Consolidation chemotherapy during neoadjuvant chemoradiation (CRT) for distal rectal cancer leads to sustained decrease in tumor metabolism when compared to standard CRT regimen

Consecutive patients with non-metastatic rectal adenocarcinoma located up to 7 cm from the anal verge (assessed by rigid proctoscopy) were eligible for the study after local IRB-approval (CAPPESQ 717/05; University of São Paulo School of Medicine). Informed consent was obtained from all individual participants included in the study. Baseline staging and assessment included full physical and digital rectal examination (DRE), rigid proctoscopy, endorectal ultrasound (ERUS) or high-resolution magnetic resonance (MR). Considering all patients underwent PET/CT, imaging additional regular chest and abdominal computerized tomography (CT) scans were omitted for systemic staging. All patients with cT2-4 N0-2 M0 were included in the study unless refusal to sign informed consent, refusal to undergo CRT, pregnancy or age <18 years were present. There was no difference in policy for the indication to neoadjuvant CRT between the two cohorts.

Clinical and radiological outcomes of the 99 patients undergoing standard CRT enrolled in the prospective study are available elsewhere [14]. Briefly, of the 99 patients, 16 developed cCR (16 %) and 7 had pCR (7 %) after radical surgery (23 % overall CR rate).

Overall, 12 patients underwent extended CRT with consolidation chemotherapy at the Angelita & Joaquim Gama Institute between 2012 and 2013. Of these, 7 patients developed cCR (58 %) and 1 had pCR (8 %) after this treatment strategy. Patient’s characteristics and baseline tumor features are available in Table 1. (Fig. 2).

Patients undergoing standard CRT had significantly more locally advanced disease when compared to consolidation CRT group in terms of cT status (cT3: 88 % vs 58 %; p < 0.001). Also, patients were less likely to develop complete pathological response or complete clinical response (23 % vs. 66 %; p = 0.004) after standard CRT.

Development of new alternative neoadjuvant regimens that could potentially increase complete tumor regression rates could have a major impact in the management and outcome of rectal cancer patients. Recently, an alternative CRT regimen incorporating additional cycles of 5FU-based chemotherapy (consolidation CRT) has resulted in significant increases in cCR rates ultimately avoiding surgery in more than half of patients with cT2/T3 rectal cancer [9]. In another recently reported phase II trial, the addition of multiple mFOLFOX6 cycles after CRT resulted in progressively higher complete pathological response rates after radical surgery [22].

It has been previously reported that a significant proportion of patients undergoing standard neoadjuvant CRT present an actual increase in SUVmax after 6 weeks from CRT completion, suggesting recuperation of metabolic activity of these tumors [19]. Patients that had an increase of metabolic activity after 6 weeks from standard CRT were found to have larger final tumor size. decreased rates of CR and decreased rates of near-complete responses. This could suggest that there was significant tumor repopulation at 6 weeks after standard CRT in a significant proportion of these patients [19]. In the present study, while 51 % of patients undergoing standard CRT had any increase in SUVmax between 6 and 12 weeks, only 18 % of patients undergoing extended CRT with consolidation chemotherapy were found to have this recuperation in metabolic activity. Altogether, these data suggest that after consolidation CRT, the average decrease in tumor metabolism is greater and tumor repopulation is less frequent when compared to standard CRT, at least between 6 and 12 weeks. Therefore, postponing assessment of tumor response after consolidation CRT until 12 weeks seems to be safer than doing so after standard CRT regimen. It may seem surprising that a rather modest increase in the amount of chemotherapy delivered after CRT may have resulted in such a significant reduction of tumor repopulation. However, one may have to consider that after a considerably high dose of radiation (54Gy), the presence of only residual microscopic foci could ultimately have been successfully eradicated by these additional cycles. In fact, the recently reported phase II trial suggests that the more additional chemotherapy, the higher chance of complete tumor regression and therefore, lesser chance of tumor cell repopulation [22]. Considering this latter study, there is a chance that not only the addition of oxaliplatin but also the use of more modern 5FU delivery options (oral or infusional) instead of bolus infusion used in our study, could contribute to increase response rates and block tumor cell repopulation.

One could argue that patients in the consolidation regimen had the last 2 PET/CTs performed while still on chemotherapy. This may have influenced the uptake of FDG by tumors cells resulting in decreased SUVmax values without representing true histological regression. This is the reason why it is recommended to perform FDG-PET imaging at least 2 weeks after completion of CRT for more reliable treatment monitoring. Still, the observed decreased SUVmax values after consolidation CRT did seem to correlate with final clinical outcomes by the overall cCR rates.

Finally, a longer follow-up with further sequential PET/CT imaging could have shown different outcomes. Ultimately, tumor repopulation after this extended CRT regimen may develop longer than 12 weeks. Therefore, longer follow-up could result in tumor recurrence (regrowths) after sufficient repopulation of cancer cells not detectable at 12 weeks due to the considerably small residual tumor burden. On the other hand, such study would require an excessive number of PET/CT imaging both in terms of cost and radiation exposure to these patients.

There have been a number of studies suggesting that a critical decrease in tumor metabolism that is associated with the development of a CR seems to be around 65 % after 6 weeks from CRT [13, 15‐18]. Therefore, tumors that exhibit an average ≥65 % decrease in SUVmax after 6 weeks from CRT are more likely to develop the single most clinically relevant outcome after CRT for rectal cancer: complete response. In our previously reported study, the average reduction in SUVmax of rectal cancers after 12 weeks from standard CRT was 63 % [19]. In that study, there was no further reduction in average SUVmax between 6 and 12 weeks from RT completion when all patients are considered [19]. However, when only patients with a complete response are considered, there is further decrease in SUV values. The critical SUVmax reduction cutoff considered to be significant for CR development was ≥67 % at 6 weeks and ≥76 % at 12 weeks. This reduction was found to be an independent predictor of CR in that series [15]. In the present study, patients undergoing neoadjuvant consolidation CRT presented an average 88 % reduction in SUVmax between baseline and 6 week-PET/CT. This SUVmax reduction was significantly greater than the observed after standard CRT regimen (88 % vs. 63 %; p < 0.001). Considering that 65 % reduction was critical to the development of a CR, one could expect that an 88 % average reduction would result in a significant increase in the CR rate of patients undergoing this novel CRT regimen. In fact, complete response rates were also significantly higher after consolidation CRT as already suggested in previous reports and in this independent group of patients enrolled in this study (66 % vs 23 %; p < 0.001). In fact, even though 12 patients may constitute a rather small number of patients, the rates of initial CR are quite similar between the reported series so far [9, 20].

Limitations of the present study are considerable and may have accounted for some of the findings. First, the number of patients included in the extended consolidation CRT assessed by sequential PET/CT imaging is rather small and results warrant further investigation in a larger sample size. As a result of a limited sample size, even though there was no change in policy for the indication of neoadjuvant CRT between the two cohorts, patients in the extended CRT group had more earlier disease stage (cT2 vs. cT3) that could potentially have influenced CR rates. Still, the observed metabolism profile and percentage reduction in SUVmax may be possibly more related to sensitivity to CRT than actual T classification. Also, baseline SUVmax was significantly lower in the consolidation CRT group. There are conflictive data to suggest that baseline SUVmax is predictive of response to CRT in patients with rectal cancer. Higher SUV values have been associated with improved response in some studies. However, our data failed to correlate baseline SUV with response [15]. In addition, percentage variation rather that crude SUV values would potentially correct any bias in this direction. Ultimately, several features may influence individual SUVmax between tumors that are difficult to control for.

Patients undergoing extended CRT with consolidation chemotherapy may develop more substantial reduction in tumor metabolism after 6 weeks from RT completion. This reduction in tumor metabolism may partially explain higher rates of complete regression after this treatment regimen. Also, the risk of developing tumor repopulation and increase in metabolism between 6 and 12 weeks is much lower after consolidation CRT. Therefore, assessment of tumor response may be safely postponed to 12 weeks in patients undergoing extended CRT (using consolidation chemotherapy) strategy.