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Strahlentherapie und Onkologie

Review Article

Induction Chemotherapy before Chemoradiotherapy and Surgery for Locally Advanced Rectal Cancer Is It Time for a Randomized Phase III Trial? Claus Rödel1, Dirk Arnold2, Heinz Becker3, Rainer Fietkau4, Michael Ghadimi3, Ullrich Graeven5, Clemens Hess6, Ralf Hofheinz7, Werner Hohenberger8, Stefan Post9, Rudolf Raab10, Rolf Sauer4, Frederick Wenz11, Torsten Liersch3

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. Material and 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. Conclusion: 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. Key Words: Rectal cancer · Induction chemotherapy · Chemoradiotherapy Strahlenther Onkol 2010;186:658–64

DOI 10.1007/s00066-010-2194-2 Induktionschemotherapie vor Radiochemotherapie und Operation beim lokal fortgeschrittenen Rektumkarzinom: Zeit für eine randomisierte Phase-III-Studie? Hintergrund: Nach Einführung der präoperativen Radiochemotherapie (RCT) und der totalen mesoerektalen Excision manifestieren sich Rezidive beim Rektumkarzinom am häufigsten als Fernmetastasen. Daher ist die Integration einer systemisch effektiveren Therapie in das multimodale Behandlungskonzept derzeit die entscheidende Herausforderung. Die Frage ist, wann und wie diese Systemtherapie mit adäquater Dosis und Intensität verabreicht werden kann. 1

Klinik für Strahlentherapie und Onkologie, Universität Frankfurt, Frankfurt am Main, Germany, Klinik und Poliklinik für Innere Medizin IV, Universität Halle, Halle, Germany, 3 Klinik für Allgemein- und Visceralchirurgie; Universität Göttingen, Göttingen, Germany, 4 Strahlenklinik, Universität Erlangen, Erlangen, Germany, 5 Klinik für Hämatologie, Onkologie und Gastroenterologie, Kliniken Maria Hilf GmbH, Mönchengladbach, Germany, 6 Klinik für Strahlentherapie und Radioonkologie, Universität Göttingen, Göttingen, Germany, 7 III. Medizinischen Klinik Hämatologie und Internistische Onkologie, Universitätsmedizin Mannheim, Mannheim, Germany, 8 Chirurgische Klinik, Universität Erlangen, Erlangen, Germany, 9 Chirurgische Klinik, Universitätsmedizin Mannheim, Mannheim, Germany, 10 Klinik für Allgemein- und Visceralchirurgie; Klinikum Oldenburg, Oldenburg, Germany, 11 Klinik für Strahlentherapie und Radioonkologie, Universitätsmedizin Mannheim, Mannheim, Germany. 2

Received: May 7, 2010; accepted: September 27, 2010 Published online: November 30, 2010

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Strahlenther Onkol 2010 · No 12 © Urban & Vogel

Rödel C, et al. Use of Induction Chemotherapy in Locally Advanced Rectal Cancer

Material und Methoden: Der Übersichtsartikel beschreibt Phase II–III Studien, deren Ziel es war, die allein 5-FU-basierte multimodale Behandlung durch Hinzunahme einer Kombinations-Chemotherapie, simultan zur Radiotherapie, adjuvant oder als Induktionstherapie, zu verbessern. Dazu diente eine Suchabfrage in Pubmed, in Referenzlisten publizierter Arbeiten sowie Abstrakts von ASCO/ASTRO/ESTRO-Konferenzen. Ergebnisse: Nach präoperativer RCT und Operation erhalten etwa ein Drittel aller Patienten wegen postoperativer Komplikationen, patientenseitiger Ablehnung oder Entscheidung des betreuenden Arztes keine adjuvante Chemotherapie. Ein innovativer Ansatz ist die Induktionschemotherapie vor präoperativer RCT und Operation, um die systemische Therapie in ausreichender Dosierung und Intensität durchführen zu können. Eine Vielzahl an Phase II-Studien, und zuletzt auch randomisierter PhaseII-Studien, zeigte, dass dieses Konzept durchführbar ist, die anschließende RCT und Operation nicht kompromittiert sowie die systemische Komponente in adäquater Dosis und Intensität applizierbar macht. Wenngleich dadurch die lokale Wirksamkeit (histopathologisch bestätigte Komplettremission, Tumorregression, R0-Resektionsrate, lokale Kontrolle) nicht verbessert wurde, könnte sich dieses Vorgehen positiv auf die systemische Tumorkontrolle auswirken. Schlussfolgerung: Eine Phase-III-Studie muss klären, ob die verbesserte Durchführbarkeit und Dosisdichte einer Induktionschemotherapie das krankheitsfreie Überleben verbessern kann. Schlüsselwörter: Rektumkarzinom · Induktionschemotherapie · Radiochemotherapie

Introduction Radiotherapy (RT) or chemoradiotherapy (CRT) and surgical resection are important elements of multimodality treatment for patients with locally advanced rectal cancer. The optimum sequence of these modalities has been addressed in several randomized trials, and preoperative RT/CRT has been shown to be superior to postoperative treatment for a variety of endpoints [24, 30, 32]. With optimized local treatment, achieved through preoperative RT/CRT and total mesorectal excision (TME) surgery, local recurrence rates are less than 10%. The development of distant metastases is now the predominant mode of failure in rectal cancer (30–35%). Thus, integrating more effective systemic therapy into combined modality programs is the challenge. Newer generation chemotherapeutics, such as oral fluoropyrimidines, oxaliplatin, irinotecan, as well as molecularly targeted agents (cetuximab, bevacizumab) have been incorporated into phase I–II studies for preoperative CRT protocols (for review see [21, 28]). Phase III trials are needed to determine whether these regimen offer an advantage compared with 5fluorouracil (5-FU)-based combined modality regimen. These studies have now been started—and partially completed—in Europe and the US (Table 1). Interestingly, early results from the ACCORD 12/0405-Prodige 2 and STAR trial did not confirm a significant improvement of early endpoints, such as the pCR rate, with the addition of oxaliplatin to preoperative 5FU-based CRT [1, 13]. Long-term results are awaited. Given the fact that the cumulative doses of the new drugs reached during preoperative RT are substantially lower than in adjuvant colon cancer trials and are probably not able to sufficiently reduce distant metastases, the question that needs to be addressed is how and when to apply systemic treatment with adequate dose and intensity. Postoperative Chemotherapy After Preoperative Radiotherapy or Chemoradiotherapy? Generally, there are no sufficient data on postoperative 5-FU chemotherapy after preoperative treatment with RT

Strahlenther Onkol 2010 · No 12

or 5-FU CRT [3]. In the EORTC 22921 trial, postoperative chemotherapy with 5-FU and folinic acid had a nonsignificant influence with improvement of relapse-free and overall survival [2]. Exploratory post hoc subgroup analyses suggest that predominantly good-prognosis patients with downsizing of cT3–4 to ypT0–2 benefit from adjuvant chemotherapy [9]. An Italian study randomized 635 patients after preoperative CRT with 5-FU and surgery to six courses of bolus 5-FU/folinic acid versus observation. Preliminary results of this trial were reported as an abstract only and showed no benefit of adjuvant chemotherapy for recurrence-free and overall survival (V. Valentini personal communication). The QUASAR study tested the value of postoperative 5-FU/folinic acid chemotherapy versus observation in (mostly) stage II colon (n = 2291) and rectal (n = 948) cancer patients [26]. Of the latter, 203 had received preoperative RT and 264 postoperative RT. There was a significant improvement of recurrence-free (HR 0.68, 95% CI 0.52–0.88, p = 0.004) and overall survival (HR 0.77, 95% CI 0.54–1.00, p = 0.05) with the addition of postoperative chemotherapy for all 948 rectal cancer patients. This effect was much the same regardless of whether patients had received preoperative RT, postoperative RT, or no RT at all, although it was not statistically significant for the preoperative RT subgroup (HR for death 0.44, 95% CI 0.25–1.10). In patients treated with 5×5 Gy preoperative RT, post-operative chemotherapy has not been evaluated so far but is currently being investigated in a randomized trial (SCRIPT, simply capecitabine in rectal cancer after irradiation plus TME). Another randomized trial (CHRONICLE), which investigated postoperative chemotherapy with capecitabine and oxaliplatin versus observation only after preoperative 5-FU-based CRT, was unfortunately closed due to poor accrual. Thus, a recent European consensus conference failed to reach a definitive recommendation regarding the use of postoperative chemotherapy after preoperative CRT/RT and surgical resection [35]. The German S3 guidelines continue to recommend postoperative 5-FU chemotherapy after preoperative CRT,

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Table 1. Ongoing or recently completed phase III trials with novel drugs and combination chemotherapy for rectal cancer patients. RT: radiotherapy, CT chemotherapy, TME total mesorectal excision; ACCORD: Actions Concertées dans les Cancers Colorectaux et Digestifs; STAR: Studio nazionaleTerapia neoAdiuvante Retto; NSABP: National Surgical Adjuvant Breast and Bowel Project; CHRONICLE: Chemotherapy or no chemotherapy in clear margins after neoadjuvant chemoradiotherapy in locally advanced rectal cancer; CAO/ARO/AIO: Chirurgische Arbeitsgemeinschaft für Onkologie/Arbeitsgemeinschaft Radiologische Onkologie/Arbeitsgemeinschaft Internistische Onkologie; ECOG: Eastern Cooperative Oncology Group; PETACC: Pan-European Trials in Alimentary Tract Cancer. Tabelle 1. Laufende oder kürzlich abgeschlossene Phase-III-Studien mit neuen Chemotherapie-Kombinationen für Patienten mit einem Rektumkarzinom. Preoperative treatment

Surgery

Postoperative treatment

Primary endpoint

Study status

ACCORD 12/0405

RT 45 Gy + Capecitabine versus RT 50 Gy + Capecitabine + Oxaliplatin

TME TME

Post-op CT free in each institution Post-op CT free in each institution

pCR

Follow-up

STAR 01

RT 50.4 Gy + 5-FU versus RT 50.4 Gy + 5-FU + Oxaliplatin

TME TME

5-FU based CT 5-FU based CT

Disease-free survival

Follow-up

NSABP R-04

RT 50.4 Gy + 5-FU versus RT 50.4 Gy + 5-FU + Oxaliplatin versus RT 50.4 Gy + Capecitabine versus RT 50.4 Gy + Capecitabine + Oxaliplatin

TME TME TME TME

(patients may enter ECOG-E5204)

Loco-regional relapse rate

Follow-up

CHRONICLE

RT ≥ 45 Gy + 5-FU ± Leucovorin or Capecitabine

TME

Observation versus Capecitabine + Oxaliplatin

Overall survival

Stopped

ECOG-E 5204

RT 40–55.8 Gy + Chemotherapy according to NSABP-04 or 5-FU PVI/Capecitabin ± Oxaliplatin or 5-FU + Leucovorin

TME TME

Oxaliplatin + 5-FU/Leucovorin versus Oxaliplatin + 5-FU/Leucovorin + Bevacizumab

Overall survival

Stopped

CAO/ARO/AIO-04

RT 50.4 Gy + 5-FU versus RT 50.4 Gy + 5-FU + Oxaliplatin

TME TME

5-FU versus 5-FU + Oxaliplatin


Follow-up

PETACC 6

RT 45 Gy + Capecitabine versus RT 45 Gy + Capecitabine + Oxaliplatin

TME TME

Capecitabine versus Capecitabine + Oxaliplatin


Recruiting

as reported in almost all recent trials, including the German CAO/ARO/AIO-94 study which included standard postoperative chemotherapy, the EORTC 22921 trial which showed a clear, albeit nonsignificant, trend for improved disease-free and overall survival, and the QUASAR study which was also positive for rectal cancer patients [33]. In North America, 4 months of postoperative chemotherapy with FOLFOX is recommended after preoperative CRT [22]. This is based on extrapolating results from adjuvant colon cancer trials to rectal cancer patients. Two multicenter phase II trial (the CORE study, and a phase II study from the German Rectal Cancer Study Group) investigated the feasibility of preoperative concomitant CRT with capecitabine and oxaliplatin (CAPOX) plus 4–6 cycles of adjuvant CAPOX chemotherapy following resection [27, 31]. The most important findings of the German phase II trial were that only 60% of the entire cohort of 103 operated patients were able to complete all four postoperative CAPOX cycles (with or without dose reduction); 27% did—for various reasons—not receive any adjuvant chemotherapy. The CORE study reported similar figures with 35% of patients not receiving any adjuvant CAPOX, and a further 14% of patients stopped adjuvant chemotherapy prematurely. Thus, it is evident that preoperative CRT, surgical complications, and the

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fact that a substantial proportion of patients will have pCR or yTNM stage I and II tumors due to downstaging effects (or initial clinical staging errors) compromise the possibility and willingness of patients (and physicians) to tolerate (or recommend) postoperative chemotherapy. Induction Chemotherapy Prior to Preoperative Chemoradiotherapy 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. This strategy, however, may also be associated with its own caveats, such as selection of radioresistant clones, induction of accelerated repopulation, possibly reduced compliance to CRT, and a substantial delay of definitive surgery [15]. Clinical results of phase II trials are given in Table 2 [6–8, 16, 18]. The largest series of Chau and colleagues (first published in 2006 with 77 patients, updated 2010 with 105 patients) examined the use of four cycles of induction capecitabine plus oxaliplation (CAPOX) followed by CRT with capecitabine [7, 8]. These authors reported a 20% pCR rate for patients with magnetic resonance imaging (MRI)-defined poor-risk tumors. Since there is an almost 6 month interval between diagnosis and surgery, the radiologic



Table 2. Phase II studies with induction chemotherapy (ICT) prior to preoperative chemoradiotherapy (CRT) with or without adjuvant chemotherapy (ACT) in rectal cancer patients. 5-FU: 5-Fluorouracil; MMC: Mitomycin C; CR: complete response; PR: partial response; SD: stable disease; bid: twice daily; PD: progressive disease; pCR: pathological complete response; CT: chemotherapy; RT: radiotherapy. Tabelle 2. Phase-II-Studien mit Induktionschemotherapie vor präoperativer Radiochemotherapie mit oder ohne adjuvanter Chemotherapie bei Patienten mit einem Rektumkarzinom. Series

n

Inclusion criteria

Treatment

Toxicity/surgical morbidity

Response

Comments

Chau et al. 2003 [6]

36

T3/T4 Nx/+ M0

Induction CT (ICT): 5-FU 300 mg/m² 12 weeks, MMC 7 mg/m² every 6 weeks CRT: Starting week 13, 5-FU 200 mg/ m² during RT 50.4–54 Gy Surgery: 4–6 weeks after CRT Adjuvant (ACT): 5-FU 300 mg/m² 12 wks, MMC 7 mg/m² every 6 weeks

ICT: G3/4: 25% CRT: G3/4 28% (skin) Surgery: 1 death (anastomotic leak with multiorgan failure), 5 further complications

ICT: 1 CR, 9 PR, 26 SD, 0 PD Objective response: 28% CRT: 6 CR, 23 PR, 5 SD, 2 PD Objective response: 81% Surgery: 1 pCR, 82% R0

22–24 weeks from start of treatment to surgery: 2 developed M1 before surgery

Chau et al. 2006; (updated Chua et al. 2010)[7,8]

105

MRI-defined poor-risk: ≤ 1 mm to mesorectum; T3 at/below levators; T3 ≥ 5 mm into fat; T4; N2; M0

ICT: Capecitabine 1000 mg/m² bid 14 days every 3 weeks, Oxaliplatin 130 mg/m² on day 1; 4 cycles CRT: Starting week 13, Capecitabine 825 mg/m² bid during RT 54 Gy Surgery: 6 weeks after CRT ACT: Capecitabine 1250 mg/m² bid 14 days every 3 weeks, 4 cycles

ICT: 5 deaths (2 pulmonary embolism, cardiac failure, myocardial infarction, neutropenic colitis), bowel perforation (n= 1), small-bowel obstruction (n= 1); G3–5 diarrhea 10%. CRT: G3–5: 42% skin Surgery: no deaths within 30 days

ICT: 3 CR, 75 PR, 16 SD, 0 PD Objective response: 74% CRT: 15 CR, 78 PR, 4 SD, 0 PD Objective response: 89% Surgery: pCR 20%; 5-year progressionfree survival: 64%

22–24 weeks from start of treatment to surgery: no PD. After amendment for cardiovascular safety, only 1 further fatal pulmonary embolism

Calvo et al. 2006 [5]

52

T3/T4 or N+ M0

ICT: Oxaliplatin 85 mg/m² on day 1; 5-FU 400 mg/m² bolus d1, followed by 600 mg/m² continuous infusion in 22 h with LV (200 mg/m²) d1–2, every 15 days, 2 cycles CRT: Starting after completion of the second FOLFOX4 course, Tegafur 400 mg given orally 3 times a day from d1–28 of RT 45–50.4 Gy Surgery: 4–6 weeks after CRT + IORTBoost (10–15 Gy) ACT: Left to the treating oncologist’s discretion

ICT: G3: 6% CRT: G3–4: 33% Surgery: 31% postoperative complications

ICT: not given CRT: not given Surgery: ypT0: 29%

14–16 weeks from start to surgery. If compared to 62 pts treated with the same CRT without ICT, no more tox., but more ypT0 (29% vs. 8%, p = 0.006)

Koeberle et 60 al. 2008 [18]

T3/T4 Nx/+ M0

ICT: Capecitabine 1000 mg/m² bid 14 days, Oxaliplatin 130 mg/m² day 1; 1 cycle CRT: Starting day 22, Capecitabine 825 mg/m² bid, d22–35 and d43–56, Oxaliplatin 50 mg/m² d 22,29,43,50 during RT 45 Gy Surgery: 5–6 weeks after CRT ACT: Left to the treating oncologist’s discretion

ICT: G3 17% diarrhea, 3% G4 infection, 1/60 died 19 days after start of CT due to neutropenic sepsis CRT: G3 17% diarrhea. Surgery: not given

ICT: not given CRT: not given Surgery: ypT0N0: 23%

13–14 weeks from start to surgery

Gunnlaugsson et al. 2009 [16]

“Nonresectable” colorectal carcinoma T4NxM0-1; 41 pts rectal

ICT: Capecitabine 1000 mg/m² bid 14 days every 3 weeks, Oxaliplatin 130 mg/m² day 1; 2 cycles CRT: Starting week 7, Capecitabine 825 mg/m² bid, Oxaliplatin 60 mg/m² weekly during RT 50.4 Gy Surgery: performed, if feasible

ICT: G3/4: 11% diarrhea CRT: G3/4: 24% diarrhea. 1 pt died due to myocardial infarction

ICT: not given CRT: 62% CR or PR Surgery: 38/49 pts received surgery; ypT0N0: 13%

Only 15% of the pts obtained all CT cycles without any dose reduction

49


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response rate was followed by MRI. After induction chemotherapy, the overall response rate was 74% which increased to 89% following the completion of CRT; no patient had progressive disease during neoadjuvant treatment. A major concern of this phase II study, however, is that nine patients had cardiac and thromboembolic toxic effects, leading to four deaths (plus one death from neutropenic colitis) during induction chemotherapy. Although after amendment of the protocol (patients with a previous history of stable angina, arrhythmia, and coronary syndrome were then excluded) only one further fatal pulmonary embolism occurred, this high incidence of fatal toxicity may well be associated with a higher susceptibility of patients with bulky pelvic tumors to such complications. Other trials with induction chemotherapy (Table 2), however, did not confirm such a high number of early fatal events. Recently, a Spanish randomized phase II trial was developed comparing the induction chemotherapy approach with conventional preoperative CRT followed by surgery and postoperative chemotherapy (Figure 1) [10]. A total of 108 patients received preoperative 50.4 Gy plus CAPOX and were randomized to receive 4 months of CAPOX either by induction or adjuvant. Notably, all 54 patients who commenced induction chemotherapy also received CRT and underwent surgery. Although the pCR rates, downstaging, and tumor regression grading were similar, both grade ≥3 toxicity was lower (19% vs. 54%, p = 0.0004) and the ability to receive all four chemotherapy cycles was higher (92% vs. 57%, p = 0.0001) with the induction approach (Table 3). 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. Another randomized phase II study from Belgium tested two cycles of modified FOLFOX6 regimen (oxaliplatin 100 mg/m², folinic acid 400 mg/m², 5-FU bolus 400 mg/m² followed by 2 g/m² as continuous infusion, d1 and d15) before preoperative CRT (45 Gy with 5-FU 250 mg/m²/day continuous infusion during RT) versus the same schedule of preoperative CRT alone [20]. In an interim analysis presented at ASCO 2010 (28 vs. 29 patients analyzed), the arm with induction chemotherapy was feasible and did not compromise CRT completion or surgery. However, as in a Spanish trial, local efficacy was not improved with induction mFOLFOX6 (pCR: 25% vs. 27%, ypT0–1: 29% versus 34%, Dworak tumor regression grading as well as T- and N-downstaging were similar) and was associated with significantly higher grade 3–4 toxicity (35% vs. 8%, p = 0.017). Thus, the paradigm that induction chemotherapy prior to CRT may not increase local efficacy—as validated in several tumor sites [15]—may well apply to rectal cancer, too. It should be noted, however, that the primary goal of adding induction chemotherapy is not to improve local efficacy, but to better control distant disease. Indirect evidence that this may indeed be achievable comes from the recently published NSABP R-03 phase III trial [30]. The design of this trial was similar to the German CAO/ARO/AIO-94 and was launched to demonstrate that preoperative CRT is superior to postoperative CRT. A total of 267 patients were accrued between 1993 and 1999, when the trial was prematurely terminated because it did not meet the target accrual of 900 patients. Unlike the German trial, preoperative treatment consisted of induction chemotherapy (6 weeks of 5-FU/folinic acid) followed by CRT (50.4 Gy plus 5-FU/LV in week 1 and week 5 of RT) and surgery plus four adjuvant cycles of 5-FU/LV. The primary endpoints of this study were disease-free survival (DFS) and overall survival. The median follow-up time for surviving patients was 8.4 years. In contrast to the German trial, the 5-year DFS was significantly improved for patients treated with preoperative compared with postoperative therapy (65% versus 53%, p = 0.011). As the 5-year cumulative incidence of locoregional recurrence was 10.7% in Figure 1. Randomized phase II trial: Grupo Cancer de Recto 3 Study in MRT-defined poor prognoeach arm, it is tempting to speculate sis patients (tumor ≤2 mm from mesorectal fascia, low-lying T3, T3N+, T4 rectal cancer) [10]. that the early onset of induction chemoAbbildung 1. Randomisierte Phase-II-Studie: Grupo Cancer de Recto 3 für Patienten mit nach therapy may have contributed to reduce MRT-Kriterien ungünstiger Prognose (Tumor ≤2 mm von der mesorektalen Faszie entfernt liegend, tief-sitzendes T3, T3N+, T4 Rektumkarzionm) [10]. distant recurrences in this trial.

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Table 3. Results of the randomized phase II Grupo Cancer de Recto (GCR) 3 trial of induction ersus adjuvant CAPOX in patients with rectal cancer [10]. Tabelle 3. Ergebnisse der randomisierten Phase-II-Studie GCR 3: Induktions- versus adjuvante CAPOX-Chemotherapie bei Patienten mit Rektumkarzinom [10]. Grupo Cancer de Recto 3 Study

Induction-CAPOX + CRT+TME

CRT+TME + adjuvant CAPOX

Number of patients

56

52

14%

13%

p value

Efficacy pCR (primary endpoint)

0.94

Downstaging

43%

58%

0.13

R0 resection rate

86%

87%

0.4

18-month failure-free survival

76%

82%

0.39

Completion of treatment per protocol

91%

54%