An estimated 39,910 patients in the United States will be diagnosed with rectal cancer in 2017. Surgery is the primary component of curative therapy, either alone for early-stage disease (T1N0 or T2N0) or as part of combined-modality therapy for locally advanced disease (T3/T4, or node-positive). The standard of care is total mesorectal excision (TME) with sharp dissection of the mesorectum en bloc, which completely removes mesorectal nodal tissue; this procedure reduces positive radial margins and improves local control compared with blunt dissection techniques. TME is performed with either low anterior resection or abdominoperineal resection (APR); in the latter procedure, the anal sphincter is removed, leaving patients with a permanent colostomy. In the current era of TME, the German Rectal Cancer Study Group demonstrated the superiority of preoperative over postoperative chemoradiotherapy (CRT).[4,5] Based on the outcomes of their studies,[4,5] neoadjuvant CRT—which consists of long-course radiation therapy (RT) with concurrent fluorouracil (5-FU)–based chemotherapy—followed by surgical resection then adjuvant chemotherapy was established as the standard of care in advanced rectal cancer. Neoadjuvant short-course RT using 25 Gy in 5 fractions with chemotherapy is an effective alternative to standard neoadjuvant CRT.[6,7]
It is important to bear in mind, however, that radical surgery combined with pelvic RT is associated with serious early and late effects. Long-term toxicities of surgery plus RT for rectal cancer can include chronic diarrhea, bowel obstruction, and permanent stoma, as well as significant rates of stoma reconstruction (for patients who undergo APR), urinary dysfunction, anastomotic strictures, and sexual dysfunction.[4,9] Further, the mortality risk of surgery should be considered; for example, the rate of mortality was 1.3% in the postoperative treatment arm of the German Rectal Cancer Study Group trial. Therefore, there is increasing interest in treatment de-escalation for lower-risk patients, with the hope of maintaining disease control in a subset of patients while sparing them from the toxicities and quality-of-life (QOL) effects associated with combined-modality therapy.
One such approach is nonoperative management, in which patients who have a clinical complete response (cCR) to CRT undergo close clinical surveillance, with surgery reserved as salvage treatment only. Nonoperative management may represent an appropriate option for select patients who have multiple comorbidities, are unable to tolerate a radical surgery, or want to avoid the potential adverse effects of TME. The rate of pathologic complete response (pCR) in patients who received neoadjuvant CRT was 8% in the German Rectal Cancer Study Group trial, but pCR rates as high as 20% have been reported in other trials of neoadjuvant CRT.[10-13] Investigators have also demonstrated that intensive chemotherapy applied during the interval between the delivery of neoadjuvant CRT and surgical treatment can further improve the pCR. A recent phase II trial demonstrated the feasibility of delivering an increasing number of chemotherapy cycles of modified FOLFOX6 (5-FU, leucovorin, oxaliplatin; mFOLFOX6) after CRT and before TME; the highest pCR rate, 38%, was reported in patients who received the greatest number of cycles of mFOLFOX6. Studies have shown that patients with rectal cancer who achieve a pCR have better long-term outcomes—including local control, distant control, disease-free survival (DFS), and overall survival (OS)—than patients who do not.[15-17] Patients who achieve a pCR after receiving neoadjuvant CRT would derive less benefit from radical surgery and may be the most appropriate candidates for nonoperative management. Table 1 highlights patient-related factors to consider when selecting patients for nonoperative management.
An inherent conundrum exists in that, by definition, nonoperative management does not involve pathologic confirmation of tumor response, so clinicians must rely on using cCR as a surrogate for pCR. Typically, clinical evaluation of tumor response is not based on any single test but rather on the combination of physical examination, endoscopic procedures, and imaging. Advances in diagnostic technologies have allowed physicians to improve prognostication for tumor response and pCR, and thereby have further optimized selection of appropriate patients for nonoperative management.
In this article, we provide a summary of nonoperative management of locally advanced rectal cancer in the modern era. Our focus is on technical details of tumor response and patient assessment after CRT, as well as a review of existing clinical data.
Tumor Response and Patient Assessment After Neoadjuvant CRT
The success of nonoperative management for rectal cancer is predicated on the accurate assessment of tumor eradication after CRT, without pathologic verification. Therefore, clinical evidence of complete response must be utilized as a marker to predict the likelihood of pCR. However, controversy exists over the appropriate duration of time between completion of CRT and assessment of clinical response, as well as the question of which nonsurgical diagnostic modalities most accurately detect the presence, or lack of, residual tumor.
The current standard of care for patients with rectal cancer typically involves tumor assessment 6 to 8 weeks after a patient has completed CRT.[18,19] Lack of consensus on the ideal timing of response assessment arises from data suggesting that longer time intervals between the end of treatment and the initial posttreatment patient assessment are perhaps associated with improved pCR rates.[20,21] Lyon R90-01 was a randomized trial comparing surgery performed 2 weeks after completion of RT vs surgery performed 6 to 8 weeks post treatment. The investigators found significantly improved rates of pathologic downstaging without any differences in treatment-related toxicities, including anastomotic complications, reoperation rates, or postoperative mortality, in the patients who waited a longer period before surgery. Importantly, the combined pCR and near-pCR rate was 26% in the long-interval group and 10% in the short-interval group. These data provide strong evidence that a posttreatment time interval of at least 6 weeks must be allowed prior to the patient follow-up assessment, in order to capture delayed tumoricidal effects of RT.
More recent studies have investigated the hypothesis that even longer time intervals between treatment and clinical assessment of patients with rectal cancer may result in greater improvements in response rates. Tulchinsky et al found that an interval greater than 7 weeks between completion of CRT and surgery was associated with improved rates of pCR and near-pCR (35% vs 17% with intervals ≤ 7 weeks), while Kalady et al demonstrated similar findings with a cutoff of 8 weeks. In a recent meta-analysis of 13 studies investigating neoadjuvant CRT followed by surgical resection for rectal cancer, time intervals greater than 6 to 8 weeks between combined-modality treatment and surgery were associated with significantly improved pCR rates (19.5% vs 13.7% with intervals of ≤ 6 weeks). Longer time intervals did not appear to negatively impact survival or surgical complication rates.
Sloothaak et al, in analyzing treatment information and clinical outcomes data on 1,593 rectal cancer patients in a large Dutch population database, found that an interval of 10 to 11 weeks between completion of RT and the date of surgery resulted in the highest pCR rate—18%, compared with pCR rates of 10% to 13% for patients undergoing surgery less than 10 weeks after RT. However, they found that the pCR rate for patients whose surgery was performed more than 11 weeks after RT was also lower, at 11.8%. GRECCAR-6 was a prospective randomized trial evaluating intervals of 7 weeks vs 11 weeks between the end of RT and the performance of surgery in 265 patients; the investigators found no significant difference in pCR rates between the two groups (15% for the 7-week group vs 17.4% for the 11-week group; P = .6). Based on the available data, the optimal timing of assessment of tumor response is likely approximately 7 to 10 weeks after completion of CRT.
There is also uncertainty regarding the appropriate diagnostic modalities for assessment of tumor response post treatment. Clinical evaluation of the patient post treatment may include digital rectal examination (DRE), endoscopy, and biomarker measurements. Preferred imaging modalities include CT, MRI, and positron emission tomography (PET). In general, DRE is the most important tool for assessment of primary tumor response, since this procedure may reveal findings that are not readily apparent on radiographic imaging. While DRE has fairly poor sensitivity for predicting complete response, its specificity is high. For example, one prospective study found that only 21% of patients with pCR had a negative preoperative DRE. Conversely, there were no instances in which DRE findings were negative and residual tumor was then discovered on pathology. Endoscopy with biopsy has also been studied, although the positive and negative predictive values of this approach may also be suboptimal, due to sampling error. In addition, the presence of residual mucosal abnormalities may not correlate well with pCR: in one series, investigators found that 19 of 31 pathologic specimens (61%) classified as ypT0 after CRT contained visible mucosal lesions, including ulceration or a polypoid mass, that precluded defining the tumor response as cCR. Another limitation of DRE and endoscopy relates to the evaluation of nodal response. The accuracy of endoscopic ultrasound in restaging nodal involvement after CRT has been reported to range between 39% and 83%.
Radiographic imaging serves as a potentially noninvasive means of evaluating both the primary site and any nodal disease. PET/CT imaging has been of particular interest, given its theoretical benefit of detecting metabolically active disease and distinguishing it from posttreatment tumor changes. Guillem et al conducted a prospective study investigating its utility in this setting but concluded that fluorodeoxyglucose-PET or CT alone did not provide adequate predictive value for distinguishing pCR from incomplete response. Among patients with a pCR, the investigators found that PET accurately detected complete response in 54% of patients and CT did so in 19%. Among 95 patients with less than a pCR, PET and CT accurately identified 66% and 95%, respectively, as incomplete responders. CT has been reported to be 62% and 82% accurate when using size cutoffs of 5 mm and 10 mm, respectively, for nodal involvement.[31,32] Although the majority of studies of PET/CT restaging after neoadjuvant CRT have focused on the primary tumor and not specifically on nodal involvement, Maffione et al reported the overall accuracy of PET/CT, with sensitivity and specificity rates of 73% and 77%, respectively. A study investigating the use of positron emission tomography (PET) for evaluation of response to neoadjuvant CRT in rectal cancer showed that after 6 weeks post CRT completion, a subset of patients demonstrated an increase in tumor metabolism, suggestive of tumor repopulation; they concluded that these “bad” responders—whom they defined as patients with an early increase in maximum standardized uptake volume at 6-week PET/CT—might benefit from individually tailored selection of CRT/surgery intervals.
MRI, including the addition of diffusion-weighted imaging (DWI), holds significant promise for accurately detecting pCR. In one prospective study, Lambregts et al found that the use of DWI in addition to standard MRI sequences improved the sensitivity of pCR detection from 0% to 40% to between 52% and 64%, while specificity remained high at 89% to 98%. These results were validated in a larger multi-institutional study, which reported sensitivity and specificity rates of 70% and 98%, respectively, for DWI. The accuracy of MRI with standard imaging sequences has been reported to be 65% for nodal staging after neoadjuvant CRT. van Heeswijk et al have shown that restaging MRI with DWI sequences can reliably predict for yN0 status after CRT, with 100% sensitivity, 14% specificity, 24% positive predictive value, and 100% negative predictive value, when differentiating between yN0 and yN-positive patients. Overall, imaging studies are useful in the restaging of primary tumor and nodal lymph nodes after neoadjuvant CRT; recent and emerging evidence support the value of PET/CT and MRI in this setting, especially with the addition of DWI sequences.
The utility of tumor markers, primarily carcinoembryonic antigen (CEA), has previously been studied in rectal cancer. Perez et al investigated the prognostic value of serum CEA levels prior to and after neoadjuvant CRT and observed a significant association between post-CRT CEA levels < 5 ng/dL and increased rates of both cCR and pCR. However, they did not find any association between pre- and post-CRT CEA level differences and rates of either cCR or pCR. Low CEA levels after CRT may indicate a higher likelihood of pCR, but this test result should be interpreted in the context of clinical and imaging data to guide management decisions. Results of the aforementioned studies suggest that multiple modalities should be used for patient assessment, in order to most accurately identify patients with pCR who may not require surgical resection after CRT.
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