Desley van Zoggel

Summary, discussion and future perspectives 141 CHAPTER 8 Summary The first chapter of this thesis is an introduction to the concept of locally recurrent rectal cancer (LRRC). It explains that whereas primary rectal cancer originates de-novo, a local recurrence is rather an outgrowth of persisting tumour cells after resection of the primary tumour. The cells of the recurrent tumour are more treatment resistant, having already survived treatment for the primary tumour. Therefore, treatment of LRRC needs to be approached differently. Achieving a resection with clear margins remains the single most important factor influencing survival in LRRC patients. However, achieving clearmargins is often a surgical challenge, as anatomical landmarks have been distorted due to primary surgery and other treatment modalities. In order to maximize the possibility of achieving clear margins, neoadjuvant treatment options are explored. The options include the already established role of chemoradiotherapy to downsize and downstage the tumour, but this thesis also introduced the principle of total neoadjuvant treatment with the addition of induction chemotherapy. A significant number of patients treated for locally recurrent rectal cancer develop local or systemic failure, especially after incomplete surgical resection. Because most patients have received preoperative (chemo)radiotherapy for their primary tumour, treatmentmodalities are limited. Even after reirradiation, incomplete resection remains an issue in LRRC patients. And even after successful treatment of the local recurrence, development of systemic disease remains the principal cause of death. We therefore investigated the importance of administering systemic chemotherapy early in the treatment plan. Induction chemotherapymight improve resectability by downsizing the local recurrence, and it may lead to an increased rate of pathological complete response resulting in better overall survival. It might even prevent early metastatic disease or offer best palliative treatment when metastatic spread is inevitable. The objective of the study in chapter 2 was to evaluate the influence of adding induction chemotherapy in LRRC patients who already underwent (chemo)radiotherapy for the primary cancer or an earlier local recurrence. In total 129 patients were included, of whom 58 were treated with a sequential neoadjuvant regimen including three to four cycles of systemic chemotherapy followed by chemoradiotherapy. These 58 patients were compared to the other 71 patients who received only chemoradiotherapy. Both groups showed similar clear resection margin rates (55 percent vs 49 percent, P = 0.506), while the induction chemotherapy group showed significantly more pathologic complete responders (17 percent vs 4 percent, P = 0.015). Furthermore, all patients who achieved pathologic complete response experienced better overall survival than others. The 3-year overall survival rate for pathologic complete responders was even 92 percent, whereas