Impact of Neoadjuvant Chemo Radiation in Carcinoma Rectum: A Tertiary Care Institute Experience
Pramod Kumar Singh*, Rajit Rattan, Rakesh Kapoor, Ritesh Kumar and Ravi Teja
Department of radiotherapy, Jk cancer institute, India
Submission: July 17, 2018; Published: October 26, 2018
*Corresponding Address: Pramod Kumar Singh, Department of radiotherapy, Jk cancer institute, Kanpur Uttar Pradesh, India,
How to cite this article: Pramod Kumar Singh, Rajit Rattan Pandita, Rakesh Kapoor, Ritesh Kumar, Ravi Teja. Impact of Neoadjuvant Chemo Radiation in Carcinoma Rectum: A Tertiary Care Institute Experience. Canc Therapy & Oncol Int J. 2018; 12(4): 555842. DOI: 10.19080/CTOIJ.2018.12.555842
Purpose: To evaluate the rate of pathologic complete response (pCR) and the toxicity ofneoadjuvant chemoradiotherapy (chemoRT) regimens for Stage T3-T4 rectal cancer.
Methods and Materials: Patients with Stage T3 or T4 rectal cancer of <12 cm from the anal verge were randomized to preoperative RT (45 Gy in 25 fractionsover 5 weeks in 1.8 Gy per fractions) with concurrent chemotherapy (5FU + levcoverine). Surgery was performed 4–8 weeks after chemoRT, and adjuvant chemotherapy 4–6 weeks after surgery.
Results: A total of 25 patients are analyzed. The median age at diagnosis was 52.00 years.23 of the patients were male, while 2 of them were female. The median 3-year disease free survival was 50%. Pathologic complete response (pCR) was 12% and the preoperative chemo RT rate of Grade 3-4 hematologic toxicity was 9% and 4% and the rate of Grade 3-4 non-hematologic toxicity was 26% and 27%, respectively.
Conclusion: Preoperative chemo RT with chemotherapy for distal rectal cancer has clinical activity (3 of 25 pCR) and acceptable toxicity.
Colorectal cancers among the 10 commonest cancers in India with >33000 cases diagnosed each year in the India. One-third of this number is contributed by rectal cancers . Despite the high rate of curability with combined modality therapy, some patients experience significant treatment-associated morbidity, and other patients develop locoregional failure or distant metastasis. In addition to achieving cure, sphincter preservation is an important goal of therapy. Improvements in clinical outcome have been realized with wide acceptance of continuous infusion 5-fluorouracil (5-FU)–based neoadjuvant chemoradiotherapy (chemoRT) and the use of total mesorectal excision.
The results of large randomized trials comparing neoadjuvant pelvic radiotherapy (RT) alone versus RT plus concurrent 5-FU have demonstrated improvement in locoregional disease control with the addition of concurrent chemotherapy [2,3]. Attempts to improve on this approach have focused primarily on testing new agents added to the backbone of 5-FU plus RT to enhance the pathologic complete response (pCR) rate. Drugs with high activity in the metastatic disease setting have been of particular interest to apply to rectal cancer clinical studies. However, the integration of new RT techniques is also pertinent to this clinical research question. The Radiation Oncology Group (RTOG) 0012 study was a Phase II trial in which patients were randomly assigned to either hyperfractionated pelvic RT plus continuous infusion 5-FU or standard pelvic RT plus continuous infusion 5-FU and irinotecan . That study was successful in that both arms achieved very high pCR rates, 26% in each arm. However, both arms were also associated with high rates of acute Grade 3 or greater toxicity (42% and 51%, respectively, for each arm), and therefore, neither regimen was suitable for further development.
From January 2011 to June 2013, 25 patients with locally advanced (fixed tumor by digital rectal exam or T3–4 tumor by computed tomography [CT]/ sonography) rectal cancer who received CCRT were retrospectively reviewed. The neoadjuvant CCRT for locally advanced rectal cancer in our hospital was 5-fluorouracil 375mg/m2 plus leucovorin 20mg/m2 intravenously for 1 hour, weekly, with concurrent with radiotherapy (180cGy/day, Monday– Friday, for 5 weeks). For radiotherapy planning image acquired using dedicated CT simulator with a slice thickness 2.5mm. then image transfer to Eclipse planning system. Clinical target volume (CTV) include thetumor bed and local-regional lymph nodes. Planning target volume (PTV) generated by giving margin of 1cm. Dose to PTV was 45Gy in 25 fraction1.8 per
fraction daily, 5 days a week, radiation portal includedanteriorposterior/
posterior-anterior, with opposed lateral fields. Beam
energies included6-MV, and 15-MV photons, patients underwent
three-dimensional treatment planning.After completion of
chemotherapy , patients underwent CT orPETCT and clinical
evaluation for disease status. Patients underwent surgery4 to
8 week after completion of CRT. Final histopathologynoted. 21
patients received adjuvant chemotherapy with FOLFOX 3 weekly
total 6 cycles. End point of study was recurrence and or metastasis.
Patients were followed every 3 months with physical examination
as well as radiological examination include as clinically indicated.
Response evaluation was done RESCIST criteria version 1.1..
For statistical analysis data was arranged SPSS 19 versions.
Descriptive studies were done for parameter, survival, diseasefree
survival, and local control rates for the entire cohort. The
log-rank test was used to analyze prognostic factors for the entire
cohort.Kaplan mair analysis used for survival analysis. P value
<0.05 is considered as statically significant.
Patient characteristics are summarized in (Table 1). Between
January 2011 to June 2013, 105 patients of carcinoma rectum
registered in our department. 25 patients had started on NACRT
protocol, 25 patients non metastatic locally advancehad complete
treatment NACRT, surgery and adjuvant chemotherapy wear
available. The median age of the patients was 52.0 years. 23
patients were males and 2 patients wear females. The median
duration of symptoms was six months. Bleeding per rectum
was the most commonpresenting symptoms followed by anal
discomfort, alteration of bowel habbit. Diarrhea and watery
discharge.On histopathologicalall patients are Adenocarcinoma
locally advance, non-metastasis.Treatment details (Table 2)
Treatment modalities consisted of neo adjuvant chemo radiation
then surgery and adjuvant chemotherapy. All patients underwent
surgery, out of which 11patients underwent APR, 14 patients
were underwent LAR.
There wear no surgical complications in form of post-operative
death or wound complications in form of post operative death or
wound complications. RT toxicity occurred in all patients in form
of grade I and grade II dermatitis and there wear grade 3 in 7%
of patients. All patient’s complete treatment with no significant
toxicity or treatment complication.
25 evaluable patients, 3 had a pCR. Tumor down staging was
observed in 10 (40%) sphincter preservation were observed
in 56% of patients, as demonstrated by the requirement for
abdominoperineal resection (APR) in 44%of patients. No
significant association was observed between the pathologic
factors (T stage, N stage and margin status) but the use of APR
had significant on overall survival (0.026) distal tumors (<6 cm
from the anal verge) were more likely to require APR.
The important goals of rectal cancer therapy include
improvement of survival, local control, and sphincter preservation.
For the development of new neoadjuvant approaches, overall
survival is indisputably the reference standard study endpoint
by which efficacy is measured. However, several studies have
demonstrated that the pCR is predictive of other clinically relevant
endpoints, including sphincter preservation, relapse-free survival,
and a reduction in distant metastasis [5–9]. Moreover, the use
of pCR appears to identify a favorable prognostic patient group
that has an improved overall survival. Neoadjuvant rectal cancer
trials have commonly adopted the use of the pCR as a reliable and
meaningful intermediate endpoint. In the present study, we found
that the combination of leucoverine and 5FU with RT results in a
promising pCR rate with acceptable toxicity at the recommended
doses. A direct comparison of the pCR rates from different studies
has limited value but can be useful as a rough approximation of
efficacy and for hypothesis generation. In this context, a general
trend toward progressive improvement in pCR can be seen in
clinical trials with newer neoadjuvant regimens for rectal cancer.
In two large multicenter Phase III studies (European
Organization for Research and Treatment of Cancer 22921 and
Federation Francophone de Cancerologie Digestive 9203), the rate
of pCR for neoadjuvant 5-FU/leucovorin plus concurrent pelvic
RT vs. RT alone was 11–14%and 4–5%, respectively [3,10]. Four
published studies that have examined the capecitabine plus pelvic
RT demonstrated pCR rates in the range of 9–23% (mean, 15%)
[11–14]. As the intensity of preoperative chemoRT is increased
in an attempt to improve the rate of pCR, attention must also be
placed on the toxicity of the therapy. In the preceding RTOG study,
RTOG 0012, both study arms (5-FU plus hyperfractionated RT and
5-FU plus irinotecan plus standard RT) showed high rates of pCR
(26%); however, both arms were associated with high rates of
acute toxicity of Grade 3 or greater, 42%and 51%, respectively .
Radiation dose is of critical importance in down staging of
cancer. The dose response of rectal cancer is steep in the dose
range of 40 to 60 Gy. Several studies have shown the impact of
radiation dose escalation on the rate of pathological complete
response to neoadjuvant therapy[15,16]. In a review of patients
at Princess Margaret Hospital who received 40 Gy, 46 Gy, or 50 Gy
in 2 Gy/fraction with continuous infusion 5-FU, the pathological
complete response was 18%, 23%, and 33% respectively for the
three dose levels . The two-year local relapse-free survival was
72%, 90%, 89% and disease-free survival 62%, 84%, and 78% for
the 40 Gy, 46 Gy, and 50 Gy levels respectively . The overall
survival was 72%, 94%, and 92% respectively. Doses of 46 Gy or
50 Gy were more effective than 40 Gy, but there was no difference
between 46 or 50 Gy. Similar results have been reported from
other studies as well.
The definitive phase III study in favor of preoperative
radiation therapy was the CAO/ARO/AIO-94 study performed by
the German Rectal Cancer group . Eight hundred twenty-three
clinically staged T3 and T4 or node-positive rectal cancers were
randomized to arm 1: Preoperative chemotherapy and radiation
therapy followed by TME 6 weeks later, or arm 2: TME followed by
postoperative chemotherapy and radiation therapy. The radiation
therapy used was 50.4 Gy in 28 fractions with a 5.4 Gy as a small
volume boost in the postoperative arm. The chemotherapy used
was 5-FU given as 1 g/m2 per day during the 1st and 5th weeks
of radiotherapy as a 120-hour continuous infusion. Both arms
received four additional cycles of 5-FU at 500 mg/m2 per day for
5 days every 4 weeks. All surgeons were trained in the use of TME
and were asked prior to treatment to evaluate the possibility of
The 5-year results revealed a pelvic recurrence ratio of 6%
versus 13% (p = 0.02) in favor of the preoperative arm. The
distant recurrence rate was 36% versus 38% (p = NSS), diseasefree
survival was 68% versus 65% (p = NSS), and overall survival
was 76% versus 74% (p = NSS) for preoperative radiation versus
postoperative, respectively. There was significant tumor down
staging after preoperative combined modality treatment with
an 8% pathological complete response rate. Nodal positivity was
25% in the preoperative versus 40% in the postoperative arm. The
sphincter preservation rate in 188 patients with low-lying tumors
(declared by the surgeon prior to randomization to require an
APR) revealed that 39% versus 19% had a sphincter-preserving
low anterior resection (p = 0.004) in the preoperative versus the
postoperative arm. There were fewer acute (27% vs. 40%) and
late toxicities (14% vs. 24%) in preoperative-treatment group.
Thus, preoperative combined preoperative chemotherapy and
radiation therapy resulted in significantly less local failures in the
pelvis by half and also provided twice the sphincter preservation.
Importantly, there was no difference in overall survival or diseasefree
survival between the two arms.
Clinical T4 tumors may not be resected completely due to
tumor fixation. Preoperative radiation treatment is recommended
to facilitate curative resections. M.D. Anderson investigators
demonstrated that preoperative chemotherapy and radiation
therapy increased overall survival (80% vs. 60%), local control
(95% vs. 66%), and the number of sphincter preserving
procedures (35% vs. 7%) as compared to radiation alone .
Memorial Sloan-Kettering Cancer Center reported a gross total
resection rate of 97%, pathological complete response rate of 25%,
4-year local control of 70%, and 4-year overall survival of 67%
when giving preoperative chemotherapy of 5-FU and leucovorin
with 50.4 Gy of radiation followed by surgery . Preoperative radiation and chemotherapy resulted in improved resectability
rates and possible improved local control and survival.
The IORT experience at MGH was reviewed by Nakfoor et al.
. Preoperative continuous infusion 5-FU plus 50.4 to 54 Gy of
radiation was given followed by a 4- to 6-week break and surgery.
No intraoperative radiation was given if metastases were present
at surgical exploration, if there were adequate margins >1 cm, or
if there was less than T4 disease. Ten to 12.5 Gy were given for
complete resection, 12.5 to 15 Gy for microscopic residual, and
17.5 to 20 Gy for gross residual disease. The 5-year local control
was 90%, 65%, 55%, and the disease specific survival at 5 years
was 65%, 45%, and 15%, for these three dose levels, respectively.
The 5-year actuarial risk of complications was 15%, however. The
risk of peripheral neuropathy was 20% for doses >15 Gy. IORT
improves local control, especially with a gross total resection, but
not survival for locally advanced rectal cancer.
We have shown that neoadjuvant pelvic RT with 5FUand
leucoverine for clinical Stage T3 and T4 rectal cancer is associated
with manageable toxicity and yields a hpCR rate. Although the
results of the RTOG 0247 trial are encouraging, they also highlight
the need to identify more effective and less toxic regimens, through
incorporation of new radiation sensitizers, novel methods of RT
delivery, and the selection of patients according to molecular