group. The difference is explainable by the consecutive change of guidelines. Third, a possible sign of selection bias is the higher proportion of ypT0 patients in the group without adjuvant chemotherapy.
In fact, clinicians are often averse to the application of adjuvant chemotherapy in pCR patients. Breugom et al. However, a meta-analysis usually reduces the risk of confounding. A more detailed analysis of surgical complications other than anastomotic leakage could not be performed. Even if the database was prospectively performed and updated, the number of parameters documenter increased over time, e.
However, anastomotic leakage, which was adequately documented in the database, is one of the most severe complications in rectal surgery and most often the reason why adjuvant chemotherapy is delayed or not started at all.
Moreover, leakage has been shown to influence the oncological outcome, and as both groups demonstrated a comparable leakage rate, this factor can be ruled out as a biasing factor. At last, the sample size is too small to be able to evaluate statistical significant difference in rare incidences such as local recurrence that occurred only once. Regardless of these limitations, the results support current guideline recommendations that in patients with ypT0—2 tumors adjuvant chemotherapy should continue to be administered, especially in ypT2 stages.
Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med.
Three months of post-surgery chemotherapy may be preferred to 6 months for some patients with colon cancer, a new study shows. People usually get at least several cycles of treatment. See Imaging for rectal cancer chapter. Screening Tests. Advance Directives.
Adjuvant chemo rectal cancer. When is chemotherapy used for colorectal cancer?
Neoadjuvant therapy A type of treatment given as a first step to shrink a tumour before main treatment usually surgery is given. However, there is not enough time for tumour downsizing with short-course radiation treatment followed by immediate surgery. Both short-course radiation treatment and long-course chemoradiation emerged as recommended management options following trials investigating either strategy that recruited simultaneously and were conducted in parallel over several years during the s and s.
Geographic preferences have emerged: for chemoradiation in the USA and Mediterranean Europe, and for radiation treatment in Scandinavia and Northern Europe. Recent RCTs comparing chemoradiation and radiation treatment have not shown any clear advantage for one strategy over the other.
This is crucial as upper cancers do not require treatment with neoadjuvant therapy, and overall management including adjuvant therapy should follow that of colon cancers. The somewhat common approximation of upper versus lower rectal cancer being situated above or below the peritoneal reflection is not accurate for each and every patient, and should not be used alone to distinguish between upper and lower rectal cancers for the purposes of deciding management.
T describes the size of the tumour and its spread into nearby tissue; N describes the spread to nearby lymph nodes and M describes metastasis spread of cancer to other parts of the body.
The Royal College of Pathologists of Australasia Structured Pathology A medical specialty that determines the cause and nature of diseases by examining and testing body tissues, for instance from laboratory examination of samples of body tissue. Reporting of Colorectal Referring to the large bowel, comprising the colon and rectum. Cancer Protocol  notes that in lieu of providing a formal T3a-d classification, the distance of invasion in millimetres may be provided in the pathology report as an alternative; although this is not prescriptive.
Within radiological MRI reporting, considerable variability has been documented as to whether T3 distance in millimetres is routinely formally reported. It is acknowledged that accuracy, especially when distinguishing between T2 and early T3 disease, is challenging but may not impact on management.
See Imaging for rectal cancer chapter. As millimetres can mean the difference between primary surgery or neoadjuvant therapy, careful multidisciplinary review and discussion is essential. For clinical stage I cT, N0, M0 rectal cancer, if there is a high level of confidence in the preoperative staging evaluation of node negative disease, surgery alone without neoadjuvant treatment is the preferred approach.
If subsequent histopathological evaluation unexpectedly results in upstaging pT3 or N disease or there are several high-risk features such as positive margins or lymphovascular invasion , then adjuvant therapy should be considered on an individual case-by-case basis. It noted several acceptable options for medically inoperable patients or those who refused surgery, including definitive radiation treatment or chemoradiation.
In patients who refuse or who are unable to tolerate surgery, definitive radiation treatment with or without chemotherapy may be considered as a potentially curative approach. There are no randomised controlled trial data to support this. See 'Watch and wait' approach after clinical complete response to neoadjuvant chemoradiation. Clinical Guidelines Network. Personal tools Create account Log in. Social links. Chemotherapy chemo is often used to treat colorectal cancer.
It's the use of drugs to kill cancer cells. Doctors give chemo in cycles, with each treatment followed by a rest period to give the body time to recover. Chemotherapy cycles generally last about 2 to 4 weeks.
People usually get at least several cycles of treatment. In most cases, 2 or more of these drugs are combined, which makes them work better. Sometimes, chemo drugs are given along with a targeted therapy drug.
Chemo drugs attack cells that are dividing quickly, which is why they work against cancer cells. But other cells in the body, such as those in the bone marrow where new blood cells are made , the lining of the mouth and intestines, and the hair follicles, are also dividing quickly. These cells can be affected by chemo too, which can lead to side effects.
Thirteen observational studies were included. When we performed a stratified analysis comparing the results from single institution and multicenter studies, there was no significant prognostic benefit of ACT. Publication bias was not observed. Further study of individual patient data from randomized trials is needed to clarify the role of ACT.
Following a landmark German trial 4 , recent National Comprehensive Cancer Network NCCN and European guidelines have recommended preoperative chemoradiotherapy CRT plus surgical resection as the standard treatment for locally advanced rectal cancer 5 , 6.
After completion of transabdominal surgery, adjuvant chemotherapy ACT has generally been recommended 5. However, the clinical efficacy of the postoperative strategy has been questioned in the era of neoadjuvant CRT. The rationale for ACT has been extrapolated from the results of colon cancer cases, as well as an earlier meta-analysis that reported improved prognosis with ACT mainly in the context of upfront surgery followed by postoperative treatment 7.
However, a long-term analysis of year data failed to show similar survival differences 3. Given the lack of randomized evidence, the indications for ACT in rectal cancer clinics are controversial 9 , 10 , 11 , 12 , Here, we performed a systematic review and meta-analysis to evaluate the impact of ACT on the survival of rectal cancer patients who achieved ypT0N0 status.
The OS outcomes of two groups, with and without the postoperative use of chemotherapy, were compared. Given the paucity of randomized trials appertaining to pCR status, the present pooled analysis provides clinical insights into the role of ACT in patients who achieved remarkable tumor eradication following CRT. A systematic search of electronic databases was conducted to identify studies that analyzed OS in locally advanced rectal cancer patients treated with ACT. Hand searches were also performed to identify other potentially eligible studies, but no additional studies were added.
No restriction on study design was considered. Studies comparing OS between postoperative ACT intervention group and observation alone comparator group in pCR patients were selected. The name of the institution or database included in the final set of eligible studies was reviewed.
When multiple studies were based on the same data, the one with a longest-duration study period and the largest number of patients was selected.
The study selection process was verified independently by a third investigator YK. When discrepancies occurred, the authors discussed to reach a consensus. Some authors of potentially eligible studies were contacted via e-mail to request required data, and one study replied Since all of the included studies were non-randomized observational studies, the Risk of Bias Assessment tool for Nonrandomized Studies RoBANS was used to assess the following six domains: the selection of participants; confounding variables; intervention measurement; blinding of the outcome assessment; incomplete outcome data; and selective outcome reporting Regarding potential discrepancies between the two authors, a consensus was obtained after further review and discussion.
In addition, a third investigator YK verified the results. The primary outcome of interest was OS. HRs were calculated using a random-effects model with the inverse variance method.
Cochrane Q tests and the I 2 index were used to evaluate heterogeneity. An additional stratified analysis comparing results from single institution and multicenter studies was performed. RevMan software ver. A flowchart of the study selection process is shown in Fig. Among the 3, studies identified initially, the titles and abstracts of 1, studies were screened. Irrelevant articles, in terms of their structure or content, were excluded, and 95 manuscripts were reviewed. Further screening then identified 16 studies with sufficient OS data on a potentially eligible pCR population.
Of these, three studies that had duplicate data i. Since four different National Cancer Database NCDB -based studies overlapped in terms of study period, we included all studies and separately conducted pooled analyses on each of them.
Although the details of the chemotherapy regimens used were not included in the NCDB-based studies, most other studies reported fluoropyrimidine-based regimens.
Most patients underwent total mesorectal excision. Although a trend toward better OS with ACT was observed, statistical significance was not consistent in the different sets of analyses HR 0.
Overall survival comparing adjuvant chemotherapy and observation alone in patients with a pathologic complete response. To compare the results from single institution and multicenter studies, a stratified analysis was performed. Using the pooled analysis set III, which included the study of Xu et al. Other subgroup results based on pooled analysis sets I, II, and IV also showed comparable results data not shown.
Representative results of stratified analysis comparing results from single institution and multicenter studies using the pooled analysis set III, including the NCDB-based study of Xu et al. No significant asymmetry was observed between the subgroup results of the multicenter and single-institution studies data not shown. The present meta-analysis reviewed multicenter analyses and single institutional series to evaluate whether rectal cancer patients who achieved a pCR after preoperative CRT could benefit from ACT.
Despite a trend toward better survival with ACT, statistical significance was not consistent in the different sets of overall pooled analyses. The stratified analysis comparing the results from single institution and multicenter studies failed to show a significant prognostic benefit.
This study provides an updated perspective on the optimal postoperative strategy in cases with a marked treatment response after neoadjuvant CRT.
Based on ambiguous guidelines, patients with more advanced disease and a poorer response to CRT are potential candidates for ACT. Fietkau et al. Based on the responsiveness to preoperative cytotoxic treatment, eradicating micrometastatic disease and further beneficial effects arising from ACT can be expected.
In this clinical setting, a meta-analytic approach with a larger number of patients can help detect a small or absent treatment effect. The results from this meta-analysis suggest there is no clear evidence to support survival benefits of ACT for pCR patients.
The trend toward a favorable prognosis with ACT was mainly based on NCDB studies, and other exploratory analyses excluding the population-based data failed to obtain any reproducible results. Specifically, the propensity score matching method used by Polanco et al. Chang also noted that the survival benefit of a certain treatment can be overestimated in the statistical setting of NCDB data Therefore, we believe that the trend toward better survival in the ACT group, with the underlying predominance of one NCDB-based study, should be interpreted with caution.
The study of Maas et al. To date, there is little randomized evidence to demonstrate the survival benefit of ACT in this patient population. To assess the clinical value of ACT, potential adverse effects also need to be considered. Among the 13 studies, only two reported ACT-related complication events 20 , In the study of Tay et al.
Time to closure of ileostomy was longer in patients with ACT, suggesting inferior quality of life and related medical morbidities Regarding the inconsistent survival outcomes in the present pooled analyses including four different NCDB-based studies, it is questionable whether the therapeutic benefit of ACT is sufficiently expected to risk treatment-related toxicities and quality-of-life problems in patients with a marked response to CRT.
This study had several limitations. First, all of the included studies were observational and inevitably suffer from confounders, such as selection bias and heterogeneity in sample characteristics and treatments Of the included studies, the method of Tierney et al. The differences between the data indirectly extracted from survival curves and the original data can induce additional bias. Due to insufficient data, the effect of ACT on DFS or treatment-related toxicities was not evaluated in the present meta-analysis.
Most of the studies included herein did not account for the presence of underlying comorbid illnesses or postoperative complications. Nevertheless, this large-scale meta-analysis provides clinically useful insights into the prognostic role of ACT in this small-sized population who achieved a pCR.
This meta-analysis could not warrant the survival benefits of ACT in patients who achieved a pCR, suggesting that routine use of ACT should not be recommended in this subset of patients with rectal cancer. Further pooled analysis of individual patient data from existing randomized trials is needed to establish guidelines for ACT in conjunction with contemporary neoadjuvant treatments.
Siegel, R. Cancer statistics, CA Cancer J Clin 68 , 7—30 Sainato, A. Radiother Oncol , — Bosset, J. Fluorouracil-based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC randomised study.
Lancet Oncol 15 , — Sauer, R. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med , — National Comprehensive Cancer Network. Rectal Cancer - Version 2. Glynne-Jones, R. Ann Oncol Gray, R. Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study.