Table of Contents  

Busse: Adjuvant and palliative systemic treatment for colon cancer

Introduction

Colorectal cancer (CRC) is the third most common cancer worldwide and accounts for 8% of cancer-related deaths in men and 9% in women.1 About 80% of patients with CRC have localized and resectable disease at diagnosis; however, more than 50% of those patients eventually develop metastatic disease.2,3 The 5-year survival rate is 90% in stage I, 70–80% in stage II and 40–65% in stage III. The risk of distant recurrence also depends on the pathological stage of the primary tumour and is 30% in stage II and 50% in stage III and occurs mainly within the first 2 years after surgery.2 Twenty per cent of patients present with metastatic CRC (mCRC) at initial diagnosis. Despite significant advances in the treatment of mCRC, median overall survival (OS) with the treatment options currently available is only about 18–30 months.4 Although multidisciplinary approaches play a role in both adjuvant and palliative treatment of CRC, systemic chemotherapy continues to be the main treatment modality for mCRC.5 In this review we describe current treatment standards and new developments in locally advanced CRC and mCRC with a focus on systemic therapy.

Adjuvant chemotherapy for colorectal cancer

The goal of adjuvant therapy for solid tumours is to cure more patients than surgery alone, or at least to prolong survival. A further aim is to gain local as well as systemic control by eliminating any micrometastatic disease.2

Adjuvant chemotherapy for locally advanced colon cancer

Adjuvant chemotherapy with 5-fluorouracil (5-FU)-based regimens has been shown to increase OS in patients with stage III colon cancer;6 however, the situation is less clear and still controversial for stage II patients. There might be a small benefit for a selected high-risk group of stage II patients, defined by poorly differentiated histology, the presence of lymphovascular invasion, the presence of perineural invasion, involvement of < 12 lymph nodes, bowel obstruction, localized perforation or positive margins. Guidelines for the adjuvant treatment of stage II colon cancer recommend a range of treatment options from observation to chemotherapy with single-agent or combination regimens, depending on the presence or absence of these high-risk features.7,8

Combination therapy of oxaliplatin with a fluoropyrimidine backbone is the current standard adjuvant therapy for stage III colon cancer (Table 1 and Figure 1)7,17 based on evidence from three randomized controlled trials. In the National Surgical Adjuvant Breast and Bowel Project (NSABP) C-07 trial, FLOX [oxaliplatin plus bolus leucovorin (LV) and 5-FU] significantly increased disease-free survival (DFS) compared with 5-FU or LV alone.9 However, FLOX did not show an OS benefit and has an unfavourable safety profile. XELOX (oxaliplatin plus oral capecitabine) significantly increased DFS and OS compared with bolus LV and 5-FU in the XELOXA trial.11 The MOSAIC (Multicenter International Study of Oxaliplatin/Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer) trial demonstrated a benefit of the addition of adjuvant oxaliplatin to a 5-FU/LV regimen compared with FOLFOX-4 (LV, 5-FU and oxaliplatin) regimen in patients with stage III disease [10-year OS 67.1% vs. 59.0%, hazard ratio (HR) = 0.80, p = 0.016].10,18 No survival benefit was seen in patients with stage II disease (10-year OS 78.4% vs. 79.5%, HR = 1.00, p = 0.980). In patients with high-risk stage II disease, defined as T4, tumour perforation or fewer than 10 lymph nodes examined, estimated 10-year OS was 75.4% versus 71.7% (p = 0.058). Moreover, subgroup analyses showed that FOLFOX-4 appeared to improve survival in both patients with BRAF mutation and those with mismatch repair-deficient (dMMR) tumours. Interestingly, BRAF mutation was not prognostic for OS but dMMR was an independent prognostic factor. Capecitabine was shown to be as efficacious as LV and 5-FU in the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial.19 No study has directly compared adjuvant capecitabine, with or without oxaliplatin, with 5-FU/LV, with or without oxaliplatin. Therefore, Schmoll et al.20 conducted a pooled data analysis of patients with resected stage III colon cancer from four randomized controlled trials. The treatment regimens in these trials were XELOX, 5-FU/LV, capecitabine, FOLFOX-4 (oxaliplatin on day 1 at the dose of 85 mg/m2 concurrently with LV 200 mg/m2 per day, followed by bolus 5-FU 400 mg/m2 and a 22-hour infusion of 5-FU 600 mg/m2 for 2 consecutive days, administered every 2 weeks) and a modified FOLFOX-6 (mFOLFOX-6) (oxaliplatin 85 mg/m2 and LV 200 mg/m2 on day 1, followed by 5-FU 400 mg/m2 bolus and then 5-FU 2400 mg/m2 over 46 hours, administered every 2 weeks). Combination therapy with oxaliplatin consistently led to improved outcomes in the adjuvant treatment of stage III colon cancer. This was irrespective of whether the fluoropyrimidine backbone was capecitabine or 5-FU/LV. Moreover, combination therapy with oxaliplatin did not negatively affect post-relapse survival. Consistent with a previous meta-analysis in mCRC,21 grade 3 hand–foot syndrome was more frequent with capecitabine than with 5-FU/LV, but oxaliplatin-related grade 3–4 events (neuropathy, neutropenia and febrile neutropenia) and overall grade 3–4 events were less frequent than with 5-FU-based regimens. Trials of mCRC revealed similar toxicity profiles for XELOX and FOLFOX.22,23 In conclusion, both capecitabine as well as infusional 5-FU/LV-based regimens can be recommended based on patients’ comorbidity and preference.

TABLE 1

Selected key clinical randomized phase III trials for adjuvant therapy of colon carcinoma

Study acronym Treatment/design Efficacy results Reference
FOLFOX
NSABP C-07 trial FLOX vs. 5-FU/LV (bolus), stage II or stage III, n = 2409 5-year OS 69.4% vs. 64.2%, HR 0.88 (95% CI 0.75 to 1.02; p = 0.08)
5-year DFS 80.2% vs. 78.4%, HR 0.82 (95% CI 0.72 to 0.93; p = 0.002)
Yothers et al.9
MOSAIC trial FOLFOX vs. 5-FU/LV (de Gramont), stage II or III, n = 2246 Stage II
10-year OS 78.4% vs. 79.5%, HR = 1.00 (95% CI 0.74 to 1.35; p = 0.980)
10-year DFS 75.2 vs. 73.6, HR 0.89 (95% CI 0.68 to 1.16, p = 0.390)
Andre et al.10
Stage III
10-year OS 67.1% vs. 59.0%, HR = 0.80 (95% CI 0.66 to 0.96; p = 0.016)
10-year DFS 62.2% vs. 53.8%, HR 0.79 (95% CI 0.67 to 0.94; p = 0.007)
NO16968 trial (XELOXA) XELOX vs. 5-FU/LV (bolus), stage III, n = 1886 7-year DFS 63% vs. 56%, HR 0.80 (95% CI 0.69 to 0.93; p = 0.004)
7-year OS 73% vs. 67%, HR 0.83 (95% CI 0.70 to 0.99; p = 0.04)
Schmoll et al.11
FOLFIRI
PETACC-382 trial FOLFIRI vs. 5-FU/LV (de Gramont), stage III, n = 2094 5-year DFS 56.7% vs. 54.3%, HR 0.90 (95% CI 0.79 to 1.02; p = 0.106)
5-Year OS 73.6% vs. 71.3% (p = 0.094)
Van Cutsem et al.12
CALGB 8980383 trial FOLFIRI vs. 5-FU/LV (bolus), stage III, n = 1264 Median OS and DFS not reached
3-year DFS probability 0.66 (95% CI 0.62 to 0.69) vs. 0.69 (95% CI 0.65 to 0.73)
3-year OS probability 0.80 (95% CI 0.76 to 0.83) vs. 0.81 (95% CI 0.78 to 0.84)
Saltz et al.13
ACCORD 0284 trial FOLFIRI vs. 5FU/LV (de Gramont), CRC with completely resectable liver-limited metastases, n = 306 Median DFS 24.7 months vs. 21.6 months, HR 0.89 (95% CI 0.66 to 1.19; p = 0.44)
Median OS not reached, 2-year OS comparable
Ychou et al.14
Bevacizumab (Avastin®, Roche, Basel, Switzerland)
NSABP C-08 trial Bevacizumab with FOLFOX vs. FOLFOX stage II or III, n = 2672 3-year DFS 77.4% vs. 75.5%, HR 0.89 (95% CI 0.76 to 1.04; p = 0.15) Allegra et al.15
Cetuximab (Erbitux®, Merck Serono, Darmstadt, Germany)
NCCTG/Intergroup N0147 trial Cetuximab with mFOLFOX6 vs. mFOLFOX6, WT KRAS patients, stage III, n = 2686 3-year DFS 75% vs. 72%, HR 1.21 (95% CI 0.98 to 1.49; p = 0.08)
3-year OS 87.3% vs. 85.6%, HR 1.25 (95% CI 0.92 to 1.68, p = 0.15)
Alberts et al.16

ACCORD, Action Clinique Coordonnées en Cancérologie Digestive; CALGB, Cancer and Leukemia Group B; CI, confidence interval; FOLFIRI, 5-FU/LV with irinotecan; FOLFOX, 5-FU/LV with oxaliplatin; KRAS, Kirsten rat sarcoma viral oncogene homologue; NCCTG, North Central Cancer Treatment Group; PETACC, Pan European Trial Adjuvant Colon Cancer; WT, wild type.

FIGURE 1

Adjuvant treatment for colon cancer.

HMJ-9-3-9-fig1.jpg

Despite the efficacy of fluoropyrimidines and oxaliplatin-based chemotherapy for patients with stage III colon cancer, one major problem is the oxaliplatin-associated toxicity, especially cumulative dose-dependent neurotoxicity.18,24 As neuroprotective strategies during oxaliplatin therapy have so far failed, one way to reduce cumulative oxaliplatin-associated toxicity is to shorten adjuvant treatment duration. One of the aims of the International Duration Evaluation of Adjuvant Chemotherapy collaboration 27 is to address the issue of whether 3 months of adjuvant therapy with oxaliplatin-based chemotherapy is non-inferior to the current standard of 6 months for patients with stage III colon cancer.25

Another option could be to switch to irinotecan-based regimens such as FOLFIRI. However, not all established treatment regimens of the metastatic setting are effective in the adjuvant situation. Adding irinotecan to 5-FU/LV does not improve DFS or OS in the adjuvant setting but does increase toxicity, as demonstrated by the Pan European Trial Adjuvant Colon Cancer (PETACC)-382 trial,12 the CALGB 8980383 trial13 and the ACCORD 0284 trial.14

The combination of chemotherapy with targeted therapies has significantly improved the outcome in the metastatic setting and therefore has recently been analysed in the adjuvant setting. Unfortunately, neither the combination of FOLFOX with bevacizumab15 nor the combination of FOLFOX with cetuximab16 resulted in a significant improvement in 3-year DFS compared with FOLFOX alone.

The optimal time from surgery to initiation of adjuvant therapy is a matter of debate. Some but not all clinical data indicate that starting earlier rather than later is beneficial.2629 Based on available retrospective data, it is generally recommended that chemotherapy commence between 3 and 8 weeks postoperatively,26 which is dependent on the general condition of the patient. Delays of over 12 weeks should be avoided30

Adjuvant chemotherapy in elderly colon cancer patients

At present, the median age at which a colon cancer is diagnosed is 68 years, with 35% of patients older than 75 years.31 Older patients are often under-represented in clinical trials; therefore, treatment strategies established in clinical trials might not be appropriate for these patients because of concerns related to comorbidity and age.32 Indeed, in clinical routine, age and comorbidity are the strongest factors predicting a requirement for adjuvant chemotherapy.33 However, independent studies in the adjuvant setting for 5-FU/LV and capecitabine, as well as a pooled analysis of seven trials comparing 5-FU/LV with observation, revealed a similar benefit in older and younger patients and found no influence of age on chemotherapy toxicity, with the exception of leucopenia.19,3436

Subset analyses of three trials, MOSAIC, NSABP C-07 and XELOXA, which addressed the issue of whether older patients benefit from oxaliplatin-based combination therapy, the current standard of care in the adjuvant setting, showed no significant benefit to OS from the addition of oxaliplatin in patients age 70 or older.9,37,38 Moreover, analysis of the MOSAIC trial revealed a much shorter post-recurrence survival in oxaliplatin-treated older patients. This weakened the observed trend towards prolongation of time to relapse.37 These clinical trial data were confirmed by Sanoff et al.,39 who analysed four datasets with regard to clinical benefit of adjuvant chemotherapy in the daily routine setting. There was a trend for improved survival with oxaliplatin (HR 0.82; 95% CI 0.51 to 1.33), which corresponded to an absolute 5% improvement in survival at 3 years compared with fluoropyrimidines alone.

Whether adjuvant therapy should be recommend to older adults, and the best choice of treatment regimen, should be evaluated individually, based on not only risk of relapse, but also estimated risk of cancer-unrelated death and estimated risk of treatment toxicity.40 Age alone is not an adequate stratification factor, as physiological ageing is heterogeneous. In addition to online tools that help to estimate life expectancy with respect to comorbidities41 (e.g. www.eprognosis.com), comprehensive geriatric assessment at baseline, but also during follow-up, may benefit the routine performance status and aid clinical decision-making.42,43 As 80% of recurrences in patients with stage III colon cancer are seen in the first 3 years after diagnosis, and approximately 90% of patients die within 5 years, adjuvant chemotherapy should also be recommended in older stage III and high-risk stage II patients, with the exception of patients expected to have short lifespans (< 5 years) and unfit/frail patients (Figure 1).42 In fit stage III patients, an oxaliplatin-based combination therapy may be considered. Oxaliplatin should be stopped as soon as toxicity, especially neurotoxicity, emerges, as the overall survival benefit is modest at the price of impaired quality of life. Moreover, in cases of (haematological) toxicity, eliminating the bolus of 5-FU from infusional regimens, dose reduction and therapy termination after 3–4 months is an option.13,44 For high-risk stage II patients or unfit patients with comorbidities, but with a life expectancy > 5 years, fluoropyrimidine monotherapy is recommended, preferentially infusional 5-FU, because capecitabine might be associated with greater toxicity in older patients.45

Treatment strategies for colorectal carcinoma with oligometastatic disease

Around 15–25% of patients with stage IV disease at diagnosis have synchronous CRC metastases, and 70–80% of these metastases are confined to the liver [colorectal cancer liver metastases (CRCLM)].46 CRCLM is defined as liver metastases detected at or before diagnosis of the primary CRC. Early and late metachronous metastases are defined as those detected ≤ 12 months and > 12 months after surgery, respectively.47 It has been reported that 45–50% of patients with stage II–III develop liver metastases within the 2 years following resection of the primary tumour.48,49 Extrahepatic sites include abdominal lymph nodes, the peritoneum and the lung. Surgical resection is the treatment of choice for patients with liver or lung metastases and leads to a significant improvement in survival compared with chemotherapy alone.

Neoadjuvant and adjuvant therapy for resectable metachronous metastases

For resectable metastases, adjuvant therapy for 6 months after surgical resection of CRC metastases, or perioperative chemotherapy (3 months before surgery and 3 months after surgery), is recommended.7,48 However, there is still no standard treatment established. Systemic chemotherapy with 5-FU with our without oxaliplatin seems to confer an advantage in terms of survival.50 As observed after resection of primary CRC, not all active drugs in advanced metastatic settings seem to be effective after resection of metastasis. The role of irinotecan-based regimens is controversial.16,51 Furthermore, the addition of bevacizumab might not provide any benefits52 and perioperative chemotherapy with cetuximab has been found to have a detrimental effect on PFS.53 The role of neoadjuvant chemotherapy in upfront resectable liver metastases is still unclear, as a benefit in terms of PFS, but not OS, has been found with the addition of perioperative chemotherapy compared with surgery alone in patients with resectable CRC liver metastases.54 Patients with potentially resectable disease should receive neoadjuvant combination chemotherapy, defined as ‘conversion therapies’.7 This approach has the benefit of down-staging the tumour.55 Moreover, neoadjuvant chemotherapy can be used to assess the responsiveness of the tumour to chemotherapy, as the initial response to chemotherapy is strongly predictive of a favourable long-term outcome.56 However, preoperative chemotherapy can induce regimen-specific liver damage in about 20–30% of patients, increasing the risk of mortality after liver resection.57,58

Colorectal carcinoma with synchronous liver metastases

Synchronous CRCLM has a less favourable cancer biology and is associated with lower expected survival than tumours with metachronous metastases.47 Only complete resection of both the primary tumour and liver metastases can offer long-term survival. Therefore, effective treatment requires both chemotherapy and surgery at the two different sites: primary colorectal tumour and CRCLM. Currently, four treatment strategies are available, whereby surgery and chemotherapy are carried out at different times and in a different order.59 The primary-first (bowel-first) approach (or traditional approach) comprises resection of the primary tumour followed by chemotherapy; subsequently liver resection is performed 3–6 months after colorectal resection. Upfront hepatectomy (reverse approach), which is the ‘true’ liver-first approach, is better for patients with asymptomatic primary tumours and initially resectable CLM. The liver-first/chemotherapy-first approach comprises three to six cycles of preoperative chemotherapy followed by liver resection, adjuvant chemotherapy and resection of the primary tumour. This strategy can be offered to patients with asymptomatic primary tumours and initially unresectable or marginally resectable CLM. At least four courses of first-line chemotherapy (doublets with targeted therapy or triplets with or without targeted therapy) are recommended for potentially resectable metastatic disease, as well as systemic therapy for a total (preoperative and adjuvant) duration of 6 months. Intra-arterial chemotherapy may be an alternative.47 Hepatic resection should not be denied to patients with stable disease after optimal chemotherapy, provided an adequate liver remnant with inflow and outflow preservation remains.47 Overall, the treatment-related mortality of these three strategies is low and survival is similar among the three groups.60 Therefore, the best strategy for the patient should be decided on an individual basis. The simultaneous resection of the primary tumour and CLM during a single operation is another strategy; however, it can be associated with significant postoperative morbidity and therefore is an option for only a highly select group of patients in specialized centres.61

Current treatment strategies for non-resectable metastatic disease

Despite all efforts in the studies described above, the 5-year OS for patients with mCRC is 13%, and < 5% of all patients with mCRC will be cured.31 The overall therapeutic goal for most patients with mCRC is to control the disease, thereby prolonging lifespan with an improved quality of life. With modern therapy, median OS reached around 24 months in recent phase III trials.4,5 Therefore, the ratio of efficacy to toxicity is one of the most important factors; in particular, cumulative toxicities from multiple lines of chemotherapy need to be considered.62 The current management of unresectable mCRC consists of systemic chemotherapy involving various agents, alone or in combination. The four main cytotoxic agents are fluoropyrimidines (intravenous 5-FU/LV and oral capecitabine), oxaliplatin and irinotecan. Targeted biological therapies, including antiangiogenic agents, such as bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies, are used as monotherapy or in combination with chemotherapy.6365 Current international guidelines recommend up to four lines of therapy, with chemotherapeutics and targeted therapies used in various combinations and schedules.7,48 For patients with good performance status and without contraindications, combination therapy is recommended, whereas monotherapy is preferable for elderly patients or those with significant comorbidities or in poor clinical condition.

First–line therapy

Increased median OS and a longer progression-free survival (PFS) in patients treated with combinations of 5-FU/LV plus oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) compared with those who received FU/LV alone have been demonstrated in several trials.66,67 A meta-analysis from 11 published phase III trials assessing combination chemotherapy of these three drugs in mCRC found that the reported median OS was significantly correlated with the percentage of patients receiving all three drugs in the course of their treatment.68 Interestingly, exposure to only three drugs (p = 0.0001), but not the use of a doublet first-line (p = 0.69), was significantly associated with OS. However, patients who received first-line chemotherapy doublets had a greater chance of receiving all three active agents in the course of their therapy, as, consistently, approximately only 50–60% of patients starting a line of therapy received a next-line therapy.69

Therefore, the standard of care is the use of doublet regimens that involve a combination of irinotecan and oxaliplatin with 5-FU/LV (Table 2). All trials comparing first-line combination superiority between oxaliplatin and irinotecan have shown equivalent survival.71 Oral capecitabine can be used instead of intravenous 5-FU/LV.77,78 XELOX may be used as an alternative to FOLFOX with similar efficacy and safety.22,79 The combination of capecitabine and irinotecan (XELIRI) has also demonstrated similar efficacy to FOLFIRI, but was associated with a higher incidence of diarrhoea.80,81 For selected patients (e.g. patients with BRAF mutations or with very high tumour burden requiring fast remission), the combination of infusional 5-FU/LV, oxaliplatin and irinotecan (FOLFOXIRI) might be an option. Improvement in response rate (60% vs. 34%, p < 0.0001), PFS (9.8 vs. 6.9 months; p = 0.0006) and OS (22.6 vs. 16.7 months; p = 0.032) has been demonstrated for patients treated with FOLFOXIRI compared with FOLFIRI; however, this was accompanied by a significant increase in toxicity, especially peripheral neurotoxicity (p < 0.001) and neutropenia (p < 0.001).

TABLE 2

Selected key clinical randomized phase III trials for combination therapies of metastatic colon carcinoma

Study acronym Treatment/design Efficacy results Reference
FOLFOX, XELOX, FOLFIRI
XELOX-1 (NO16966A) XELOX vs. FOLFOX-4, first-line, n = 2034 mPFS 8.0 months vs. 8.5 months, HR 1.04 (97.5% CI 0.93 to 1.16)
mOS 19.8 months vs. 19.6 months, HR 0.99 (97.5% CI 0.88 to 1.12)
Cassidy et al.22
GERCOR trial FOLFIRI followed by FOLFOX vs. FOLFOX followed by FOLFIRI, first-line, second-line, n = 222 mOS 21.5 months vs. 20.6 months (p = 0.99)
mPFS 8.5 months vs. 8.0 months (p = 0.26)
RR 56% vs. 54% (p = NS)
Tournigand et al.70
GOIM trial FOLFIRI vs. FOLFOX, first-line, n = 360 mOS 14 months vs. 15 months (p = 0.28)
mTTP 7 months vs. 7 months (p = 0.64)
RR 31% vs. 34% (p = 0.6)
Colucci et al.71
FOLFOXIRI
GONO trial FOLFOXIRI vs. FOLFIRI, first-line, n = 244 mOS 22.6 months vs. 16.7 months, HR 0.70 (95% CI 0.50 to 0.96; p = 0.032)
mPFS 9.8 months vs. 6.9 months, HR 0.63 (95% CI 0.47 to 0.81; p = 0.0006)
RR 60% vs. 34% (p < 0.0001)
Falcone et al.72
Combination therapy with bevacizumab and cetuximab/panitumumab (Vectibix®, Amgen, Thousand Oaks, CA)
Meta-analysis Efficacy and safety of bevacizumab in mCRC Bevacizumab plus chemotherapy vs. chemotherapy, first-line: AVF2107, NO16966, ARTIST, AVF0780, VF2192 and AGITG MAX, second-line E3200, n = 3763 OS HR 0.80 (95% CI 0.71 to 0.90; p = 0.003)
PFS HR 0.57 (95% CI 0.46 to 0.71; p < 0.0001)
Hurwitz et al.73
CRYSTAL trial Cetuximab with FOLFIRI vs. FOLFIRI, first-line, n = 1198 WT KRAS (n = 666)
mOS 23.5 months vs. 20.0 months, HR 0.796 (95% CI 0.670 to 0.946; p = 0.0093)
mPFS 9.9 months vs. 8.4 months, HR 0.696 (95% CI 0.558 to 0.867; p = 0.0012)
RR 57.3% vs. 39.7% (p = 0.001)
No significant difference in efficacy in patients with mutant KRAS
Van Cutsem et al.64
PRIME trial Panitumumab with FOLFOX vs. FOLFOX, first-line, n = 1183 WT KRAS (n = 656)
mOS 23.9 months vs. 19.7 months, HR 0.83 (95% CI 0.67 to 1.02; p = 0.072)
mPFS 9.6 months vs. 8.0 months, HR 0.80 (95% CI 0.66 to 0.97; p = 0.02)
Negative effect in the mutant KRAS subgroup
Douillard et al.74
FIRE-3 trial FOLFIRI plus cetuximab vs. FOLFIRI plus bevacizumab, first-line WT All-RAS (n= 342)
RR 65.5% vs. 59.6% (p = 0.32)
mPFS 10.4 months vs. 10.3 months, HR 0.93 (95% CI 0.74 to 1.17; p = 0.54)
OS 33.1 months vs. 25.6 months, HR 0.70 (95% CI 0.53 to 0.92; p = 0.011)
No benefit of cetuximab in RAS mutant subgroup
Heinemann et al.65 Stintzing et al.75
CALGB 80405 trial FOLFIRI/mFOLFOX-6 plus bevacizumab vs. FOLFIRI/mFOLFOX-6 plus cetuximab, first-line WT All-RAS (n = 526)
mPFS 11.3 months vs. 11.4 months, HR = 1.1 (95% CI 9.9 to 1.3; p = 0.31)
mOS 32.1 months vs. 32 months, HR = 0.9 (95% CI 0.7 to 1.1; p = 0.40)
RR 53.8% vs. 68.6% (p < 0.01)
Lenz et al.76

CRYSTAL, Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer; GERCOR, Groupe Coopérateur Multidisciplinaire en Oncologie; GOIM, Gruppo Oncologico dell’Italia Meridionale; GONO, Gruppo Oncologico del Nord Ovest; mOS, median overall survival; mPFS, median progression-free survival; mTTP, median time to progression; NS, not significant; PRIME, Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy; RR, response rate.

Combinations of chemotherapy with targeted therapies have significantly improved the survival of mCRC patients. Bevacizumab was the first antiangiogenic drug to be approved by the US Food and Drug Administration (FDA), in 2004, for mCRC as first-line therapy based on data from the AVF2107 study.82 It is a recombinant humanized monoclonal IgG-1 antibody against soluble vascular endothelial growth factor (VEGF)-A. As a single agent, it has almost no activity, but in combination with different chemotherapy regimens (including FOLFOX, FOLFIRI and FOLFOXIRI) in patients with advanced CRC (compared with patients receiving systemic chemotherapy alone) led to improvements in PFS and OS that could exceed 30 months, as shown by a recent meta-analysis73 and the TRIBE trial.83 The treatment effect was not significantly different across molecular subgroups but mutational status seems to be of prognostic value. This is in accordance with the FIRE-3 study and the results from the phase III AGITG MAX trial (Capecitabine Alone or in Combination With Bevacizumab and Mitomycin in Advanced Colorectal Cancer).65,73,84,85 Therefore, in the absence of contraindications, bevacizumab plus chemotherapy can be used in both first-line and second-line regimens in mCRC.

In addition to blocking angiogenesis, anti-EGFR therapies have been integrated in the treatment of stage IV colon cancer. Cetuximab and panitumumab are monoclonal antibodies targeting EGFR and block activation of downstream signalling pathways. Cetuximab is a chimeric IgG1 monoclonal antibody, whereas panitumumab is a fully humanized IgG2 monoclonal antibody. Cetuximab was evaluated in the CRYSTAL study, which tested FOLFIRI alone versus FOLFIRI with cetuximab in patients with EGFR-positive tumours in first-line therapy.64,86 The efficacy was dependent on the molecular subtype; only in patients with WT KRAS did FOLFIRI with cetuximab significantly improve OS (23.5 vs. 20.0 months; p = 0.01), PFS (9.9 vs. 8.4 months; p = 0.001) and response rate (57.3% vs. 39.7%; p < 0.001) compared with FOLFIRI alone. No significant difference in efficacy was observed in patients with mutant KRAS. BRAF mutations were not predictive, but a strong indicator of poor prognosis. Interestingly, the COIN trial found no benefit of cetuximab when added to XELOX or FOLFOX.87

Panitumumab was evaluated in the PRIME trial,74 which tested FOLFOX with or without panitumumab as a first-line therapy, regardless of EGFR or KRAS status. In the subset with WT KRAS (60% of the study population), treatment with panitumumab and FOLFOX significantly improved PFS compared with FOLFOX alone (9.6 vs. 8.0 months, respectively; p = 0.02), but did not lead to a significant OS benefit. In the mutated KRAS population, panitumumab had a detrimental effect. Further analysis of the PRIME trial showed that not only were mutations in codons 12 and 13 in exon 2 of KRAS a negative predictive marker for response to anti-EGFR treatment, but mutations in exons 3 and 4 of KRAS and exons 2, 3 and 4 of NRAS were also negative markers.88 Therefore, mutational analysis of the RAS genes is important in patients with mCRC and the use of cetuximab and panitumumab should be limited to patients in whom a RAS gene mutation is excluded.

The FIRE-3 study suggested cetuximab + FOLFIRI as the best option for WT KRAS patients. The trial was designed to determine whether WT KRAS (only exon 2) patients should be treated with FOLFIRI combined with cetuximab or bevacizumab.65 Overall response rates were comparable in both arms (62% vs. 58%, p = 0.183), but significantly better PFS and OS were seen in the FOLFIRI plus cetuximab arm (28.8 months vs. 25.0 months, p = 0.016), although this was a secondary endpoint. When extending the analysis to several other mutations beyond exon 2, as well as BRAF (V600E), WT all-RAS patients had 33.1 months OS with FOLFIRI + cetuximab in comparison with 25.6 months with FOLFIRI + bevacizumab (HR = 0.70; p = 0.011). In KRAS-mutant patients, this difference was not observed. No difference in PFS was seen in the WT KRAS group (p = 0.54); however, interestingly, in patients with a mutated KRAS gene PFS was better in the bevacizumab arm (12.2 months vs. 6.1 months; p = 0.004).75 Moreover, the smaller PEAK trial showed a benefit of panitumumab plus mFOLFOX6 over bevacizumab plus mFOLFOX6 in terms of OS (41.3 months vs. 28.9 months; p = 0.058).89

The CALGB 80405 trial, which compared FOLFOX or FOLFIRI plus either cetuximab or bevacizumab in the same patient setting, failed to confirm improvements in OS or PFS for cetuximab. In the WT all-RAS population, median PFS was about 11 months for both arms (HR = 1.1; p = 0.31) with a median OS of 31–32 months (HR = 0.9; p = 0.40).76 The differences in these trials were partly explained by different chemotherapy backbones; in particular, in the CALGB trial, two-thirds of patients received the oxaliplatin partner, which is thought to be an inferior companion for cetuximab. Moreover, responders to anti-EGFR agents might be different from responders to anti-VEGF agents despite similar PFS, in that tumour shrinkage might be greater with cetuximab/panitumumab than with bevacizumab and this would translate to a better OS even with no difference in PFS.90

Chemotherapy for recurrent or progressive disease

Second-line treatment options for patients with mCRC will be based on the treatment received in the first-line setting, or on previous adjuvant treatment in some patients. After progression of first-line doublet therapy, irinotecan- and oxaliplatin-based doublets should be interchanged whenever feasible. The GERCOR trial showed that the sequence of regimens, FOLFIRI followed by FOLFOX-6 at the time of tumour progression, or FOLFOX-6 as first-line therapy followed by FOLFIRI, does not influence OS (mOS 20.4 vs. 21.5 months).70 In addition, response rate, PFS and second PFS did not differ significantly. In general, second-line regimens were less effective. As expected, toxicity profiles were different, but both regimens were well tolerated. However, one might prefer FOLFIRI as first-line regimen, as most patients developed neurotoxicity after oxaliplatin, and some were even forced to stop first-line therapy before tumour progression.

To prevent cumulative toxicity of first-line therapy, such as oxaliplatin-induced neurotoxicity, the so-called OPTIMOX approach, which entails the re-induction of first-line therapy after maintenance therapy, remains the preferred option.91 Today, maintenance therapy will include targeted agents such as bevacizumab or an anti-EGFR antibody plus fluoropyrimidine.9294

Recently, the FDA approved TAS-102 (Lonsurf®, Taiho Pharmaceutical, Tokyo, Japan) for use as a third- or fourth-line treatment in refractory mCRC based on data from the RECOURSE trial. TAS-102 is a combination of trifluridine and tipiracil and acts as an antimetabolite and inhibitor of thymidylate synthase.95 TAS-102 was associated with a clinically relevant prolongation of OS and PFS, higher disease control rate and better control of symptoms in a study population with more than 90% of patients refractory to treatment with fluoropyrimidines. The clinical benefit was irrespective of prior treatment with regorafenib (Stivarga®, Bayer, Leverkusen, Germany) or KRAS status. The main side-effect was neutropenia.

Targeted therapies for recurrent or progressive disease

Several antiangiogenic agents are available for the second-line therapy, including bevacizumab, aflibercept (Zaltrap®, Sanofi-Aventis, Paris, France) and ramucirumab (Cyramza®, Eli Lilly and Company, Indianapolis, IN, USA) (FDA approved). All three share the characteristic toxicities of anti-VEGF agents. After combination of chemotherapy doublet with anti-EGFR antibodies or no biological, bevacizumab can be added. Addition of bevacizumab to second-line therapy in the E3200 study increased PFS (7.3 months vs. 4.7 months) and OS (12.9 months vs. 10.8 months) in bevacizumab-naive patients.96 In patients who already received bevacizumab during first-line therapy, the continuation of bevacizumab in second-line therapy led to an improvement in OS, as demonstrated by the ML18147 study (TML trial)97 and data from the observational BriTE (Bevacizumab Regimens: Investigation of Treatment Effects and Safety)98 and ARIES (The Avastin Registry–Investigation of Effectiveness and Safety) studies.99

Aflibercept and ramucirumab are alternatives to bevacizumab in second-line treatment. Addition of aflibercept (VELOUR trial)100 or ramucirumab (RAISE trial)101 to FOLFIRI significantly improved OS in mCRC patients previously treated with an oxaliplatin-based regimen. Moreover, both trials confirmed the concept of antiangiogenic therapy beyond progression, because they included bevacizumab-pretreated patients.102 However, no head-to-head comparison of all the three antibodies has been undertaken and no data regarding cross-resistance are available.

For WT KRAS patients, the anti-EGFR antibodies cetuximab and panitumumab are available for second- and third-line therapies. They can be used as monotherapy or based on the EPIC (Erbitux Plus Irinotecan for Metastatic Colorectal Cancer) trial,103 PICCOLO (Panitumumab and Irinotecan Versus Irinotecan Alone for Patients With KRAS Wild-Type, Fluorouracil-Resistant Advanced Colorectal Cancer) trial104 and study 20050181105 in combination with irinotecan-based therapy after previous treatment with oxaliplatin and 5-FU. All three trials showed an improvement in PFS, but not in OS. However, it should be noted that the EPIC trial was conducted before RAS testing and that study 20050181 was confounded by crossover. Cetuximab and panitumumab have also been shown to be effective as monotherapies in last-line treatment for WT KRAS tumours106,107 with similar efficacy, as demonstrated by the phase III ASPECCT trial.108

In contrast to bevacizumab, an anti-EGFR treatment beyond progression is currently not recommended. Although patients with no mutation of the KRAS, NRAS, BRAF or PIK3CA genes (‘quadruple’ WT), and without acquired resistance to prior anti-EGFR-based regimens, might respond to further anti-EGFR therapy.109112

For patients who have not responded to multiple lines of therapy, regorafenib, an oral multikinase inhibitor (TKI), is a further option in addition to TAS-102. It was approved in 2012 based on data from the CORRECT trial, which showed improved OS in patients progressing on all standard treatments, including bevacizumab (6.4 months vs. 5 months).113 This was confirmed in the Asian CONCUR trial.114 However, common side-effects of TKIs, such as diarrhoea, fatigue, rash, hand–foot syndrome and hypertension, were observed. This needs to be considered in a highly palliative situation.115 Mutations in KRAS, BRAF or PI3KCA were not predictive of a response to regorafenib.115 However, next-generation sequencing suggested that those with chromosomal instability are the predominant subgroup to benefit from regorafenib.116

New developments

Treatment options for patients with advanced CRC have significantly improved in recent years. Nevertheless, mCRC treated with surgery, chemotherapy or new targeted therapies will progress in the majority of patients’ over time. Therefore, there is a need to develop alternative therapeutic strategies.

Immunotherapy – a therapeutic option for colorectal cancer?

Immunotherapy has been evaluated in various solid cancers and might be also an option for mCRC. In CRC, the immune system seems to play a role not only in development,117 but also in treatment and prognosis of CRC.118 In the past, different kinds of immunotherapy have been investigated in CRC and clinical trials using genetically modified T cells, chimeric antigen receptor T-cells and immune-modulating agents, such as indoleamine 2,3-dioxygenase inhibitors or Toll-like receptor agonists, are currently ongoing. However, until recently, early clinical studies using vaccines and oncolytic viruses and adoptive T-cell therapy in CRC have yielded modest clinical responses, and with severe toxicities. However, cancer immunotherapy was announced as the breakthrough of the year in Science Magazine, 2013,119 due in part to its success in checkpoint blockade. The physiological role of checkpoints is to maintain self-tolerance and modulate physiological immune responses in peripheral tissues. Tumours use these molecules as a major mechanism of immune resistance – particularly against tumour-specific T-cell response.120 CTLA4 and PD-1 are two such checkpoints. Tumours express PD-L1 constitutively or up-regulate PD-L1 expression during an ongoing immune response.120 Checkpoint blockade has become an integral part of the clinical management strategy for some solid tumours, including melanoma and lung and renal cancer. The role of immune checkpoint inhibition in the management of CRC has recently been tested. Only CRC patients with mismatch-repair-deficient (MSI-H) tumours showed high response rates to anti-PD-1 therapy with pembrolizumab (Keytruda®, Merck & Co., Inc., Kenilworth, NJ, USA) relative to those with mismatch-repair-proficient cancers in a phase II trial (immune-related overall response rate 40% vs. 0%, 20-week PFS 70% vs. 11% and OS not reached vs. 5 months).121 These results provide the rationale for the ongoing KEYNOTE-164 trial, which is testing pembrolizumab monotherapy in MSI-H CRC (NCT02460198), and the Checkmate-142 trial, which is testing the combination of nivolumab (Opdivo®, Bristol-Myers Squibb, New York, NY, USA) and ipilimumab (Yervoy®, Bristol-Myers Squibb, New York, NY, USA) in MSI-H CRC (NCT02060188).

Overcoming resistance to anti-EGFR therapy

Epidermal growth factor receptor-directed monoclonal antibodies are used in combination with chemotherapy or as monotherapy and have substantially improved the outcome for mCRC patients with WT KRAS/NRAS. However, patients responsive to anti-EGFR therapy have been known to ultimately develop resistance. Besides mutation of the EGFR gene, mutations in RAS genes have been identified as a mechanism for resistance to cetuximab or panitumumab.122,123 These mutations could be either acquired mutations caused by anti-EGFR therapy or the selection of pre-existent KRAS mutant clones. In RAS-mutated CRC, anti-EGFR antibodies show no benefit or even have a deleterious effect, as the mutant KRAS protein is continuously active and appears independent of EGFR regulation. Therefore, mitogen-activated protein kinase (MAPK) pathway inhibition downstream of RAS is under investigation in patients with a mutated RAS gene. Rapidly accelerated fibrosarcoma (RAF) inhibitors are tested in monotherapy or in combination with chemotherapy124 or MEK (mitogen-activated protein kinase kinase) inhibitors to enhance their efficacy (see https://clinicaltrials.gov). Moreover, MEK inhibitors are tested in combination with chemotherapy or inhibitors of EGFR, but also with inhibitors of the mTOR (mammalian target of rapamycin) pathway (see https://clinical trialsgov). Preclinical studies have suggested that concurrent targeting of the PI3K (phosphoinositide 3-kinase)-AKT (protein kinase B)-mTOR and Ras-Raf-MEK-ERK (extracellular signal-regulated kinase) pathways is an active combination in various solid malignancies.125 Moreover, alterations in the PI3K-AKT-mTOR pathway may be the reason why some patients do not initially respond to EGFR inhibitors. This includes PI3K mutations or loss of PETN (phosphatase and tensin homologue), but also overexpression of activators of the PI3K-AKT-mTOR pathway, such as IGF-R1 (insulin-like growth factor receptor 1) or human epidermal growth factor receptors Her-2 and Her-3. These factors, and agents targeting these molecules, are currently under study.123,126

Epidermal growth factor receptor TKIs are under investigation in combination therapies. Dual EGFR and VEGF blockade with bevacizumab and erlotinib (Tarceva®, Roche, Basel, Switzerland) during maintenance therapy was evaluated in the Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) DREAM/OPTIMOX3 trial and showed promising results. Median OS from maintenance was 24.9 months (95% CI 21.4 to 28.9) in the bevacizumab plus erlotinib group and 22.1 months (95% CI 19.6 to 26.7) in the bevacizumab group.127

The V600E mutation of the BRAF gene is found in 10% of CRC and, as described above, is associated not only with typical clinical characteristics, but also with poor prognosis. In contrast to melanoma, monotherapy with a BRAF inhibitor showed no activity due to feedback activation of EGFR, mediated through the MAPK/ERK pathway.128 Based on in vitro data, recent early clinical trials evaluated BRAF inhibition in different combination therapeutic approaches. BRAF inhibition combined with MEK inhibition or anti-EGFR monoclonal antibodies showed only low activity.129,130 However, a combination of MEK inhibition with EGFR and BRAF inhibition was superior to a combination of EGFR and BRAF inhibition only (response rate 26% vs. 10%).131

Conclusion

Although much progress has been made in the therapy of CRC, the prognosis of advanced CRC still remains poor despite the introduction of anti-EGFR monoclonal antibodies or antiangiogenic agents. Primary and secondary resistance to targeted agents is a challenge in the treatment of mCRC. New treatment strategies to overcome this resistance are in development. These include combination therapy with new targeted agents, but also immunotherapeutic approaches. One prerequisite for future successful therapy will be to identify subgroups of patients who will most likely respond to specific treatment modalities. Identification of prognostic and predictive biomarkers beyond mutation profiling and analysis of MSI status are focus of current research.132134

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