Abstract
Recent literature suggests that the benefit of adjuvant chemotherapy (aCT) for rectal cancer patients might depend on the response to neoadjuvant chemoradiation (CRT). Aim was to evaluate whether the effect of aCT in rectal cancer is modified by response to CRT and to identify which patients benefit from aCT after CRT, by means of a pooled analysis of individual patient data from 13 datasets. Patients were categorised into 3 groups: pCR (ypT0N0), ypT1-2 tumour and ypT3-4 tumour. Hazard ratios for the effect of aCT were derived from multivariable Cox regression analyses. Primary outcome measure was recurrence-free survival (RFS). 1723(52%) of 3313 included patients received aCT. 898 patients had a pCR, 966 had a ypT1-2 tumour and 1302 had a ypT3-4 tumour. For 122 patients response category was missing and 25 patients had ypT0N+. Median follow-up for all patients was 51 (0-219) months. Hazard ratios for RFS with 95%CI for patients treated with aCT were 1.25(0.68-2.29), 0.58(0.37-0.89) and 0.83(0.66-1.10) for patients with pCR, ypT1-2 and ypT3-4 tumours, respectively. The effect of aCT in rectal cancer patients treated with CRT differs between subgroups. Patients with a pCR after CRT may not benefit from aCT, whereas patients with residual tumour had superior outcomes when aCT was administered. The test for interaction did not reach statistical significance, but the results support further investigation of a more individualized approach to administer aCT after CRT and surgery based on pathologic staging.
Keywords: rectal cancer, neoadjuvant treatment, adjuvant chemotherapy, survival, response
Introduction
Currently, adjuvant chemotherapy is indicated for colorectal cancer patients at increased risk for metastatic disease, typically established through postoperative histopathological risk factors like involved lymph nodes, poor differentiation grade or lymphatic or venous invasion.1 For rectal cancer, the shift from adjuvant to neoadjuvant (chemo)radiation2 has complicated the use of postoperative histopathology to determine the indication for adjuvant chemotherapy, as chemoradiation (CRT) often leads to downstaging of tumour and nodes and the histopathological staging may no longer reflect the initial stage. The pre-CRT baseline imaging could be used for decision making, but the available imaging modalities are only moderately accurate in lymph node assessment3, 4, a risk factor that is considered pivotal in decision making about adjuvant chemotherapy. Another option is to guide the decision on post-CRT histopathological staging, but this strategy carries the risk of undertreating patients whose lymph nodes have been sterilised. A highly pragmatic approach is to consider all tumors that receive neoadjuvant chemoradiation also at risk for distant recurrence and treat accordingly with adjuvant chemotherapy. However, this strategy carries the risk of overtreatment, as some distally located smaller tumors are also treated with neoadjuvant chemoradiation. What complicates this issue further is the fact that the evidence for survival benefit of adjuvant chemotherapy is weaker in rectal cancer than for colonic cancer, with conflicting results from meta-analyses and some experts questioning its routine role in modern rectal cancer management.5, 6
The question remains as to which subgroups of patients could benefit from adjuvant chemotherapy after CRT for rectal cancer.7 An early subgroup analysis of a randomized EORTC trial suggested a beneficial effect of adjuvant chemotherapy for patients with ypT0-2 tumours, not seen in ypT3-4 tumours.8 The significant difference between both response groups was no longer observed after long-term follow-up. Another report questioned the benefit of adjuvant chemotherapy for pathologic complete responders (ypT0N0) after CRT.9 Therefore, the aim of this study was to evaluate whether the effect of adjuvant chemotherapy after CRT is modified by the histopathological stage after CRT using a pooled analysis of individual patient data.
Material and methods
Individual patient data from a previous pooled analysis on the prognostic value of a pCR after CRT for locally advanced rectal cancer were used. For that pooled analysis, studies were included when they evaluated patients with primary locally advanced rectal cancer that were treated with CRT and reported long-term outcome and response as well as patient and treatment characteristics. More details on the search strategy can be found in an earlier publication.10 From the primary literature search, 17 papers were identified of which 14 authors consented to participation in the previous analysis. For the present analysis, information was needed on the administration of adjuvant chemotherapy and/or about the ypT and ypN-stage. Such information was missing in three of these 14 datasets and these three datasets were not included for the current analysis.11-13
From one of the three datasets that could not be included at the time of the earlier publication, data was available for the current study.14, 15 Additionally, to increase the sample of patients with a pCR after CRT,- we contacted the first author of a study on the long-term outcome of a large group of patients with a pCR after CRT, who agreed to share the dataset.9 Thus, data from 13 centres were included for the present analysis.9, 14-26 Five studies were prospective17, 23, 27-29 and eight were retrospective9, 18, 20-22, 24, 25, 30, 31, for one dataset data was derived from an RCT.23 Baseline staging of patients before treatment consisted of endorectal ultrasound and computed tomography mostly. Interval between chemoradiation and surgery was generally 6-8 weeks. Surgery consisted of total mesorectal excision for all patients. Individual patients were excluded from the current pooled analysis for the following reasons: (1) data about administration of adjuvant chemotherapy was missing, (2) patients were treated with preoperative radiation only without concomitant chemotherapy, (3) radiotherapy dose ≤ 25 Gy, (4) presence of synchronous metastasis, (5) locally recurrent disease or (6) an incomplete resection (R1 or R2). Included for analysis were data on gender, age, clinical T- and N-stage, distance between tumour and anal verge, pathologic T- and N-stage, type of surgery (low anterior resection, abdominoperineal resection or other surgery e.g. Hartmann's procedure or exenteration), type of adjuvant chemotherapy and information on dates of events and/or follow-up times to events.
Based on histopathology of the resection specimen patients were categorised into: (1) pCR, defined as ypT0N0, (2) ypT1-2 and (3) ypT3-4. For an additional analysis to evaluate the effect of adjuvant chemotherapy in patients with ypN0 and ypN+, patients were categorised into subgroups according to pathological N-status (ypN-stage). For 147 patients (4%) the response category was missing (n=122) or was not consistent with one of the abovementioned categories (n=25, ypT0N+). These data, however, were included in the analysis to evaluate the effect of adjuvant chemotherapy in the total group of patients. The primary outcome measure was recurrence-free survival (RFS). Recurrence was defined as a local and/or distant recurrence during follow-up.
Statistical analysis
Baseline characteristics were compared between patients who did and did not receive adjuvant chemotherapy. Differences in baseline characteristics were tested for statistical significance with the independent samples t-test for the comparison of means and the Χ2-test for comparison of proportions. Outcome measures were RFS, defined as the absence of any recurrence (local or distant) during follow-up; disease-free survival (DFS), defined as the absence of both local and distant recurrence and death by any cause during follow-up; and overall survival (OS), defined as the absence of death from any cause during follow-up. Separate analyses were performed for local control (defined as the absence local recurrence and death by any cause during follow-up) or distant control (defined as the absence distant recurrence and death by any cause during follow-up). Follow-up time was calculated from the date of surgery to the date of the event of interest or the date of last follow-up (censoring date).
Multivariable Cox proportional hazards models with stratification for study centre were used to adjust for differences in baseline characteristics between patients who did and did not receive adjuvant chemotherapy within response groups. The proportional hazard assumption was evaluated graphically with log-minus-log plots.32 Trend tests based on Schoenfeld residuals were also used to assess departure of proportionality.32 Hazard ratios (HR) with 95% confidence intervals (CI) were calculated. The HRs that correspond with the variable coding for whether the patient received adjuvant chemotherapy or not indicate the relative risks of having an event during follow-up. A HR<1 indicates that the patients who received adjuvant chemotherapy had a lower probability of having an event.
To evaluate whether the effect of adjuvant chemotherapy was modified by the degree of response to CRT an interaction term for adjuvant chemotherapy and response to CRT was entered into the multivariable model. The three response groups were coded by two dummy variables using the response group with pCR as reference group. The HR associated with the interaction terms represent the ratio between the HR for response group ypT1-2 (or response group ypT3-4) and the HR of the reference group of patients with a pCR, indicating to what extent the effect of adjuvant chemotherapy is modified by the response to CRT. A similar analysis was performed with an interaction term for ypN-stage and adjuvant chemotherapy.
Analyses were performed with SPSS 16.0 and STATA 11.0. P-values<0.05 were considered statistically significant.
Results
In total 3313 patients were included, of whom 1723 (52%) underwent adjuvant chemotherapy. Adjuvant chemotherapy consisted of 5-FU with leucovorin in almost all patients. Some patients had additional other chemotherapeutic agents (e.g. oxaliplatin) together with 5-FU. Chemoradiation consisted of 45-50.4Gy in 25-28 fractions combined with FU-based chemotherapy. There were 898 patients with a pCR, 966 with ypT1-2 tumours and 1302 with ypT3-4 tumours. Approximately half of the patients with pCR (441/898) came from the study by Capirci et al, accounting for the relatively high number of patients with pCR.9 The majority of patients had a ypN0 status (n=2591, 80%). Median follow-up for all patients was 51 (range 0-219) months. Additional information and baseline characteristics per study are shown in table 1.
Table 1.
Overview of baseline characteristics per included study.
| Valentini | Crane | Capirci | Rödel | Nash | Kuo | Glynne-Jones | Garcia-Aguilar | Suárez | Calvo | Pucciarelli | Biondo | Theodoropoulos | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | 582 | 517 | 441 | 350 | 329 | 245 | 160 | 156 | 119 | 117 | 106 | 103 | 88 |
| Study type | Prospective cohort study | Retrospective cohort study | Retrospective cohort study | Prospective cohort study (RCT arm) | Retrospective cohort study | Retrospective cohort study | Prospective cohort study | Retrospective cohort study | Retrospective cohort study | Prospective cohort study | Retrospective cohort study | Prospective cohort study | Retrospective cohort study |
| Age | 61±11 | 57±12 | 62±10 | 67±9 | 59±12 | 58±13 | 63±12 | 60±12 | 68±10 | 65±11 | 60±9 | 59±10 | 63±11 |
| Gender (male) | 61% (357/582) | 63% (326/517) | 67% (293/439) | 70% (246/350) | 66% (216/329) | 59% (145/245) | 70% (112/159) | 55% (86/156) | 70% (83/119) | 67% (78/117) | 63% (67/106) | 73% (75/103) | 72% (63/88) |
| Missing | 0% | 0% | 1% (2/441) | 0% | 0% | 0% | 1% (1/160) | 0% | 0% | 0% | 0% | 0% | 0% |
| Follow-up | 50 (1-219) | 56 (0-168) | 39 (0-154) | 92 (3-156) | 69 (5-188) | 33 (1-121) | 37 (0-140) | 32 (1-111) | 42 (3-86) | 71 (0-143) | 61 (9-141) | 41 (0-94) | 33 (2-95) |
| cT-stage | |||||||||||||
| cT1 | 1% (4/512) | 0% (1/509) | 0% (1/438) | 0% | 0% (1/295) | 0% | 0% | 1% (2/156) | 0% | 0% | 0% | 0% | 0% |
| cT2 | 4% (19/512) | 6% (30/509) | 6% (28/438) | 5% (15/280) | 11% (31/295) | 7% (16/245) | 4% (6/158) | 5% (8/156) | 7% (8/118) | 3% (3/116) | 11% (11/104) | 2% (2/103) | 0% |
| cT3 | 82% (420/512) | 85% (433/509) | 85% (370/438) | 87% (244/280) | 84% (249/295) | 85% (207/245) | 49% (77/158) | 83% (130/156) | 88% (104/118) | 87% (101/116) | 70% (73/104) | 92% (95/103) | 94% (83/55) |
| cT4 | 14% (69/512) | 9% (45/509) | 9% (39/438) | 8% (21/280) | 5% (14/295) | 9% (22/145) | 47% (75/158) | 10% (16/156) | 5% (6/118) | 10% (12/116) | 19% (20/104) | 6% (6/103) | 6% (5/88) |
| Missing | 12% (70/582) | 2% (8/517) | 1% (3/441) | 20% (70/350) | 10% (34/329) | 0% | 1% (2/160) | 0% | 1% (1/119) | 1% (1/117) | 2% (2/106) | 0% | 0% |
| cN-stage | |||||||||||||
| cN+ | 76% (419/551) | 54% (277/509) | 40% (169/418) | 18% (59/329) | 54% (137/252) | 86% (182/212) | 53% (82/156) | 72% (112/156) | 42% (50/118) | 48% (54/113) | 65% (67/103) | 81% (79/98) | 48% (42/88) |
| Missing | 5% (31/582) | 2% (8/517) | 5% (23/441) | 6% (21/350) | 23% (77/329) | 14% (33/245) | 3% (4/160) | 0% | 1% (1/119) | 3% (4/117) | 3% (3/106) | 5% (5/103) | 0% |
| Distance from anal verge | NR | NR* | |||||||||||
| · · · | 65% (317/485) | 52% (267/517) | 44% (150/338) | 40% (131/329) | 50% (123/245) | 57% (91/159) | 37% (57/156) | 48% (57/119) | 43% (45/105) | 42% (45/106) | 55% (50/91) | ||
| > 5 cm | 35% (168/485) | 48% (250/517) | 56% (188/338) | 60% (198/329) | 50% (122/245) | 43% (68/159) | 64% (99/156) | 52% (62/119) | 57% (60/105) | 58% (61/106) | 45% (41/91) | ||
| Missing | 17% (97/582) | 0% | 3% (12/350) | 0% | 0% | 1% (1/160) | 0% | 0% | 10% (12/117) | 0% | 12% (12/103) | ||
| ypT-stage | |||||||||||||
| ypT0 | 20% (98/486) | 22% (111/512) | 100% (441/441) | 11% (38/348) | 22% (72/329) | 17% (42/242) | 22% (34/158) | 15% (24/156) | 14% (17/119) | 9% (10/117) | 18% (19/106) | 16% (16/103) | 19% (17/88) |
| ypT1 | 6% (31/486) | 6% (32/512) | 0% | 6% (22/348) | 8% (26/329) | 3% (7/242) | 4% (6/158) | 5% (8/156) | 4% (5/119) | 9% (11/117) | 8% (8/106) | 6% (6/103) | 1% 1(1/88) |
| ypT2 | 28% (138/486) | 30% (152/512) | 0% | 31% (109/348) | 32% (106/329) | 26% (63/242) | 15% (24/158) | 30% (46/156) | 25% (30.119) | 34% (40/117) | 43% (45/106) | 31% (32/103) | 21% (18/88) |
| ypT3 | 42% (205/486) | 37% (189/512) | 0% | 49% (169/348) | 38% (124/329) | 51% (124/242) | 53% (84/158) | 48% (75/156) | 53% (63/119) | 39% (46/117) | 31% (33/106) | 47% (48/103) | 55% (48/88) |
| ypT4 | 3% (16/486) | 6% (28/512) | 0% | 3% (10/348) | 0% (1/329) | 2% (6/242) | 6% (10/158) | 2% (3/156) | 3% (4/119) | 9% (10/117) | 1% (1/106) | 1% (1/103) | 5% (4/88) |
| Missing | 17% (96/582) | 1% (5/517) | 0% | 1% (2/350) | 0% | 1% (3/245) | 1% (2/158) | 0% | 0% | 0% | 0% | 0% | 0% |
| ypN-stage | |||||||||||||
| ypN+ | 25% (138/555) | 25% (123/492) | 0% | 30% (104/350) | 0% | 33% (80/245) | 25% (37/147) | 31% (47/154) | 24% (28/119) | 20% (23/117) | 19% (20/106) | 25% (26/103) | 33% (29/88) |
| Missing | 5% (27/582) | 5% (25/517) | 0% | 0% | 0% | 0% | 8% (13/160) | 1% (2/156) | 0% | 0% | 0% | 0% | 0% |
| Type of surgery | |||||||||||||
| LAR | 69% (400/582) | 66% (343/517) | 77% (339/441) | 68% (238/350) | 86% (282/329) | 82% (202/245) | 38% (60/160) | 60% (57/156) | 74% (88/119) | 59% (69/117) | 87% (92/106) | 60% (62/103) | 64% (56/88) |
| APR | 18% (103/582) | 28% (145/517) | 23% (100/441) | 25% (89/350) | 14% (47/329) | 14% (34/245) | 59% (95/160) | 38% (59/156) | 24% (28/119) | 41% (48/117) | 12% (13/106) | 40% (41/103) | 36% (32/88) |
| Other | 14% (79/582) | 6% (29/517) | 1% (2/441) | 7% (23/350) | 0% | 4% (9/245) | 3% (5/160) | 3% (4/156) | 3% (3/119) | 0% | 1% (1/106) | 0% | 0% |
| Missing | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 0% | 0% | |
| Response category | |||||||||||||
| ypT0N0 (pCR) | 20% (95/485) | 18% (90/491) | 100% (441/441) | 10% (36/346) | 22% (72/329) | 15% (36/236) | 18% (28/152) | 14% (21/153) | 14% (17/119) | 9% (10/117) | 18% (19/106) | 16% (16/103) | 19% (17/88) |
| ypT1-2 | 35% (169/485) | 38% (184/491) | 0% | 38% (131/346) | 40% (132/329) | 30% (70/236) | 20% (30/152) | 35% (54/153) | 29% (35/119) | 44% (51/117) | 50% (53/106) | 37% (38/103) | 22% (19/88) |
| ypT3-4 | 46% (221/485) | 44% (217/491) | 0% | 52% (179/346) | 38% (125/329) | 55% (130/236) | 62% (94/152) | 51% (78/153) | 56% (67/119) | 48% (56/117) | 32% (34/106) | 48% (49/103) | 59% (52/88) |
| Missing | 17% (97/582) | 5% (26/517) | 0% | 1% (4/350) | 0% | 4% (9/245) | 5% (8/160) | 2% (3/156) | 0% | 0% | 0% | 0% | 0% |
| Adjuvant chemotherapy | |||||||||||||
| Yes | 18% (107/582) | 73% (375/517) | 18% (81/441) | 85% (296/350) | 83% (272/329) | 60% (147/245) | 19% (31/160) | 21% (32/156) | 82% (97/119) | 62% (73/117) | 57% (60/106) | 100% (103/103) | 56% (49/88) |
| Type of chemotherapy | 5-FU | 5-FU and LV | 5-FU and LV or FA or FOLFOX | 5-FU | 5-FU and LV/OX/IRIN | 5-FU and LV (+/− levamisole) | 5-FU and LV | 5-FU and LV | 5-FU or CAP or XELOX | 5-FU and LV | 5-FU and LV | 5-FU and LV | 5-FU and LV |
For patients from this study, distance from the anal verge was categorized in ≤7cm or >7cm and therefore distance from anal verge could not be retrieved.
LAR=low anterior resection; APR=abdominoperineal resection; pCR=pathologic complete response (=ypT0N0). NR=not reported. 5-FU=5-fluorouracil; LV=leucovorin; FA=folic acid; FOLFOX=folic acid with 5-fluorouracil and oxaliplatin; OX=oxaliplatin; IRIN=irinotecan; CAP=capecitabine; XELOX=capecitabine with oxaliplatin.
Baseline characteristics for all patients and patients who did and did not undergo adjuvant chemotherapy are shown in table 2. Patients who underwent adjuvant chemotherapy were significantly younger than patients who did not undergo adjuvant chemotherapy. Furthermore, patients who underwent adjuvant chemotherapy had more proximal tumours, underwent a low anterior resection more often and had more advanced pathologic stages (higher ypT- and ypN-stage) than patients who did not undergo adjuvant chemotherapy (all p<0.0001).
Table 2.
Baseline characteristics for all patients and for patients categorized according to administration of adjuvant chemotherapy.
| All | No adjuvant chemotherapy (n=1590) | Adjuvant chemotherapy (n=1723) | p-value | |
|---|---|---|---|---|
| Age (years) | 61 (12) | 63 (11) | 60 (12) | p<0.0001 |
| Gender (male) | 64% (2119/3313) | 63% (1001/1590) | 65% (1118/1723) | 0.258 |
| Missing | 0% (3/3298) | 0% (2/1575) | 0% (1/1723) | |
| Clinical T-stage | ||||
| cT1 | 0% (9/3122) | 1% (7/1489) | 0% (2/1618) | |
| cT2 | 6% (177/3122) | 6% (93/1489) | 5% (84/1618) | 0.093 |
| cT3 | 83% (2586/3122) | 81% (1225/1489) | 84% (1361/1618) | |
| cT4 | 11% (350/3122) | 12% (179/1504) | 11% (171/1618) | |
| Missing | 6% (191/3313) | 5% (86/1590) | 6% (105/1723) | |
| Clinical N-stage | ||||
| cN+ | 56% (1729/3103) | 56% (846/1508) | 55% (883/1595) | 0.678 |
| Missing | 6% (210/3313) | 5% (82/1590) | 7% (128/1723) | |
| Distance from anal verge (cm) | ||||
| · · · | 50% (1333/2650) | 55% (606/1099) | 47% (727/1551) | <0.0001 |
| > 5 cm | 50% (1317/2650) | 45% (493/1099) | 53% (824/1551) | |
| Missing | 20% (663/3313) | 31% (491/1590) | 10% (172/1723) | |
| Type of surgery | ||||
| LAR | 70% (2324/3313) | 68% (1073/1590) | 73% (1251/1723) | |
| APR | 25% (834/3298) | 26% (416/1590) | 24% (418/1723) | <0.0001 |
| Other | 5% (155/3298) | 6% (101/1590) | 3% (54/1723) | |
| Missing | 0% | 0% | 0% | |
| Response category | ||||
| pCR | 28% (898/3166) | 41% (608/1478) | 17% (290/1688) | |
| ypT1-2 | 31% (966/3166) | 27% (400/1478) | 34% (566/1688) | <0.0001 |
| ypT3-4 | 41% (1302/3166) | 32% (470/1478) | 49% (832/1688) | |
| Missing | 4% (147/3313) | 7% (112/1590) | 2% (35/1723) | |
| Pathological N-stage | ||||
| N+ | 20% (655/3246) | 13% (194/1538) | 27% (461/1708) | <0.0001 |
| Missing | 2% (67/3313) | 3% (52/1590) | 1% (15/1723) | |
| Median follow-up time (months) | 51 (0-219) | 47 (0-219) | 55 (0-188) | <0.0001 |
Cm=centimetre; LAR=low anterior resection; APR=abdominoperineal resection; pCR=pathologic complete response (=ypT0N0).
In table 3 information on baseline characteristics are shown and compared per response category. Almost all patients had cT3 tumours before CRT (82% in the pCR group, 84% in the ypT0-2 group and 82% in the ypT3-4 group). In every of the 3 groups approximately half of patients had involved nodes before CRT.
Table 3.
Baseline characteristics for patients categorized according to their response to chemoradiation.
| pCR (n=898) | ypT1-2 (n=966) | ypT3-4 (n=1302) | p-value | |
|---|---|---|---|---|
| Age (years) | 61 (±11) | 61 (±11,5) | 61 (±12,0) | p=0.819 |
| Gender (male) | 66% (589/896) | 65% (632/966) | 65% (843/1302) | p=0.894 |
| Missing | 0,2% (2/898) | 0% | 0% (1/1302) | |
| Clinical T-stage | ||||
| cT1 | 0,5% (4/878) | 0,3% (3/924) | 0,1% (1/1215) | |
| cT2 | 8% (71/878) | 9% (81/924) | 2% (21/1215) | |
| cT3 | 82% (723/878) | 84% (776/924) | 82% (999/1215) | p<0.0001 |
| cT4 | 9% (80/878) | 6% (64/924) | 16% (194/1215) | |
| Missing | 2% (20/898) | 4% (42/966) | 7% (87/1302) | |
| Clinical N-stage | ||||
| cN+ | 50% (431/855) | 55% (501/907) | 59% (486/1198) | p<0.0001 |
| Missing | 5% (43/898) | 6% (59/966) | 8% (104/1302) | |
| Tumour height (cm) | ||||
| · · · | 53% (230/434) | 54% (491/912) | 45% (545/1201) | |
| > 5 cm | 47% (204/434) | 46% (421/912) | 55% (656/1201) | p<0.0001 |
| Missing | 52% (464/898) | 6% (54/966) | 8% (102/1302) | |
| Type of surgery | ||||
| LAR | 76% (680/898) | 71% (686/966) | 68% (882/1302) | |
| APR | 22% (196/898) | 25% (238/966) | 28% (367/1302) | p=0.001 |
| Other | 2% (22/898) | 4% (42/966) | 4% (53/1302) | |
| Missing | 0% | 0% | 0% |
Cm=centimetre; LAR=low anterior resection; APR=abdominoperineal resection; pCR=pathologic complete response.
Table 4 provides information on the prognostic value of ypT- and ypN- staging by showing the 5-year Kaplan Meier estimates of RFS, DFS and OS for patients not treated with adjuvant chemotherapy according to histological ypTN categories.
Table 4.
5-year Kaplan Meier estimates (wih 95% confidence intervals) of patients with varying response to CRT with regard to T- and N-stage who were not treated with adjuvant chemotherapy.
| Recurrence free survival | Disease-free survival | Overall survival | |
|---|---|---|---|
| pCR | 90% (87-93) | 87% (84-90) | 87% (83-90) |
| According to ypT-stage | |||
| ypT1-2 | 84% (79-87) | 78% (74-83) | 86% (81-89) |
| ypT3-4 | 60% (55-65) | 52% (46-57) | 63% (58-68) |
| According to ypN-stage | |||
| ypN0 | 81% (79-84) | 76% (73-79) | 81% (79-84) |
| ypN+ | 52% (43-60) | 47% (38-55) | 59% (50-67) |
| According to combined ypT- and ypN-stage | |||
| ypT1-2N0 | 85% (80-88) | 79% (74-83) | 86% (81-90) |
| ypT1-2N+ | 78% (59-89) | 76% (58-88) | 88% (70-95) |
| ypT3-4N0 | 68% (62-74) | 59% (52-64) | 69% (63-75) |
| ypT3-4N+ | 43% (32-53) | 36% (26-46) | 50% (38-60) |
pCR=pathologic complete response; RFS=relapse-free survival; DFS=disease-free survival; OS=overall survival.
Multivariable analyses
Multivariable Cox regression analyses were performed with inclusion of the following factors as independent variables: age, gender, clinical T-stage, clinical N-stage, type of surgery, administration of adjuvant chemotherapy. The proportional hazards assumption was not violated. When analyzing the combined data of all patients, the adjusted HRs indicated a better prognosis for patients who received adjuvant chemotherapy than for patients who did not. The adjusted HR for the effect of adjuvant chemotherapy on RFS was 0.81 (95%CI 0.66-0.99), for DFS the HR was 0.75 (95%CI 0.62-0.90) and for OS the HR was 0.69 (95%CI 0.56-0.85).
Figure 1 shows the forest plots displaying the HRs and 95%CIs for administration of adjuvant chemotherapy per ypT and per ypN-stage for RFS, DFS and OS. For patients with a pCR, the hazard ratios vary around ‘1’ with wide 95%CIs. For RFS, the HR was 1.25 (95%CI: 0.68-2.29) for patients with pCR. For DFS and OS the HRs for this response group were 0.94 (95%CI: 0.53-1.69) and 0.88 (95%CI: 0.48-1.59), respectively. For patients with ypT1-2 and ypT3-4 the HRs for RFS were 0.58 (0.37-0.89) and 0.83 (0.66-1.10), respectively. For DFS and OS the HRs were all <1 showing an obvious benefit for administration of adjuvant chemotherapy in these patient groups. A similar effect was seen when analysing the data for local recurrence and distant metastasis separately (data not shown). For patients with ypN0 the HR for adjuvant chemotherapy on RFS was 0.74 (95%CI: 0.57-0.96), while in patients with ypN+ the HR was 0.98 (95%CI: 0.71-1.36). For DFS similar results were found and for OS the difference in the HRs for adjuvant chemotherapy between patients with ypN0 and ypN+ was less pronounced: HR 0.67 (95%CI: 0.52-0.87) for ypN0 and HR 0.74 (95%CI: 0.49-1.12) for ypN+.
Figure 1.
Forest plots displaying the hazard ratios with 95% confidence interval derived from the comparison of patients treated with adjuvant chemotherapy and not treated with adjuvant chemotherapy (reference group) for the three response groups. (A) Recurrence-free survival, (B) disease-free survival and (C) overall survival. Factors in the multivariable Cox regression analyses were age, gender, cT-stage, cN-stage, type of surgery, ypN-stage and obviously administration of adjuvant chemotherapy. These analyses were stratified for the data providing centre.
To evaluate the robustness of the results for patients with pCR, we repeated the analysis without the patients with pCR from Capirci et al.9 The resulting HR of 1.24 (95%CI: 0.52-2.97) for RFS suggested no benefit from adjuvant chemotherapy for this subgroup.
Interaction
For RFS, the HRs for the interaction terms suggest a stronger effect of adjuvant chemotherapy in the response groups ypT1-2 (HR= 0.71 with 95%CI: 0.38-1.33, p=0.280) and ypT3-4 (HR=0.80 with 95%CI: 0.45-1.42, p=0.450) than in the subgroup with pCR, but the estimated interaction effects do not reach statistical significance. This analysis was repeated with an interaction term for ypN status and adjuvant chemotherapy. For RFS, the HR for the interaction term was 0.80 (95%CI: 0.55-1.16, p=0.241), indicating a larger effect of adjuvant chemotherapy in patients with ypN0 stage. For DFS and OS the interaction HRs were also non-significant.
Discussion
This pooled analysis suggests that the histological staging after chemoradiation and surgery for rectal cancer correlates with the effect of subsequent adjuvant chemotherapy. patients with pCR appear to have an excellent prognosis regardless of use of aCT. The potential benefit of aCT in patients with a pCR after CRT would appear to be small if it exists at all; however, proving the absence of such a small benefit would require a large randomized prospective trial and may not be warranted10. The results for patients with residual tumour that receive adjuvant chemotherapy are compatible with an improvement of the long-term outcome, with the largest benefit for the patients with ypT1-2 tumours after CRT.
In 2010 a review of randomized trials suggested that the effect of adjuvant chemotherapy in patients with rectal cancer treated with CRT was limited at best, and no single trial was large enough to detect a 5% improvement in 5-year survival.5 In 2012 a meta-analysis of 9785 patients with rectal cancer by the Cochrane collaboration found a significant improvement of DFS and OS with HRs of 0.75 and 0.83, respectively, when adjuvant 5FU based chemotherapy was administered. It was pointed out that there is much uncertainty as to which patient groups (according to TNM stage) might benefit most, particularly in the setting of multimodality neoadjuvant treatment. The results of this present pooled analysis with a HR for RFS of 0.81 (95%CI 0.66-0.99) are in accordance with a trend towards a survival benefit from adjuvant chemotherapy that was shown in two randomized trials that were included in the Cochrane review and used neoadjuvant treatment in a part of the patients.33, 34 Subgroup results of the QUASAR trial focusing on patients with rectal cancer showed a HR of 0.60 (95%CI: 0.30-1.20), in favor of adjuvant chemotherapy.33
Our finding that the effect of aCT is stronger in the ypT1-2 group than in the ypT3-4 group is consistent with the results from the subgroup analysis of the EORTC trial as published in 2007, where adjuvant chemotherapy was clearly beneficial for ypT0-2 tumours and no benefit was reported in patients with ypT3-4.34 A hypothesis is that the same factors drive both tumour sensitivity for the primary treatment with chemoradiation and sensitivity for adjuvant chemotherapy aimed at microscopic distant disease.8 The finding in the current pooled analysis that adjuvant chemotherapy seems to have an effect in patients with ypN0 tumours, but not in patients with ypN+ tumours also supports this hypothesis. However, a recent update from the EORTC trial with a median follow-up of 10 years did not confirm the earlier findings of the different effect or chemotherapy according to the response, and with again no overall benefit of adjuvant 5FU systemic therapy.35 One of the issues with the EORTC trial is the poor adherence to chemotherapy with <43% of patients receiving the planned dose in the predefined time. The authors suggested that this poor adherence to chemotherapy could explain the lack of effect of chemotherapy in the intention to treat analysis of the randomized trial, whereas the current pooled analysis is based on actual received treatment. Given these conflicting results the definitive effect of chemotherapy on long-term outcome in (subgroups of) rectal cancer remains unclear.
In colon cancer (not treated with neoadjuvant therapy) the decision to administer aCT is guided by the pathologic N-stage: patients with pathologic N+ stage have an indication for aCT. However, given the findings in this pooled analysis, in patients with rectal cancer who have been treated with CRT and have a pathologic N+ status might not benefit from aCT. These results show that decision making about aCT should be approached differently in neoadjuvantly treated patients with rectal cancer than in patients with colon cancer.
The results of this pooled analysis should be interpreted with caution because data were not derived from randomized trials. Due to confounding by indication the distribution of prognostic factors for survival may have differed between patients who received adjuvant chemotherapy and those who did not. An attempt was made to eliminate this bias by adjustment for these differences in a multivariable Cox regression model, but it is possible that some relevant prognostic factors were not captured in these multivariable analyses. For instance, no information was available on post-operative complications or co-morbidity of patients. Both factors may have guided the decision to withhold adjuvant chemotherapy. As a result, the group of patients who did not receive adjuvant chemotherapy may have had an elevated risk of death due to other diseases than rectal cancer. Such an imbalance would result in bias towards favoring adjuvant chemotherapy for the outcomes DFS and OS. However, the HRs for RFS are less likely to be biased, because this outcome does not comprise deaths and can therefore be considered a more valid and thus reliable estimate of effectiveness of adjuvant chemotherapy.
A limitation is that the majority of patients received 5-FU-based adjuvant chemotherapy. For colon cancer it has been shown that adding oxaliplatin to 5-FU and leucovorin improves DFS for stage III patients and leads to a (non-significant benefit) of 5.4% for stage II patients.36 It remains unclear whether the results of the present study are reproducible with a regimen that includes oxaliplatin.
A third limitation is that, although the results of the current pooled analysis support the presence of differential effects of adjuvant chemotherapy within different subgroups, there is no definite proof of treatment-by-response interaction. The HRs for the interaction terms suggest a stronger effect of adjuvant chemotherapy in the response groups ypT1-2 and ypT3-4 than in the subgroup with pCR, but the estimated interaction effects do not reach statistical significance. Tests for interaction are known to have limited power. Therefore, despite the large sample size, the power of this analysis to detect a significant interaction effect of this magnitude was only 39%. However, it cannot be concluded that lack of statistical significance indicates absence of interaction. The considerable differences in effect of adjuvant chemotherapy between the response groups strongly suggest the presence of effect modification by response to CRT even though the interaction test was not significant. Unfortunately, resolving the limitations that are inherent to pooled analyses of non-randomized individual patient data, a randomized controlled trial (RCT) or a pooled analysis of data from RCTs, would be the best design. However, again, a very large sample size is needed to achieve enough power to detect small but clinically relevant improvements in survival. This is particularly challenging when trying to obtain a large enough sample size of patients with a pCR, as the prevalence is only around 15-20%.10 Additionally, as chemotherapeutic regimens are often updated with newer (and possibly more effective) agents, the results of a RCT with the currently applied chemotherapeutic agents might no longer be clinically relevant upon completion of the RCT. Therefore, to provide definite evidence with a RCT will be very challenging. Whilst awaiting the results of such a RCT, the results of the current pooled analysis might therefore be used when contemplating on the use of adjuvant chemotherapy in individual patients.
Conclusion
Adjuvant chemotherapy in patients treated with CRT for locally advanced rectal cancer results in improved prognosis and treatment effects differ between subgroups. Patients with a pCR after CRT may not benefit from adjuvant chemotherapy, whereas patients with residual tumour do. Although the test for interaction did not reach statistical significance, the results strongly support further investigation of a more individualized approach to administer adjuvant chemotherapy after CRT and surgery based on final pathologic staging.
Novelty and impact of the paper.
Most patients with locally advanced rectal cancer receive adjuvant chemotherapy after neoadjuvant treatment and surgery. However, this paper shows that the benefit of adjuvant chemotherapy differs between subgroups, based on the response of patients to neoadjuvant chemoradiation. Patients with a complete response after CRT may not benefit from adjuvant chemotherapy, whereas patients with residual tumour have superior outcomes when adjuvant chemotherapy was administered.
Abbreviatons
- aCT
adjuvant chemotherapy
- CRT
chemoradiation
- RFS
recurrence free survival
- DFS
disease free survival
- OS
overall survival
- 95%CI
95% confidence interval
- pCR
pathologic complete response
- HR
hazard ratio
- RCT
randomized controlled trial
Footnotes
There are no acknowledgements for this paper.
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