Chronicling Strides in Understanding and Managing Rectal Cancer

Over the last few decades, major strides have been made in understanding and managing rectal cancer, including new surgical techniques and treatment modalities. The question posed in the article by Benson et al is this: Have these advances made a significant difference to patients with rectal cancer in terms of local recurrence, long-term survival, and quality of life? The authors chronicle the advances made by reviewing some of the landmark studies.

They start by examining surgical techniques and pathologic assessment, emphasizing the importance of total mesorectal excision (TME) in the surgical treatment of rectal cancer. Initially described by Heald and colleagues in 1982, TME has undergone some modifications but is now the gold standard in surgical treatment of rectal cancer. Its irrefutable advantages include significantly reduced rates of local recurrence and improved quality of life. In addition, the authors point out advances in laparoscopy, especially with colon cancer resection, as demonstrated by the Clinical Outcomes of Surgical Therapy (COST) trial in 2004. However, some of those advantages have not been shown in rectal cancer resection. In fact, in men with rectal cancer, laparoscopy negatively affects sexual function, and of even greater concern is its association with a higher likelihood of a positive circumferential resection margin (CRM). It is hoped that ongoing randomized controlled trials comparing laparoscopic vs open TME will better address the key relationships among TME, CRM, laparoscopy, and local recurrence rates.

Preoperative staging modalities are also discussed. They are important in determining treatment options. In the United States, preoperative staging is typically done with endorectal ultrasound (ERUS), whereas Europeans prefer to use contrast-enhanced MRI. Clearly, the changes in diagnostic and surgical techniques over the years have tended to positively impact the postoperative outcome.

The authors elucidate the dilemma of neoadjuvant therapy in patients with nonfixed disease who are at increased risk of recurrence, as well as the problems of undertreatment or overtreatment as demonstrated by multiple studies. Before 2004, the conventional treatment approach for T3 or node-positive rectal cancer was surgery followed by chemoradiation. However, the results of the German CAO/ARO/AIO trial showed a significant increase in sphincter-preservation surgery and decrease in local recurrence with preoperative chemotherapy (as compared with postoperative chemoradiation), although survival rates were the same. The authors note no change in sphincter preservation in the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial yet emphasize its limitations. Whatever the interpretation, most clinicians believe there is a benefit to neoadjuvant chemoradiation, and it is presently a standard of care in the United States.

Benson et al then address the selective use of radiation therapy. Clinicians in the United States and Europe have clearly different opinions about use of radiation therapy in the preoperative setting. The European literature features the opinion that liberal use of the combined-treatment modality (chemoradiotherapy [CMT]) in the United States leads to overtreatment, as demonstrated in the German trial. Preoperative chemoradiation for T3Nany rectal cancer remains the standard of care in the United States.

With regard to new chemoradiation regimens, the authors review several studies, focusing on two major outcomes measures: the pathologic complete response (pCR) rate and toxicity. Of four randomized controlled trials, three found that use of oxaliplatin (Eloxatin) in preoperative CMT not only did not improve the pCR rate but also increased toxicity. The authors allude to the unclear treatment effect of new biologic agents such as bevacizumab (Avastin). They also briefly comment on new and still-rudimentary radiation techniques such as 3-D and intensity-modulated radiation therapy (IMRT), both of which have been shown to decrease the volume of small bowel in the radiation field. Routine use of those techniques is actually rare.

In their article, Benson et al address the relatively low survival rate of rectal cancer patients in relation to the issue of adjuvant chemotherapy. In patients who have a pCR after neoadjuvant chemoradiation, adjuvant chemotherapy remains controversial. The European Organisation for Research and Treatment of Cancer (EORTC) 22921 and the Fdration Francophone de Cancrologie Digestive (FFCD) 9203 studies did not definitively show any improvement in survival of rectal cancer patients who underwent adjuvant chemotherapy. However, as the authors point out, a limitation of the EORTC study was that just 43% of patients underwent more than 95% of the planned postoperative chemotherapy. The authors extrapolate from the multiple colon cancer studies that adjuvant chemotherapy after neoadjuvant chemoradiation and surgery actually improves survival in rectal cancer patients; that conclusion, though likely true, has not yet been sufficiently proven by any randomized trials. Thus, in the United States, unlike in some European countries, rectal cancer patients undergo 4 months of adjuvant chemotherapy. The authors note that, as suggested by a subgroup analysis of the EORTC study, rectal cancer patients who respond to neoadjuvant chemoradiation derive a survival benefit from adjuvant chemotherapy. In addition, they point out that such a survival benefit was also demonstrated in the MD Anderson Cancer Center retrospective series and in a Canadian retrospective study.

One criticism is that the authors did not address local excision (LE), an alternative to TME for early rectal cancer. LE is associated with lower morbidity and mortality, but the local recurrence rate is increased when LE is used alone. Preliminary results from the American College of Surgeons Oncology Group (ACOSOG) Z6041 trial assessing neoadjuvant chemoradiation and LE for T2N0 rectal cancer showed 44% of patients achieved a pCR.[1] Long-term results of LE after neoadjuvant chemoradiation for T2 and T3 rectal cancer published by Nair et al also showed a 43% pCR and a 5-year survival rate of 81%.[2] Although more research needs to be done, in the future selected patients might be treated routinely with limited operations or watchful waiting after neoadjuvant chemoradiation.[3]

Undoubtedly, advances in the treatment of rectal cancer over the last few decades have led to clinical improvement. Some changes, such as TME and CMT, have lengthened survival time and enhanced the quality of life. However, radiation therapy may have a negative impact on quality of life, especially in males. Future research needs to focus not only on survival but also on postoperative quality of life.

Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Garcia-Aguilar J, Shi Q, Thomas CR Jr, et al. A phase II trial of neoadjuvant chemoradiation and local excision for T2N0 rectal cancer: preliminary results of the ACOSOG Z6041 trial. Ann Surg Oncol. Jul 14, 2011. Epub ahead of print.

2. Nair RM, Siegel EM, Chen D-T, et al. Long-term results of transanal excision after neoadjuvant chemoradiation for T2 and T3 adenocarcinomas of the rectum. J Gastrointest Surg. 2008;12:1797-806.

3. Habr-Gama A, Perez RO. Non-operative management of rectal cancer after neoadjuvant chemoradiation. Br J Surg. 2009;96:125-7.