| Abstract|| |
Introduction: Neoadjuvant chemoradiation (CRT) is standard of care for locally advanced rectal cancer. However short course radiotherapy (SCRT) was developed for the benefit of a shorter treatment duration and early surgical intervention which also helped in reducing the case burden to the hospital. SCRT is routinely practised in European countries, Indian experience with the SCRT is limited and hence a pilot study was conducted to compare the morphological difference and pathological response between SCRT and CRT. Objectives: A) Evaluate the morphological changes and pathological response between SCRT and CRT. B) Compare the pathologic response with outcome between SCRT and CRT. Materials and Methods: All rectal cancer patients in clinical stage II and III diagnosed during 2016 to 2020, who underwent SCRT or CRT were selected. Altered histopathologic findings due to therapy such as tumor cell morphology, necrosis and stromal response along with pathological response between the study groups were compared along with the outcome. Results: Ten (12.6%) patients were subjected to SCRT and 69 (87.4%) patients underwent CRT. Morphological changes such as necrosis was noted in nine (90%) and eight (11.5%) cases in SCRT and CRT group respectively. Pathologic complete response (pCR) was noted in 12 (17.5%) cases of CRT only. Near complete response was seen in one (10%) and 14 (20.5%) cases of SCRT and CRT respectively. Despite lower rates of pCR in SCRT, no difference in survival or outcome was noted between the two study groups. Conclusion: pCR as expected is less in patients who received SCRT, despite this the outcome during follow up was similar in both the groups. Indian data is very limited and large multi-centre studies should be carried as SCRT offers an advantage of early definitive surgical intervention in addition to shorter duration of hospitalisation when compared with CRT.
Keywords: Neoadjuvant chemoradiation, pathologic response, rectal cancer, short course radiotherapy
|How to cite this URL:|
Nagarjun BR, Shah A, Gami A, Gandhi J, Parikh A, Modi V. Comparison of pathological response of standard chemoradiotherapy versus short course radiotherapy in rectal carcinoma: A pilot study. Indian J Pathol Microbiol [Epub ahead of print] [cited 2023 Sep 24]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=358855
| Introduction|| |
The standard of care followed in locally advanced rectal cancer (LARC) is neoadjuvant chemoradiation (CRT) followed by surgery after 8-12 weeks interval. Purpose of this combined modality is to downsize the tumor prior to surgery. Following surgery, definitive response to CRT is ultimately determined by histopathologic examination (HPE) and achieving pathologic complete response (pCR) is the ultimate goal of tumor downsizing as these patients have low local recurrence rates and better disease-free survival rates compared to patients without CRT.,,
Short course chemoradiation (SCRT) which is known to be less toxic compared to CRT was primarily developed in Northern European countries and is routinely followed for the benefit of patients who can't tolerate the CRT. This regimen is less demanding for the patient as duration of radiotherapy is for shorter period with lower total dose radiation (25 Gy instead of conventional dose of 45-50 Gy) but by delivering high dose per fraction and providing equivalent results as CRT.,
Although both the latest National Comprehensive Cancer Network (NCCN) guidelines version 6.2020. and the European Society for Medical Oncology (ESMO) guidelines recommend preoperative SCRT as one of the standard treatments for LARC, most of the countries including India is not routinely following SCRT due to historical evidence of CRT and its limited experience with SCRT. Histopathologic changes following SCRT and the extent of pathologic response has not been studied. Also the morphologic alterations in rectal carcinomas following CRT and SCRT and their potential impact on outcome have not been well characterized. A pilot study was conducted at regional cancer centre in Western India with the aim of studying the histomorphological response in SCRT and CRT and also compare the pathologic response with outcome between SCRT and CRT groups.
| Materials and Methods|| |
The retrospective cross-sectional study comprised a total 79 patients, 10 patients were in SCRT and 69 patients in CRT. All patients diagnosed with LARC from January 2015 to February 2020 were enrolled. Biopsy proven carcinoma rectum patients, were staged radiologically by assessing extent of the disease by ultrasound, MRI or CT and chest radiograph. Patients with clinical and radiologic evidence of LARC (T3/4 or N1/2) and were considered in respective study groups after multidisciplinary meeting.
Patients with localized disease (T1/2 and N0) were treated with upfront surgery, those with extrapelvic disease (M1) at diagnosis and those unfit for chemoradiation were excluded.
Chemotherapy Details: Patients in CRT cohort received concurrent chemotherapy with capecitabine or 5-fluorouracil on 1st day of every week for 5 weeks. In SCRT, same adjuvant chemotherapy was planned post-surgery for 6-8 cycles.
Radiation Details: Concurrent radiation in CRT cohort was 45-50 Gy in 25 fractions, each fraction of 1.8-2 Gy over a 5-week period. SCRT consisted of 25 Gy in 5 fractions of 5 Gy in 1 week.
Surgical Details: Patients underwent abdomino-perineal resection (APR) or a low anterior resection (LAR), based on tumor location. The interval from the completion of SCRT and CRT to surgery was 1-2 weeks and 4-6 weeks, respectively.
Pathological Details: Operated specimen received for HPE was grossed as per the institute protocol and slides were reviewed as per proforma which consisted of primary grade of tumor, histologic changes following therapy, tumor regression, necrosis, stromal changes, lymphovascular emboli, number of lymph nodes retrieved, positive nodes, and pathologic TNM staging. The two separate reviewing pathologists were blinded regarding the pretreatment therapy to ensure unbiased reporting. The above mentioned findings in both the study groups were documented and significant difference in findings was reviewed again and reached to a consensus.
Pretreatment biopsy: Biopsy slides was reviewed, histologic type, and differentiation were documented.
Post treatment resection:
- Overall pathologic response and residual tumor stage
Pathologic response to treatment was assessed by modified Ryan scheme. The pathologic stage of the residual tumor (ypT) was determined by the deepest residual viable tumor and staged as per 8th Ed of AJCC cancer staging manual. The pathologic staging of the residual tumor was compared with the pretreatment clinical staging by MRI to determine tumor down-staging. Based on modified Ryan scheme for tumor regression, pCR is defined as complete absence of residual viable tumor. Near pathological complete response (near pCR) was defined when only 5% of residual viable tumor was present. Residual cancer with evidence of tumor regression was deemed to have partial response. No response was recorded when extensive residual cancer with no evident tumor regression was noted. Extensive sampling of the lesion and two deeper levels were examined before pCR was reported.
- Morphological assessment
- Tumor cell morphology: Cytoplasmic changes (eosinophilia, vacoulations), marked nuclear pleomorphism was considered when nuclei was more than 3 times the size of adjacent nuclei.
- Stromal change: Stromal response to radiation was either in form of fibrosis or fibroinflammation (when more than 25% of fibrotic component comprised inflammatory cells) and was recorded when it was replacing the neoplastic glands.
- Other findings: Therapy induced changes include tumor necrosis and mucin pools. Percentage of tumor necrosis was quantified.
The observational study was conducted in accordance with ethical standards of responsible committee on human experimentation and with Helsinki declaration of 1964, as revised in 2013. Study was conducted after institutional ethical board approval.
Two study groups consisting of CRT and SCRT were compared using Statistical Package for Social Science (SPSS) software version 28 (IBM SPSS Statistics for windows, Armonk, NY: IBM Corp.). The categorical variables were calculated as percentage and the pathological response rate between the two study groups compared using Chi-square test and P value (0.001) was considered significant.
| Results|| |
Of the 79 patients included in the study, 10 (12.6%) patients underwent SCRT and 69 (87.4%) patients were treated by CRT. Median age of SCRT was slightly higher compared to CRT (52.5 years versus 49.0 years). In both the cohorts male patients were predominant [Table 1].
|Table 1: Overall characteristic of patients including extent of pathologic findings in chemoradiation (CRT) and short course radiotherapy (SCRT) study group|
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On pretreatment MRI, 67 patients were in stage T3 of which 09 (90%) underwent SCRT and 58 (85.2%) were treated with CRT. 11 patients were in stage T4 of which one (10%) underwent SCRT and 10 (14.8%) cases treated with CRT. Eight (80%) in SCRT and 49 (72%) cases in CRT had enlarged (possible positive) nodes. Pretreatment staging of one patient could not be done as the imaging findings were not available.
Pretreatment biopsy: The histopathology report of the 10 patients treated with SCRT, one well differentiated adenocarcinoma and one adenocarcinoma with mucinous component, six moderately differentiated and two poorly differentiated adenocarcinoma. In the CRT group, all cases were adenocarcinoma – 18 well differentiated, 38 moderately differentiated, three poorly differentiated and five cases each was carcinoma with signet ring cell morphology and adenocarcinoma with mucinous component. Grading was based on AJCC, cancer staging manual 8th Ed.
Post treatment resection specimen was microscopically evaluated for extent of residual viable tumor and overall pathologic response, nodal status and residual tumor stage was determined. In univariate analysis, pCR was noted in 12 (17.6%) patients who underwent CRT and in none who underwent SCRT. One case with complete regression of primary site in SCRT but continued to show four metastatic nodes. One case of CRT had pathologic stage higher than pretreatment stage. Extent of pathologic response is mentioned in [Table 1]. Number of examined lymph nodes and ratio of positive to examined nodes were significantly higher in SCRT compared to CRT. Median number of nodes examined in SCRT was 11 nodes compared to seven nodes in CRT. In multivariate analysis, the probability of pCR was significantly lower in the SCRT compared to CRT group (OR = 0.3, 95% CI, 0.2-0.7 adjusted for cT and cN stage).
- Tumor cell morphology:
Tumor cell morphology was compared on pretreatment biopsy with resection specimen. Cytoplasmic changes characterized by eosinophilia and cytoplasmic vacoulations were seen in six (66.7%) cases of SCRT and 36 (65%) cases of CRT. Cytology was unaltered in one (10%) case of SCRT and five (7.2%) cases of CRT. Marked nuclear pleomorphism post treatment was noted in two (20%) and 13 (22.8%) cases of SCRT and CRT, respectively. Treatment induced necrosis was seen in all SCRT cases, four (40%) cases had necrosis accounting for 40-60% of tumor, five (50%) cases had 10-40% of necrosis and one (10%) case had five percent of necrosis. In CRT, eight (11.5%) cases had treatment induced necrosis accounting for 10-40% of tumor, nine (13.0%) cases had necrosis accounting to 5%, and 52 (75.3%) cases had no evidence of necrosis [Figure 1].
|Figure 1: Histomorphologic changes following short course radiotherapy (a) Predominantly shows therapy induced necrosis with small foci of viable tumor in lower left quadrant 20x. (b) Marked cytoplasmic eosinophilia and vacoulations (inset: compare the tumor cell morphology with minimal response to treatment in the same case noted at different site) 40x. Stromal response to neoadjuvant therapy (c) Fibrotic type of stroma with minimal inflammatory cells is replacing the tumor. 20x (d) Fibroinflammatory type of stromal response characterized by lymphoplasmacytic cell infiltrate along with foamy macrophages in background of fibrotic stroma. 20x Hematoxylin and Eosin stain|
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- Stromal response: Tumor regression was characterized by either fibrosis or fibroinflammatory type of stroma with lymphoplasmacytic cells. Fibrosis was seen in two (20%) and 37 (55%) cases of SCRT and CRT respectively [Figure 1]c. Fibroinflammatory type of response was seen in seven (70%) of SCRT and in 27 (38%) of CRT [Figure 2]. Minimal or no response was seen in one (10%) and five (7.2%) cases SCRT and CRT, respectively.
|Figure 2: Kaplan–Meier recurrence – free survival curve of 69 patients in CRT group. SCRT group did not have any events as recurrence X-axis: proportion recurrence-free. Y-axis: recurrence free survival time in (months)|
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Tumor cells with mucin pools were seen in four (40%) cases of SCRT versus 22 (32%) cases of CRT. Five (7.2%) cases in CRT group with pCR showed only acellular mucin pools without any viable residual tumor cells.
Lymphovascular permeation was noted in five (50%) cases of SCRT and six (8.6%) cases of CRT patients, two cases of CRT with lymphovascular emboli developed metastasis. Perineural invasion (PNI) was identified in three (30%) SCRT and seven (10.1%) CRT cases, four cases belonging to CRT group presented with metastasis. Both lymphovascular invasion and PNI was noted only in CRT group and accounted for seven (10.1%) cases and three of them progressed to have metastasis.
In SCRT during the median follow-up period of 19 months (1- 30), six cases were uneventful, three died due to operative complications and one was lost for follow-up. In CRT median follow-up period was 24.5 months (1-57), 49 cases had uneventful follow-up, 12 developed metastasis, four (6.0%) cases had local recurrence and four cases were lost for follow-up, one death was recorded. Metastasis was noted in 12 (17.6%) cases of CRT group out of which six cases with metastasis had no pathologic response to CRT. Metastasis was observed at sites such as liver, abdomen, lung, and thigh. Recurrence free survival is plotted on Kaplan-Meier analyzes [Figure 2]. No recurrence or metastasis was noted in SCRT group.
| Discussion|| |
Twelve (17.5%) cases had pCR in CRT and no pCR was noted in SCRT which is supported by an Indian study in which pCR was 11.4% in CRT and 2.4% in SCRT. These findings are not far from expected as the effective radiation dose is less when compared to CRT. However during follow-up, cases with pCR and near pCR did not show local recurrence or metastasis in both study groups despite lower pathological response in SCRT. Many studies suggest that pCR and downstaging are associated with better outcome.,, pCR rates are lower in patients treated SCRT. No difference in survival or outcome was noted between the two study groups and three death noted in SCRT groups was a result of surgical complications. Other studies groups have also found no difference in survival between SCRT and CRT groups.,,, downstaging in SCRT was five (50%) cases which was in agreement with Hoendervangers S et al. and Chung et al. but finding is variable in CRT group among different studies.,
Neoadjuvant treatment followed by surgery is an effective treatment modality in rectal carcinoma and data suggest that pre-operative treatment reduces tumor size and has less toxicity compared to postoperative therapy. Cytologic alteration in residual cancer cells were noted focally or extensively and was characterized by increased eosinophilia and vacoulations in cytoplasm, marked nuclear pleomorphism and extent of these findings were almost similar in both the groups. However, extent of treatment induced necrosis was seen in all cases of SCRT cases when compared to 17 (24.7%) cases in CRT. Therapy induced changes which result in tumor regression occurs by disappearance of tumor cells and replacement by either only fibrosis or fibroinflammatory response. TGF-beta is known to play key role in radiation induced fibrosis and begins to appear within 24 hrs of irradiation. This could explain almost similar extent of stromal response in both groups (90% versus 92%)., No association was found between types of stromal response with extent of tumor regression. As mentioned by Shinde et al., histomorphology did not have any significant association with to extent of pathologic response.
Increased mucin production and mucin pools are seen as response to treatment. Five cases in CRT group had complete response with only pools of acellular mucin.
In SCRT, yield of mean number of lymph nodes was higher compared to CRT group (11 versus 7) as the yield of lymph nodes is known to be affected by radiotherapy. Higher mean metastatic/examined lymph node ratio (LNR) was observed in SCRT which is supported by Hoendervangers et al. A good yield of nodes after therapy is associated with improved survival and local recurrence rates. High LNR is known to have to decrease overall and disease free survival. However, this is debatable since clinical outcome is not well established.
One patient in the study group upstaged from T3 to T4 in CRT study group. This could be possibly due to improper clinical staging or tumor progression during therapy.
| Conclusion|| |
To the best of our knowledge, this is first study conducted in India which describes the pathologic response rates and morphological findings between SCRT and CRT in LARC. Sample size in SCRT group was the limitation and exact interval to surgery in order to obtain the near to complete pathological response is not clear. Nevertheless, SCRT which was targeted towards elderly patient who were not candidates for CRT, currently is been extended towards CRT candidates as well. Follow-up results of SCRT when compared with CRT has been encouraging. Because of the lower number of fractions of radiotherapy and early surgery in SCRT compared to CRT, the treatment is patient compliant with lower expense and also reduces the burden of caseload to the hospital. In view of very limited Indian data and small sample size of SCRT group, performing large multicentric institutional studies would be helpful for better management of rectal cancer patients with SCRT and also ascertain the exact relation with the pathological response and outcome.
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[Figure 1], [Figure 2]