Neoadjuvant Chemotherapy without Radiation in Colorectal Cancer

Abstract

In colon cancer, primary surgery followed by postoperative chemotherapy represents the standard of care. In rectal cancer, the standard of care is preoperative radiotherapy or chemoradiation, which significantly reduces local recurrence but has no impact on subsequent metastatic disease or overall survival. The administration of neoadjuvant chemotherapy (NACT) before surgery can increase the chance of a curative resection and improves long-term outcomes in patients with liver metastases. Hence, NACT is being explored in both primary rectal and colon cancers as an alternative strategy to shrink the tumor, facilitate a curative resection, and simultaneously counter the risk of metastases. Yet, this lack of clarity regarding the precise aims of NACT (downstaging, maximizing response, or improving survival) is hindering progress. The appropriate cytotoxic agents, the optimal regimen, the number of cycles, or duration of NACT prior to surgery or in the postoperative setting remains undefined. Several potential strategies for integrating NACT are discussed with their advantages and disadvantages.

Colorectal cancer (CRC) is a common malignancy and a leading cause of death. Surgery is the mainstay of treatment, but postoperative adjuvant chemotherapy has traditionally been offered to selected patients who have had a curative resection. Appropriate selection for chemotherapy has been based on adverse pathological features in the surgical specimen. ^{1 2} The presence of tumor within lymph nodes (LNs) (stage III) is regarded as an absolute indication for adjuvant chemotherapy as this is both prognostic and predictive. Other clinical and pathological features have been defined which are associated with inferior prognosis and a high risk of recurrence: that is, T4 lesions, less than 12 examined LNs, bowel perforation and obstruction, extramural vascular invasion (EMVI), lymphovascular involvement, poorly differentiated histology, perineural invasion, and elevated carcinoembryonic antigen (CEA). These represent potentially “high-risk” features to recommend adjuvant chemotherapy. ^{3 4 5} Despite considerable citations, immunological and molecular aspects of the tumor are not being routinely analyzed. ^{6 7 8}

In colon cancer, postoperative adjuvant chemotherapy has improved both disease-free survival (DFS) and overall survival (OS) in stage III. Further small improvements in DFS have been reported with capecitabine ⁹ and in both DFS and OS in three subsequent landmark trials, where oxaliplatin was added to fluoropyrimidine (5-FU). ^{10 11 12} There is no proven role for the addition of biological agents in the postoperative adjuvant setting. Data supporting the benefit of adjuvant 5-FU-based chemotherapy in stage II colon cancer is largely derived from the Quasar trial ¹³ bolstered by subgroup analysis of randomized trials, or retrospective pooled analyses of these trials and population studies. The efficacy of adjuvant chemotherapy is diluted by longer intervals between surgery and starting chemotherapy. ¹⁴

In contrast, in rectal cancer, the concept that postoperative adjuvant chemotherapy improves DFS and OS after preoperative chemoradiation (CRT) and surgery has not been proven in the few small underpowered randomized trials that have been performed to date, often with slow recruitment that required many years to complete.

Hence, preoperative CRT concurrent with 5-FU followed by total mesorectral excision (TME) remains the international standard treatment for patients with locally advanced rectal cancer (LARC). ^{15 16 17} CRT offers the chance to enhance downstaging to achieve a curative resection, allows sphincter/organ preservation if a complete clinical response is achieved, and improves local control. However, up to 30% of patients with LARC still subsequently develop metastatic disease. ¹⁸

Neoadjuvant, or induction, therapy is defined as therapy administered prior to definitive local treatment. Neoadjuvant chemotherapy (NACT) prior to surgery is an effective strategy in esophageal cancer ¹⁹ and gastric cancer. ²⁰ In CRC, NACT has an established role in downstaging patients with initially borderline or unresectable liver metastases. ²¹

A population-based study from the Netherlands in locally advanced colon cancer suggests that NACT is only used routinely in <5% of cases, ²² but might achieve more R0 resections and better long-term outcomes if more accurate preoperative imaging and routine multidisciplinary team (MDT) discussions were available. A pathologically involved radial margin (defined as tumor present at the cut edge of the mesentery or nonserosal colon) is not uncommon in colon cancer surgery. ²³

Computed tomography (CT) is the standard modality for local and distant staging, and is modestly accurate in discriminating between locally and nonlocally advanced colon cancers (T3 and T4). ^{24 25 26} Magnetic resonance imaging (MRI) can give additional information. ²⁷ MRI in rectal cancer enables an exact T-staging with a quantifiable precise evaluation of the relationship of a tumor to the mesorectal fascia (MRF). ²⁸ Yet, nodal status may not be reliably detectable by imaging studies alone—particularly in right-sided tumors—and a pathologic evaluation of LNs is rarely performed prior to surgery. Hence, concerns have been raised that NACT might allow inappropriate treatment selection leading to overtreatment in a substantial proportion of patients.

The paradigm of CRT has also been challenged in several phase III trials, which compared standard CRT against short-course preoperative radiotherapy (SCPRT) followed by systemic chemotherapy in borderline resectable LARC. ^{29 30} Hence, recently, there has been more enthusiasm for integrating systemic chemotherapy in the neoadjuvant setting in both colon and rectal cancers to increase downstaging and response and to lessen the risk of metastatic disease.

Major tumor response to chemotherapy can allow secondary resection of metastatic lesions. ³¹ This principle has been extrapolated to locally advanced borderline or unresectable CRCs with the addition of biological agents. Trials in metastatic disease suggest that maximal shrinkage is usually achieved after 3 to 4 months. Recently, the concepts of early tumor shrinkage and depth of response (DoR) have been derived from post hoc analyses to capture the level of efficacy of treatment. A pilot study, Fluoropyrimidine Oxaliplatin and Targeted Receptor Pre-Operative Therapy (FOxTROT) ³² and the preliminary results of the randomized PRODIGE 22 trial ^{33 34} partially support the rationale for NACT.

In this review, the authors aim to examine the rationale for NACT in colon cancer and assess the current available evidence regarding the risks and benefits. We also examine the role of NACT alone without radiotherapy in rectal cancer to assess whether NACT can be effective and tolerable with acceptable acute toxicity and surgical morbidity. We offer suggestions for future investigations.

Methods

We searched Medline, Embase, and the Cochrane Library from January 1990 to December 2015 for the MeSH and free terms: “colon,” “rectum,” “colorectal cancer,” “carcinoma,” “tumor,” “tumour,” or “neoplasm,” and drug therapy or chemotherapy and neoadjuvant or preoperative combined with appropriate study design filter as described in section 6.4.11 of the Cochrane Handbook of Systematic Reviews of Interventions . We restricted the chemotherapy administration to oral or intravenous chemotherapy and excluded studies which used chemotherapy delivered by suppositories or arterial chemotherapy. We also excluded studies with less than 10 patients with locally advanced disease. No date or language restrictions were applied. Additional searches were performed by hand-searching reference lists of included studies and relevant reviews. Randomized prospective and retrospective trials comparing preoperative systemic chemotherapy with no chemotherapy or postoperative chemotherapy in operable rectal cancer were identified ( Fig. 1 ).

Fig. 1.

PRISMA literature selection flow diagram. NAC, neoadjuvant chemotherapy; SA, surgery alone; RCT, randomized controlled trial; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analysis.

Results

Only two complete published randomized trials comparing preoperative systemic chemotherapy with either no chemotherapy or postoperative chemotherapy in operable CRC were identified. ^{35 36} A pilot for a randomized phase III with no late outcomes, ³² two small phase II prospective studies ^{25 37 38} a retrospective study from Navarra, ^{39 40} an audit from the National Cancer Data Base Audit ⁴¹ ( Table 1 ), and a single meta-analysis ⁴² were the only published studies found in colon cancer.

Table 1. Presented data/published studies of neoadjuvant chemotherapy without radiation in colon cancer.

	No. of pts a	Eligibility	Induction chemotherapy	Toxicity	pCR b	R0	Late outcome
CARMOFUR Kotake et al (2002) 35 COLON	326	Clinically estimated Dukes' B or C and expected cure	Oral carmofur (HCFU) for 14 d or more prior to surgery	Surgical morbidity not reported	Not reported	Not reported	5-y OS 71.8 vs. 75.4% for the control
Randomized phase III COLON colorectal cancer chemotherapy study group 2003 36	1,355	Resectable colorectal carcinoma (colon 755, rectum 600) cT3/4 or cN+	5-FU: intravenous, 320 mg/m 2 /d × 5 d 1 course only	“Generally mild” Surgical morbidity not reported	Not reported	Not reported	5-y OS 77.3 and 75.7% for colon cancer and 67.2 and 69.2% for rectal
FOxTROT pilot phase III COLON Foxtrot Collaborative Group, (2012) 32 Assigned (2:1) NCT00647530	150	T3 (> 5 mm) or T4 colon cancer assessed by CT scan	3 cycles of OxMdG (6 wk) then surgery —9 cycles postop vs. postop 12 cycles OxMdG. (wild-type K-Ras randomly assigned (1:1) to panitumumab	34% (32/94) preoperative and 31% (12/39) postoperative chemotherapy patients grade 3 or worse acute toxicity	2/100 2%	95/99	No data
COLON Arredondo et al (2014), 39 Arredondo et al (2017) 40	65	Clinical stage III	Oxaliplatin and capecitabine 2 weekly	Postop complications in 15.4% with no mortality	3/44 pCR and pNo progressions	No data	5-y actuarial RFS 85.6% 5-y actuarial OS was 95.3%
COLON Danish Phase II Jakobsen et al (2015) 25	77	T3 tumor invasion > 5 mm or T4 on CT	XELOX 3 cycles (+panitumumab if RAS WT)	≥ G3 acute toxicity 9%	3/71 pCR (4%) Primary end point—patients not for adjuvant chemo so converted, i.e., stage 0, I, or low-risk II 42% in the wild-type group vs. 51% in mutated (4%)	No data	3-y DFS 94% for converted to low risk vs. 63% not ( p  = 0.005)
Shanghai single arm Phase II COLON Liu et al (2016) 37 NCT02415829	47	CT-defined T4 or lymph node-positive resectable	Min CapOX 2 cycles then surgery Mean 2.7 cycles then another 5 cycles postop	4/47 G3, no G4 toxicity wound infection (1/47, 2%). Mean postop hospital stay 9.4 d	1/47 (2%) pCR	47/47 (100%)	No data
Chinese single arm Phase II COLON Zhou et al (2016) 38 NCT02688023	23	Clinical stage IIIb colon cancer	XELOXIRI repeated at 2-wk intervals) for 4 cycles. Postop 6 cycles of FOLFOXIRI or XELOX Clinically all T4aN2M0	13/23 (56.5%) patients had grade 3/4 acute toxicity. Dose reductions required in 7/23 (30.4%)	1/23 (4%) pCR 2/23 increased tumor volumes	20/23 R0	The 2-y OS rate 95.7% (22/23), 2-y DFS rate 73.9% (17/23)
National Cancer Data Base Audit COLON Dehal et al (2018) 41	921 of 27,575 (3%)	T3 or T4 resected colon cancer	NACT				T4b colon cancer treated with NACT had a 23% lower risk of death at 3 y vs. adjuvant chemo ( p  = 0.04)

Abbreviations: CT, computed tomography; DFS, disease-free survival; NACT, neoadjuvant chemotherapy; OS, overall survival; postop, postoperative; pts, patients; RFS, relapse-free survival; 5-FU, fluoropyrimidine.

^aNumber entering study.

^bNumber having had surgery.

In rectal cancer, a single published randomized phase III trial was identified, ⁴³ and two randomized phase II studies, ^{44 45} nine prospective phase II, ^{46 47 48 49 50 51 52 53 54} and a single retrospective study ⁵⁵ have been presented/published ( Table 2 ).

Table 2. Published studies of neoadjuvant chemotherapy without radiation in rectal cancer.

	No of pts a	Eligibility	Induction chemotherapy	Toxicity	pCR b	R0	Late outcome
Randomized phase III trial FOWARC trial RECTAL Deng et al (2016) 43	163	MRI or CT + EUS stage II (T3-4/N0) or stage III (T1-4/N1-2), M0, <12 cm above anal verge	Modified FOLFOX6 alone	Low	10/152 (6·6%)	136/152 (89%)	No data
Randomized phase II trial GRECCAR 4 trial RECTAL Rouanet et al (2017) 44	10	MRI defined cT3 ≥ c, cT4 or predicted CRM ≤1 mm	FOLFIRINOX	Grades 3–4 toxicity in 7/11 (63·6%)	1/10 (10%)	10/10 (100%)	No data
Randomized phase II trial RECTAL BACCHUS Glynne-Jones et al (2017) 45	20	MRI defined high risk >T3b	Modified FOLFOX6 alone FOLFOXIRI plus Bevacizumab	1 pelvic sepsis 2 wound infections No leaks	2/20 10%	17/18 (94%) resected	2 y OS 80%
Phase II RECTAL Ishii et al (2010) 46	26	T3/T4 N0-2	Irinotecan (80 mg/m 2 ), FUFA days 1, 8, and 15 for 4 wk	Not stated	1/15 (7%)	Not stated	5 y RFS 74% OS 84%
Phase II RECTAL Fernandez-Martos et al (2014) 47	46	T3 middle third tumors ≥2 mm from the mesorectal fascia	Capox + bev	2 acute toxic deaths 13% rate of anastomotic leak higher than expected (1 death)	9/46 (19·5%)	96·4%	No data
Phase II RECTAL Uehara et al (2013) 48	32	T3 >5 mm, T4, N2, CRM involved/at risk	Capox + bev	Postop complication in 43%	8/32 (12.5%)	84·3%	No data
Phase II RECTAL Schrag et al (2014) 49	32	T2N1, T3 any N (not N2 bulky) Not T4 5–12 cm from anal verge	FOLFOX + bev (6 cycles bev 1–4)	2 pts withdrew (angina arrhythmia)	8/32 (25%)	100%	RFS 92% OS 91%
Phase II RECTAL AlGizawy et al (2015) 50	45	C stages II and III	6 cycles of FOLFOX 6	3 pelvic collections 2 delayed wound healing	8/45 (17·8%	No data	3 y DFS 68% 3 y OS 81%
Phase II Hasegawa et al (2017) 51 RECTAL (UMIN000005654)	60	C stages II and III	mFOLFOX6) + bev or cetuximab, depending on KRAS status	Postop complication rate (≥grade 2) 21·7%	10/60 (16·7%)	98·3%	No data
Phase II trial RECTAL Ueki et al (2016) 52	31	Clinical stage II/III lower rectal cancer	XELOX	Grades 3–4 adverse events in 9/31 (31%)	3/29 (10·3%)	96·5%	No data
CORONA 1 phase II trial RECTAL Kamiya et al (2016) 53	41	cT3/T4 cN+	XELOX	Major complication in 6/40 patients (15·0%)	5/41 (12·2%)	37/41 90·3%	No data
Phase II FACT trial RECTAL Koike et al (2017) 54	52	T3 or T4 stage II/III rectal cancer	FOLFOX	Safe	5/42 resected (11·9%) 5/52 overall	91%	No data
Retrospective RECTAL Matsumoto et al (2015) 55	15	cT3/cT4a, cN+	FOLFOX (60%) IRIS FOLFIRI	3/15 (20%) grade 3/4 adverse events	2/15 (13·3%)	100%	5-y RFS rate 66·7 and 62·6% in NACT and non-NACT groups

Abbreviations: CT, computed tomography; DFS, disease-free survival; MRI, magnetic resonance imaging; NACT, neoadjuvant chemotherapy; OS, overall survival; postop, postoperative; pts, patients; RFS, relapse-free survival.

^aNumber entering study.

^bNumber having had surgery.

We found one completed phase III FOxTROT (NCT00647530) and five ongoing (either recruiting or completed) randomized phase III trials—a Chinese trial (NCT02777437), NEOCOL (NCT01918527), the OPTICAL trial (NCT02572141) ⁵⁶ and a Spanish trial ELECLA (EudraCT: 2016-002970-10). We also found two randomized phase II trials—VOLFI (NCT01328171) ⁵⁷ and ECKINOXE PRODIGE-22 (NCT01675999) ^{33 34} in colon cancer.

We also found four unpublished ongoing (either recruiting or completed) randomized phase III trials in rectal cancer—PROSPECT (NCT01515787), the French UNICANCER trial NEOFIRINOX (NCT01804790), the Japanese JCOG1310 PRECIOUS trial (UMIN000017603), ⁵⁸ and (NCT02288195) and three randomized phase II trials—Chinese trial (NCT01211210), KSCC1301 (NCT02280070), and (NCT03043729) with nine small prospective phase II trials.

The published randomized phase III studies in colon cancer used very short durations (1–2 weeks) of NACT and did not significantly improve long-term oncological outcomes. ^{35 36} The FOxTROT trial (ISRCTN 87163246) phase II/III trial also only used a short duration with three courses of FOLFOX. Preliminary data from the initial 150 patients reported on early alternative end points. ³² This feasibility study showed significant tumor downstaging compared with the postoperative group ( p  = 0.04), with significantly less apical node involvement (1 vs. 20%, p  < 0.0001) and fewer positive margins (4 vs. 20%, p  = 0.002, but there were no data on disease progression or survival outcomes yet reported. For the phase III comparison, the primary end point is 2-year freedom from recurrent or persistent disease. Preliminary results presented in abstract suggest FOxTROT is a negative trial in terms of the primary endpoint, but data are not yet published. A meta-analysis of six RCTS (some of which used intrahepatic chemotherapy or suppositories) showed a nonsignificant reduction in overall recurrences (21.86 vs. 25.15%, relative risk [RR]: 0.70, 95% confidence interval [CI]: 0.32–1.56, p  = 0.09 and significantly fewer metastases (15.58 vs. 23.80%, RR: 0.66, 95% CI: 0.50–0.86, p  = 0.002). ⁴²

In rectal cancer, tolerability and compliance with NACT prior to CRT is better than CRT and postoperative adjuvant chemotherapy. ^{59 60} A feasibility study from the Memorial Sloan Kettering Cancer Center using NACT alone with FOLFOX + bevacizumab without radiotherapy. ⁴⁹ The study showed good compliance but did not report surgical morbidity. The BACCHUS trial showed early exposure to a triplet NACT combination, FOLFOXIRI with bevacizumab did not impact adversely on compliance or surgical morbidity. ⁴⁵ The Chinese randomized FOWARC study in rectal cancer show neoadjuvant FOLFOX without chemoradiotherapy achieves similar tumor downstaging rates of R0 resection, with lower rates of surgical morbidity than CRT. ⁴³ Ongoing trials include a randomized phase II trial exploring the best sequence of CRT and NACT (NCT02008656) and the PROSPECT trial investigating NACT with FOLFOX and a selective use of CRT in early-stage patients with cT2N1 and cT3N0-1 rectal cancer.

We could find no studies investigating the relationship between the numbers of cycles of NACT or whether the total amount of perioperative chemotherapy affects the prognosis of patients with CRC. Do patients who respond require more and those who fail to respond well need less NACT? And should patients with marked pathological downstaging (i.e., ypNo or yp stage and I and II) receive more or less postoperative adjuvant chemotherapy.

We found no evidence to support whether biologically targeted agents should be added to chemotherapy in the neoadjuvant setting for resectable patients, even though these more aggressive strategies can result in high response rates.

Discussion

The use of NACT has advantages that include downstaging and the possibility of measuring early in vivo response to systemic treatment delivered when primary tumor is treatment naïve with an intact vasculature, undisrupted by radiation or surgery and their immunosuppressive effects and has not upregulated resistance mechanisms. NACT might also incapacitate cancer cells shedded during surgical manipulation and reduce the risk of locoregional, intracoelomic, and distant recurrence. NACT also allows treatment of potentially occult disease and may avoid surgery altogether in those few patients with highly aggressive and rapidly progressive disease as a result of primary resistance to chemotherapy.

NACT is also a potentially useful therapeutic approach for locally advanced primarily unresectable or borderline resectable colon and rectal cancers. The objective in borderline resectable patients is to reduce the risk of an incomplete tumor excision (R1/R2) and achieve sufficient cytoreduction to limit supraradical/exenterative resections and modify potentially postoperative morbidity as well as to facilitate a margin-free curative R0 resection.

However, only around 5 to 10% of patients fulfill the criteria for “unresectable.” Despite a rationale for the use of NACT in this setting, the eligibility for the major trials in both colon and rectal cancers require patients to be resectable ( Tables 1 and 2 ). In rectal cancer, because CRT is the standard of care, low cancers within 5 cm of the anal verge, patients with T4 tumors, and/or with potential involvement of the MRF are usually excluded from chemotherapy alone studies.

NACT might therefore be a more effective option for patients with CRC who would require adjuvant chemotherapy according to clinical and histological parameters, and CT/MRI-based imaging if these patients could be robustly identified preoperatively. However, few studies have delivered more than 4 to 6 weeks of chemotherapy in the preoperative setting and most allow further adjuvant chemotherapy postoperatively. Hence, trials of NACT to date have not shown any benefit.

Initial interest in NACT in rectal cancer was sparked by results of a selected group of patients prospectively treated at the Royal Marsden Hospital. NACT prior to CRT was associated with substantial tumor regression, rapid improvement in symptoms, a high complete resection (R0) rate, and a pathological complete response (pCR) rate of 24% with no patient experiencing disease progression during preoperative treatment. ^{61 62} The magnitude of benefit may nowadays be diluted by the major improvements in the quality of surgery for CRC, achieved over the past two decades ⁶³ leading to better OS, particularly in stage II colon cancer. ⁶⁴

Selection of High-Risk Patients Suitable for NACT

The Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) is a crucial selection factor, as patients with PS ≥ 2 are unlikely to tolerate intensive cytotoxic regimens particularly triplet chemotherapy. In addition, the presence of metastatic disease and the extent/resectability of the primary tumor are important to consider. Yet, there are no unequivocal agreed features that would require NACT apart from local unresectability.

European Society for Medical Oncology guidelines for rectal cancer state “For patients with LARC, treatment decisions regarding neoadjuvant therapy should be based on preoperative, MRI-predicted CRM (≤1 mm), EMVI and more advanced T3 substages (T3c/T3d), which define the risk of both local recurrence and/or synchronous and subsequent metastatic disease.” ⁶⁵ Others also recommend selection for chemotherapy according to these biomarkers). ^{66 67}

Although trials in rectal cancer have defined high-risk prognostic factors, there is no evidence that these are predictive factors, since there was no evidence of any benefit for any single factor or combination with the use of adjuvant 5-FU alone after SCPRT ⁶⁸ or the addition of oxaliplatin in stage II after CRT. ⁶⁹ Hence, prognostic factors cannot be used as predictive factors for neoadjuvant or adjuvant therapy. Nor are there predictive markers to define which high-risk patients will be disadvantaged by the use of NACT. If the DNA damage from cytotoxic chemotherapy is either repaired or partially repaired, then hypoxia, epithelial-mesenchymal transition (EMT), and more aggressive invasiveness and tumor motility may be enhanced. ⁷⁰

Trials in colon cancer have failed to show a significant benefit for postoperative adjuvant 5-FU in terms of OS in stage II (Quasar Collaborative Group) ¹³ or for the combination with oxaliplatin (André et al, 2004) ¹⁰ even in high-risk stage II. ⁷¹ There is even a question regarding benefit in terms of OS in patients with pN1 (André et al, 2015). ⁷¹ Such benefit may be limited to patients <70 years old. ^{72 73}

More recent adjuvant trials have been specifically directed at stage II (60% of a total of 1,982 patients had vascular invasion, 22% <12 LNs examined and 15% had T4 tumors) using 1-year of postoperative adjuvant chemotherapy with oral Tegafur-Uracil (UFT). UFT failed to show any OS benefit (OS at 5 years was 94.3% [95% CI: 92.6–95.6]) in the control group and 94.5% in the UFT. Cox's regression analysis showed pT4, elevated preoperative CEA, EMVI, non–D3 LN dissection, older age, and male gender, all had independent effects on worse relapse free survival (RFS). Interestingly, the recurrence rate was 13.2% for control and 10.1% for UFT, and UFT almost halved the incidence of subsequent liver metastases. ⁶⁴ However, as previously highlighted, outcomes in both colon and rectal cancers are improving as the quality of surgery continues to improve thus inevitably diluting the potential magnitude of benefit from both postoperative adjuvant chemotherapy or NACT. ⁶³

CEA has been used as a biomarker to detect the presence of metastasis in early CRC but has limitations in terms of sensitivity and specificity ⁷⁴ and using TNM staging and CEA to identify patients at risk of developing metastases is ineffective.

Concerns remain regarding the accuracy of clinical staging and whether NACT overtreats substantial numbers of patients The small randomized PRODIGE 23 trial reported on 99 patients (surgery alone n  = 51 and four cycles of FOLFOX prior to surgery n  = 48). Significant downstaging was reported ( p  = 0.02) with reduction in stage III cases 61 versus 40%, pT4 and N2 cases in the NACT arm 59 versus 37.5%, and a reduction in cases with vascular emboli, lymphatic and/or perineural invasion 49 versus 19% ( p  = 0.001). No patient in the control arm had stage I disease. However, given the controversial benefit of chemotherapy in stage II, up to one-third may have received oxaliplatin unnecessarily as the control arm showed pathological stage II in 20/51 (39%).

Compliance/Tolerability

The Grupo Cáncer de Recto 3 study ⁵⁹ demonstrated that NACT could be delivered at full systemic doses to 92% of patients with rectal cancer in the induction arm prior to CRT compared with only 51% in postoperative adjuvant arm ( p  = 0.0001), although this strategy did compromise the delivery of capecitabine during CRT. However, the pCR rates for the different arms were 13.5 and 14.3%, respectively, and DFS was not improved despite higher compliance to NACT. Similarly, in colon cancer, both the PRODIGE 23 trial ³⁴ and the FOxTROT pilot study ³² using NACT alone showed that NACT is feasible with acceptable toxicity and perioperative morbidity in locally advanced operable primary colon cancer, and the FOxTROT investigators proceeded to a phase III (now completed). Prisma flow diagram is shown in Fig. 1 .

What Is the Optimal Regimen?

Tumor response to chemotherapy is still mainly determined by sequential measurement of tumor size in CRC because the level of shrinkage may correlate with oncological outcomes, ⁷⁵ but simple tumor shrinkage has no clear oncological outcomes validation. Historically, World Health Organization criteria used a bidimensional measurement of tumor lesions to determine a reduction of 50%. Currently, the most widely applied system is Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, which relies on the use of unidimensional (linear) measures for overall evaluation of tumor burden and recommends a >30% reduction in size to be defined as a partial response. ⁷⁶ This cutoff is overly generous and probably overestimates the real clinical benefit to the individual. The challenges of response assessment after immunotherapy add a further level of complexity.

Exposure to all drugs 5-FU/LV, oxaliplatin, and irinotecan at some point during the treatment in metastatic CRC (mCRC) produces the best results in mCRC. ⁷⁷ Treating patients with all three agents as first-line therapy, that is, triplet schedules (FOLFOXIRI) with or without biological agents demonstrates high response rates in metastatic disease. Although the overall response rate was 66% in the pivotal trial by Falcone et al, ⁷⁸ others show stable disease in 31.3% of patients and progression under treatment in 25.5%. ⁷⁹ When FOLFOXIRI was compared with FOLFIRI as first-line therapy, FOLFOXIRI showed better PFS (9.8 vs. 6.9 months) and median OS (22.6 vs. 16.7 months median). ⁷⁸ Retrospective analyses of prospective data suggest R0 resections in patients with CRC liver metastases may also be increased with triplet chemotherapy compared with doublet regimens. ^{78 79 80} If the primary overriding aim is to achieve maximum response, then is it legitimate to use irinotecan and either bevacizumab or anti-epidermal growth factor receptor (EGFR) monoclonal antibodies in addition to FOLFOX chemotherapy in wild-type tumors even for a right-sided primary tumor? There is no evidence for a benefit in long-term outcomes from the use of irinotecan in the adjuvant setting after a curative resection in the CALGB 89803, PETACC-3, and ACCORD2 trials. ^{81 82 83 84 85}

The addition of novel targeted agents either incorporated into chemotherapy schedules or used alone has extended survival of patients with mCRC. These agents include EGFR/HER-2 and VEGFR targeted agents (cetuximab, panitumumab, bevacizumab, aflibercept, and regorafenib and even trastuzumab). These agents offer exciting possibilities for the future if response and downstaging is the aim. The same question regarding legitimacy could be asked regarding bevacizumab or anti-EGFR monoclonoal antibodies in addition to FOLFOX chemotherapy in wild-type tumors even for a right-sided primary tumor.

Bevacizumab added to standard cytotoxic chemotherapy may be associated with higher complete pathological response rates in patients undergoing resection of colorectal liver metastases ⁸⁶ and can be safely administered without increasing postsurgical complications. ^{87 88}

The randomized VOLFI trial evaluated activity and safety of mFOLFOXIRI + panitumumab versus FOLFOXIRI in the neoadjuvant setting for patients with unresectable colonic primary tumors, and achieved exceptionally high clinical response rates compared with FOLFOXIRI alone in RAS wild-type cancers, but varied according to tumor sidedness. Toxicity was substantial, but high secondary resection rates were observed (Geissler et al). ⁵⁷

Is Response Alone Sufficient?

Shrinking large colonic and rectal tumors before surgery might also make surgery easier, minimize the perioperative shedding of viable tumor cells, facilitate more curative (R0) resections, and in some cases potentially allow less extensive radical surgery. The degree of pathological response to NACT determined at resection of hepatic metastases is an independent predictor of 5-year OS in patients with stage IV CRC. ⁸⁹

The FOxTROT pilot in colon cancer showed NACT was associated with significant downstaging of TNM5 compared with the postoperative group ( p  = 0·04), including less apical node involvement (1% [1 of 98] vs. 20% [10 of 50], p  < 0.0001) and pathological nodal involvement (40% [39 of 99] pN1/pN2 vs. 52% [26 of 50]. ³² Yet, in rectal trials, reductions of nodal involvement of 30% were not associated with improvements on DFS or OS. ^{15 18} Hence, we should not necessarily expect improvements in these long-term oncological outcomes as both arms receive standard adjuvant FOLFOX. A meta-analysis of NACT versus adjuvant studies in breast cancer have not demonstrated benefit of NACT over postoperative chemotherapy in terms of DFS or OS. ⁹⁰ Also, even if there is a small reduction in R1 resections in the retroperitoneum in the FOxTROT trial as a result of the NACT, there is no data to suggest that as in rectal cancer that this finding will impact on local recurrence or metastatic disease. ⁹¹

Alternatively, outcomes might simply be determined by the initial response and DoR to chemotherapy provided the interval is not overextended beyond 8 weeks.

What Is the Optimal Number of Cycles?

With FOLFOX, despite substantial initial responses, mCRC eventually becomes resistant to oxaliplatin, with a median time to progression of about 8 to 9 months. The ideal duration might be expected to be shorter—in the range of 3 to 6 months. In the Intergroup Trial N9741, the median time to response in metastatic disease in FOLFOX-treated patients was 2.2 months (7 weeks), and grade 2 sensorimotor neurotoxicity developed at a median of 5 months with a median PFS of 7.7 months. ⁹² This finding suggests that three cycles of FOLFOX or two cycles of XELOX are appropriate as the minimum duration of NACT FOLFOX and 4 months as the maximum duration (eight cycles of FOLFOX and five cycles of XELOX) if maximal response is the aim of treatment. However, in view of the results of the International Duration Evaluation of Adjuvant therapy (IDEA) analysis 4 cycles of XELOX are likely to represent the appropriate maximum duration, if improving DFS is the aim. Hence, our recommendation would be to scan after four cycles of FOLFOX (6–8 weeks) or after three cycles of XELOX (6–9 weeks). For responding patients, there is an option to continue FOLFOX for a further three or XELOX for a further two cycles depending on MDT review, but this plan could be modified for nonresponders. In future, early end points may be available after 2 to 3 weeks, such as early metabolic imaging, measuring ctDNA after 14 days of treatment in terms of tumor-specific mutations and monitoring these levels or examining changes in sophisticated cellular signaling signatures. However, early response to two to three cycles of NACT (after 4–6 weeks) does not necessarily imply that prolonging the duration of treatment will deliver further shrinkage.

Timing of Surgery following Stopping Chemotherapy

Response to chemotherapy is transient and often followed by regrowth during continuing chemotherapy, which occurs more rapidly after stopping chemotherapy. In the randomized trials, specifically investigating treatment-free intervals versus maintenance chemotherapy, the median interval from the end of chemotherapy treatment until obvious RECIST progression was identified was only 3.0 to 4.1 months. Retrospective studies suggest a rapid regrowth of liver metastases in the interval to surgery following completion of chemotherapy (2.3% per week), with a calculated median tumor doubling time (DT) of 46 days, ⁹³ as opposed to a much longer DT of 63 to 112 days when untreated. ^{94 95} This rapid tumor regrowth could influence DFS and OS after resection. Any decrease in the size of the primary tumor may indicate a parallel effect in terms of destroying micrometastases if present, whereas the rebound growth of primary tumor after stopping chemotherapy may not be associated with the recovery of micrometastases if they have been eradicated.

Conclusion

Better surgical techniques and increasing precision have led to improvements in OS in CRC, but the risk of metastases after surgery remains substantial. Progress in the postoperative adjuvant setting has stalled, and there has been a shift to use NACT as an alternative strategy in both colon and rectal cancers rather than postoperatively. Either systemically active doublet or triplet cytotoxic chemotherapy (with or without biological agents) or immunotherapy would seem important to reduce the risk of these metastases. NACT has been explored in numerous small prospective studies, but the long-term oncological results of randomized phase II and phase III studies are not yet available. Previous phase II and phase III trials in NACT appear to have had heterogeneous inclusion criteria, nonstandardized imaging with CT and MRI, and uncertain surgical quality, which make the results difficult to interpret. The long-term results of the FOxTROT trial will be crucial to our future approach to the use of NACT in colon cancer.

Yet, NACT is feasible and has high levels of efficacy on the primary tumor. NACT prior to CRT does not substantially compromise CRT. Surgical morbidity is not significantly increased unless bevacizumab is used and only if a short interval to surgery is employed. The utility of NACT alone could be explored compared with SCPRT or CRT in selected patients with resectable rectal cancer where the impact of radiotherapy on DFS and OS is marginal.

The optimal combination regimen, the ideal intensity and duration of treatment prior to surgery, and the safest interval between the end of chemotherapy and surgery remain undefined. The results of the IDEA collaboration have, if any, made conclusions more opaque.

So In future, alternative assessments of response such as a major decrease of FDG uptake or reduction in ctDNA after one or two cycles of NACT may discriminate responders from nonresponders. Nonresponders could switch to an alternative strategy. In breast cancer, sophisticated molecular tools now help select and guide treatment. In future, this strategy may be tempered by considerations for manipulating or reinvigorating immune competence. Robust biomarkers will be needed to predict the RRs of local recurrence, metastatic disease, and patients with pharmacogenomics to predict toxicity of chemotherapy and late effects from radiotherapy. Only then, will we be truly able to individualize treatment.