The best treatment option for elderly patients with LARC remained controversial due to lacking in prospective clinical data[16, 17]. Though neoadjuvant chemoradiotherapy combined with TME surgery is the current standard treatment, many elderly patients can’t finish the whole treatment procedure because of comorbidities, treatment related morbidities and other personal reasons[7, 9, 16, 18-20]. Our study enrolled 85 patients at least 75 years with LARC. Fifty-six patients (65.9%) completed the scheduled neoadjuvant treatment and surgery procedure. We achieved promising survival outcomes with acceptable treatment related toxicities and complications.
Many studies have reported the incidence of neoadjuvant chemoradiotherapy related toxicity in elderly patients with LARC[12, 19-22]. Tougeron D, et al retrospectively evaluated safety of chemoradiotherapy in 125 patients with LARC over 70 years, about 15% of enrolled patients developed G3+ adverse events. In the study of ACCOR 12/PRODICE 2 phase III trial, the incidence of severe grade 3/4 preoperative chemoradiotherapy related toxicity in elderly patients (≥70 years) was 25.6%, while it was only 15.8% in younger patients (<70 years). A case-matched control study from Korea also showed higher rate of G3+ acute hematologic toxicity in elderly patients (≥70 years), compared with that in patients younger than 70 years (16.1% vs 9.0%). In our study, nine patients (16.1%) developed G3/4 neoadjuvant treatment related toxicities, which was comparable with the above studies. Compared with our previous report which included patients with a median age of 59 years (range: 50-67 years), patients in the present study also experienced more G3+ toxicities. Based on these findings, the incidence of neoadjuvant treatment related toxicity in elderly patients with LARC is indeed higher than that in younger patients, but it is quite acceptable. On the other hand, all patients in our study completed the radiotherapy procedure and only five patients experienced prolonged radiotherapy. This also indicated that neoadjuvant treatment is well tolerated in elderly patients with LARC. Surgery morbidity and mortality are another concerns for clinicians when performing surgery in elderly patients. It was reported that the mortality rate after TME surgery was at least 2-5%, and even higher in older patients. With the improvement of surgical and anesthesiological techniques, postoperative nutritional support and physical activity interventions, postoperative morbidity and mortality in most elderly patients are no longer different from their younger counterparts. In a prospective cohort study, the rates of postoperative complications for elderly patients and younger counterparts were 38.5% and 34.7%. As for the present study, most TME surgeries were performed with laparoscopic technique (85.4%), the postoperative morbidity rate was only 12.5%.
The rate of pCR is an important factor for assessing the effect of neoadjuvant chemoradiotherapy and it is also related with improved survival outcomes. The pCR rate is significantly influenced by the escalated dose to primary tumor. When receiving≥60 Gy irradiation, the pooled pCR rate was 20.4% in a mata-analysis. A prospective study from China recruited 63 patients with LARC, patients received IMRT with pelvic to 41.8Gy in 22 fractions and primary tumor to 50.6Gy simultaneously. The pCR rate was as high as 31.0%. Zhu, et al also investigated the effect of concomitant boost irradiation on pCR rate in a phase II study. The prescribed doses to the pelvic area and primary tumor were 50Gy in 25 fractions and 55Gy in 25 fractions, respectively. A total of 18 in 78 patients (23.7%) obtained pCR after surgery. However, when patients were treated without primary tumor dose escalation, the reported pCR rates only varied from 11.4% to 19.2[2, 26-28]. Regarding elderly patients with LARC, Jacobs L, et al retrospectively reviewed 42 patients aged≥70 years receiving neoadjuvant chemoradiotherapy, the irradiation dose to pelvic region was 50Gy in 25 fractions without primary tumor boost, pCR was merely observed in 3 patients (7.5%). In the present study, 91.8% of eligible patients received IMRT with boost irradiation to primary tumor of 55Gy in 25 fractions. The pCR rate was 21.4%, which was consistent with the previous meta-analysis. Another propensity-score matching analysis reported that the pCR rate wasn’t significantly different between elderly and younger patients (14.8% vs 17.1%, P=0.433). Obviously, elderly patients can also get benefit from dose escalation radiotherapy as their younger counterparts do.
The present study showed a significant relationship between surgery and survival outcomes. Patients who received surgery experienced better 3-year OS, DSS, DFS and LC than those who didn’t (85.5% vs 33.2%, 85.5% vs 51.9%, 78.0% vs 44.9%, 90.9% vs 61.4%). Similar to our study, Wang and colleagues evaluated outcomes with multimodal therapy for patients with LARC aged 75 years or older, they found that surgery brought significant benefit to patients who received radiotherapy. The 5-year cancer specific survival (CSS) for patients receiving surgery or not after chemoradiotherapy were 70.5% and 27.7% (P<0.001), respectively. A SEER based analysis also identified the important role of surgery on elderly patients with LARC, patients treated with non-operatively had inferior survival than those receiving surgery (HR 0.71, P=0.001). The cornerstone role of surgery in elderly patients with LARC was also unshakable.
There is another key point that should not be ignored. With increasing age, more patients would die from other comorbidities, such as cardiovascular, nervous system and pulmonary diseases. Eight patients died of comorbidities instead of rectal cancer, accounting for 25.8% of all deceased in our study. Considering this, DSS, DFS and LC are more suitable for evaluating the efficacy of multimodal therapy in elderly patients with LARC. Our study reported that the 3-year and estimated 5-year DSS, DFS and LC for patients receiving multimodal therapy were 85.5% and 73.3%, 78.0% and 63.2%, 90.9% and 84.4%, respectively. These results were quite comparable to the previous studies regarding elderly patients[12, 20-22, 29]. Notably, the oncologic outcomes of our study were not inferior than younger patients in other studies[2, 15, 21]. In the study of FFCD 9203, the reported 5-year progression free survival (PFS) and local recurrence rate (LRR) were 59.4% and 8.1%. Zhao, et al explored the use of concomitant dose escalation with HT in patients younger than 70 years with LARC. The estimated 5-year DFS and LC were 70.9% and 95.5%, which were similar with ours. Recently, Sung SY, et al conducted a propensity-score matching study to compare oncologic outcome and morbidity between elderly and younger patients after neoadjuvant chemoradiotherapy and TME surgery. Though the rates of acute hematologic toxicity and late complications were higher in elderly patients, no significant difference was observed regarding 5-year recurrence free survival (RFS) between elderly and younger patients (65.5% vs 67.7%, P=0.483). Thus, age may not be a determining factor when clinicians develop treatment strategies for elderly patients with LARC.
Watch-and-watch policy is an alternative for patients with cCR after neoadjuvant treatment, especially for elderly or frail patients[30-32]. With this approach, patients can avoid the inconvenience of colostomy and other surgery complications without the expense of survival, which may further led to a good quality of life. A meta-analysis enrolled 23 studies including 867 patients with respect to watch-and-wait strategy and surgery for patients with LARC. The pooled 2-year local regrowth was 15.7%, and most patients (95.4%) received salvage therapies. No significant difference was observed regarding non-regrowth recurrence, CSS, DFS and OS between patients with cCR after neoadjuvant treatment managed with watch-and-wait approach and surgery. Eleven patients obtained cCR after chemoradiotherapy in our study. Watch-and-wait approach was performed in seven patients. By the end of follow-up, only one patient suffered regrowth recurrence. The number of patients with cCR in present study was too small to draw meaningful conclusions, but to some extent, it showed promise to implement this approach in elderly patients with LARC.
Elderly patients were defined as patients older than 70 years in most of the previous studies[9, 12, 18, 21, 22]. However, rectal cancer mainly affects elderly people with a peak incidence of over 80 years. When people reach their 80th year, there is still life expectancy of nearly 10 years for both men and women. From this prospective, our study including patients 75 years or older might be more representable for geratic patients regarding rectal cancer. Limitations still exist in our study. The major limitation must be the retrospective nature, some patients’ medical records were incomplete which might compromise our conclusions. Another shortage is the relatively small number of our study group. Though we included patients treated ten years ago (2008), few elderly patients with LARC underwent neoadjuvant treatment before 2012 at our institute.