Skip to main content
Erschienen in: memo - Magazine of European Medical Oncology 3/2020

Open Access 15.04.2020 | short review

Neoadjuvant chemoradiotherapy in rectal cancer

Are there new drug combinations on the horizon?

verfasst von: Christoph Reinhold Arnold, MD, PhD, Julian Mangesius, MD, Robert Jäger, MD, Ute Ganswindt, MD

Erschienen in: memo - Magazine of European Medical Oncology | Ausgabe 3/2020

download
DOWNLOAD
print
DRUCKEN
insite
SUCHEN

Summary

Neoadjuvant chemoradiotherapy is a well-established standard treatment for locally advanced rectal cancer and has led to a remarkable improvement in local control. However, distant recurrences still pose a notable threat and local failure, albeit increasingly rare, can lead to unfavorable clinical situations. In this short review, we discuss three promising new strategies to improve rectal cancer treatment: total neoadjuvant therapy, short course radiotherapy, and immune checkpoint inhibitors.
Hinweise

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Introduction

Combined-modality therapy (CMT) consisting of surgery, radiation therapy, and chemotherapy still remains the standard treatment for stage II (T3/4 N0 M0) and III (N + M0) rectal cancer. Using this approach, the high rate of local recurrences after sole surgery has been markedly improved. Several studies have investigated the optimal array of the constituents of CMT. Today, the sequence of neoadjuvant chemoradiotherapy or short-course radiation followed by surgery (total mesorectal excision, TME) and, if necessary, adjuvant chemotherapy is most widely used. As a result, distant metastases have superseded local recurrences as the major cause of treatment failure [13]. Therefore, the focus has shifted from improving local control to reducing systemic failure.

Total neoadjuvant therapy

Improvements in chemoradiotherapy have led to a significantly improved local control. However, this did not translate into improved disease-specific survival (DSS) or overall survival (OS) with distant metastases being substantially more common than local recurrence. Consequently, efforts have been undertaken to improve systemic therapy. Adjuvant chemotherapy after neoadjuvant (chemo)radiotherapy has been extensively studied but results are controversial. There is decent evidence favoring the use of adjuvant chemotherapy. In a Cochrane meta-analysis, Petersen and colleagues found a significant improvement in both disease-free survival (DFS) and OS following adjuvant chemotherapy [4]. Additionally, the CAO/ARO/AIO-04 trial and the ADORE trial, two randomized controlled trials, showed that the addition of oxaliplatin to a 5-fluorouracil (5-FU) based chemotherapy leads to a further improved DFS [5, 6]. For patients with ypN2 status and minimally regressed tumors, oxaliplatin even improved OS. Therefore, adjuvant chemotherapy is currently recommended by several guidelines, at least for high-risk tumors [7, 8]. However, there are also studies that show no improvement in DFS or OS following adjuvant chemotherapy [912]. Poor compliance with or delayed start of adjuvant therapy due to postoperative complications and suboptimal chemotherapy regimens may explain these unsatisfactory results [13]. As a consequence, clinical trials have assessed the role of pre- rather than postoperative chemotherapy, commonly referred to as total neoadjuvant therapy (TNT) [14]. Several advantages have been attributed to TNT, including early systemic treatment to address micrometastases, improved response rates, enhanced R0 resection rates, decreased toxicity, earlier reversal of diverting ileostomy, and the possibility to better select patients for a potential watch-and-wait strategy [6, 15]. TNT usually consists of an oxaliplatin-containing polychemotherapy, such as FOLFOX (folinic acid, fluorouracil, oxaliplatin), CAPOX (capecitabine, oxaliplatin), or FLOX (fluorouracil, oxaliplatin). While there is no level‑I evidence regarding the comparison of TNT with neoadjuvant chemoradiotherapy and adjuvant chemotherapy, there is an increasing body of level-II evidence that suggests that TNT is a viable alternative. For instance, in a recently published retrospective cohort analysis from the Memorial Sloan Kettering Cancer Center, Cercek and colleagues analyzed 320 patients who received neoadjuvant chemoradiotherapy with planned adjuvant chemotherapy and 308 patients who received oxaliplatin-based TNT [16]. Importantly, more patients in the TNT cohort completed the planned chemotherapy and the complete response (CR) rates (both pathologic CR [pCR] and clinical CR [cCR] for at least 12 months) were higher in this group (36% vs. 21%). Additionally, significantly more patients after TNT received minimally invasive surgery and ileostomy closure was more likely to be performed within 15 weeks postsurgery in the TNT cohort. However, due to the relatively short follow-up, no data on DFS or OS are shown. There is also no data on treatment-related toxicity. Furthermore, a recent meta-analysis by Petrelli and colleagues has evaluated 28 studies with 2688 patients treated with TNT and 891 patients treated with standard neoadjuvant chemoradiotherapy [17]. Although most of the included studies were prospective cohort studies, the authors showed a significant increase in pCR rates and a significantly better OS. Importantly, this meta-analysis did not address the value of adjuvant chemotherapy. Since optimal scheduling of chemotherapy and chemoradiotherapy in TNT is not clear, the German Rectal Cancer Study Group conducted a multicenter, randomized, phase 2 study in which 306 patients were assigned to induction chemotherapy either before or after neoadjuvant chemoradiotherapy. Interestingly, chemoradiotherapy-related toxicity, compliance with chemoradiotherapy, and pCR rates were significantly better when chemotherapy was given after chemoradiotherapy [18]. Therefore, this TNT sequence is currently being tested in an organ preservation phase II trial (CAO/ARO/AIO-16; NCT05361142) and has been selected for additional phase III comparison with standard neoadjuvant chemoradiotherapy (CAO/ARO/AIO-18).

Short-course radiotherapy

Neoadjuvant short-course radiotherapy (SCRT) with 25 Gy delivered in 5 fractions is an accepted alternative to conventional long-course chemoradiotherapy (LCRT) with 45–50 Gy in 1.8–2 Gy per fraction with concomitant 5‑FU-based chemotherapy [7, 8]. Albeit SCRT was introduced more than 20 years ago in the Swedish Rectal Cancer Trial [19], its role in rectal cancer treatment remains controversial and it is not clear which form of neoadjuvant treatment provides better tumor control and long-term outcomes. Two recent meta-analyses have tried to answer this question. Wang and colleagues analyzed 11 trials (5 prospective and 6 retrospective studies) with nearly 2000 patients and additionally performed a trial sequential analysis (TSA) to account for repeated significance testing. The authors conclude that SCRT is as effective as LCRT in terms of OS, DFS and 3‑year local control [20]. Similarly, Ma and colleagues found no differences in these parameters [21]. However, in the latter meta-analysis, the authors showed an advantage of LCRT in terms of pCR (OR 0.05, p < 0.01), which did not translate into a higher sphincter preservation rate (OR 1.62, p = 0.25). In contrast, SCRT was associated with fewer grade 3/4 acute toxicities, while severe late toxicities were equal between the two regimes. Additionally, the recently published Stockholm III trial showed that delaying surgery for 4–8 weeks after SCRT (as compared to 1 week) does not compromise oncological results but significantly reduces postoperative complications and gives an opportunity optimize patients and plan surgery well in advance [22]. It furthermore allows for administration of a neoadjuvant chemotherapy after SCRT. This approach has been investigated by the Polish Colorectal Study Group. In a randomized phase III trial, this group compared SCRT followed by consolidation chemotherapy (CCT), consisting of three cycles of FOLFOX (5-FU, folinic acid, and oxaliplatin), with LCRT (with 5‑FU, leucovorin, and oxaliplatin). Preoperative treatment toxicity was lower in the SCRT with CCT group and R0 resection rates showed a trend towards favoring SCRT with CCT over LCRT (p = 0.07) [23]. Interestingly, early benefits for SCRT with CCT in terms of OS did not persist after a longer follow-up and superiority of SCRT with CCT over chemoradiotherapy could not be demonstrated [24]. Similarly, the randomized phase III RAPIDO trial [NCT01558921] compares conventional neoadjuvant LCRT with SCRT followed by six cycles of CPAEOX (capecitabine and oxaliplatin) and subsequent surgery [25]. However, first results are still pending.

New substances

Immunotherapy with immune checkpoint inhibitors (ICI) turned out to be a quantum leap forward in the systemic treatment of various types of cancer, including colorectal carcinoma (CRC) [26]. Utilizing an ICI-based approach response rates were as high as 40% in patients with metastatic CRC with a deficient mismatch repair (MMR) system [27, 28]. However, in MMR proficient mCRC the efficacy of ICI is very low. In this context, RT has been shown to induce the antigen release from tumors with a low neo-antigen burden, such as MMR proficient CRC. This in turn leads to an anti-tumor immune response, mainly driven by CD8+ T lymphocytes. Interestingly, neoadjuvant chemoradiotherapy has been shown to induce long-lasting PD-L1 overexpression in patients with rectal cancer, and this upregulation of PD-L1 is associated with a favorable prognosis [29, 30]. Additionally, the combination of ICI and RT has been shown to exhibit synergistic effects in inhibiting tumor growth in animal models of various tumor types and additionally improves local tumor control in nonirradiated secondary tumors, a phenomenon generally termed abscopal effect [3134]. Several retrospective studies also support the synergistic effect of ICI and chemoradiotherapy in the neoadjuvant setting [30, 3538]. Taken together, these findings strongly suggest the integration of ICI in the neoadjuvant setting for the management of rectal cancer. There are several clinical trials investigating this combination: the AVANA trial (NCT03854799) is a phase II trial that investigates the addition of avelumab (α-PD-L1) to standard neoadjuvant chemoradiotherapy with the primary endpoint being the pCR rate. Similarly, the R‑IMMUNE trial (NCT03127007) aims at evaluating safety and efficacy of atezolizumab (α-PD-L1) combined with neoadjuvant chemoradiotherapy. In contrast, the PEMREC trial (NCT04109755) seeks to evaluate safety and efficacy of neoadjuvant pembrolizumab (α-PD-1) combined with SCRT without chemotherapy. Importantly, while the concomitant use of ICI and radiation therapy in these trials is certainly appealing and backed up by a myriad of preclinical findings [39], this approach is not clinically validated in any tumor type. In contrast, a consolidative strategy with ICI upon radiation is being tested in two phase II trials: the TARZAN trial (NCT04017455) and the CHINOREC trial (NCT04124601). In the former neoadjuvant treatment with atezolizumab and bevacizumab (α-VEGF) following RT is investigated, while in the latter neoadjuvant ipilimumab and nivolumab after chemoradiotherapy is being tested. This sequential approach is more substantially supported by the positive results regarding DFS and OS of the PACIFIC trial [40]. Interestingly however, in this trial of patients with stage III non-small cell lung cancer (NSCLC), patients who received ICI at the latest 14 days after radiation therapy had the highest benefit [41]. First results of trials investigating neoadjuvant ICI and (chemo)radiotherapy are eagerly awaited and will determine whether these treatments will be pursued in phase III trials.

Conclusion

Although the prognosis for patients with rectal cancer is distinctly better than for many other malignant diseases, refinement of rectal cancer therapy is still mandatory. TNT may improve OS, while SCRT could reduce the burden on patients by shortening treatment time without sacrificing oncologic outcomes. However, one still has to keep in mind that conventional neoadjuvant chemoradiotherapy has been the standard of care for decades which entails a lot of experience with this regime. Regarding new therapeutic options, it will certainly be exciting to see which position ICI will acquire in the treatment of rectal cancer.
Take home message
  • Neoadjuvant chemoradiotherapy still remains the standard of care for stage II/III rectal cancer.
  • Total neoadjuvant therapy may improve oncologic outcomes and is being investigated in clinical trials.
  • Neoadjuvant short-course radiotherapy is an alternative to conventional neoadjvuant long-course chemoradiotherapy.
  • Neoadjuvant immune-checkpoint inhibitors are being testes in several clinical trials.

Conflict of interest

C. Arnold, J. Mangesius, R. Jäger, and U. Ganswindt declare that they have no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://​creativecommons.​org/​licenses/​by/​4.​0/​.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Unsere Produktempfehlungen

Abo für kostenpflichtige Inhalte

Literatur
1.
Zurück zum Zitat van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12(6):575–82.CrossRef van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, et al. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011;12(6):575–82.CrossRef
2.
Zurück zum Zitat Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30(16):1926–33.CrossRef Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, et al. Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 2012;30(16):1926–33.CrossRef
3.
Zurück zum Zitat Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, et al. Colorectal cancer. Lancet. 2010;375(9719):1030–47.CrossRef Cunningham D, Atkin W, Lenz HJ, Lynch HT, Minsky B, Nordlinger B, et al. Colorectal cancer. Lancet. 2010;375(9719):1030–47.CrossRef
5.
Zurück zum Zitat Hong YS, Kim SY, Lee JS, Nam BH, Kim KP, Kim JE, et al. Oxaliplatin-based adjuvant chemotherapy for rectal cancer after preoperative chemoradiotherapy (ADORE): long-term results of a randomized controlled trial. J Clin Oncol. 2019;37(33):3111–23.CrossRef Hong YS, Kim SY, Lee JS, Nam BH, Kim KP, Kim JE, et al. Oxaliplatin-based adjuvant chemotherapy for rectal cancer after preoperative chemoradiotherapy (ADORE): long-term results of a randomized controlled trial. J Clin Oncol. 2019;37(33):3111–23.CrossRef
6.
Zurück zum Zitat Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015;16(8):979–89.CrossRef Rodel C, Graeven U, Fietkau R, Hohenberger W, Hothorn T, Arnold D, et al. Oxaliplatin added to fluorouracil-based preoperative chemoradiotherapy and postoperative chemotherapy of locally advanced rectal cancer (the German CAO/ARO/AIO-04 study): final results of the multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2015;16(8):979–89.CrossRef
7.
Zurück zum Zitat Glynne-Jones R, Wyrwicz L, Tiret E, Brown G, Rodel C, Cervantes A, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv22–iv40.CrossRef Glynne-Jones R, Wyrwicz L, Tiret E, Brown G, Rodel C, Cervantes A, et al. Rectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2017;28(suppl_4):iv22–iv40.CrossRef
8.
Zurück zum Zitat Benson AB, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, et al. Rectal cancer, version 2.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2018;16(7):874–901.CrossRef Benson AB, Venook AP, Al-Hawary MM, Cederquist L, Chen YJ, Ciombor KK, et al. Rectal cancer, version 2.2018, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2018;16(7):874–901.CrossRef
9.
Zurück zum Zitat Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, et al. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol. 2014;25(7):1356–62.CrossRef Glynne-Jones R, Counsell N, Quirke P, Mortensen N, Maraveyas A, Meadows HM, et al. Chronicle: results of a randomised phase III trial in locally advanced rectal cancer after neoadjuvant chemoradiation randomising postoperative adjuvant capecitabine plus oxaliplatin (XELOX) versus control. Ann Oncol. 2014;25(7):1356–62.CrossRef
10.
Zurück zum Zitat Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, et al. Fluorouracil- based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15(2):184–90.CrossRef Bosset JF, Calais G, Mineur L, Maingon P, Stojanovic-Rundic S, Bensadoun RJ, et al. Fluorouracil- based adjuvant chemotherapy after preoperative chemoradiotherapy in rectal cancer: long-term results of the EORTC 22921 randomised study. Lancet Oncol. 2014;15(2):184–90.CrossRef
11.
Zurück zum Zitat Breugom AJ, van Gijn W, Muller EW, Berglund A, van den Broek CB, Fokstuen T, et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol. 2015;26(4):696–701.CrossRef Breugom AJ, van Gijn W, Muller EW, Berglund A, van den Broek CB, Fokstuen T, et al. Adjuvant chemotherapy for rectal cancer patients treated with preoperative (chemo)radiotherapy and total mesorectal excision: a Dutch Colorectal Cancer Group (DCCG) randomized phase III trial. Ann Oncol. 2015;26(4):696–701.CrossRef
12.
Zurück zum Zitat Sainato A, Cernusco Luna Nunzia V, Valentini V, De Paoli A, Maurizi ER, Lupattelli M, et al. No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT). Radiother Oncol. 2014;113(2):223–9.CrossRef Sainato A, Cernusco Luna Nunzia V, Valentini V, De Paoli A, Maurizi ER, Lupattelli M, et al. No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT). Radiother Oncol. 2014;113(2):223–9.CrossRef
13.
Zurück zum Zitat Carvalho C, Glynne-Jones R. Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer. Lancet Oncol. 2017;18(6):e354–e63.CrossRef Carvalho C, Glynne-Jones R. Challenges behind proving efficacy of adjuvant chemotherapy after preoperative chemoradiation for rectal cancer. Lancet Oncol. 2017;18(6):e354–e63.CrossRef
14.
Zurück zum Zitat Ludmir EB, Palta M, Willett CG, Czito BG. Total neoadjuvant therapy for rectal cancer: an emerging option. Cancer. 2017;123(9):1497–506.CrossRef Ludmir EB, Palta M, Willett CG, Czito BG. Total neoadjuvant therapy for rectal cancer: an emerging option. Cancer. 2017;123(9):1497–506.CrossRef
15.
Zurück zum Zitat Franke AJ, Parekh H, Starr JS, Tan SA, Iqbal A, George TJ Jr.. Total neoadjuvant therapy: a shifting paradigm in locally advanced rectal cancer management. Clin Colorectal Cancer. 2018;17(1):1–12.CrossRef Franke AJ, Parekh H, Starr JS, Tan SA, Iqbal A, George TJ Jr.. Total neoadjuvant therapy: a shifting paradigm in locally advanced rectal cancer management. Clin Colorectal Cancer. 2018;17(1):1–12.CrossRef
16.
Zurück zum Zitat Cercek A, Roxburgh CSD, Strombom P, Smith JJ, Temple LKF, Nash GM, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol. 2018;4(6):e180071.CrossRef Cercek A, Roxburgh CSD, Strombom P, Smith JJ, Temple LKF, Nash GM, et al. Adoption of total neoadjuvant therapy for locally advanced rectal cancer. JAMA Oncol. 2018;4(6):e180071.CrossRef
18.
Zurück zum Zitat Fokas E, Allgauer M, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12. J Clin Oncol. 2019;37(34):3212–22.CrossRef Fokas E, Allgauer M, Polat B, Klautke G, Grabenbauer GG, Fietkau R, et al. Randomized phase II trial of chemoradiotherapy plus induction or consolidation chemotherapy as total neoadjuvant therapy for locally advanced rectal cancer: CAO/ARO/AIO-12. J Clin Oncol. 2019;37(34):3212–22.CrossRef
19.
Zurück zum Zitat Swedish Rectal Cancer T, Cedermark B, Dahlberg M, Glimelius B, Pahlman L, Rutqvist LE, et al. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med. 1997;336(14):980–7.CrossRef Swedish Rectal Cancer T, Cedermark B, Dahlberg M, Glimelius B, Pahlman L, Rutqvist LE, et al. Improved survival with preoperative radiotherapy in resectable rectal cancer. N Engl J Med. 1997;336(14):980–7.CrossRef
20.
Zurück zum Zitat Wang X, Zheng B, Lu X, Bai R, Feng L, Wang Q, et al. Preoperative short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer: Meta-analysis with trial sequential analysis of long-term survival data. PLoS ONE. 2018;13(7):e200142.CrossRef Wang X, Zheng B, Lu X, Bai R, Feng L, Wang Q, et al. Preoperative short-course radiotherapy and long-course radiochemotherapy for locally advanced rectal cancer: Meta-analysis with trial sequential analysis of long-term survival data. PLoS ONE. 2018;13(7):e200142.CrossRef
21.
Zurück zum Zitat Ma B, Gao P, Song Y, Huang X, Wang H, Xu Q, et al. Short-course radiotherapy in neoadjuvant treatment for rectal cancer: a systematic review and meta-analysis. Clin Colorectal Cancer. 2018;17(4):320–330e5.CrossRef Ma B, Gao P, Song Y, Huang X, Wang H, Xu Q, et al. Short-course radiotherapy in neoadjuvant treatment for rectal cancer: a systematic review and meta-analysis. Clin Colorectal Cancer. 2018;17(4):320–330e5.CrossRef
22.
Zurück zum Zitat Erlandsson J, Holm T, Pettersson D, Berglund A, Cedermark B, Radu C, et al. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol. 2017;18(3):336–46.CrossRef Erlandsson J, Holm T, Pettersson D, Berglund A, Cedermark B, Radu C, et al. Optimal fractionation of preoperative radiotherapy and timing to surgery for rectal cancer (Stockholm III): a multicentre, randomised, non-blinded, phase 3, non-inferiority trial. Lancet Oncol. 2017;18(3):336–46.CrossRef
23.
Zurück zum Zitat Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Krynski J, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016;27(5):834–42.CrossRef Bujko K, Wyrwicz L, Rutkowski A, Malinowska M, Pietrzak L, Krynski J, et al. Long-course oxaliplatin-based preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for cT4 or fixed cT3 rectal cancer: results of a randomized phase III study. Ann Oncol. 2016;27(5):834–42.CrossRef
24.
Zurück zum Zitat Cisel B, Pietrzak L, Michalski W, Wyrwicz L, Rutkowski A, Kosakowska E, et al. Long-course preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study. Annals of oncology : official journal of the European Society for. Med Oncol. 2019;30(8):1298–303. Cisel B, Pietrzak L, Michalski W, Wyrwicz L, Rutkowski A, Kosakowska E, et al. Long-course preoperative chemoradiation versus 5 x 5 Gy and consolidation chemotherapy for clinical T4 and fixed clinical T3 rectal cancer: long-term results of the randomized Polish II study. Annals of oncology : official journal of the European Society for. Med Oncol. 2019;30(8):1298–303.
25.
Zurück zum Zitat Nilsson PJ, van Etten B, Hospers GA, Pahlman L, van de Velde CJ, Beets-Tan RG, et al. Short- course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer—the RAPIDO trial. BMC Cancer. 2013;13:279.CrossRef Nilsson PJ, van Etten B, Hospers GA, Pahlman L, van de Velde CJ, Beets-Tan RG, et al. Short- course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer—the RAPIDO trial. BMC Cancer. 2013;13:279.CrossRef
26.
Zurück zum Zitat Passardi A, Canale M, Valgiusti M, Ulivi P. Immune checkpoints as a target for colorectal cancer treatment. Int J Mol Sci. 2017;18:6.CrossRef Passardi A, Canale M, Valgiusti M, Ulivi P. Immune checkpoints as a target for colorectal cancer treatment. Int J Mol Sci. 2017;18:6.CrossRef
27.
Zurück zum Zitat Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD‑1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.CrossRef Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD‑1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.CrossRef
28.
Zurück zum Zitat Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182–91.CrossRef Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182–91.CrossRef
29.
Zurück zum Zitat Chiang SF, Huang CY, Ke TW, Chen TW, Lan YC, You YS, et al. Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers. Cancer Immunol Immunother. 2019;68(2):283–96.CrossRef Chiang SF, Huang CY, Ke TW, Chen TW, Lan YC, You YS, et al. Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers. Cancer Immunol Immunother. 2019;68(2):283–96.CrossRef
30.
Zurück zum Zitat Hecht M, Buttner-Herold M, Erlenbach-Wunsch K, Haderlein M, Croner R, Grutzmann R, et al. PD-L1 is upregulated by radiochemotherapy in rectal adenocarcinoma patients and associated with a favourable prognosis. Eur J Cancer. 2016;65:52–60.CrossRef Hecht M, Buttner-Herold M, Erlenbach-Wunsch K, Haderlein M, Croner R, Grutzmann R, et al. PD-L1 is upregulated by radiochemotherapy in rectal adenocarcinoma patients and associated with a favourable prognosis. Eur J Cancer. 2016;65:52–60.CrossRef
31.
Zurück zum Zitat Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687–95.CrossRef Deng L, Liang H, Burnette B, Beckett M, Darga T, Weichselbaum RR, et al. Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. J Clin Invest. 2014;124(2):687–95.CrossRef
32.
Zurück zum Zitat Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74(19):5458–68.CrossRef Dovedi SJ, Adlard AL, Lipowska-Bhalla G, McKenna C, Jones S, Cheadle EJ, et al. Acquired resistance to fractionated radiotherapy can be overcome by concurrent PD-L1 blockade. Cancer Res. 2014;74(19):5458–68.CrossRef
33.
Zurück zum Zitat Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, et al. Anti-PD‑1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2):343–9.CrossRef Zeng J, See AP, Phallen J, Jackson CM, Belcaid Z, Ruzevick J, et al. Anti-PD‑1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2):343–9.CrossRef
34.
Zurück zum Zitat Ngwa W, Irabor OC, Schoenfeld JD, Hesser J, Demaria S, Formenti SC. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer. 2018;18(5):313–22.CrossRef Ngwa W, Irabor OC, Schoenfeld JD, Hesser J, Demaria S, Formenti SC. Using immunotherapy to boost the abscopal effect. Nat Rev Cancer. 2018;18(5):313–22.CrossRef
35.
Zurück zum Zitat Wu CT, Chen WC, Chang YH, Lin WY, Chen MF. The role of PD-L1 in the radiation response and clinical outcome for bladder cancer. Sci Rep. 2016;6:19740.CrossRef Wu CT, Chen WC, Chang YH, Lin WY, Chen MF. The role of PD-L1 in the radiation response and clinical outcome for bladder cancer. Sci Rep. 2016;6:19740.CrossRef
36.
Zurück zum Zitat Saigusa S, Toiyama Y, Tanaka K, Inoue Y, Mori K, Ide S, et al. Implication of programmed cell death ligand 1 expression in tumor recurrence and prognosis in rectal cancer with neoadjuvant chemoradiotherapy. Int J Clin Oncol. 2016;21(5):946–52.CrossRef Saigusa S, Toiyama Y, Tanaka K, Inoue Y, Mori K, Ide S, et al. Implication of programmed cell death ligand 1 expression in tumor recurrence and prognosis in rectal cancer with neoadjuvant chemoradiotherapy. Int J Clin Oncol. 2016;21(5):946–52.CrossRef
37.
Zurück zum Zitat Lim SH, Hong M, Ahn S, Choi YL, Kim KM, Oh D, et al. Changes in tumour expression of programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with squamous oesophageal cancer. Eur J Cancer. 2016;52:1–9.CrossRef Lim SH, Hong M, Ahn S, Choi YL, Kim KM, Oh D, et al. Changes in tumour expression of programmed death-ligand 1 after neoadjuvant concurrent chemoradiotherapy in patients with squamous oesophageal cancer. Eur J Cancer. 2016;52:1–9.CrossRef
38.
Zurück zum Zitat Jomrich G, Silberhumer GR, Marian B, Beer A, Mullauer L. Programmed death-ligand 1 expression in rectal cancer. Eur Surg. 2016;48(6):352–6.CrossRef Jomrich G, Silberhumer GR, Marian B, Beer A, Mullauer L. Programmed death-ligand 1 expression in rectal cancer. Eur Surg. 2016;48(6):352–6.CrossRef
39.
Zurück zum Zitat Hader M, Frey B, Fietkau R, Hecht M, Gaipl US. Immune biological rationales for the design of combined radio- and immunotherapies. Cancer Immunol Immunother. 2020;69(2):293–306.CrossRef Hader M, Frey B, Fietkau R, Hecht M, Gaipl US. Immune biological rationales for the design of combined radio- and immunotherapies. Cancer Immunol Immunother. 2020;69(2):293–306.CrossRef
40.
Zurück zum Zitat Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342–50.CrossRef Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342–50.CrossRef
41.
Zurück zum Zitat Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919–29.CrossRef Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, et al. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017;377(20):1919–29.CrossRef
Metadaten
Titel
Neoadjuvant chemoradiotherapy in rectal cancer
Are there new drug combinations on the horizon?
verfasst von
Christoph Reinhold Arnold, MD, PhD
Julian Mangesius, MD
Robert Jäger, MD
Ute Ganswindt, MD
Publikationsdatum
15.04.2020
Verlag
Springer Vienna
Erschienen in
memo - Magazine of European Medical Oncology / Ausgabe 3/2020
Print ISSN: 1865-5041
Elektronische ISSN: 1865-5076
DOI
https://doi.org/10.1007/s12254-020-00594-0

Weitere Artikel der Ausgabe 3/2020

memo - Magazine of European Medical Oncology 3/2020 Zur Ausgabe