Which Patients With Rectal Cancer Do Not Need Radiotherapy?

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Which Patients with Rectal Cancer Do Not Need Radiotherapy? Ines Joye MD, Karin Haustermans MD PhD

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To appear in: Semin Radiat Oncol

Cite this article as: Ines Joye MD, Karin Haustermans MD PhD, Which Patients with Rectal Cancer Do Not Need Radiotherapy?, Semin Radiat Oncol , http://dx.doi.org/10.1016/j.semradonc.2016.02.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Which patients with rectal cancer do not need radiotherapy?

Ines Joye, MD,1,2 Karin Haustermans, MD PhD,1,2

1

KU Leuven - University of Leuven, Department of Oncology, B-3000 Leuven, Belgium

2

University Hospitals Leuven, Department of Radiation Oncology, B-3000 Leuven, Belgium

Corresponding author Karin Haustermans, University Hospitals Leuven Herestraat 49, 3000 Leuven, Belgium Tel: (+32) 16-346902 Fax: (+32) 16-346905 E-mail: [email protected]

Conflict of interest: none

1

Abstract According to current guidelines, the standard treatment for locally advanced rectal cancer patients is preoperative (chemo)radiotherapy followed by total mesorectal excision surgery and adjuvant chemotherapy. Improvements in surgical techniques, imaging modalities, chemotherapy regimens and radiotherapy delivery have reduced local recurrence rates to less than 10%. The current challenge in rectal cancer treatment lies in the prevention of distant metastases, which still occur in more than 25% of the patients. The decrease in local recurrence rates, the need for more effective systemic treatments and the increased awareness of treatment-induced toxicity raise the question as to whether a more selective use of radiotherapy is advocated.

2

Background With the implementation of total mesorectal excision (TME) surgery and the administration of preoperative (chemo)radiotherapy, local recurrence rates of locally advanced rectal cancer have decreased from 30-50% to less than 10%.1-10 Despite the clear reduction in local recurrences, the benefit of radiotherapy in terms of overall survival is limited. The gains in outcome have to be balanced against the acute and late adverse effects of radiotherapy. Preoperative radiotherapy increases

surgical

morbidity,

consequently

delaying

the

administration

of

adjuvant

chemotherapy.11,12 Radiotherapy also impacts on sexual, anorectal and urinary function and is associated with an increased risk of secondary malignancies.13,14 A more selective use of radiotherapy in low-risk rectal cancer patients will avoid radiation-induced morbidity and can improve patients’ quality of life.15 A more selective use of radiotherapy can also be considered for patients at high risk for distant metastases. With the current treatment paradigm, full-dose systemic therapy is delayed until 4 months after diagnosis, which is disadvantageous regarding the risk of distant tumor spread. Early administration of full-dose systemic therapy is likely to have a beneficial effect on distant metastases rates and is currently being investigated in several trials.

Which patients can be candidates for upfront surgery? Risk factors for local recurrence Since its major merit is to reduce local recurrence rates, the standard use of radiotherapy in low-risk rectal cancer patients can be questioned. Various clinicopathological features have been associated with an increased risk of local recurrences. The most important risk factor for a local recurrence after rectal cancer surgery is the plane of surgery achieved. In patients included in the CR07 and NCIC-CTG CO16 trials, Quirke et al. demonstrated that both an uninvolved circumferential resection margin (CRM) (defined as tumor at a minimum distance of 1 mm from the CRM on pathology) and a superior plane of surgery achieved, 3

were associated with low local recurrence rates.16 The prognostic impact of CRM involvement has also been demonstrated outside clinical trials. In a population-based study with 3196 patients who were mostly treated with surgery alone, Bernstein et al. found a 5-year local recurrence rate of 23.7% in patients with a CRM of 0-2 mm, compared with 8.9% in those with wider margins.17 The importance of an uninvolved mesorectal fascia (MRF) was demonstrated by Frasson et al. who found that T3N0/N+ or T2N+ rectal cancer patients treated with upfront TME had a 5-year local recurrence rate of 19.4% and 5.4% with and without threatened MRF as assessed on preoperative MRI, respectively.18 Upper rectal tumors have a lower risk for local recurrence because their location above the peritoneal reflection facilitates the ability to obtain clear resection margins. Some of the landmark phase III trials that reported on local recurrences with and without preoperative radiotherapy, stratified local recurrence data according to tumor location (Table 1). After a median follow-up of 13 years, the Swedish rectal cancer trial demonstrated that a short-course regimen of preoperative radiotherapy reduced local recurrences (9% vs. 26%, p=0.008) and improved survival (38% vs. 30%, p<0.001) among patients with rectal cancer.5 A lower local recurrence rate was seen at all tumor heights, although this was not statistically significant for tumors located more than 10 cm from the anal verge. The Dutch TME trial randomly assigned 1861 patients with resectable rectal cancer either to preoperative radiotherapy (5 x 5 Gy) followed by TME surgery or to TME surgery alone.6 Local recurrence rates at two years decreased from 8% with TME alone to 2% when radiotherapy was added (p<0.001). This statistically significant difference in local recurrence rate was shown for midand low-rectal cancer, but could not be demonstrated for tumors located above 10 cm from the anal verge (p<0.17). Surprisingly, the 12-year follow-up results showed that the effect of radiotherapy became stronger as the distance from the anal verge increased.7 However, when patients with positive margins were excluded from the analysis, the effect on the reduction in local recurrences was independent of the distance of the tumor from the anal verge. This observation can be explained 4

by the fact that radiotherapy cannot compensate for a positive CRM, which was present in a substantial proportion of patients with distal tumors.19 The MRC CR07/NCIC-CTG C016 trial randomized 1350 rectal cancer patients to preoperative short-course radiotherapy and to selective postoperative chemoradiotherapy in case of involved circumferential resection margins.8 At three years of follow-up, there was a reduction of 61% in the relative risk of local recurrence for patients receiving preoperative radiotherapy (p<0.0001). Unfortunately, no evidence of an effect of tumor location on local recurrences could be detected, perhaps because of the low number of events. Another factor influencing the risk on local recurrences is the tumor extension. While it is beyond question that T1-2 tumors rarely need preoperative radiotherapy and that T4 tumors benefit from preoperative (chemo)radiotherapy, T3 rectal cancers constitute a heterogeneous group and the indication for radiotherapy in these tumors is less clear. The outcome of patients with T3 tumors depends on the depth of extramural spread: patients with more than 5 mm of extramural spread have a markedly worse prognosis than patients who have T3 tumors with 5 mm or less of spread. Merkel et al. suggested a subdivision of T3 tumors according to the histological measurement of the maximal tumor invasion beyond the outer border of the muscularis propria: pT3a (up to 5 mm) and pT3b (more than 5 mm).20 This subclassification identified two groups of rectal cancer patients with a distinct outcome: locoregional recurrence rates were 10.4% and 26.3% for pT3a and pT3b tumors respectively (p<0.0001). The cancer-related 5-year survival rates were 85.4% for pT3a and 54.1% for pT3b lesions (p<0.0001). The Mercury study group further extended this subclassification into four groups: ‘T3a’ (<1 mm), ‘T3b’ (1-5 mm), ‘T3c’ (5-15 mm), ‘T3d’ (>15 mm) and demonstrated that magnetic resonance imaging (MRI)

and histopathologic assessments of tumor spread were

equivalent to within 0.5 mm.21 An overview of the rectal cancer risk categories is provided in Table 2.

5

Prerequisites for a more selective treatment Precise risk-classification by MRI and high-quality TME surgery are prerequisites before a more selective use of preoperative (chemo)radiotherapy can be considered. MRI as a selection tool MRI-based risk-classification is crucial for the selection of patients who may not benefit from radiotherapy. Prognostic features such as MRF involvement, tumor location and tumor extension into the mesorectal fat, but also perineural invasion, extranodal deposits and extramural vascular invasion can be assessed on MRI. Unfortunately, the detection of lymph nodes metastases remains a diagnostic problem with a sensitivity and specificity of MRI of 66% and 76%.22 By providing information on tumor characteristics, MRI can help in distinguishing patients with a low, intermediate or a high risk on local recurrence. As stated before, upper rectal tumors have a low risk on local recurrences. MRI has shown to be helpful in detecting a high-risk subset of upper rectal cancer patients with sacral-side wall involvement and mesorectal invasion of >5 mm on MRI.23 The importance of MRI-based risk assessment has also been demonstrated by the MERCURY study group. The relationship between preoperative CRM staging on MRI, TNM stage, and clinical variables with overall survival, disease-free survival and time to local recurrence was evaluated in 374 rectal cancer patients.24 MRI-involved CRM was the only preoperative staging parameter that remained significant for overall survival, disease-free survival and local recurrence on multivariate analysis. In another analysis, the Mercury study group investigated the outcome of patients with MRI-predicted ‘good prognosis’ tumors treated by surgery alone.25 'Good prognosis’ patients were defined as having a safe CRM and T2/T3a/T3b rectal tumors, regardless of N-stage. One hundred twenty-two patients were treated with upfront surgery without postoperative radiotherapy. Fiveyear overall survival and disease-free survival rates were 68% and 85% respectively and the local recurrence rate was 3%. This study demonstrated that MRI can be used as a selection tool to safely defer ’good prognosis’ rectal cancer patients from radiotherapy.

6

High-quality surgery With the implementation of TME surgery, which is a sharp dissection of the rectum with the mesorectal fascia, local recurrence rates have dropped from above 20% to less than 10%.1-3 High quality of surgery is one of the major successes in rectal cancer over the last decade. Quality indicators such as resection margins, completeness of excision and number of resected lymph nodes have been established. The CRM is the most important margin in rectal cancer surgery as it is strongly correlated with local control. In a review about the importance of the CRM, positive resection margins were associated with a hazard ratio of 2.0 for local recurrence when patients were treated with surgery alone.26 After neoadjuvant therapy, the hazard ratio increased to 6.3. Data from the MRC CR07/NCIC-CTG CO16 trials showed that three-year local recurrence rates were 6% and 17% for patients who had a negative and positive resection margin respectively.16 The same authors demonstrated that the plane of surgery achieved after TME also affected the risk of a local recurrence. The estimated 3-year local recurrence rates were 4% for mesorectal, 7% for intramesorectal and 13% for muscularis propria groups. The plane of surgery and the CRM are closely related since an intramesorectal or a muscularis propria resection increases the risk of a positive CRM. The quality of TME surgery can be influenced both by patient-related factors (age, comorbidity) as well as by disease-related (T-stage, distance from the anal verge) and surgery-related factors (intraoperative complications, surgeon’s case volume).27 Indicators of surgical quality have gained importance and should be routinely documented in the pathology report.

Which patients can be candidates for upfront chemotherapy? The current challenge in rectal cancer treatment lies in the prevention of distant metastases, which still occur in more than 25% of stage II-III rectal cancer patients. The standard treatment approach for rectal cancer does not allow administration of full-dose systemic chemotherapy until four to five months after initial diagnosis. This large time interval might lead to the dissemination of micrometastases. Earlier use of more intensive systemic therapy addresses potential micrometastatic 7

disease and may reduce the distant recurrence rates. Several small single-arm trials investigated the use of upfront preoperative chemotherapy without radiotherapy.28-32 (Table 3). While response rates and long-term outcome in these studies were encouraging, toxicity was substantial, especially in the trials in which bevacizumab was administered. The currently recruiting PROSPECT trial uses the response to preoperative chemotherapy as a tool for a more selective administration of radiotherapy. Patients are randomized between standard chemoradiotherapy followed by surgery and upfront chemotherapy. Patients in the experimental arm receive 6 cycles of neoadjuvant FOLFOX and their subsequent treatment is customized based on the response to this neoadjuvant chemotherapy. If there is more than 20% tumor regression as assessed on MRI and ERUS, patients are referred to surgery. If the response to the chemotherapy is less than 20%, patients undergo chemoradiotherapy. The primary endpoints of the PROSPECT trial are R0 resection rate, disease-free survival and time to local recurrence. This randomized trial will clarify whether pelvic radiation remains an essential component of curative treatment in the era of optimal imaging (MRI), surgical technique (TME) and better systemic treatment. Table 4 represents an overview of other currently ongoing trials that are investigating the possibility of omitting radiotherapy from the treatment paradigm.

Future directions In most randomized trials, there is a large heterogeneity regarding tumor location, tumor extent and nodal involvement. This non-uniformity in clinical characteristics masks both the group of patients with a low risk on local recurrence who might not benefit from local radiotherapy and the subset of patients with a high risk on distant metastases who would benefit from intensified chemotherapy. Efforts should be directed to develop trials in which treatment is tailored to the clinical characteristics and tumor responsiveness. Novel imaging techniques, molecular markers and genetic mapping may help to select those patients who benefit from a certain treatment strategy.33-34

8

Conclusions While the current guidelines advocate (chemo)radiotherapy for patients with locally advanced rectal cancer, it is unlikely that all patients with resectable tumors benefit from preoperative (chemo)radiotherapy. Patients with a low risk of local recurrence can be offered upfront surgery on condition that patients are selected based on high-quality MRI and are treated with good quality TME surgery. If it is important to shrink the tumor (e.g. threatened MRF, invasion into the sphincter or into adjacent organs), then chemoradiotherapy remains the preferred treatment strategy. Clinical trials are needed in which treatment is tailored to both clinical features and tumor responsiveness. Such customized treatment strategies can make trial design more complex, but will broaden the therapeutic window by reducing radiation-induced toxicity on one hand while improving tumor response on the other hand. This approach fits well within the era of precision medicine in which physicians try to address the heterogeneity in tumor biology and disease presentation.

9

References 1. Heald RJ, Ryall RD: Recurrence and survival after total mesorectal excision for rectal cancer. Lancet 1(8496):1479-82, 1986 2. Enker WE, Thaler HT, Cranor ML, et al: Total mesorectal excision in the operative treatment of carcinoma of the rectum. J Am Coll Surg 181(4):335-46, 1995 3. MacFarlane JK, Ryall RD, Heald RJ: Mesorectal excision for rectal cancer. Lancet 341 (8843):45760, 1993 4. Improved survival with preoperative radiotherapy in resectable rectal cancer. Swedish Rectal Cancer Trial. N Engl J Med 336(14):980-7, 1997 5. Folkesson J, Birgisson H, Pahlman L, et al: Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol 23(24):5644-50, 2005 6. Kapiteijn E, Marijnen CA, Nagtegaal ID, et al.: Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 345(9):638-46, 2001 7. Van Gijn W, Marijnen CA, Nagtegaal ID, 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 12(6):575-82, 2011 8. Sebag-Montefiore D, Stephens RJ, Steele R, et al: Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 373(9666):811-20, 2009

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9. Sauer R, Becker H, Hohenberger W, et al: Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351(17):1731-40, 2004 10. Sauer R, Liersch T, Merkel S, 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, 2012 11. Stelzmueller I, Zitt M, Ajgner F, et al: Postoperative morbidity following chemoradiation for locally advanced low rectal cancer. J Gastrointest Surg 13(4):657-67, 2009 12. Swellengrebel HA, Marijnen CA, Verwaal VJ, et al: Toxicity and complications of preoperative chemoradiotherapy for locally advanced rectal cancer. Br J Surg 98(3):418-26, 2011 13. Birgisson H, Pahlman L, Gunnarsson U, et al: Occurrence of second cancers in patients treated with radiotherapy for rectal cancer. J Clin Oncol 23(25):6126-31, 2005 14. Peeters KC, van de Velde CJ, Leer JW, et al: Late side effects of short-course preoperative radiotherapy combined with total mesorectal excision for rectal cancer: increased bowel dysfunction in irradiated patients--a Dutch colorectal cancer group study. J Clin Oncol 23(25):6199-206, 2005 15. Stephens RJ, Thompson LC, Quirke P, et al: Impact of short-course preoperative radiotherapy for rectal cancer on patients' quality of life: data from the Medical Research Council CR07/National Cancer Institute of Canada Clinical Trials Group C016 randomized clinical trial. J Clin Oncol 28(27):4233-9, 2010 16. Quirke P, Steele R, Monson J, et al: Effect of the plane of surgery achieved on local recurrence in patients with operable rectal cancer: a prospective study using data from the MRC CR07 and NCIC-CTG CO16 randomised clinical trial. Lancet 373(9666):821-8, 2009 17. Bernstein TE, Endreseth BH, Romundstad P, et al: Circumferential resection margin as a prognostic factor in rectal cancer. Br J Surg 96(11):1348-57, 2009 18. Frasson M, Garcia-Granero E, Roda D, et al: Preoperative chemoradiation may not always be needed for patients with T3 and T2N+ rectal cancer. Cancer;117(14):3118-25, 2011 11

19. Marijnen CA, Nagtegaal ID, Kapiteijn E, et al: Radiotherapy does not compensate for positive resection margins in rectal cancer patients: report of a multicenter randomized trial. Int J Radiat Oncol Biol Phys 55(5):1311-20, 2003 20. Merkel S, Mansmann U, Siassi M, et al: The prognostic inhomogeneity in pT3 rectal carcinomas. Int J Colorectal Dis 16(5):298-304, 2001 21. Mercury Study Group: Extramural depth of tumor invasion at thin-section MR in patients with rectal cancer: results of the MERCURY study. Radiology 243(1):132-9, 2007 22. Bipat S, Glas AS, Slors Fj, et al: Rectal cancer: local staging and assessment of lymph node involvement with endoluminal US, CT, and MR imaging--a meta-analysis. Radiology 232(3):77383, 2004 23. Chang JS, Lee Y, Lim JS, et al: The magnetic resonance imaging-based approach for identification of high-risk patients with upper rectal cancer. Ann Surg 260(2):293-8, 2014 24. Taylor FG, Quirke P, Heald RJ, et al: Preoperative magnetic resonance imaging assessment of circumferential resection margin predicts disease-free survival and local recurrence: 5-year follow-up results of the MERCURY study. J Clin Oncol 32(1):34-43, 2014 25. Taylor FG, Quirke P, Heald RJ, et al: Preoperative high-resolution magnetic resonance imaging can identify good prognosis stage I, II, and III rectal cancer best managed by surgery alone: a prospective, multicenter, European study. Ann Surg 253(4):711-9, 2011 26. Nagtegaal ID, Quirke P. What is the role for the circumferential margin in the modern treatment of rectal cancer? J Clin Oncol 26(2):303-12, 2008 27. Garlipp B, Ptok H, Schmidt U, et al: Factors influencing the quality of total mesorectal excision. Br J Surg 99(5):714-20, 2012 28. Ishii Y, Hasegawa H, Endo T, et al: Medium-term results of neoadjuvant systemic chemotherapy using irinotecan, 5-fluorouracil, and leucovorin in patients with locally advanced rectal cancer. Eur J Surg Oncol 36(11):1061-5, 2010

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29. Cercek A, Weiser MR, Goodman K, et al: Complete pathological response in the primary of rectal or colon cancer treated with FOLFOX without radiation. J Clin Oncol 28:15S, 2010 30. Uehara K, Hiramatsu K, Maeda A, et al: Neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy for poor-risk rectal cancer: N-SOG 03 Phase II trial. Jpn J Clin Oncol 43(10):964-71, 2013 31. Fernandez-Martos C, Brown G, Estevan R, et al: Preoperative chemotherapy in patients with intermediate-risk rectal adenocarcinoma selected by high-resolution magnetic resonance imaging: the GEMCAD 0801 Phase II Multicenter Trial. Oncologist 19(10):1042-3, 2014 32. Schrag D, Weiser MR, Goodman KA, et al.: Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol 32(6):513-8, 2014 33. De Heer P, de Bruin EC, Klein-Kranenbarg E, et al: Caspase-3 activity predicts local recurrence in rectal cancer. Clin Cancer Res 13(19):5810-5, 2007 34. He Y, Van’t Veer LJ, Mikolajewska-Hanclich I, et al: PIK3CA mutations predict local recurrences in rectal cancer patients. Clin Cancer Res 15(22):6956-62, 2009

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Table 1: Local recurrences with and without preoperative radiotherapy

Trial

Ref

Swedish rectal cancer trial

4

Treatment

5 x 5 Gy + surgery vs. surgery alone

5

Dutch trial

TME

6

5 x 5 Gy +TME vs. TME alone

8

Median follow-up

Patient group

LR (RT vs. no RT)

p-value

553 vs. 557

5 years

all

11% vs. 27%

<0.001

454 vs. 454 136 vs. 146 185 vs. 198 133 vs. 110 924 vs. 937

13 years

all

9% vs. 26%

<0.001

≤5 cm

10% vs.27%

0.003

6-10 cm

9% vs. 26%

<0.001

≥11 cm

8% vs. 12%

0.3

all

2% vs. 8%

<0.001

≤5 cm

6% vs. 10%

0.05

5.1-10 cm

1% vs. 10%

<0.001

1% vs. 4%

0.17

10 years

10.1-15 cm all

5% vs. 11%

<0.0001

10 years

CRM-, M0

3% vs. 9%

<0.0001

3 years

All

4% vs. 11%

<0.0001

0-5 cm

5% vs. 10%

NA

>5-10 cm

5.0% vs. 9.8% 1.2% vs. 6.2%

NA

2 years

237 vs. 253 372 vs. 350 262 vs. 271 17481

7

MRC CR07 NCIC-CTG

Number at risk

5 x 5 Gy + surgery vs. surgery with selective postoperative CRT in CRM+

691 vs. 691 674 vs. 676 229 vs. 217 345 vs. 337 95 vs. 112

>10-15 cm

NA

Abbreviations: CRM = circumferential resection margin; CRT = chemoradiotherapy; LR = local recurrence; ref = reference; TME = total mesorectal excision; vs. = versus. 1

1748 patients with macroscopically complete resection

14

Table 2: Risk of local recurrence according to tumor characteristics

Risk on local recurrence

Tumor characteristics

Proposed treatment

Low

• • •

cT1 sm 1/2 N0 (all locations) ≤cT4a upper rectum cT1sm3–cT2 middle/lower third of rectum

Upfront surgery

Intermediate

•

T3a/b N0-1, MRF –

Grey zone

High

• •

T4b upper rectum >T3b, MRF–, middle/lower rectum T3/4, MRF+, positive lateral lymph nodes Very low tumors, APE required

Preoperative CRT

• •

Abbreviations: APE = abdominoperineal excision; CRT = chemoradiotherapy; MRF = mesorectal fascia

15

Table 3: Phase I/II trials of upfront chemotherapy without radiation Trial

N patients

Tumor

Induction chemotherapy

Toxicity

Tumor response

Late outcome

Ishii 2010

26

T3-4/N02M0

G3 neutropenia: 1/26 (4%)

pCR: 1/26 (4%) Downstaging: 15/26 (58%)

5y RFS: 74% 5y OS: 84%

Cercek 2010 29

20

NS

pCR: (35%)

7/20

NS

Uehara 30 2013

32

3 cycles oxaliplatin (d1), bevacizumab (d1) and capecitabin (2dd d114), followed by 1 cycle of oxaliplatin (d1) and capecitabin (2dd, d114), q3w

G3-4 toxicity: 8/32 (25%), Postoperative complication: 13/30 (43%)

*pCR: 4/30 (13%) R0: 27/30 (90%) Good regression: 11/30 (37%)

NS

FernandezMartos 31 2014

46

stage II/III rectal cancer (n=6); metastatic colorectal cancer (n=14) MRIdefined poor risk rectal cancer (MRF+ or ≥T3c or N2) M0 T3, middle third, MRFon MRI (candidates for R0)

2 cycles irinotecan (80mg/m²), 5-FU (500mg/m²) and leucovorin (250mg/m²) d 1-8-15 (q4w) FOLFOX without radiotherapy (n=6) FOLFOX ± bevacizumab (n=14)

3 cycles oxaliplatin, bevacizumab and capecitabin, followed by 1 cycle of oxaliplatin and capecitabin

pCR: 9/46 (20%) Tdownstaging: 22/46 (48%) R0: 46/46 (100%)

2y LR: 2% 2y DFS: 75%

Schrag 32 2014

32

G3-4 toxicity: 28/46 (61%), postoperative complication: 6/46 (13%) 3 treatmentrelated deaths (pulmonary embolism, multiorgan failure due to diarrhea, peritonitis) 2 withdrawn due to angina and arrhythmia

pCR: 8/32 (25%) R0: 32/32 (100%)

4y LR: 0% 4y DFS: 84% 4y OS: 92%

28

Stage II/III, no T4 (candidates for sphinctersparing surgery)

4 cycles FOLFOXbevacizumab followed by 2 cycles of FOLFOX alone; if stable or progressive disease patients received radiation prior to TME

Abbreviations: DFS = disease-free survival, LR = local recurrence, MRF = mesorectal fascia, NS = not stated, OS = overall survival, pCR = pathological complete remission, TME = total mesorectal excision; *30 patient underwent surgery 16

Table 4: Ongoing clinical trials investigating whether radiotherapy can be omitted Trial

Design

BACCHUS (NCT01650428 )

Randomize d multicenter phase II trial

Foresee n inclusio n n=60

Patients characteristics

Treatment arms

Primary outcom e

Secondary outcome

-

T3 tumors extending ≥4 mm beyond the muscularis propria N0-2 OR threatening/involvin g the peritoneal surface OR macroscopic extramural venous invasion AND for tumors below the peritoneal reflection, MRF > 1 mm Distal border 4-12 cm from anal verge

FOLFOX + bevacizuma b vs. FOLFOXIRI + bevacizuma b

pCR rate

RECIST response rate, CRM negative resection rate, T- and Ndownstaging , PFS, DFS, OS, LC, 1ycolostomy rate, frequency and severity of adverse events, compliance to CT, TRG, tumor cell density pCR rate, LR, OS, sphinctersaving surgery rate, R0 resection rate, predictive biomarkers, quality of life, toxicity, convenience pCR, OS, adverse event profiles, rates of receiving preor postoperativ e 5-FU CRT

-

-

-

-

FOWARC (NCT01211210 )

Randomize d multicenter phase II trial

n=495

-

Stage II-III tumors Distal border <12 cm from anal verge

5-FU with radiation vs. FOLFOX with radiation vs. FOLFOX alone

3y DFS

PROSPECT (NCT01515787 )

Randomize d multicenter phase II/III trial

n=1060

-

T2N1, T3N0, T3N1 5-12 cm from the anal verge Sphincter-sparing surgical resection possible

5-FU CRT + surgery + FOLFOX (8 cycles) vs. FOLFOX (6 cycles) and response assessment by MRI or ERUS.

R0 resectio n rate, DFS, time to LR

-

17

-

If > 20% regressi on: surgery If < 20% regressi on: CRT If all borders are clear after surgery: FOLFOX (6 cycles) If not: CRT + FOLFOX (4 cycles)

Abbreviations: CRM = circumferential resection margin; CRT = chemoradiotherapy; DFS = diseasefree survival; LC = local control; LR = local recurrence; MRF = mesorectal fascia; OS = overall survival; pCR = pathological complete remission; PFS = progression-free survival

18