4. Resultados
4.2 INTERACCION ENTRE EL USUARIO Y LA TARJETA
The combined modality treatment in locally advanced rectal cancer has considerably decreased the local recurrence as evident from the results of pivotal German trial discussed in section 1.9.2.1 (Sauer, et al., 2005). However, this approach does not translate into improvement in overall survival in these patients. In addition, pathological complete response has emerged as new and valid surrogate marker of DFS (Mass, et al. 2010). Various treatment strategies can achieve higher percentages of complete pathological response. Continuous infusion of concurrent chemotherapy compared to boluses and increased radiation doses can achieve significantly higher pathological complete response in approximately 50% of cases (Mohiuddin, et al., 2000). Currently there is no consensus on the optimal timing of surgery after finishing long course CRT. Another strategy is to delay the interval between CRT and surgery to allow more time for the tumour to shrink and thus increasing the possibility of pathological down staging. In the large randomized trials discussed in the section 1.9.2.1 (Sauer, et al., 2004) and the section 1.9.3 (Bosset, et al., 2006 and Gerard, et al., 2006), the median time interval to surgery was 5-6 weeks. Randomized data on the time interval between the completion of chemoradiotherapy and surgery is very limited. Lyons R90-01 is the only trail that randomized patients to have surgery at 2 week and 6-8 week time intervals after long course CRT. Patients in longer interval group experienced significant greater down staging as compared to the patients who had surgery within two weeks (26% vs. 10% (Francois, et al. (1999). As a result of this trial, delaying the surgery up to 6 weeks after radiotherapy completion was established as the standard of care.
However the retrospective analyses of case-series and analysis of non-randomized trials later showed the relevance of the time interval to increasing clinical and pathological down staging of rectal tumour. Further delaying the surgery beyond conventional 4 to 6 week window can lead to greater tumour response to long course chemoradiotherapy in a time
35
dependent fashion. In a retrospective pilot study by Johnston, et al. (2009) at the Colchester University Hospital, an on-going radiological tumour response for up to 12 weeks after completion of long course CRT was demonstrated when assessed by performing serial MRIs. There was significant decrease in T-stage from 6% on MRI performed at 6 week interval to 41.2% on the MRI performed just before surgery (P <0.001). Similarly, Moore, et al. (2004) observed a non-significant trend towards increased pathological complete response in their retrospective analyses of 157 rectal cancer patients treated with long course CRT. The rate of pathological complete response increased from 9% in the interval of 30-40 days, to 16% in 41-49 days and to 23% in >49 days. A retrospective cohort study showed significant increase in complete pathological response for the patients operated beyond 7 weeks after long course CRT than for the patients operated earlier than 7 weeks (35% vs. 17% P=0.03) (Tulchinsky, et al., 2008). In a prospective nonrandomized study by Garcia-Aguilar, et al. (2011), 25.4% of patients demonstrated complete pathological response at 11 week as compared to 18% at 6 week time interval (P<0.05). A recent meta- analysis of 13 studies (n-3584 patients) that mainly included retrospective or prospective case series and one non-randomized phase II trial, demonstrated that an interval beyond classical 6-8 weeks to surgery after finishing CRT, results in significantly improved pathological complete response from 14% to 20% (RR=1.42 CI: 1.19 -1.68, p<0.0001) (Petrelli, et al., 2016).
As it is evident from the discussion above that with the delay of surgical interval after CRT, there is a corresponding increase in tumour regression but there is little evidence about its short-term effect on surgical morbidity and long-term oncological outcomes. Conventional time interval of 4-6 weeks is optimal enough to allow for the resolution acute radiation reaction before surgery. By prolonging the time interval to surgery beyond this conventional time period can theoretically make TME technically more difficult because of radiation induced pelvic fibrosis. This might result in increase in surgical complications. In the meta- analysis (Petrelli, et al., 2016), the data on post-operative complications was available for 7
36
studies out of 13 in total. No difference was observed in the R0 resection, sphincter- preservation, wound and anastomotic complications for the patients operated beyond 8 weeks. None of the studies included in the meta-analysis individually reported any significant influence of time interval on the post-operative complications. Instead, longer time interval post CRT could decrease perioperative morbidity as reported by Kerr, Norton and Glynne- Jones (2008) in their retrospective analysis of 189 patients. This study demonstrated that shorter interval by 1 week (median interval 10 weeks) independently predicted anastomotic leakage (OR 0·97, 95% CI 0·94 to 1·00) and perineal wound complications (OR 0.97, 95% CI 0.95 to 0.99).
As for surgical morbidity, the meta-analysis (Petrelli, et al., 2016) did not demonstrate any difference in long-term OS and DFS rates between the shorter and longer interval (beyond 8 weeks) groups (6- studies, n-1360 patients). None of the studies comparing shorter and longer time interval to surgery after CRT has demonstrated any significant positive influence on overall survival despite achieving increasing rate of pathological complete response in the longer interval group. Long-term results of the Lyons R90-01 trial showed no significant difference in overall survival rate between the short-interval and long-interval groups (69% vs. 66% P=0.880) (Glehen, et al., 2003). Conversely, in the retrospective analysis of 102 patients treated with neo-adjuvant radiotherapy alone, the time interval to surgery from diagnosis longer than 16 weeks was significantly associated with decrease in OS and metastasis free survival (OR 2.05, P=0.05) (Supitot, et al., 2006). This highlights the detrimental effect on patient survival if surgery is delayed beyond 12 weeks as there is a potential risk for the subclinical tumour in situ to grow and spread in that time interval. Conversely, the retrospective study by Habr-gama, et al., (2008) showed the deferral of surgery for up to 12 weeks and beyond was safe. There was no difference in disease free survival overall survival between the patients operated before or after 12 weeks.
37