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Abstract

Keywords

antiangiogenesis therapy chemotherapy EGFR inhibitor rectal cancer surgery synchronous

Introduction

Colorectal cancer (CRC) affects nearly 1.4 million new patients each year worldwide.¹ The treatment algorithm for local or locally advanced colon and rectal cancer (RC), and also for patients with never-resectable metastases, is well established.^2–4 However, the optimal strategy in patients with synchronous metastasis is more controversial and, especially in patients with RC, several modalities must be combined to achieve the most favorable outcome. Before the introduction of total mesorectal excision (TME) a local recurrence was frequently seen in 30–40% of patients with locally advanced RC.⁵ Neoadjuvant long-course chemo-radiation (LC-CRT) or short-course radiotherapy (SC-RT) followed by appropriate TME has reduced local recurrence (LR) rates to 5% or even less as shown not only in randomized trial with selected patients but also in population cohorts.^6,7 However, the role and timing of neoadjuvant radiation is less well defined in patients presenting with synchronous metastasis. Randomized studies have focused on one treatment modality (e.g. preoperative LC-CRT or SC-RT in patients with resectable RC or chemotherapy in the setting of widespread nonresectable metastatic disease) but the sequence of different modalities (surgery, chemotherapy, and radiation) has not been studied in a randomized strategy trial. Based on lack of consensus regarding the optimal sequence of surgery, systemic therapy and radiotherapy for patients with stage 4 RC treated with curative intent, a ‘multidisciplinary session: synchronous liver metastases in RC: which treatment first?’ was organized by the European Society for Medical Oncology (ESMO) and presented during the ESMO 2017 conference in Madrid, Spain. Three distinct lectures focused on the radiation therapy perspective, the surgical oncology perspective, and the medical oncology perspective. The present paper is a summary of those three lectures with focus on a multidisciplinary approach and with an update on recent literature.

All patients must be evaluated by a multidisciplinary team

Many strategies are possible in patients with RC with synchronous metastases. There are numerous overviews but no randomized trial to guide us on the optimal strategy. A network meta-analysis (no phase III study) including 3605 patients with synchronous colorectal liver metastases (CRLM) demonstrated no clear statistical surgical outcome or survival advantage toward any particular strategy.⁸ Therefore, selecting the optimal treatment strategy in patients with synchronous metastatic RC is a difficult task due to lack of good evidence. There are trials evaluating systemic therapy in patients with metastatic CRC (mCRC) and there are trials with radiotherapy for patients with localized RC but there are no trials for patients with both manifestations. In particular, there are no randomized trials to evaluate the best sequence of therapy and no widely accepted standard of treatments. Thus treatment is not evidence based but mainly rests upon expert opinion and short-term oncological goals.

There are at least four scenarios for the management of patients with synchronous metastatic RC. In patients with resectable CRLM, the primary could be asymptomatic or symptomatic. Similarly, in patients with nonresectable CRLM the primary could also be asymptomatic or symptomatic. The decision for timing of the resection of either the primary or the CRLM should be individualized for each patient, considering technical, oncological and patient factors. An alternative approach in addition to ‘liver first’ or ‘rectal first’ is ‘the interval strategy’ that involves the administration of LC-CRT followed by the resection of the CRLM in the interval between RT and rectal surgery.^9,10 For these reasons, all patients must be evaluated by a specialist multidisciplinary team (MDT).

At the MDT, the following questions must be asked: what is the burden of metastatic disease? Are there other sites of metastases, and if so, are these extrahepatic metastases potential curable (e.g. a small resectable lung metastases)? There should be a detailed magnetic resonance imaging (MRI) assessment of the primary, and the performance status and the patient’s comorbidity must be well known. There is a need for randomized controlled trials to further investigate the optimal treatment strategy in patients with synchronous metastatic RC (mRC).

Analysis of the Surveillance, Epidemiology and End Results database including more than 60,000 patients from 1988 to 2010 showed that the majority of patients with mCRC had undergone primary tumor resection but beginning in 2001, there was a trend toward fewer resections.¹¹ Despite a declining resection rate, an increased overall survival (OS) was found. A recent individual patient data analysis of trials in mCRC showed an improved survival in synchronous mCRC patients if the primary was resected.¹² Such analyses are open to bias because the reasons that resection is not performed are not available. Hence, presently, it’s not known whether the primary should be resected or not. Several randomized studies like CAIRO4 are evaluating this problem in patients receiving palliative therapy but if the overall aim is cure then the primary must of course be resected.

In patients with easy resectable primary and CRLM, perioperative FOLFOX before and after liver resection is the recommended treatment strategy, and in selected cases, the primary may be resected concurrently.³ Recommendations are to administer chemotherapy for a total of at least 6 months.

In patients with nonresectable liver-limited CRLM, patients should start with best systemic therapy and patients should be restaged and evaluated by the MDT every 2 months.

The classical way of treating patients with RC and metastases was to start with LC-CRT and then resect the primary. The major problem with this strategy is that administration of effective systemic treatment is postponed for months and during this period, there is a risk of further progression of metastatic disease which may convert potential curable disease to never-resectable disease. At the ESMO consensus meeting, all participants agreed on upfront chemotherapy in case of metastatic disease and asymptomatic primary.²

Magnitude of the problem

How many patients with RC are diagnosed with synchronous metastasis? In a nationwide study covering 98% of Swedish RC cases from 2007 to 2011 (total 9158 patients), it was found that 20% of patients had mRC at the time of diagnosis, 75% of mRC patient had synchronous liver metastases and one half had liver-limited disease (LLD). Resection rate was 23% in RC patients with LLD, however, with huge variation from 8.5% to 32.1% between regions.¹³ Preoperative chemotherapy was administered to 33% of patients who had resection.

Efficacy of systemic therapy on colorectal liver metastases

According to the current ESMO consensus guidelines,³ a preoperative strategy with FOLFOX may be used in patients with good prognosis and easily resectable metastasis but if a conversion or downsizing strategy is recommended by the MDT then the best systemic therapy must be initiated. It is well known that a higher overall response rate (ORR) increases the chance for resection of CRLM^14,15 and therefore a combination that produces the highest ORR is recommended in fit patients. In general, double regimens (e.g. FOLFOX, FOLFIRI, CapOx) compared with monotherapy, and triplet regimens (e.g. FOLFOXIRI) compared with double regimens produce higher ORRs.³

When epidermal growth factor receptor (EGFR) inhibitors (cetuximab or panitumumab) are added to combination regimens like FOLFIRI or FOLFOX, all efficacy parameters are improved (Table 1); ORRs are increased and progression-free survival (PFS) and OS are prolonged but this benefit is restricted to patients who are RAS wildtype and BRAF wildtype.^16–19 A similar consistency has not been observed when bevacizumab was added to modern regimens³ and in the largest randomized study, bevacizumab did not improve ORR.²⁰ Nevertheless, the optimal combination of chemotherapy and targeted therapy has been discussed for many years. Three studies have directly compared efficacy of EGFR inhibitors and bevacizumab in mCRC patients (Table 2A). In the randomized phase III FIRE-3,^21,22 the primary endpoint, ORR, was not achieved but the secondary endpoint, OS, was significantly longer, particularly in the subgroup with RAS and BRAF wildtype tumors. In the randomized phase II PEAK study,²³ there was a significantly longer PFS and numerically longer OS, but no difference in ORR. In CALGB 80405, double chemotherapy with cetuximab resulted in higher ORR but with no significant difference in PFS or OS.^24,25 Several studies have shown that left-sided CRC are more dependent on EGFR-related pathways and therefore it was evident to do subgroup analysis in patients with left-sided tumors (Table 2B). Within this subgroup analysis, the picture became much more homogenous showing higher ORR and prolonged OS in patients with left-sided primary (including rectal) treated with EGFR inhibitors compared with bevacizumab.^26,27 In the two reviews, it was concluded that the preferred treatment option in patients with left-sided RAS and BRAF wildtype tumor is doublet chemotherapy with EGFR inhibitors.

Table 1.

Doublet chemotherapy with or without anti-EGFR in patients with RAS wild-type metastatic colorectal cancer.^[16-19].

Authors (trial name)	Regimen	N	RR(%)	Δ %RR	PFS(mo)	Δ PFS (mo)	OS(mo)	Δ OS (mo)
Van Cutsem, (CRYSTAL) JCO 2015	FOLFIRI	189^$	39	+28	8.4	+3.0	20.2	+8.2
Van Cutsem, (CRYSTAL) JCO 2015	FOLFIRI + Cet	178^$	66*	+28	11.4*	+3.0	28.4*	+8.2
Bokemeyer, (OPUS) EJC 2015	FOLFOX	49^$	29	+28	5.8	+6.2	17.8	+2.0
Bokemeyer, (OPUS) EJC 2015	FOLFOX + Cet	38^$	56*	+28	12.0*	+6.2	19.8	+2.0
Douillard, (PRIME) NEJM 2013	FOLFOX	253^$	48	+9	7.9	+2.2	20.2	+5.6
Douillard, (PRIME) NEJM 2013	FOLFOX + Pan	259^$	57*	+9	10.1*	+2.2	25.8*	+5.6
Qin, (TAILOR) ESMO 2016	FOLFOX	200^‡	40	+21	7.4	+1.9	17.8	+2.9
Qin, (TAILOR) ESMO 2016	FOLFOX + Cet	193^‡	61*	+21	9.2*	+1.9	20.7*	+2.9

Significant difference.

^$Retrospective evaluation of RAS status.

^‡All patients were RAS wildtype at inclusion.

RR, response rate; PFS, progression-free survival; OS, overall survival; Cet, cetuximab; Pan, panitumumab.

Table 2A.

Bevacizumab or anti-EGFR in patients with RAS wild-type/BRAF wild-type metastatic colorectal cancer.^[22-24]

Authors (trial name)	Regimen	N	RR(%)	Δ %RR	PFS(mo)	Δ OS (mo)	OS(mo)	Δ OS (mo)
Stintzing (FIRE-3) Lancet Onc 2016	FOLFIRI + Bev	201	59	+6	10.2	+0.1	25.0	+8.1
Stintzing (FIRE-3) Lancet Onc 2016	FOLFIRI + Cet	199	65	+6	10.3	+0.1	33.1*	+8.1
Schwartzberg (PEAK) JCO 2014	FOLFOX + Bev	82	61	+3	9.5	+3.5	28.9	+12.4
Schwartzberg (PEAK) JCO 2014	FOLFOX + Pan	88	64	+3	13.0*	+3.5	41.3	+12.4
Venook (CALGB 80405) JAMA 2017	Double + Bev	256	54	+15	11.3	+0.1	31.2	+0.8
Venook (CALGB 80405) JAMA 2017	Double + Cet	270	69*	+15	11.4	+0.1	32.0	+0.8

Significant difference.Unselected according to primary location. Results are shown as difference in efficacy to substantiate the difference in effect.

Bev, bevacizumab; Cet, cetuximab; OS, overall survival; Pan, panitumumab; PFS, progression-free survival; RR, response rate.

Table 2B.

Bevacizumab or anti-EGFR in left-sided RAS wild-type/BRAF wild-type metastatic colorectal cancer.^[22,23,25]

Authors (trial name)	Regimen	N	RR(%)	Δ %RR	PFS(mo)	Δ OS (mo)	OS(mo)	Δ OS (mo)
Stintzing (FIRE-3) Lancet Onc 2016	FOLFIRI + Bev	149	62	+7	10.7	0	28.0	+10.3
Stintzing (FIRE-3) Lancet Onc 2016	FOLFIRI + Cet	157	69	+7	10.7	0	38.3*	+10.3
Schwartzberg (PEAK) JCO 2014	FOLFOX + Bev	54	57	+7	11.5	+3.1	32.0	+11.4
Schwartzberg (PEAK) JCO 2014	FOLFOX + Pan	53	64	+7	14.6	+3.1	43.4	+11.4
Venook (CALGB 80405) ASCO 2016	Double + Bev	152	58	+11	11.2	+1.5	32.6	+6.7
Venook (CALGB 80405) ASCO 2016	Double + Cet	173	69*	+11	12.7	+1.5	39.3*	+6.7

Significant difference

Bev, bevacizumab; Cet, cetuximab; OS, overall survival; Pan, panitumumab; PFS, progression-free survival; RR, response rate.

A number of randomized studies have evaluated triplet chemotherapy in patients with mCRC, often unselected by stage and tumor biology but elected by younger age and excellent performance status (Table 3A). Two Italian phase III trials^28,29 showed that triplet chemotherapy, with or without bevacizumab, increased ORR and prolonged PFS and OS. Other studies have shown comparable and promising results. Bevacizumab was added to all combinations and we can therefore only conclude that triplet chemotherapy with bevacizumab is tolerable but the additional benefit of bevacizumab cannot be evaluated from these studies. In the OLIVIA trial,³⁰ in which mCRC patients with LLD were included, triplet chemotherapy with bevacizumab produced an impressing ORR of 81% (Table 3A). Consistently, all studies evaluating triplet chemotherapy with bevacizumab produced a high ORR of at least 60%.

Table 3A.

Randomized trials evaluating triplet chemotherapy with or without bevacizumab in patients with metastatic colorectal cancer unselected for RAS status.^[28-33]

	Falcone (GONO),JCO 2007		Cremolini (TRIBE),Ann Oncol 2015		Bendell (STEAM),JCO 2016			Schmoll (CHARTA),ASCO 2017		Falcone (MOMA),Ann Oncol 2016		Gruenberger (OLIVIA),Ann Oncol 2014
	FOLFIRIn = 122	TRIPLEn = 122	FOLFIRIBevn = 256	TRIPLEBevn = 252	FOLFOXBevn = 95	sTRIPLEBevn = 92	cTRIPLEBevn = 93	FOLFOXBevn = 121	TRIPLEBevn = 121	TRIPLEBevn = 117	TRIPLEBevn = 115	FOLFOXBevn = 39	TRIPLEBevn = 41
Age (years)	64	62	60	60	58	56	58	62	60	61	62	57	63
PS 0, %	61%	61%	90%	90%	54%	57%	67%	47%	53%	85%	85%	80%	56%
RR (%)	41	66*	53	65*	47	62	60	61	70	68	58	62	81*
PFS (months)	6.9	9.8*	9.7	12.3*	9.5	11.4	11.9	10.3	12.0	9.5	10.6	11.5	18.6
OS (months)	16.7	22.6*	25.8	29.8*	30.7	28.3	34.0	24.0	28.0	–	–	–	–

Significant difference

cTRIPLE, continuous TRIPLE; OS, overall survival; PFS, progression-free survival; PS, performance status; RR, response rate; sTRIPLE, sequential TRIPLE; TRIPLE, combination of 5-fluorouracil, oxaliplatin, and irinotecan.

A number of phase II studies have combined triplet chemotherapy with EGFR inhibitors, mainly including mCRC KRAS wildtype (Table 3B). All studies showed a very high ORR of more than 70%, but the additional benefit of EGFR inhibitors cannot be evaluated. The first study to evaluate triplet chemotherapy with or without targeted therapy was presented at ESMO 2017. In a randomized phase II trial, patients with RAS wildtype mCRC patients were randomized to modified FOLFOXIRI ± panitumumab.⁴⁰ The authors found that triplet + panitumumab produced a significant higher ORR (86% versus 61%), not only in left-sided tumors but also with right-sided location. Unpredictably they also found a high ORR (71%) in patients with BRAF-mutated tumors.

Table 3B.

Triplet chemotherapy with anti-EGFR in metastatic colorectal cancer.^[34-40]

	Garufi (POCHER),BJC 2010	Assenat (FRENCH), Oncologist 2011	Folprecht (GERMAN),BMC Cancer 2014	Saridaki (GREEK)BJC 2012	Fornaro (TRIP),Ann Oncol 2013	Cremolini (MACBETH),JAMA Oncol 2018		Geissler (VOLFI), Ann Oncol 2017
	TRIPLECetn = 43	TRIPLECetn = 42	TRIPLECetn = 20	TRIPLECetn = 30	TRIPLEPann = 37	TRIPLECetn = 59	TRIPLECetn = 57	TRIPLEn = 33	TRIPLEPann = 63
RR (%)	79	81	75	70	89	68	75	61	86*
PFS (months)	14	9.5	16	10.2	11.3	11.2	9.3	10.5	10.8
OS (months)	37	24.7	33	30.3	–	–	–	–	–

Significant difference

Cet, cetuximab; OS, overall survival; Pan, panitumumab; PFS, progression-free survival; RR, response rate; TRIPLE, combination of 5-fluorouracil, oxaliplatin, and irinotecan.

Efficacy of systemic therapy on the primary cancer

ORR in patients with metastatic disease is close to 50%³ but what is the response rate in the primary to systemic therapy? It is difficult to measure tumor shrinkage in the primary according to RECIST 1.1, since it arises in a hollow distensible organ and the longest diameter can hardly be defined on axial images, but regression in the primary is comparable with that seen in metastatic sites. However, perhaps pathological complete response (pCR) is a more relevant measure, since it is reproducible and there is an excellent correlation with OS.⁴¹ After RT and delayed surgery, a pCR of around 10% can be expected, but this increases to around 15% if chemotherapy, mainly 5- fluorouracil (5-FU), is used as a radiation sensitizer. If systemic therapy is added after SC-RT or LC-CRT, a pCR of at least 20% can be achieved. Garcia-Aguilar and colleagues conducted four consecutive phase II trials in patients with localized RC, and after LC-CRT, they added sequentially more and more cycles of FOLFOX and found that LC-CRT followed by 3 months of FOLFOX resulted in a pCR of 38%.⁴²

The traditional method for treating high-risk primary RC includes the delivery of neoadjuvant LC-CRT followed by TME. However, the use of preoperative chemotherapy as an alternative has increased in popularity and is presently being studied in ongoing trials. Preoperative chemotherapy has the potential to impact on the viability of distant micrometastases early in the evolution of the disease, and could thereby reduce systemic failures, in addition to facilitating local control by surgical resection, avoiding the long-term toxic effects of CRT. A number of small studies have evaluated pCR rate after chemotherapy without RT.^43–48 Response rate is more than 50% in all studies and pCR is around 15% (range from 5% to 25%). Perhaps even more interesting, the risk of PD is 0%, except for one study where one patient developed PD during therapy: thus, the response to preoperative chemotherapy could also select patients for either CRT or upfront surgery, which should result in decreased morbidity for some patients.

These promising data may question the use of RT in patients with metastatic RC but until more solid data are available, we will recommend SC-RT if the strategy is with curative intent. This is supported by data from a Chinese randomized three-arm phase III including almost 500 patients with locally advanced RC.⁴⁹ Patients were essentially randomized to LC-CRT (with 5-FU), LC-CRT (with FOLFOX), or FOLFOX without RT. Preoperative FOLFOX alone resulted in lower pCR rate than LC-CRT (the rate of pCR was 14%, 28%, and 7%, respectively) but there was no difference in R0 resection rate (around 90% in all three arms).

Efficacy of radiotherapy on the primary cancer

Classically, there are two possible choices for preoperative radiotherapy: SC-RT (25 Gy/5 fractions) or LC-CRT (45–50.4 Gy/25–28 fractions), which are equally effective in resectable cancers.^4,50–51 Preoperative RT induces pCR in around 15% without clear-cut difference in frequency between LC-RT and SC-RT if there is a planned delay of 6–8 weeks before surgery to allow shrinkage of the primary tumor. In the Stockholm III trial, there was no difference in local recurrence rate after SC-RT or LC-RT if surgery was delayed in both situations.⁵²

The short overall treatment time (OTT) of SC-RT, usually in 5 consecutive days with immediate surgery, is a highly flexible treatment strategy, which is associated with high compliance and low toxicity, in part reflecting an insufficient interval to express the normal tissue reactions and systemic inflammatory effects from radiation before the rectum is surgically removed.^6,53

There are at least two questions in RC patients with CRLM. Do patients need radiotherapy at all and if so, which out of SC-RT or LC-CRT? Findings from a pooled analysis of individual patient data from several institutions⁴¹ showed that patients who obtained a pCR after preoperative LC-CRT had a significantly longer OS than those with residual disease and this may be an argument for recommendation of RT even in patients with synchronous mRC.

Is there a role for radiotherapy to the primary tumor in patients with resectable stage IV rectal cancer?

Patients are unlikely to be cured without surgery and patients are less likely to be cured without chemotherapy. Radiotherapy has only a minor impact on curability, but so far, RT is indicated if the plan is to resect metastases and the primary. Otherwise, RT is only indicated in the case of palliation of symptoms. In a phase II study in patients with near-obstruction lesions, SC-RT and chemotherapy allowed most patients to avoid surgery even those with near-obstruction lesions.⁵⁴ In the RAPIDO trial, patients with ‘high-risk RC’ were randomized to standard LC-CRT or SC-RT followed by 6 cycles of CapOx before TME.⁵⁵ Unfortunately, results from the RAPIDO trial will not be available until 2020.

What is the downside of radiotherapy? LC-CRT may delay the application of full doses of chemotherapy or worsen the compliance to systemic doses of chemotherapy. However, SC-RT can be administered between full doses of systemic therapy with no or only minimal delay of administration. SC-RT combined with systemic therapy has primarily been used in Europe but the first US experience with SC-RT as part of the multidisciplinary management of mRC has recently been reported with promising results.⁵⁶

Timing of resection of the liver metastasis and the rectal cancer

If a patient presents either with resectable liver metastasis or is converted to resectable disease after systemic therapy, the timing of liver resection is more crucial than the resection of the primary. We have learned throughout the last 15 years that patients should get their resection of liver metastasis as soon as possible after evaluating the benefit of systemic therapy. Interestingly, the more aggressive/effective the therapy is, the faster a resection can be offered. In the background is the fact that the remaining liver after resection has to recover and function quickly especially after major hepatectomy. Evaluable literature clearly demonstrates that length of chemotherapy correlates with morbidity and mortality after liver resection.⁵⁷ In the only prospective international trial evaluating the systemic therapy potential to convert unresectable LLD into resectable disease, two patients died due to liver failure after receiving more than 6 months of treatment.³⁰ We therefore advocate repeat MDT discussions every 2 months to identify resectable patients as soon as possible.

Timing of resection of the rectal primary is crucial on two points: first, the best waiting period on maximum local remission after RT or CRT in resectable RC and second, the best downsizing therapy prior to potential curative resection in initially locally advanced noncurable resectable disease.

Conclusion

The optimal sequence and use of the individual modalities remain undefined, but should be employed on an individual basis. Multidisciplinary approach and decision making are essential in patients with RC and synchronous metastases. In the MDT, the treatment aim must be defined upfront and there should be a regular follow up with re-evaluation and rediscussion every 2 months.

Unless the primary and the few liver metastases are ‘easily resectable’, we recommend beginning with the most effective systemic chemotherapy (often triplet chemotherapy with targeted therapy, depending on RAS status) with re-evaluation at the MDT every 2 months. We also recommend liver surgery first as soon as CRLM becomes resectable and to continue systemic treatment before (and perhaps after) resection of the primary for a total of at least 6 months. SC-RT can be added to systemic chemotherapy at virtually any point with no or minimal delay.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare that there is no conflict of interest.

ORCID iDs

Thomas Gruenberger

Robert Glynne-Jones

References

Ferlay

Soerjomataram

Dikshit

et al . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136: E359–E386.

Schmoll

Van Cutsem

Stein

et al . ESMO Consensus guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012; 23: 2479–2416.

Van Cutsem

Cervantes

Adam

et al . ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol 2016; 27: 1386–1422.

Glynne-Jones

Wyrwicz

Tiret

et al.;

on behalf of the ESMO Guidelines Committee. Rectal cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017; 28(Suppl. 4): iv22–iv40.

Fischer

Hellmich

Jackisch

et al . Outcome for stage II and III rectal and colon cancer equally good after treatment improvement over three decades. Int J Colorectal Dis 2015; 30: 797–780.

Kapiteijn

Marijnen

Nagtegaal

et al.;

for the Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Engl J Med 2001; 345: 638–646.

Glimelius

Myklebust

TÅ

Lundqvist

et al . Two countries – Two treatment strategies for rectal cancer. Radiother Oncol 2016; 121: 357–363.

Kelly

Spolverato

et al . Synchronous colorectal liver metastasis: a network meta-analysis review comparing classical, combined, and liver-first surgical strategies. J Surg Oncol 2015; 111: 341–351.

Salvador-Rosés

López-Ben

Casellas-Robert

et al . Oncological strategies for locally advanced rectal cancer with synchronous liver metastases, interval strategy versus rectum first strategy: a comparison of short-term outcomes. Clin Transl Oncol. Epub ahead of print 22 December 2017. DOI: 10.1007/s12094–017–1818–8.

10.

Salvador-Rosés

López-Ben

Planellas

et al . Treatment strategies for rectal cancer with synchronous liver metastases: surgical and oncological outcomes with propensity-score analysis. Clin Transl Oncol 2018; 20: 221–229.

11.

C-Y

Bailey

You

et al . Time trend analysis of primary tumor resection for stage IV colorectal cancer less surgery, improved survival. JAMA Surg 2015; 150: 245–251.

12.

Van Rooijen

Shi

Goey

KKH

et al . Prognostic value of primary tumour resection in synchronous metastatic colorectal cancer: individual patient data analysis of first-line randomised trials from the ARCAD database. Eur J Cancer 2018; 91: 99–106.

13.

Noren

Eriksson

Olsson

et al . Selection for surgery and survival of synchronous colorectal liver metastases; a nationwide study. Eur J Cancer 2016; 53: 105–114.

14.

Folprecht

Grothey

Alberts

et al . Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol 2005; 16: 1311–1319.

15.

Okuno

Hatano

Nishino

et al . Does response rate of chemotherapy with molecular target agents correlate with the conversion rate and survival in patients with unresectable colorectal liver metastases? A systematic review. EJSO 2017; 43: 1003–1012.

16.

Van Cutsem

Lenz

Kohne

et al . Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol 2015; 33: 692–700.

17.

Bokemeyer

Kohne

Ciardiello

et al . FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur J Cancer 2015; 51: 1243–1252.

18.

Douillard

Oliner

Siena

et al . Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med 2013; 369: 1023–1034.

19.

Qin

Wang

et al . First-line FOLFOX-4 ± cetuximab in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC): the open-label, randomized phase 3 TAILOR trial. Ann Oncol 2016; 27(Suppl. 2): ii141.

20.

Saltz

Clarke

Diaz-Rubio

et al . Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008; 26: 2013–2019.

21.

Heinemann

Von Weikersthal

Decker

et al . FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 2014; 15: 1065–1075.

22.

Stintzing

Modest

Rossius

et al . FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol 2016; 17: 1426–1434.

23.

Schwartzberg

Rivera

Karthaus

et al . PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 2014; 32: 2240–2247.

24.

Venook

Niedzwiecki

Lenz

H-J

et al . Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer a randomized clinical trial. JAMA 2017; 317: 2392–2401.

25.

Venook

Niedzwiecki

Innocenti

et al . Impact of primary tumor location on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol 2016; 34(Suppl.): abstract 3504.

26.

Arnold

Lueza

Douillard

J-Y

et al . Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol 2017; 28: 1713–1729.

27.

Holch

Ricard

Stintzing

et al . The relevance of primary tumour location in patients with metastatic colorectal cancer: a meta-analysis of first-line clinical trials. Eur J Cancer 2017; 70: 87–98.

28.

Falcone

Ricci

Brunetti

et al . Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol 2007; 25: 1670–1676.

29.

Cremolini

Loupakis

Antoniotti

et al . Early tumor shrinkage and depth of response predict long-term outcome in metastatic colorectal cancer patients treated with first-line chemotherapy plus bevacizumab: results from phase III TRIBE trial by the Gruppo Oncologico del Nord Ovest. Ann Oncol 2015; 26: 1188–1194.

30.

Gruenberger

Bridgewater

Chau

et al . Bevacizumab plus mFOLFOX-6 or FOLFOXIRI in patients with initially unresectable liver metastases from colorectal cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol 2015; 26: 702–708.

31.

Bendell

Tan

Reeves

et al . Overall response rate in STEAM, a randomized, open-label, phase 2 trial of sequential and concurrent FOLFOXIRI-bevacizumab vs FOLFOX-bevacizumab for the first-line treatment of patients with metastatic colorectal cancer. J Clin Oncol 2016; 34(Suppl. 4): abstract 492.

32.

Schmoll

H-J

Meinert

Cygon

et al : “CHARTA”: FOLFOX/bevacizumab vs FOLFOXIRI/bevacizumab in advanced colorectal cancer—Final results, prognostic and potentially predictive factors from the randomized phase II trial of the AIO. J Clin Oncol 2017; 35(Suppl. 15): abstract 3533.

33.

Falcone

Cremolini

Loupakis

et al . FOLFOXIRI plus bevacizumab (bev) followed by maintenance with bev alone or bev plus metronomic chemotherapy (metroCT) in metastatic colorectal cancer (mCRC): the phase II randomized MOMA trial. Ann Oncol 2016; 27(Suppl. 6): LBA21.

34.

Garufi

Torsello

Tumolo

et al . Cetuximab plus chronomodulated irinotecan, 5-fluorouracil, leucovorin and oxaliplatin as neoadjuvant chemotherapy in colorectal liver metastases: POCHER trial. Br J Cancer 2010; 103: 1542–1547.

35.

Assenat

Desseigne

Thezenas

et al . Cetuximab plus FOLFIRINOX (ERBIRINOX) as first-line treatment for unresectable metastatic colorectal cancer: a phase II trial. Oncologist 2011; 16: 1557–1564.

36.

Folprecht

Hamann

Schütte

et al . Dose escalating study of cetuximab and 5-FU/folinic acid (FA)/oxaliplatin/irinotecan (FOLFOXIRI) in first line therapy of patients with metastatic colorectal cancer. BMC Cancer 2014; 14: 521.

37.

Saridaki

Androulakis

Vardakis

et al . A triplet combination with irinotecan (CPT-11), oxaliplatin (LOHP), continuous infusion 5-fluorouracil and leucovorin (FOLFOXIRI) plus cetuximab as first-line treatment in KRAS wt, metastatic colorectal cancer: a pilot phase II trial. Br J Cancer 2012; 107: 1932–1937.

38.

Fornaro

Lonardi

Masi

et al . FOLFOXIRI in combination with panitumumab as first-line treatment in quadruple wild-type (KRAS, NRAS, HRAS, BRAF) metastatic colorectal cancer patients: a phase II trial by the Gruppo Oncologico Nord Ovest (GONO). Ann Oncol 2013; 24: 2062–2067.

39.

Cremolini

Antoniotti

Lonardi

et al . Activity and safety of cetuximab plus modified FOLFOXIRI followed by maintenance with cetuximab or bevacizumab for RAS and BRAF wild-type metastatic colorectal cancer a randomized phase 2 clinical trial. JAMA Oncol 2018; 4: 529–536.

40.

Geissler

Martens

Knorrenschield

et al . mFOLFOXIRI + panitumumab versus FOLFOXIRI as first-line treatment in patients with RAS wild-type metastatic colorectal cancer m(CRC): a randomized phase II trial of the AIO (AIO-KRK-0109). Ann Oncol 2017; 28(Suppl. 5): 475O.

41.

Maas

Nelemans

Valentini

et al . Longterm outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol 2010; 11: 835–844.

42.

Garcia-Aguilar

Chow

Smith

et al . Effect of adding mFOLFOX6 after neoadjuvant chemoradiation in locally advanced rectal cancer: a multicentre, phase 2 trial. Lancet Oncol 2015; 16: 957–966.

43.

Ishii

Hasegawa

Endo

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 2010; 36: 1061–1065.

44.

Hasegawa

Nishimura

Mizushima

et al . Neoadjuvant capecitabine and oxaliplatin (XELOX) combined with bevacizumab for high-risk localized rectal cancer. Cancer Chemother Pharmacol 2014; 73: 1079–1087.

45.

Hasegawa

Goto

Matsumoto

et al . A multicenter phase 2 study on the feasibility and efficacy of neoadjuvant chemotherapy without radiotherapy for locally advanced rectal cancer. Ann Surg Oncol 2017; 24: 3587–3595.

46.

Matsumoto

Hasegawa

Zaima

et al . Outcomes of neoadjuvant chemotherapy without radiation for rectal cancer. Dig Surg 2015; 32: 275–283.

47.

Schrag

Weiser

Goodman

et al . Neoadjuvant chemotherapy without routine use of radiation therapy for patients with locally advanced rectal cancer: a pilot trial. J Clin Oncol 2014; 32: 513–518.

48.

Fernández-Martos

Pericay

Aparicio

et al . Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imagingdefined, locally advanced rectal cancer: Group cancer de recto 3 study. J Clin Oncol 2010; 28: 859–865.

49.

Deng

Chi

Lan

et al . Modified FOLFOX6 with or without radiation versus fluorouracil and leucovorin with radiation in neoadjuvant treatment of locally advanced rectal cancer: initial results of the Chinese FOWARC multicenter, open-label, randomized three-arm phase III trial. J Clin Oncol 2016; 34: 3300–3307.

50.

Bujko

Nowacki

Nasierowska-Guttmejer

et al . Long-term results of a randomized trial comparing preoperative short-course radiotherapy with preoperative conventionally fractionated chemoradiation for rectal cancer. Br J Surg 2006; 93: 1215–1223.

51.

Ngan

Burmeister

Fisher

et al . Randomized trial of short course radiotherapy versus long-course chemoradiation comparing rates of local recurrence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology Group Trial 01.04. J Clin Oncol 2012; 31: 3827–3833.

52.

Erlandsson Holm

Pettersson

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: 336–346.

53.

Sebag-Montefiore

Stephens

Steele

et al . Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomized trial. Lancet 2009; 373: 811–820.

54.

Tyc-Szczepaniak

Wyrwicz

Kepka

et al . Palliative radiotherapy and chemotherapy instead of surgery in symptomatic rectal cancer with synchronous unresectable metastases: a phase II study. Ann Oncol 2013; 24: 2829–2834.

55.

Nilsson

van Etten

Hospers

GAP

et al . Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer – the RAPIDO trial. BMC Cancer 2013; 13: 279.

56.

Holliday

Hunt

You

et al . Short course radiation as a component of definitive multidisciplinary treatment for select patients with metastatic rectal adenocarcinoma. J Gastrointest Oncol 2017; 8: 990–997.

57.

Karoui

Penna

Amin-Hashem

et al . Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg 2006; 243: 1–7.

Synchronous liver metastases in patients with rectal cancer: can we establish which treatment first?

Abstract

Keywords

Introduction

All patients must be evaluated by a multidisciplinary team

Magnitude of the problem

Efficacy of systemic therapy on colorectal liver metastases

Efficacy of systemic therapy on the primary cancer

Efficacy of radiotherapy on the primary cancer

Is there a role for radiotherapy to the primary tumor in patients with resectable stage IV rectal cancer?

Timing of resection of the liver metastasis and the rectal cancer

Conclusion

Footnotes

Funding

Conflict of interest statement

ORCID iDs

References