Konda B; Bakhiran K; Rajdev L

Review Article

Austin J Med Oncol. 2014;1(2): 11.

Systemic Treatment of Colon Cancer

Konda B, Bakhiran K and Rajdev L*

Department of Medical Oncology, Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, USA

*Corresponding author: Rajdev L, Department of Medical Oncology, Albert Einstein College of Medicine/ Montefiore Medical Center, 1695 Eastchester Road, Bronx, NY 10461, USA

Received: August 23, 2014; Accepted: October 17, 2014; Published: October 20, 2014

Abstract

Colorectal cancer is the third most common cancer worldwide, and is the third leading cause of cancer mortality with an estimated 50, 310 deaths occurring in 2014 in the United States. There has been a steady decline in the incidence of colorectal cancer over the past 30 years, which is largely due to early endoscopic screening. Surgical management remains the mainstay of treatment for early and locally-advanced non-metastatic colon cancers, and in patients with initially resectable liver or lung-only metastases. Systemic therapies have shown to significantly improve outcomes when given in the neo-adjuvant and/or adjuvant setting in these patients, and when used as principal therapy in patients with unresectable metastatic disease. The addition of adjuvant chemotherapy in patients with Stage III and high risk stage II disease significantly improves recurrence free survival. Patients with oligometastatic Stage IV colorectal cancer (CRC) who receive post-operative chemotherapy have a median OS that exceeds 5 years in some studies. The advent of targeted molecular therapies has further helped improve outcomes in patients with metastatic CRC cancer. Patients with unresectable metastatic disease who receive a combination of systemic chemotherapy and targeted agents have a median overall survival over 2 years today. It is important that patients be exposed to all active agents during their disease course to achieve this survival benefit. In this review article we summarize important clinical trials that have led to an evidence-based approach to the management of colon cancer.

Introduction

Colorectal cancer is the third most common cancer worldwide, and accounts for over 1 million new cases of cancer each year. It is the fourth most frequent cause of cancer death worldwide [1]. In the US, colorectal cancer (CRC) is the third most common cancer [2], with an estimated 96,830 new cases diagnosed in 2014 [3]. CRC is the third leading cause of cancer mortality in the US [2] with 50,310 deaths predicted to occur in 2014 [3].

Most cases (80%) of colon cancer cases are sporadic [4]. Although increasing age appears to be a strong risk factor, several modifiable risk factors are widely recognized in the development of sporadic colon cancer. These include obesity, tobacco use, alcohol consumption, and certain dietary patterns such as diet rich in red meat, and low in fiber [5]. Other risk factors include inflammatory bowel disease, history of colonic polyps, and prior history of colon cancer [4,6].

Approximately 20% of patients with CRC have a familial predisposition with 5-10% of these cases inherited in an autosomal dominant fashion [7]. The two most common hereditary forms of CRC are hereditary non polyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). HNPCC (Lynch syndrome), is an autosomal dominant disorder with a high penetrance rate, and represents about 3% of all CRC [8]. Lynch syndrome is also associated with multiple extracolonic neoplasms, commonly involving the endometrium, stomach, and ovary [8]. HNPCC is associated with germ-line mutations in DNA nucleotide mismatch-repair (MMR) genes, with over 90% of them occurring in MLH1, MSH2 and MSH6 genes [9]. FAP accounts for about 2% of all CRC [7]. Multiple colonic adenomas develop at an early age and become malignant by fourth-fifth decade of life. A highly penetrant germ-line APC mutation produces a truncated protein which can be detected by PCR in most FAP patients [10].

Colon cancer can be divided into 4 stages based on the TNM staging system. This is presented in a simplified version in Table 1[1]. Stages I and II are categorized as early-stage colon cancer, Stage III as locally-advanced cancer, and Stage IV as metastatic disease [11]. Surgery can be curative not only in patients with early-stage and locally- advanced colon cancer, but also in patients with liver-only or lung-only metastases (oligometastatic disease). For instance, hepatic metastetectomy results in a 38 percent 5-year survival in patients with liver-only metastases [12]. Systemic chemotherapy used before and/or after surgical resection has shown to significantly improve outcomes in patients with locally-advanced and oligometastatic CRC [13,14]. The use of systemic chemotherapy in combination with targeted molecular therapies in patients with unresectable metastatic CRC has improved median OS to over 2 years today [15-18]. Nonetheless, CRC has a 35% disease-specific mortality [19] and this demands heightened awareness of the treatment options in these patients.

Table 1: Simplified Colon cancer staging (11).



  
    Stage (TNM)
    Description
  
  
    I
    T1N0 and T2N0 (Tumor invades submocosa and muscularis propria)
  
  
    II
    IIA, IIB, IIC (T3N0 through T4bN0 -tumor invades through    muscularis propria, through the viscera and directly invades or adherent to    other organs, respectively, without nodal involvement)
  
  
    III
    IIIA, IIIB, IIIC (T1-T4B and N1-N2b without distant    metastastic spread)
  
  
    IV
    IVa and IVb (any T, any N, M1a and M1b, respectively)



Table 1:  Simplified Colon cancer staging (11).

Table 2: Role of adjuvant chemotherapy in Stage I, II, and III CRC.



  
    Stage
       
       
       
       
    Group A^*
       
    Group B*
       
    5-yr DFS^# (%)
      (A v B)
    p-value
    5-yr OS^# (%)
      (A v B)
    p-value
  
  
    II
    Bolus 5FU/LV [26] (IMPACT)
    S alone
    71 v 62
      (3-yr EFS)
    NR
    83 v 78
      (3-yr OS)
    NR
  
  
    II and III
    5-FU based^**[38]  
      (MSS and MSI-L tumors)
    S alone
      (MSS and MSI-L tumors)
    70 v 59
       
       
       
    0.01^{^}
       
    76 v 68
       
       
    0.02^{^}
       
  
  
    II and III
    5-FU based^**[3 8]
      (MSI-H tumors)
    S alone (MSI-H tumors)
    69 v 83
       
       
    0.11^{^}
       
    71 v 88
       
    0.07^{^}
       
  
  
    II and III
    5FU based [39] 
      pMMR patients
    S alone
    64 v 53
       
    0.02⁺
       
    71 v 62
       
    0.11⁺
  
  
    II and III
    5FU based [39] 
      dMMR patients
    S alone
    72 v 76
       
    0.56⁺
    75 v 81
       
    0.95⁺
  
  
    MOSAIC trial and subgroup analysis
     
  
  
    II and III
    FOLFOX4 [15]  
      (MOSAIC)
    Infusion 5FU/LV
    73 v 67
       
    0.003
    79 v 76
      (6-yr OS)
    0.046
  
  
    II
    FOLFOX4 [15]  
      (MOSAIC subgp analysis)
    Infusion 5FU/LV
       
    84 v 80
       
    0.258
    87 v 87
      (6-yr OS)
    0.986
       
  
  
    III
    FOLFOX [15]  
      (MOSAIC subgp analysis)
    Infusion 5FU/LV
    66 v 59
       
    0.005
    73 v 69
      (6-yr OS)
    0.023
  
  
    NSABP C-07 trial and subgroup    analysis
  
  
    II and III
    FLOX [31,119]  
      (NSABP C-07)
    Bolus 5FU/LV
    69 v 64
    0.002
    80 v 78
       
    0.08
  
  
    II
    FLOX [119]  
      (NSABP C-07 subset analysis)
    Bolus 5FU/LV
       
    82 v 80
    0.67
    90 v 90
    0.84
  
  
    III
    FLOX [15]  
      (NSABP-C07 subset analysis)
    Bolus 5FU/LV
    64 v 58
    <0.001
    77 v 74
       
    0.052



Table 2:  Role of adjuvant chemotherapy in Stage I, II, and III CRC.

Systemic chemotherapy in the adjuvant setting

Adjuvant therapy refers to treatment given in addition to, or following primary, oftentimes surgical treatment. It is aimed at elimination of residual microscopic disease, with the intention of cure and to lower the risk of cancer recurrence. Adjuvant chemotherapy plays no role in Stage I colon cancer given a 93.1% five-year survival with surgery alone [20]. The important trials in patients with Stage II and III CRC are detailed in table 2.

5-Fluorouracil (5FU) is an antimetabolite and pyrimidine analogue, which acts by irreversible inhibition of the enzyme thymidylate synthetase involved in DNA replication, and forms the chemotherapy backbone in CRC [21]. 5-FU has predominantly gastrointestinal side effects, such as nausea, vomiting, diarrhea, and stomatitis. Other reported toxicities are palmar-plantar erythrodysesthesia (hand-foot syndrome), and leukopenia [22].

Leucovorin (LV) is a reduced form of folic acid that acts synergistically with 5-FU, trapping thymidylate synthetase in its inactive form [23], and thus enhancing 5-FU’s antimetabolite effect [24]. Since the late 1980s, 5-FU and LV therapy have become the standard first-line adjuvant chemotherapeutic options in advanced CRC. The addition of LV to 5FU produces a two-fold increase in response rate compared to 5-FU monotherapy (21% v 11%; odds ratio (OR), 0.53; 95% CI, 0.44 to 0.63; p, <0.0001) [25].

The IMPACT investigators conducted a pooled analysis of three large randomized trials comparing adjuvant 5FU/LV to surgery alone in patients with colon cancer where the tumor has penetrated the bowel wall, without or without lymph node involvement [26]. Patients who received adjuvant 5FU/LV had a higher 3-year event free survival (EFS) (71% v 62%), a greater OS (83% v 78%), a 22% reduction in mortality (p, 0.029), and a 35 percent reduction in events (p, < 0.0001) when compared to those who had surgery alone [26].

Toxicities of 5FU are largely dependent on the mode of administration, with better tolerability when given as a continuous infusion via a portable pump when compared to bolus administration. In addition, infusion 5FU is associated with significantly higher response rates (30% for infusion 5FU v 7% for bolus 5FU; p, <0.001) [27]. However, an infusion pump requires central venous access which has potential thrombotic and infectious complications.

This led to the development of capecitabine (xeloda), an oral pro-dug of 5FU. Capecitabine undergoes a multi-step reaction before its conversion to active 5-FU. The Xeloda colorectal cancer group conducted a large phase III multicenter randomized clinical trial (RCT) that compared infusion 5-FU to capecitabine. Capecitabine was non-inferior to 5FU, with fewer cases of stomatitis, alopecia, and neutropenia, but with a higher incidence of hand-foot syndrome and hyperbilirubinemia [28]. The X-ACT trial showed that adjuvant capecitabine had comparable disease-free survival (DFS), better relapse-free survival (HR 0.86; p, 0.04), similar OS, and significantly fewer adverse events when compared to the adjuvant 5-FU/LV group of patients with Stage III colon cancer [29].

Oxaliplatin is another chemotherapeutic agent used in the adjuvant setting in colon cancer. It is a third generation antineoplastic platinum agent that inhibits DNA cross-linking. It has enhanced antitumor activity when used in combination with 5-FU/LV. Peripheral neuropathy is a common and dose-limiting toxicity of oxaliplatin [15,30,31]. Other common side effects include nausea, vomiting, diarrhea, liver sinusoidal injury, elevation in transaminases and alkaline phosphatase, thrombocytopenia, and hypersensitivity reactions [32].

In the pivotal MOSAIC trial, stage II and III colon cancer patients were randomized following resection with curative intent, to receive either 5-FU/LV or 5-FU/LV plus oxaliplatin (FOLFOX4) [33]. Patients in the oxaliplatin-containing group had a 23% reduction in the risk of recurrence at 3-year median follow-up. A subgroup analysis of stage II patients showed no difference in OS between the two groups [15]. In another phase III trial (NSABP C-07), that included patients with stage II and III colon cancer, there was a significant improvement in DFS with the addition of oxaliplatin to 5-FU/LV (FLOX) regimen (4-year DFS: 73.2% for FLOX v 67% for 5-FU/LV) [31]. This led to FOLFOX being the new standard.

Adjuvant chemotherapy for stage II disease remains controversial, with survival rates of 82.5% with surgery alone [20]. Various prognostic factors and tools have been investigated to assist with risk stratification and identification of those stage II patients who would benefit from adjuvant chemotherapy.

High-risk clinicopathologic features include T4 tumors, poorly differentiated tumors, presence of lymphovascular invasion, perineural invasion, or bowel obstruction, pre-operative elevation in CEA levels, close, indeterminate, or positive margins, and inadequately sampled lymph nodes [15,34,35] . Additionally, genetic alterations have been used as predictive markers for response to chemotherapy. MMR genes, primarily MLH1 and MSH2 are responsible for the production of MMR proteins involved in repair of microsatellite instability (MSI) occurring during DNA replication. Mutations in MMR genes are seen in HNPCC [7], and may occur in about 15% of patients with sporadic colon cancer [36]. This leads to MSI that can be categorized based on degree of instability into MSI-high (MSI-H), MSI- low (MSI-L), or microsatellite sTable (MSS) [36].

MMR status is a prognostic and predictive factor in colon cancer. The presence of an MMR gene mutation correlates with a better prognosis. In fact, patients who express MMR gene proteins i.e. MMR proficient (pMMR) patients have been shown to have an increased rate of death from recurrent disease compared to their MMR deficient (dMMR) counterparts (32.8% v 8.8%; p, <0.0001). Similar outcomes were noted in MSI-L/MSS v MSI-H patients (35.1% v 10.7%, p, 0.0002) [37].

While survival is better for dMMR patients, these patients may have a detrimental outcome with adjuvant chemotherapy [38,39]. Ribik et al showed that in the absence of adjuvant chemotherapy, patients with MSI-H tumors had significantly longer OS than patients with MSI-L and MSS tumors (HR for death, 0.31, 95% CI, 0.14-0.72; p, 0.004). When analysis was limited to the group receiving adjuvant chemotherapy, patients with MSI-L and MSS benefited from chemotherapy, while MSI-H patients did not (HR for death, 2.17; p, 0.10) [38]. Sargent et al. [39] also demonstrated that when compared to surgery alone, adjuvant 5FU improved DFS in pMMR patients (HR, 0.67; p, 0.02), while this benefit was not seen in dMMR patients receiving adjuvant chemotherapy (HR, 1.10; p, 0.85). Moreover, adjuvant chemotherapy in stage II dMMR patients led to a lower OS in comparison to surgery alone (HR, 2.95; p, 0.04). Multiple gene assays have been developed for stage II and III colon cancer patients to identify those who would benefit from chemotherapy. Oncotype DX colon cancer assay measures the expression of seven recurrence risk genes and five reference genes, and has been shown to adequately estimate recurrence risk [40], with higher scores corresponding to an increased absolute benefit with oxaliplatin therapy [41].

Adjuvant systemic chemotherapy in elderly patients

Elderly patients (65 years and older) have the highest incidence of colon cancer [19] and are often underrepresented in large clinical trials. The decision on chemotherapy in this group can be challenging given their multiple comorbidities and medical unfitness for chemotherapy. A pooled analysis of seven phase 3 RCTs evaluating the role of 5FU-based chemotherapy in patients with resected stage II or III colon cancer, showed a higher 5-year OS in patients who received adjuvant chemotherapy (71% v 64%; (HR, 0.76; 95% CI, 0.68 - 0.85). There was no significant interaction between age and efficacy of treatment. The incidence of toxicities was not increased among patients older than age 70, except for an increased risk of leukopenia in one study [42].

To further support these findings, a recent subgroup analysis of the MOSAIC trial established no statistically significant interaction between DFS, time to recurrence, or OS among 315 stage II and stage III patients aged between 70 and 75 who received chemotherapy with 5-FU/LV and oxaliplatin (FOLFOX) versus 5-FU/LV alone [43] .

Metastatic Colorectal Cancer (mCRC)

Patients with CRC with distant metastases at initial diagnosis (also known as synchronous metastases [43]) account for approximately 20% of all colorectal cancers, and have only a 12% five-year survival rate [19]. Patients with early-stage or locally advanced disease, who later develop metastatic disease (also known as metachronous metastases [43]) account for 20-25% of all CRC cases [45].

Surgical treatment of Mcrc

Patients with CRC with isolated liver or lung metastasis, can potentially be cured surgically. With advances in surgical techniques and use of perioperative chemotherapy, the median survival in patients with liver-only or lung-only metastasis undergoing surgical resection, has risen close to 5 years, with minimal operative mortality. These patients can either be treated with surgery upfront or with chemotherapy prior to surgery. Tables 3 and 4 detail the survival statistics following metastatectomy in patients with liver-only and lung-only metastasis respectively. Patients with potentially resecTable disease can be given chemotherapy in an attempt to make tumor resecTable (referred to as conversion therapy) [46]. Studies have shown that 12.5 to 36% of patients with initially unresecTable/ potentially resecTable liver-only metastasis, were successfully resected after conversion therapy with 5FU/LV, oxaliplatin, and/or irinotecan [47-50]. More recently, the addition of cetuximab to chemotherapy (arm A) in Chinese patients with initially unresecTable KRAS WT colorectal liver-only metastases, was compared to chemotherapy alone (arm B). Patients in arm A had a significantly better rate of complete tumor resection (R0 resection: 25.7% v 7.4%; p, <0.01), a higher 3-year OS rate (41% v 18%; p, 0.013), and longer median survival time (30.9 v 21 months; p, 0.013) [51], when compared with patients randomized to arm B [51].

Table 3: Survival following resection of Liver-only metastases in CRC.



  
    Author
    Year
    No.    of patients
    %    of pts
      who    received CT^{^}
    Synchronous
      /Metachronous
      metastases
       
    Operative    mortality (%)
    Median    survival^# (mo)
    5-yr    survival (%)
    10-yr    survival (%)
    Median    F/u
      (mo)
  
  
    Scheele    et al. [120] 
    1960-1992
    434
    0 systemic
    44/56
    4
    40
    39
    24
    NR
  
  
    Tomlinson    et al. [121] 
    1985-1994
    612
    NR
    NR
    5
    44
    35
    17
    NR
  
  
    Choti    et al. [122] 
    1984-1999
    226
    52^*b
    30/70
    1
    46
    40
    26
    121 (1984-1992)
      22 (1993-1999)
       
  
  
    Fong    et al. [123] 
    1985-1998
    1001
    NR
    29/71
    3
    42
    37
    22
    32
  
  
    Wei    et al. [124] 
    1992-2002
    423
    32^c
    32/68
    2
    53
    47
    28
    31
  
  
    Morris    et al. [125]  
    1998-2004
    3116
    NR
    NR
    NR
    NR
    44
    NR
    ?36
  
  
    Giuliante    et al. [126] 
    1992-2007
    251
    35^b
    41/59
    1
    46
    39
    24
    37 (mean)



Table 3:  Survival following resection of Liver-only metastases in CRC.

Author	Year	No. of patients	% of pts who received chemo	Operative mortality^# (%)	Median survival^# (mo)	5-yr survival (%)	10-yr survival (%)	F/u (mo) median
Kanzaki et al. [127]	1980-2008	156	49	0	43^**	56	NR	NR
Iida et al. [128]	1990-2008	1030	23^*	NR	70	54	38	40
Onaitis et al. [129]	1998-2007	378	68	1	NR	56	NR	NR
Blackmon et al. [130]	2000-2010	229	50	0	70	55	NR	37

Author	Group A	Group B	PFS/TTP^# (A v B) (mo)	p-value	Median OS^# (A v B) (mo)	p-value
De Gramont et al. (Phase III)[60]	FOLFOX4^*	5FU/LV^**	9 v 6 (PFS)	0.0003	16 v 15	0.12
Colucci et al. ^a (Phase III) [73 ]	FOLFOX4	FOLFIRI	7 v 7 (TTP)	0.64	15 v 14	0.28
Hurwitz et al. (Phase III) [83]	FOLFOX4/ Bevacizumab	FOLFOX4	11 v 6 (PFS)	<0.001	20 v 16	<0.001
Saltz et al. (Phase III) [131 ]	FOLFOX4 (CapeOx)/ bevacizumab	FOLFOX4	9 v 8 (PFS)	0.0023	21 v 20	0.077
Bokemeyer et al. [94] (Phase II; OPUS)	FOLFOX4 / Cetuximab	FOLFOX4	8 v 7⁺⁺ (PFS)	0.0064⁺⁺	23 v 19⁺⁺	0.39⁺⁺
Van Cutsem et al. [18] (Phase III)	FOLFIRI/ Cetuximab	FOLFIRI	10 v 8⁺⁺ (PFS)	0.0012⁺⁺	24 v 20⁺⁺	0.0093⁺⁺
Douillard et al. [109] (Phase III; PRIME updated)	FOLFOX4/ Panitumumab	FOLFOX4	10 v 9 (PFS)	0.01	24 v 20	0.17/0.03^u
Schwartzberg et al. [17] (Phase II; PEAK)	mFOLFOX6^***/ Panitumumab	mFOLFOX6^***/ Bevacizumab	Similar⁺⁺ Favored A^{^} (PFS)	0.35⁺⁺ 0.029^{^}	34 v 24⁺⁺ 41 v 29^{^}	0.009⁺⁺ 0.058^{^}
Heinemann et al. [16] (Phase III; FIRE-3) Stintzing et al. [102] (Phase III; FIRE-3)	FOLFIRI/ Cetuximab FOLFIRI/ Cetuximab	FOLFIRI/ Bevacizumab FOLFIRI/ Bevacizumab	10 v 10⁺⁺ (PFS) 11 v 10^{^} (PFS)	0.69⁺⁺ 0.627^{^}	29 v 25⁺⁺ 33 v 26^{^}	0.0164⁺⁺ 0.010^{^}

Systemic Treatment of Colon Cancer

Abstract

Introduction

Systemic chemotherapy in the adjuvant setting

Adjuvant systemic chemotherapy in elderly patients

Metastatic Colorectal Cancer (mCRC)

Surgical treatment of Mcrc

Systemic therapy in mCRC

Targeted therapies

Other Targeted agents

Role of maintenance therapy

Conclusions

References