A total of 33 patients were accrued in the study between February 2020 to July 2021. Patients were randomised into standard and interventional arms with the help of computer-generated block randomisation. Seventeen patients were recruited in the long-course CTRT arm (standard arm-A), and 16 were recruited in the short-course RT followed by the chemotherapy arm. The median age of patients recruited was 44.6 in arm A and 46.3 in arm B. All patients presented with the symptom of per rectal bleeding. All the patient-related characteristics were comparable in both arms (Table 1). Baseline CEMRI was performed in all recruited patients along with a complete metastatic workup, including chest imaging, carcinoembryonic antigen (CEA) levels and routine haematological investigations to ascertain the exact stage of disease and to rule out distant metastasis before treatment. CEA value less than or equal to 5 ng/ml was considered normal. In the colonoscopy, distance from the anal verge and total length of disease was noted if the scope was negotiable. Mesorectal fascia involvement was seen in one-third of all recruited patients and distributed equally between the two arms. A higher proportion of patients in the standard arm had lymph nodal metastasis at presentation compared to the study arm (94% versus 62.5%). The rate of treatment interruption was significantly lower in the SCRT/Chemotherapy arm compared to the long-course CTRT arm (p-value = 0.038). All patients in the SCRT arm completed treatment within one week, whereas four patients in the long-course CTRT arm had treatment interruptions of more than ten days. The rest of the tumour workup and treatment-related details were comparable, as shown in Table 2.
Table 1: Baseline demographic and clinical characteristics of intention to treat population.
Characteristic
|
Standard Arm(A)
|
Interventional Arm(B)
|
p-value
|
Age
|
44.6 ± 13.9
|
46.3 ± 16.5
|
0.738
|
Male
|
8 (47.1)
|
5(31.2)
|
0.353
|
Female
|
9 (52.9)
|
11(68.7)
|
0.353
|
Serum CEA
Normal
Elevated
|
13(76.5)
4(23.5)
|
13(81.2)
3(18.7)
|
0.737
|
Initial imaging
MRF positive
LN involved
Organ infiltration
Tumour length
|
7(41.2)
16(94.1)
3(17.6)
7(3.5-13)
|
4(25)
10(62.5)
2(12.5)
6.2(2.7-10)
|
0.325
0.026
0.680
0.169
|
Colonoscopy
Scope not passed
Length
Distance from AV
|
4(23.5)
8(4-10)
4(0-10)
|
2(12.5)
6(3-10)
4(0-10)
|
0.412
0.125
0.413
|
Initial clinical T stage
T3
T4a
T4b
|
12(70.6)
2(11.8)
3(17.6)
|
12(75)
2(12.5)
2(12.5)
|
0.919
|
Initial clinical N stage
N0
N1a
N1b
N2a
N2b
|
1(5.9)
1(5.9)
5(29.4)
8(47.0)
2(11.8)
|
6(37.5)
3(18.7)
2(12.5)
4(25)
1(6.2)
|
0.112
|
Initial stage group
IIA
IIIB
IIIC
|
1(5.9)
10(58.8)
6(35.3)
|
6(37.5)
5(31.2)
5(31.2)
|
0.071
|
Table 2: Details of surgery and pathological findings.
Characteristic
|
Standard Arm(A)
|
Interventional Arm(B)
|
p-value
|
Surgery
Done
Not done
|
11(68.7)
5(31.2)
|
12(75)
4(25)
|
0.694
|
Type of surgery
LAR
APR
ISR
Exenteration
EL only
|
6(54.5)
4(36.4)
0(0)
0(0)
1(9.1)
|
4(33.3)
4(33.3)
3(25)
1(8.3)
0
|
0.252
|
Pathological T stage
T0
T1
T2
T3
T4b
|
2(20)
0
0
8(80)
0
|
3(27.3)
1(9.1)
2(18.2)
4(36.4)
1(9.1)
|
0.240
|
Pathological N stage
N0
N1a
N1b
N2b
|
7(70)
0
1(10)
2(20)
|
9(81.8)
1(9.1)
1(9.1)
0(0)
|
0.360
|
Pathological stage group
0
I
IIA
IIC
IIIA
IIIB
IIIC
|
2(20)
0(0)
5(50)
0(0)
0(0)
1(10)
2(20)
|
3(27.3)
2(18.2)
3(27.3)
1(9.1)
1(9.1)
1(9.1)
0
|
0.353
|
Table 3: Clinical response assessment, radiological and pathological tumour regression rates. TRG, tumour regression grade.
Variable
|
Standard arm(A)
|
Interventional arm(B)
|
Difference
|
p-value
|
Distance from AV
Baseline
Post-treatment
|
3.6 ± 1.9
2.9 ± 2.0
|
3.4 ± 1.9
3.25 ± 2.4
|
0.2(-1.2 – 1.5)
-0.3(-2.2 – 1.5)
|
0.785
0.718
|
Decreased anal tone
Baseline
Post-treatment
|
3(17.6%)
2(12.5%)
|
2(12.5%)
1(6.7%)
|
|
0.680
0.583
|
Fixed disease
Baseline
Post-treatment
|
2(11.8%)
4(30.8%)
|
2(12.5%)
1(8.3%)
|
|
0.948
0.161
|
Location
Baseline
Circumferential
Anterior
Posterior
Lateral
Post-treatment
Circumferential
Anterior
Posterior
Lateral
|
14(82.3%)
1(5.9%)
2(11.8%)
0(0%)
12(93.3%)
0(5.9%)
1(7.7%)
0
|
11(68.5%)
2(12.5%)
1(6.2%)
2(12.5%)
8(66.7%)
2(16.7%)
2(16.7%)
0
|
|
0.392
0.212
|
Radiological TRG
TRG 1
TRG 2
TRG 3
TRG 4
TRG 5
|
3(23.1%)
2(15.4%)
5(38.5%)
2(15.4%)
1(7.7%)
|
5(35.7%)
3(21.4%)
2(14.3%)
2(14.3%)
2(14.3%)
|
|
0.683
|
Pathological TRG
TRG 0
TRG 1
TRG 2
TRG 3
|
2(20%)
2(20%)
2(20%)
4(40%)
|
3(30%)
4(40%)
2(20%)
1(10%)
|
|
0.446
|
Table 4: Summary of published studies comparing total neoadjuvant therapy with standard CTRT in locally advanced rectal cancer, compared with current study results.
Study
|
Eligibility(n)
|
Primary outcome
|
Treatment regimen
|
PCR rates (%)
|
Grade 3+ GI toxicity (%)
|
Results
|
Remarks
|
PRODIGE 23
|
c T3/T4 (461)
|
DFS at 3 years
|
Long course CTRT
6 Cycles NACT (FOLFIRINOX) + CTRT
|
12
28
|
12
6
|
3-year DFS significantly better with NACT.
|
SCRT was not part of the protocol
|
RAPIDO trial
|
High risk MRI features (c T4a or T4b /c N2/ EMVI/ MRF+) (920)
|
Disease-related treatment failure
|
Long course CTRT
SCRT + 6 cycle CAPOX/9 cycle FOLFOX
|
14
28
|
9
17
|
Significantly lower disease-related treatment failure in the experimental arm.
|
Primarily aimed to reduce distant metastasis,
99% of patients received CAPOX.
|
Polish II trial
|
Fixed T3/ T4(541)
|
R0 resection rate
|
Long course CTRT
SCRT + 3 cycle FOLFOX
|
12
16
|
26
14
|
No difference in R0 resection rates, the 3-year OS favoured SCRT/CCT arm, but 8 years OS was not different.
|
64% of patients in long course CTRT arm received oxaliplatin
|
STELLAR trial
|
c T3-T4 or N+(599)
|
DFS at 3 years
|
Long course CTRT
SCRT + 4 cycle CAPOX
|
11.8
16.6
|
7.5
10.4
|
DFS was similar in the 2 arms.
|
Proved non-inferiority of experimental regimen
|
Present study
|
c T3-T4 or MRI risk factors (33)
|
Clinical and radiological response assessment after neoadjuvant treatment
|
Long course CTRT
SCRT + 3 cycle CAPOX
|
20
30
|
5.9
31.2
|
Trends toward better response in the experimental arm
|
Proved feasibility of regimen in Indian population.
|
Primary Outcomes
31 out of 33 patients were available for response assessment. One patient in the interventional arm could not complete treatment due to myocardial infarction after finishing radiation therapy. One patient of long course CTRT arm succumbed to death due to severe diarrhoea and hypovolemic shock, leading to cardiac arrest after one week of radiotherapy completion. After completion of neoadjuvant treatment, five patients had a complete clinical response with no growth palpable in clinical examination. Clinical response assessment was done by assessing the palpability, tone, mobility, location and distance from the anal verge before and after treatment. There was no significant difference in the proportion of non-palpable disease after neoadjuvant therapy between the two arms. The mean distance from the anal verge to the condition in the baseline was 3.6 and 3.4 cm, respectively, in the long-course CTRT and SCRT arms which reduced in response assessment to 2.9 and 3.2 cm. reduced distance to disease from the anal verge can be an indicator of disease progression and involvement of lower rectum. Although the absolute difference in the reduction is more in the long-course CTRT group, it was statistically insignificant. The reduced anal tone is associated with tumour infiltration of anal sphincters and impaired sphincter functioning. The number and percentage of patients with loss of anal tone decreased in both groups post-treatment. However, the magnitude of this change in both groups was not significantly different. 2 patients each presented with a clinically fixed disease in both groups (restricted mobility of the growth on per rectal examination likely due to involvement of adjacent organs or pelvic side wall). At response assessment, four patients had fixed conditions in the long-course arm compared to only one in the SCRT arm. This difference was also not statistically significant (p = 0.162) (Table 3).
Radiological tumour regression grade was compared between the two treatment groups. Four out of the 31 patients developed distant metastasis, two patients to the liver and one each to the lung and sacral bone. Out of these, three patients were in the standard arm, while 1 with liver metastasis was in the experimental arm. Tumour regression grading (TRG) was not performed in the patients who developed metastatic disease. Hence, 27 patients were analysed. Complete tumour regression was seen in 8 patients – 3 in arm A and 5 in arm B. The rates of complete radiological response were higher in the SCRT group (35.7% versus 23.1%) though it was not statistically significant. Most patients in the long-course CTRT group presented with moderate tumour regression (TRG 3 – in 38.5%).
Secondary outcomes
Out of the 23 patients who underwent surgery, pathological tumour regression grading was available for 20 patients. 5 patients had a pathological complete response – 2 in the standard arm and 3 in the interventional arm (Table 3). Complete and near complete tumour regression (TRG 0& 1 combined) was observed in 70% of patients in the SCRT arm compared to 40% in the long-course CTRT arm.
The most commonly observed acute toxicity was acute bowel toxicity characterised by diarrhoea and pain abdomen in both groups. 4 out of 17 patients in the standard arm and 9 out of 16 patients in the interventional arm experienced at least grade 2 bowel toxicities (p-value = 0.085). A higher proportion of patients in the experimental arm presented with grade 3 bowel toxicities requiring inpatient care (5 patients). Apart from the one death caused by bowel toxicities, no grade 3 or more bowel complaints were seen in patients receiving standard chemoradiotherapy. All acute toxicities subsided within one month of completion of treatment. Acute grade 2 or more skin toxicities were observed in the long course CTRT arm only (p value = 0.136). One patient had grade 3 dermatitis requiring inpatient care. The most common haematological toxicity was anaemia. 2 patients in long course CTRT arm and one patient in short course CTRT arm presented with grade 2anaemia. No grade 3 or more haematological toxicities were observed. Commonly observed chronic toxicity was rectovaginal fistula seen in 3 out of 15 patients in the SCRT arm. No postoperative complications were observed in the long-course CTRT arm. Two patients in the SCRT arm presented with postoperative complications, one with urinary retention and bleeding from the stoma, both managed conservatively.