Induction chemotherapy before chemoradiotherapy and surgery for locally advanced rectal cancer : is it time for a randomized phase III trial?
BACKGROUND
in the era of preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME), the development of distant metastases is the predominant mode of failure in rectal cancer patients today. Integrating more effective systemic therapy into combined modality programs is the challenge. The question that needs to be addressed is how and when to apply systemic treatment with adequate dose and intensity.


METHODS
this review article focuses on phase II-III trials designed to improve 5-fluorouracil (5-FU)-based combined modality treatment for rectal cancer patients through the inclusion of concurrent, adjuvant or, most recently, induction combination chemotherapy. Computerized bibliographic searches of PubMed were supplemented with hand searches of reference lists and abstracts of ASCO/ASTRO/ESTRO meetings.


RESULTS
after preoperative CRT and surgical resection, approximately one third of patients do not receive adjuvant chemotherapy, mainly due to surgical complications, patients' refusal, or investigator's discretion. In order to be able to apply chemotherapy with sufficient dose and intensity, an innovative approach is to deliver systemic therapy prior to preoperative CRT rather than adjuvant chemotherapy. Emerging evidence from several phase II trials and, recently, randomized phase II trials indicate that induction chemotherapy is feasible, does not compromise CRT or surgical resection, and enables the delivery of chemotherapy in adequate dose and intensity. Although this approach did not increase local efficacy in recent trials (e.g., pathological complete response rates, tumor regression, R0 resection rates, local control), it may help to improve control of distant disease.


CONCLUSIONS
whether this improvement in applicability and dose density of chemotherapy will ultimately translate into improved disease-free survival will have to be tested in a larger phase III trial.
Klinik für Strahlentherapie und Onkologie, Universität Frankfurt, Frankfurt am Main, Germany. claus.roedel@kgu.de
Claus
C
Rödel
Dirk
D
Arnold
Heinz
H
Becker
Rainer
R
Fietkau
Michael
M
Ghadimi
Ullrich
U
Graeven
Clemens
C
Hess
Ralf
R
Hofheinz
Werner
W
Hohenberger
Stefan
S
Post
Rudolf
R
Raab
Rolf
R
Sauer
Frederick
F
Wenz
Torsten
T
Liersch
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003131:Combined Modality Therapy; D018450:Disease Progression; D005240:Feasibility Studies; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D018714:Radiotherapy, Adjuvant; D016032:Randomized Controlled Trials as Topic; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery*; D012007:Rectum / Q000473:pathology / Q000601:surgery
D005472:Fluorouracil