Preliminary results of SG1 and SG2 from the Timing of Rectal Cancer Response to Chemoradiation study indicate that giving two cycles of chemotherapy (mFOLFOX-6) after CRT, and increasing the time interval between completion of CRT and TME (to an average of 11 weeks) may increase the pCR rate without significantly increasing CRT- or chemotherapy-related AEs, operative difficulty or post-operative complications, compared to traditional neoadjuvant CRT and an average waiting time of 6 weeks. Whether our observed increase in tumor response is attributable to the additional neoadjuvant chemotherapy or the longer CRT-to-surgery interval can not be conclusively determined by this trial.
Several retrospective case series have investigated the time interval between neoadjuvant therapy and surgery as a predictor of tumor response.10–12
Tulchinsky, et al assessed whether the time interval between neoadjuvant CRT and surgery affected operative and post-operative morbidity, pCR rate and disease recurrence in 132 patients with locally advanced rectal cancer treated with CRT and surgery. They found that patients operated on more than 7 weeks after CRT had a pCR rate of 35%, compared to 17% for patients operated on less than 7 weeks after CRT (p=0.03). The rate of peri-operative complications was similar in both groups. A longer CRT-to-surgery interval was also associated with significantly better disease-free survival.10
Their results were supported by Moore, et al who found a 19% pCR rate in patients operated on more than 44 days after CRT compared to 12% in patients operated within 44 days of CRT,11
and by Kalady, et al who reported a 31% pCR rate in patients operated on more than 8 weeks after CRT compared to 16% in patients operated on within 8 weeks of CRT.12
In Kalady’s study, an extended interval from CRT-to-surgery was the only factor associated with a higher pCR. In contrast, other studies report no difference in pCR rates with longer CRT-to-surgery intervals using similar, though not identical criteria.13–15
These discrepancies may be explained by differences in CRT regimens, arbitrary selection of the CRT-to-surgery intervals, and likely different definitions of tumor response.
The Lyon R90-01 study, the only prospective trial in which patients with locally advanced rectal cancer treated with radiation therapy were randomly assigned to have surgery at two different time intervals following CRT, showed that a 6–8 week interval resulted in a higher response rate compared to a 2-week interval. Furthermore, at a median follow-up of 33 months, no differences were found in morbidity, local recurrence, or survival between the two groups, suggesting that a longer interval from radiation to surgery increases tumor down-staging, with no detrimental effect on toxicity or early clinical results.16,17
However, in this study patients did not receive sensitizing chemotherapy during radiation, and the interval between radiation and surgery was only 8 weeks, closer to the short interval chosen in our study.
The effect of a more intense neoadjuvant regimen consisting of capecitabine and oxaliplatin before and concurrent with pre-operative radiotherapy in patients with locally advanced rectal cancer was initially investigated by Koeberle, et al. Surgery was performed 5 weeks after CRT. Most patients (98%) had an R0 resection, and 23% had a pCR.18
Unfortunately in this study pCR was defined as a complete or near complete pathologic response, and therefore their results can not be compared to ours. More recently, Chua, et al reported their results in stage II and III rectal cancer patients who received 12 weeks of capecitabine and oxaliplatin followed by CRT using capecitabine as radio-sensitizer. Patients had surgery 47 days (median) after finishing CRT. Twenty-one (20%) patients had a pCR,19
a rate lower than the 25% observed among patients of SG2 in our trial who only received 4 weeks of neoadjuvant chemotherapy before surgery. Although the chemotherapy used in both trials was different, comparison of the results suggests that the increase in pCR rate observed in SG2 of our study may be attributable in part to the longer CRT-to-surgery interval.
Habr-Gama, et al also studied the effect of a more intense neoadjuvant regimen on tumor response by adding chemotherapy.20
In their trial, patients with T3 or T4 tumors were treated with bolus infusion 5-FU-based CRT (total radiation dose, 54.0 Gy) followed by 3 additional cycles of bolus 5-FU over 9 weeks. Tumor response was assessed by clinical exam at protocol completion. A total of 22 out of 29 (76%) patients entered in the study had a complete clinical response and did not undergo surgery; 4 patients had recurrence within 12 months and required additional treatment. In total, 18 out of 29 (62%) patients had a sustained clinical response and had avoided surgery for at least 12 months. However, the follow-up in this study is still too short and the possibility that clinically occult cancer cells may remain viable and lead to a delayed tumor relapse can not be excluded.
The impact of delaying surgery on surgical difficulty and post-operative morbidity is an important consideration before a longer surgery interval between CRT and surgery can be recommended. Our study shows that delaying surgery does not affect the proportion of patients having an R0 resection or a sphincter-saving procedure. Surgeons in our study reported more pelvic fibrosis in patients operated on 11 weeks compared to 6 weeks after CRT, but these results should be interpreted with caution because the surgeons were not blinded to the timing of surgery. Interestingly, the increase in fibrosis did not translate into a significant increase in technical difficulty of the operation and more importantly, addition of chemotherapy during the longer CRT-to-surgery interval, did not increase the risk of post-operative complications, confirming previous observations. 21
A concern of the opponents of a longer CRT-to-surgery interval is the possibility of tumor spread that may ultimately lead to impaired survival. The trial by Francois, et al suggested there was no difference in survival when the CRT-to-surgery interval was 8 weeks,16
but a trial by Supiot, et al suggested otherwise.22
They examined the influence of delayed surgery on survival after pre-operative radiotherapy in T2-T4, N0-N1 M0 rectal cancer and found that an interval of more than 16 weeks between diagnosis and surgery may reduce overall survival for patients treated with pre-operative radiation. Their conclusions were that surgery should be performed shortly after completion of radiation. However, neither of these studies used systemic chemotherapy during the longer CRT-to-surgery interval. In our trial, patients received some of the systemic chemotherapy before surgery. The impact of splitting chemotherapy before and after surgery will need a longer follow-up.
There are a number of limitations of our trial that deserve mention. First, the primary study objective was to compare the pCR rate to CRT for stage II and stage III rectal cancers at different CRT-to-surgery intervals. However, given the trial design of sequential SGs, the study was not powered to determine statistically significant differences in pCR rate between SG1 and SG2 as might be considered in a larger multi-arm trial. Second, there were differences in treatment compliance between SG1 and SG2. CRT and radiation dosage was higher in SG2 compared to SG1, which could account for the higher pCR rate. However, it did not seem to influence the complication rate. Thirdly, it is worth noting that there were differences in tumor stage between SG1 and SG2. A higher proportion of patients in SG2 had T2 tumors compared to SG1 and this may explain the higher pCR rate observed in SG2. However, slightly more patients in SG2 had positive lymph nodes on clinical exam compared to patients in SG1 so this could equally affect the pCR rate. Lastly, the results presented are preliminary and a longer follow-up is needed to determine long-term outcomes of this regimen on recurrence and survival.
In conclusion, our preliminary results suggest that adding chemotherapy after CRT and extending the interval between CRT and surgery is well-tolerated by most patients and may lead to an increase in pCR rate without increasing the risk of surgical complications. Studies are underway to assess the impact of adding additional cycles of chemotherapy and further extending the interval between CRT and surgery.