Background
Although standard treatment options for rectal cancer include surgery, chemotherapy, and radiation therapy,1,2 treatment of deficient DNA mismatch repair (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC) presents a totally different landscape.3–6 Evidence has emerged that immune checkpoint inhibitors (ICIs) as neoadjuvant therapy or curative-intent therapy in the management of dMMR/MSI-H CRC are very promising. It has been consistently reported that PD-1 blockades are highly effective in dMMR/MSI-H CRCs in the neoadjuvant setting, with a major pathologic response rate of 94% to 100% and pathologic complete response (pCR) rate of 60% to 88%.7,8
The remarkable pCR rate led to testing the hypothesis of using nonoperative management in patients with dMMR/MSI-H low-lying rectal cancer who experience complete clinical response (cCR) following neoadjuvant ICI therapy. In 2019, Zhang et al9 reported on a patient with dMMR locally advanced rectal cancer (LARC) who experienced cCR after neoadjuvant treatment with PD-1 blockades and was successfully managed using a watch-and-wait (WW) approach, and similar cases were reported by Demisse et al10 and our team.11,12
The milestone study was reported by Cercek et al,13 demonstrating that all 12 patients with dMMR/MSI-H LARC experienced cCR after 6 months of anti–PD-1 therapy. With a median follow-up time (from study enrollment) of 12 months, no progression or recurrence was observed, suggesting the potential of PD-1 antibody as a curative-intent therapy. Subsequently, a larger cohort (n=19) from our team reinforced the exceptional short-term outcome of the WW strategy in patients with dMMR/MSI-H rectal cancer who experienced cCR after neoadjuvant anti–PD-1 treatment—with a median follow-up time of 17.1 months, no recurrence was observed.11 In addition, Chen et al14 also reported a similar result in a cohort of 9 patients who achieved cCR and were then managed with the WW strategy. Collectively, this evidence suggests the potential of anti–PD-1 treatment as a curative-intent therapy and a treatment alternative for organ and function preservation in patients with dMMR/MSI-H LARC. However, the long-term outcomes of the WW approach in this population remain largely unknown, primarily due to the relatively short follow-up time in previous studies.
In this study, we aimed to investigate the long-term outcomes of patients with dMMR/MSI-H rectal cancer who experienced cCR following anti–PD-1 therapy and received nonoperative management.
Methods
Study Design and Patient Selection
This was a multicenter retrospective cohort study. Patients with dMMR/MSI-H nonmetastatic rectal cancer who received at least 1 dose of PD-1 blockade at 1 of 4 medical centers in China between March 2018 and May 2022 were screened. Those who met the following criteria were included: (1) pathologically confirmed rectal adenocarcinoma, (2) dMMR and/or MSI-H status, (3) stage II/III or stage I with tumor located in the distal rectum, (4) received at least 1 cycle of PD-1 inhibitors, (5) experienced cCR and decided to be managed with a nonoperative approach, and (6) followed up for at least 1 year after cCR. Patients treated with chemotherapy or chemoradiotherapy after experiencing cCR were excluded. Informed consent from patients was waived due to the retrospective nature of this study, and the study protocol was approved by the ethics committee of each study center.
Study Procedures
Data were collected from each center using a standardized electronic form, and the data mainly included information on demographics, clinical and genomic characteristics, treatments, and follow-ups.
Tumor response was evaluated according to RECIST (version 1.1)15 after every 2 to 3 cycles of anti–PD-1 immunotherapy. cCR was defined as the absence of residual tumor on digital rectal examination, colonoscopy, and pelvic MRI, accompanied by a normal serum CEA level and negative findings on chest and abdominal CT scans. PET/CT was not mandatory. Adverse events were evaluated according to CTCAE, version 5.0. After completing treatment, patients were followed up every 3 months. The last day of follow-up was May 10, 2023.
Statistical Analysis
Continuous variables were described as medians with ranges, and categorical variables were shown as frequency. Survival analysis was calculated using the Kaplan-Meier method.
The starting timepoint in this study was the day cCR was achieved. The primary endpoint was disease-free survival, which was defined as the absence of any recurrence, including at the local site and distant recurrence, and death as a result of any cause. Overall survival was defined as the absence of death from any cause. Analyses were performed using SPSS Statistics, version 22.0 (IBM Corp.).
Results
Baseline Characteristics
From March 2018 to May 2022, a total of 61 patients with dMMR/MSI-H nonmetastatic rectal cancer received at least 2 doses of PD-1 blockades at 1 of 4 medical centers. A cCR was experienced by 44 (72.1%) patients. Among them, 41 patients decided to pursue organ preservation and were consequently managed with a WW strategy. Among these patients, 24 were followed up ≥1 year after experiencing cCR and were finally included in the analysis (Figure 1). Median age at diagnosis was 51.0 years (range, 19.0–77.0 years), and 58.3% of the patients were male. Baseline characteristics are provided in Table 1, and details regarding individual patients are provided in Table 2.
Study profile.
Abbreviations: cCR, clinical complete response; dMMR, deficient DNA mismatch repair; MSI-H, microsatellite instability-high.
Citation: Journal of the National Comprehensive Cancer Network 22, 3; 10.6004/jnccn.2023.7096
Patient Baseline Characteristics (N=24)
Details of Patients Who Received PD-1 Blockade (N=24)
Treatment and Outcome
All patients received at least 2 cycles of PD-1 inhibitors, including pembrolizumab, nivolumab, sintilimab, camrelizumab, tislelizumab, and toripalimab, and the median course of treatment was 8.5 (range, 2.0–36.0) for the entire cohort. Most patients (83.3%) received at least 8 cycles of treatment. Two patients (8.3%) received PD-1 blockades after failure of neoadjuvant treatment with chemotherapy or chemoradiotherapy. Fifteen patients (62.5%) received PD-1 blockades as monotherapy, and the remaining patients received combined therapy (PD-1 blockade in combination with CTLA-4 inhibitor, chemotherapy, or targeted therapy; Table 2).
The median treatment course was 6.0 (range, 1.0–12.0), and median time to reach cCR was 5.0 months (range, 0.7–9.5 months). The majority of patients (21/24; 87.5%) experienced cCR after at most 8 courses of anti–PD-1 blockades. Notably, 9 (37.5%) patients discontinued their treatments after achieving cCR, with a median treatment course of 8.0 (range, 2.0–10.0). For those who continued to receive PD-1 blockades after cCR, the median overall treatment course was 17.0 (range, 3.0–36.0), and median treatment duration was 13.9 months (range 2.1–26.6 months). All patients avoided surgery for the reason of organ preservation and were subsequently managed with a WW strategy after treatment completion.
The occurrence of any grade of treatment-related toxicities was 62.5% (Table 3), which was acceptable. Two patients experienced grade ≥3 adverse events and therefore had treatment interruptions. It is worth noting that patient #3 developed refractory dermatitis 30 months after completion of the treatment, which was finally diagnosed as immunotherapy-related dermatitis. This patient experienced symptom relief after treatment with halometasone and localized symptomatic treatment.
Treatment-Related Adverse Events (N=24)
Follow-Up
The median follow-up after the first dose of PD-1 blockade was 34.5 months (range, 19.1–51.3 months), and the median follow-up after achievement of cCR was 29.1 months (range, 12.6–48.5 months). All patients remained alive at the cutoff of follow-up (Figure 2). In patient #22, suspected para-aortic and common iliac artery lymph node metastases were detected by CT scan 14 months after cCR (Figure 3), but the CT-guided biopsy found inflammation rather than viable tumor cells. Those lymph nodes decreased in size on PET/CT scan 8 months later, which was further considered no evidence of disease, although their standardized uptake values (SUVs) were slightly elevated. Thus, no local regrowth or distant metastasis was observed during the follow-up, and therefore the 3-year disease-free and overall survivals were both 100%.
Swimmer plot of the patients receiving PD-1 blockade in this cohort (N=24).
Abbreviation: CR, complete response.
Citation: Journal of the National Comprehensive Cancer Network 22, 3; 10.6004/jnccn.2023.7096
Radiologic and pathologic images of an abnormal node in patient #22. Axial CT images showing (A) area of the left common iliac artery at baseline, (B) timepoint at which cCR was achieved, and (C) 14 months and (E) 22 months after cCR was achieved. (D) Fine-needle aspiration image of the node found no tumor cells but did find evidence of infiltration of lymphocytes and inflammation (hematoxylin-eosin; original magnification ×10). (E) Axial CT image and (F) 18F-FDG PET/CT image showing the decrease in nodal size and the FDG uptake at the left common iliac artery. Red arrows indicate the enlarged node.
Abbreviation: cCR, clinical complete response.
Citation: Journal of the National Comprehensive Cancer Network 22, 3; 10.6004/jnccn.2023.7096
Discussion
In the current study, we presented an exceptional long-term outcome of the WW approach for patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who experienced cCR after anti–PD-1 treatment. Our results reinforced that a WW approach could be a safe treatment alternative for patients with dMMR/MSI-H rectal cancer.
Previous studies3–6,16 have shown that PD-1 blockades were highly effective for dMMR/MSI-H metastatic CRC (mCRC), and the benefit was durable. In CheckMate 142, ongoing responses were observed in 48% of responders with a median follow-up of 50.9 months, with responses lasting ≥36 months in 52% of these patients.5 In the final analysis of KEYNOTE-177, 76% of the patients who received first-line anti–PD-1 treatment had ongoing responses after 36 months.4 These long-lasting benefits in mCRC strongly suggest the curative potential of ICI treatment, motivating further investigation in the neoadjuvant setting. Cercek et al13 reported that 12 patients had cCR after completing 9 cycles of single-agent PD-1 blockades, after which a WW approach was used. No progression or recurrence was observed in a median follow-up time of 12 months from enrollment. Similarly, in a multicenter cohort, we observed no local or distant recurrence in 19 patients with dMMR/MSI-H LARC who achieved cCR after anti–PD-1 treatment, with a median follow-up of 17.1 months from the date of cCR.11 Similar results were later observed in several smaller cohorts.14,17,18 These promising short-term outcomes provided preliminary evidence of the role of neoadjuvant ICI as a curative therapy. Herein, we expanded upon these findings, demonstrating no progression or recurrence during a median follow-up of 29.1 months (range, 12.6–48.5 months) from the date of cCR in a multicenter cohort of 24 patients who achieved cCR after ICI treatment. This provides robust evidence for nonoperative management in patients with dMMR/MSI-H rectal cancer who achieve cCR following anti–PD-1 therapy.
The treatment of patients with dMMR/MSI-H rectal cancer who achieve cCR after neoadjuvant anti–PD-1 treatment presents another intriguing question. Patients with dMMR/MSI-H mCRC were recommended to receive PD-1 blockade for up to 2 years according to KEYNOTE-164 and KEYNOTE-177.4,16 In the scenario of neoadjuvant treatment in the study by Cercek et al,13 all patients discontinued their treatment after 9 cycles of PD-1 inhibitors and were then managed with a WW strategy. In our study, 15 (62.5%) patients continued to receive PD-1 inhibitors after experiencing cCR, whereas 9 patients stopped the treatment. There are several possible explanations for the discrepancy in duration of treatment after achieving cCR. First, there is still no consensus on real-world practices regarding the duration of treatment. Second, it remains difficult to precisely evaluate a pCR. A cCR usually falls behind a pCR. Furthermore, it might take much longer for a bulky tumor to achieve cCR compared with a small tumor. In the current study, patient #22 presented initially with a stage T4b tumor and experienced cCR after 12 cycles of treatment. Subsequently, the patient received an additional 5 cycles of treatment. Third, the regimens might have had an impact. In the NICHE study, the combination of CTLA-4 and PD-1 inhibitors demonstrated the potential to accelerate the responses,7 and for patients who receive dual immunotherapy, fewer courses of immunotherapy after cCR may be needed than for patients who receive monotherapy. To date, the optimal duration of treatment still needs to be determined. Further research is needed to explore the necessity of continuous use of treatment beyond achieving cCR and a shorter duration of treatment even before achieving cCR.
The optimal surveillance strategy after cCR remains largely unknown. Although a proportion of patients experience cCR after chemoradiotherapy and can then be managed with a WW strategy,19–21 local regrowth is a concern, with a 15% to 34% risk reported for these patients.21–24 Most of the local regrowth occurred within 1 year from attaining cCR,21,25 and Fernandez et al26 reported that the probability of remaining free from local regrowth within 2 years after achieving cCR was 88.1% for patients who sustained cCR for 1 year. These results indicate that the intensity of surveillance for these patients could be reduced if they achieve and maintain cCR for 3 years. For patients managed with a WW approach after ICI treatment, the current surveillance strategy follows the strategy implemented after chemoradiotherapy. The response patterns for these 2 treatments are different, but whether they have similar local recurrence patterns remains unclear. In mCRC, the final results of KEYNOTE-177 indicated that most of the disease progression or death occurred within the first 2 years after randomization, but evidence in the neoadjuvant setting was limited. In the current study, no local regrowth or distant recurrence was observed within a median follow-up of 29.1 months after achieving cCR, and preliminarily demonstrated that the risk of local recurrence was low in the first 2 years and, consequently, the intensive surveillance might not be necessary after 2 years of achieving cCR. Further evidence is still required to establish appropriate follow-up strategies.
It should be noted that pseudoprogression might occur during surveillance, which is quite different from the observation in patients achieving cCR following chemoradiotherapy. In the current study, patient #22 had suspected para-aortic and common iliac artery lymph node metastases detected by CT scan and an elevated serum CEA level (11.6 ng/mL) during surveillance 14 months after achieving cCR and 11 months after treatment was discontinued. However, the CT-guided biopsy found no viable tumor cells, but rather inflammation with immune cell infiltration. Furthermore, the retroperitoneal lymph nodes were slightly smaller after 8 months of observation and the serum CEA level decreased (8.87 ng/mL), which further excluded the possibility of recurrence. Enlarged lymph nodes after immunotherapy have been reported to be granulomatous/sarcoid-like lesions (GSLs)27–30 or nodal immune flare (NIF),31 which were also considered to be immune-related adverse events. These granulomas are associated with the aggregation of immune cells such as giant cells and macrophages due to the activation of effector T cells and the increase of immune-active cytokines after administration of ICIs. According to Cascone et al,31 the incidence of GSLs or NIF is not rare after neoadjuvant ICI treatment in non–small cell lung cancer, occurring in 16% (7/44) of their cohort, which was remarkably higher than in patients with melanoma.32 Reports of GSLs or NIF in the ICI treatment of CRC were scarce. Unlike most lesions located in the thoracic lymph nodes in previous reports,28,31,33 the enlarged lymph nodes of patient #22 were found in para-aortic and common iliac artery lymph nodes, indicating the different pattern of GSLs or NIF in patients with CRC who receive ICIs. Given that GSLs or NIF also have higher SUVs on PET/CT scans,28,31 invasive biopsy is recommended to distinguish real tumor recurrence from GSLs or NIF. For patient #22, although core needle biopsy did not confirm retroperitoneal lymph node metastasis, the CEA level (8.87 ng/mL) did not return to normal and the SUV was still slightly elevated on PET/CT scan, suggesting that metastasis could be completely ruled out and that long-term close follow-up is essential.
The occurrence of GSLs or NIF suggests that radiologic pseudoprogression may also occur during posttreatment surveillance and more biologic markers should be explored to help optimize monitoring. Circulating tumor DNA (ctDNA) has shown promising potential as a predictor of recurrence in several tumors, including CRC.34–37 The dynamic changes in ctDNA could reflect residual tumor burden,38 suggesting that it may be a valuable approach for detecting molecular residual disease to support treatment decisions and early detection of relapse.39–41 Nevertheless, the efficacy of ctDNA requires further validation by clinical trials.
There are several limitations to our study. First, this study is a retrospective cohort study, which is subject to inherent biases, such as heterogeneity of regimens, selection bias, and confounding bias. Second, the sample size of the study cohort was relatively small, which may limit the generalizability of the findings. Nevertheless, to our knowledge, this is the largest cohort with the longest follow-up in patients with dMMR/MSI-H locally advanced or low-lying rectal cancer treated with a WW approach after experiencing cCR from neoadjuvant anti–PD-1 treatment.
Conclusions
Our results indicated that patients with dMMR/MSI-H locally advanced or low-lying rectal cancer who achieved cCR after anti–PD-1–based therapy had promising long-term outcomes. A prospective clinical trial with a larger sample size is required to further validate our findings.
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