Review

Organ preservation in rectal cancer: have all questions been answered? Corrie A M Marijnen

Improved treatment strategies have eliminated local control as the major problem in rectal cancer. With increasing awareness of long-term toxic effects in survivors of rectal cancer, organ-preservation strategies are becoming more popular. After chemoradiotherapy, both watchful waiting and local excision are used as possible alternatives for radical surgery. Although these seem attractive strategies, many issues about the safety of organ preservation remain. Additionally, radiotherapy strategies are mainly aimed at intermediate and high-risk rectal tumours, and adaptation of this standard practice for a completely new treatment indication has yet to start. This Review will discuss the options and problems of organ preservation, and address the research questions that need to be answered in the coming years, with a specific focus on radiotherapy.

Introduction Different viewpoints exist about the optimal (neo)-adjuvant treatment for rectal cancer. Preoperative radiotherapy provides significantly better local control than postoperative radiotherapy.1,2 However, there is no international consensus about the radiation schedule or patient selection for radiotherapy for rectal cancer. Results from two studies3,4 with total mesorectal excision have shown a significant reduction in local recurrences after short-course preoperative radiotherapy (5 × 5 Gy, followed by immediate surgery). In many countries patients are treated with preoperative radiotherapy (45–50 Gy) in combination with chemotherapy based on the results of the FFCD 92035 and EORTC 229216 studies. Results from two studies7,8 comparing the efficacy of short-course radiotherapy with chemoradiation showed no significant difference in local recurrences. Surgery is the mainstay of cure for rectal cancer, but is, unfortunately, associated with serious adverse events1,9,10 both for patients with and without a permanent colostomy.11 In the past few years, the awareness of the delicate balance between cure and quality of life has risen, and the role of radical surgery for all patients with rectal cancer is increasingly questioned. The introduction of population screening has led to improved survival and to a shift towards more early detection of rectal cancers, with 35% of tumours detected by screening being Dukes stage A versus 14% in a non-screened population.12 If this finding is taken into account, together with the negative effects of rectal cancer treatment on quality of life for cancer survivors, treatment initiatives aimed at organ preservation are very timely.

Organ preservation Local excision is increasingly used instead of total mesorectal excision in early rectal cancers (figure 1). Findings from two studies13,14 showed good outcomes in selected T1 tumours, but not in high-risk T1 or T2–3 tumours. Although different techniques are used for local excision (varying from a simple mucosectomy to an extensive local excision, which can occasionally include www.thelancet.com/oncology Vol 16 January 2015

regional lymph nodes), transanal endoscopic microscosurgery is thought to be the standard of care because improved outcomes can be achieved as a result of superior accessibility, visualisation, and precision of resection compared with conventional local excision. Interest in organ preservation for T2–3 tumours has risen because of a series of publications by Habr-Gama and colleagues,15,16 showing that, in patients with a clinical complete response after chemoradiotherapy, close observation instead of radical surgery led to acceptable outcomes. A review17 shows that the positive results achieved by this group can be reproduced in some studies but not in others. Analyses of a large populationbased database incorporating nearly 40 000 patients with stage I colorectal cancer showed that local excision of T1–2 rectal cancer after neoadjuvant therapy might be a safe approach.18 Inclusion of patients in studies for organ preservation strategies varies greatly, with some studies including cT1–2 tumours, whilst others incorporate cT3–4 tumours.16, 19–22 In a review including individual data from 2323 patients who underwent chemoradiotherapy, a clear association was shown between the clinical T-stage and the likelihood of achieving a pathological complete response. With pathological complete responses of 58%, 28%, 16%, and 12% for cT1, cT2, cT3 and cT4, respectively,23 the success of the watch and wait approach clearly depends on the initial tumour stages included.

Lancet Oncol 2015; 16: e13–22 Department of Clinical Oncology, Leiden University Medical Center, Leiden, Netherlands (Prof C A M Marijnen PhD) Correspondence to: Prof Corrie A M Marijnen, Department of Clinical Oncology, Leiden University Medical Center, 2300 RC Leiden, Netherlands [email protected]

Assessment of clinical response Assessment of clinical complete response is difficult and probably the most limiting factor for safe introduction of the watch and wait strategy. Recommendations about assessment of clinical response are mainly eminence-based, and vary between different authors.19,24 As a result, the concordance between clinical and pathological complete response has proven to be challenging in many studies, as reviewed by Glynne-Jones and colleagues.25 26 A retrospective study in operated patients used the criteria for clinical complete response as defined by e13

Review

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B

Figure 1: Difference between total mesorectal excision specimen (A), including all mesorectal fat and anal sphincter and total mesorectal excision specimen (B), not including any lymph nodes

Habr-Gama and colleagues and identified a disappointing sensitivity of 26% with a specificity of 97% and a false positive rate of 27%. Additionally, twothirds of patients with ypT0 (ie, pathological T0 after neoadjuvant therapy) had residual mucosal abnormalities, and could not be regarded as having a complete clinical response according to the used definition. However, because only histological data were used in this study, the results might have been better if digital rectal examination had also been used. The ACOSOG Z6041 trial defined clinical complete response as the complete disappearance of a tumour on proctoscopic examination and reported a sensitivity of 85% and a specificity of 67% as a predictor of pathological complete response.27 The false positive rate was 33%. These results strengthen the idea that assessment of mucosal abnormalities is insufficient, and alternative ways to confirm pathological complete response need to be identified. Endoscopic biopsy is by far the easiest way to obtain tissue for histopathological examination, but retrospective series show poor accuracy in predicting a pathological complete response after neoadjuvant treatment (

Organ preservation in rectal cancer: have all questions been answered?

Improved treatment strategies have eliminated local control as the major problem in rectal cancer. With increasing awareness of long-term toxic effect...
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