Adjuvant therapy in colon cancer—what, when and how?

review

Annals of Oncology 17: 1347–1359, 2006 doi:10.1093/annonc/mdl029 Published online 8 March 2006

Adjuvant therapy in colon cancer—what, when and how? I. Chau* & D. Cunningham Department of Medicine, Royal Marsden Hospital, London and Surrey, UK

Received 3 January 2006; revised 22 January 2006; accepted 23 January 2006

introduction Colorectal cancer (CRC) represents a major public health problem accounting for over 1 million cases of new cancers and about half a million deaths worldwide [1]. Despite curative surgery in those presenting early, the risk of recurrence is significantly high. Hence much work has been done in search of effective adjuvant therapy for the eradication of micrometastases. In colon cancer, chemotherapy is the principal adjuvant therapy and the addition of radiotherapy to chemotherapy has not been shown to improve outcome [2]. Recently, newer drugs with significant impact in the treatment of metastatic CRC such as irinotecan, oxaliplatin and oral fluoropyrimidines have all completed phase III randomised testing in the adjuvant setting of colon cancer. In this review, we have focused on the implications of these trial results on the everyday management decisions of adjuvant therapy in colon cancer.

what is the efficacy of adjuvant therapy in colon cancer? The establishment of adjuvant chemotherapy as standard treatment in stage III colon cancer was based on an *Correspondence to: Dr I. Chau, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44 208 642 6011; Fax: +44 208 643 9414; E-mail: [email protected]

ª 2006 European Society for Medical Oncology

improvement in overall survival (OS) compared to surgery alone. However, using OS as the primary endpoint requires many years of follow-up and may delay the introduction of effective treatment into routine clinical practice. There have been contemporary interests in using disease free survival (DFS) as a surrogate endpoint for OS for both colon cancer [3–6] and other solid tumours [7–12]. This is especially true in cancer types in which a number of treatment options exist for recurrent disease such as breast cancer [7–12], but not in those in which treatment options are limited such as lung cancer [13, 14] or pancreatic cancer [15], where OS is more often used as the primary endpoint for adjuvant treatment. Pooling individual patient data from 20 898 patients in 18 randomised controlled trials (RCTs) for colon cancer, a high correlation has been shown between 3-year DFS and 5-year OS with formal statistical surrogacy criteria being met [16]. However, all these studies used 5-FU ± leucovorin (LV) ± levamisole as adjuvant treatment. Whether these results can be extrapolated to combination adjuvant treatment with oxaliplatin or irinotecan remains to be seen. Similar to breast cancer, with the plethora of new treatment options in advanced CRC, the benefit of adjuvant treatment in improving DFS will have a diluted effect on OS. One cautionary tale would be the use of adjuvant anastrazole in breast cancer in which DFS advantage over tamoxifen did not translate into OS benefit [17]. Longer follow-up with 10-year OS rate rather than the traditional 5-year OS may be needed to truly evaluate the impact of these new agents on OS in colon cancer.

review

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

Bolus fluorouracil and leucovorin has been accepted as the standard adjuvant therapy in stage III colon cancer for many years. New drugs such as irinotecan, oxaliplatin and oral fluoropyrimidines have all completed phase III randomised evaluation in colon cancer. Several of these studies have been reported in the last 24 months. Oxaliplatin-based chemotherapy is now emerging as the new standard of care in adjuvant treatment of stage III colon cancer. The advent of monoclonal antibodies such as cetuximab and bevacizumab has further broadened the treatment horizon for colorectal cancer and they are the focus of the on-going randomised studies in adjuvant therapy of colon cancer. In stage II colon cancer, adjuvant treatment remains controversial and is not routinely recommended in all medically fit patients by the current American Society of Clinical Oncology guidelines, except several subsets including poorly differentiated histology, T4 lesions, bowel perforation presentation and inadequately sampled lymph nodes (<13). This review focuses on the relative merits of these agents, their safety, duration of treatment, timing of commencing treatment after surgery and the role of adjuvant therapy in stage II colon cancer, thereby assisting clinicians in deciding the optimal adjuvant treatment for patients in routine clinical practice. Key words: colon cancer, adjuvant therapy, oxaliplatin, irinotecan, capecitabine

review

Bolus 5-FU/leucovorin (LV) Although clinical trials began in the 1960s, no definite survival advantage was seen with adjuvant therapy compared with surgery alone until the late 1980s [19]. National Surgical Adjuvant Breast and Bowel Project (NSABP) C-01, reported in 1988, was the first study to report a survival advantage for adjuvant chemotherapy [20]. Although adjuvant chemotherapy initially demonstrated both DFS and OS advantage over surgery alone [20], this improvement was lost with prolonged follow-up at 10 years (hazard ratio [HR]: 1.12; 95% confidence interval (CI): 0.91–1.38; P = 0.27) [21]. Interestingly, bacillus CalmetteGue´rin treatment in this study did not prevent tumour recurrence, but an OS benefit was seen at 10 years compared with surgery (HR: 1.27; 95% CI: 1.03–1.56; P = 0.02). This improvement in OS appeared to be due to a smaller number of deaths from co-morbidities including cardiac-related deaths, deaths after second primary non-colonic cancer and deaths from non-malignant conditions [21]. The Intergroup 0089 compared 5-FU/levamisole with 5-FU/ low dose LV, 5-FU/ high dose LV and 5-FU/low dose LV/ levamisole in 3561 patients [22]. Whereas no significant differences in DFS or OS were seen among the four treatment arms, with prolonged follow-up (median 10 years), the trial shed some light on the natural history of patients with high risk colon cancer. In particular, between 5 and 10 years, about 10% of patients would have a further cancer-related event (an absolute decrease of 10% in DFS) and about 14% of patients died (an absolute decrease of 14% in OS). The long term results from NSABP C-01 also showed a 16% decrease in DFS and 18% decrease in OS between 5 and 10 years in patients receiving adjuvant chemotherapy [21]. More recent European adjuvant studies aimed to confirm results from the USA. Table 1 shows selected randomised studies evaluating bolus 5-FU based adjuvant chemotherapy in colon cancer [23–29]. Collectively, the evidence emerging from these USA and European studies shows that: (i) 5-FU/low dose LV (20 mg/m2) is equivalent to 5-FU/high dose LV (200–500 mg/ m2); (ii) 5-FU/LV given for 6 months is as good as given for 12 months; (iii) there is no significant difference between the

1348 | Chau & Cunningham

two most commonly used bolus 5-FU/LV dose schedules: 5-FU 425 mg/m2 and LV 20 mg/m2 days 1–5 every 4 weeks for six cycles (Mayo clinic regimen) and 5-FU 500 mg/m2 and LV 500 mg/m2 weekly ·6 every 8 weeks for three to four cycles (Roswell Park regimen); (iv) 5-FU/levamisole given for 6 months is inferior to the same treatment given for 12 months; (v) interferon produces no additional survival benefit at the expense of excessive toxicities.

Continuous infusion 5-FU Continuous infusion of 5-FU resulted in less haematological toxicities and a small, but statistically significant survival advantage over bolus regimens in advanced CRC, thus provided the rationale to investigate continuous infusion 5-FU as adjuvant therapy. Three RCTs have been performed to compare continuous infusion 5-FU with bolus 5-FU as adjuvant therapy in colon cancer. Table 2 shows the details of these three studies [30–33]. In all three studies, no statistical significant differences were seen in either DFS or OS, whereas toxicity profile was more favourable for continuous infusion 5-FU (as discussed later). It is reasonable to consider continuous infusion 5-FU instead of bolus 5-FU/LV as adjuvant therapy depending on treating clinicians’ and patients’ preference. These data also supported the use of LV5FU2 (a continuous infusion 5-FU/LV regimen) as control arms in phase III studies evaluating combination of oxaliplatin or irinotecan with LV5FU2. The Pan-European Trials in Adjuvant Colon Cancer (PETACC) 2 trial compared three different continuous infusion 5-FU schedules with bolus 5-FU/LV and final data are still awaited. Other continuous infusion schedules may be as effective as LV5FU2 in adjuvant therapy for colon cancer. However, continuous infusion is cumbersome to use and compromises patients’ independence. Moreover, the ports and pumps required for continuous infusion with the associated complications of central intravenous catheters may result in considerable patients’ inconvenience and treatment delivery costs. Oral fluoropyrimidines Oral fluoropyrimidines may overcome some of the shortfalls in delivering continuous infusion 5-FU, potentially translating into cost-saving measures. In advanced CRC, capecitabine has been shown to increase the response rate and has equivalent survival while achieving a more favourable toxicity profile compared to bolus 5-FU/LV [34]. Two studies investigated the efficacy of oral fluoropyrimidines as adjuvant therapy in colon cancer. Table 3 shows the details of these two studies [35, 36]. The X-ACT study was designed to demonstrate the equivalence of capecitabine and bolus 5-FU/LV in terms of DFS and it met its primary endpoint (HR: 0.87; 95% CI: 0.75–1.00; P < 0.001 for equivalence) [35]. NSABP C-06 again did not show any difference in efficacy between UFT/LV and bolus 5-FU/LV [36]. A further pooled analysis of three randomised trials of oral fluoropyrimidines and mitomycin C versus observation alone performed in Japan has been published [37]. 5233 stage II and III patients were included in this analysis. As all three trials were initiated before 1990, observation alone after surgery for stage III patients was justified. Oral fluoropyrimidines treatment

Volume 17 | No. 9 | September 2006

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

However, the definitions of DFS vary among studies and this could lead to quite different conclusions in individual studies [3, 4]. The events that generally contribute to the DFS definition include recurrence of disease, second CRC and death from any cause. Some studies also included development of second noncolorectal cancers as an event whereas others do not [18]. Inclusion of second non-colorectal cancer would capture the potential complications of treatment-induced second malignancies, a factor particularly pertinent in assessing the use of monoclonal antibodies as adjuvant treatment where very limited long-term safety data are currently available. However, whether second non-colorectal cancer is included or not as an event in DFS, the effect is likely to be small when DFS is assessed at 3 years. If the impact of the definition on the study conclusion is important, it suggests that conclusions either way may be premature or of lessened clinical importance [18]. In other cancers, DFS does include occurrence of second cancers other than the primary (ipsilateral or contralateral) site [7–9].

Annals of Oncology

Study [Author]

Stage of disease

Treatment arms

Treatment duration

No. of eligible patients (total)

3–5 year disease/relapse free survival

P

3–5 year overall survival

P

Comments

NACCP [29] Holland 1990–1996

II (46%) & III (54%)

A: Observation B: 5-FU (450 mg/m2)/LEV Days 1–5 then weekly from day 29

– 12 months

515 514 (Total: 1029)

NR NR

NR

58% (5 year)

0.007 68%

Both colon and rectal cancers are included

AGO [25] Germany 1991–1994

III

A: 5-FU (450 mg/m2)/LEV Days 1–5 then weekly from day 29 B: 5-FU (450 mg/m2)/LV (100 mg/m2) Days 1–5 every 4 weeks

12 months

331

49 months (median)

0.037

65.3% (4 year)

0.0089

12 months

349 (Total: 680)

58 months (median)

A: 5-FU (450 mg/m2)/LEV Days 1–5 then weekly from day 29 B: 5-FU (450 mg/m2)/LEV/LV (200 mg/m2) days 1–5 then weekly from day 29 C: 5-FU (450 mg/m2)/LEV/IFN (66106IU thrice weekly) days 1–5 then weekly from day 29

52 weeks 52 weeks

282 295

52.3% (5-year) 61.6%

1-sided P test 0.007 (A vs. B)

60.5% (5-year) 72%

1-sided P test 0.004 (A vs. B)

52 weeks

278 (Total: 855)

56.3%

0.137 (A vs. C)

62.7%

0.382 (A vs. C)

A: 5-FU (370 mg/m2)/ LV (175 mg fixed dose) Weekly or 4-weekly Vs. B: 5-FU (370 mg/m2)/LV (25 mg fixed dose) Weekly or 4-weekly C: 5-FU (370 mg/m2)/high or low dose LV/LEV Weekly or 4-weekly Vs. D: 5-FU (370 mg/m2)/high or low dose LV/placebo Weekly or 4-weekly

6 months

2464

36% (3 year)

0.94 (A vs. B)

70.1% (3 year)

0.43 (A vs. B)

6 months

2463

35.8%

6 months

2429

37.0%

6 months

2434 (Total: 4927)

34.9%

6 months

844

58% (5-year)

6 months

859 (Total: 1703)

60%

Country Period of study

QUASAR [26] UK 1994–1997

I (0.2%) & II (28%) & III (72%)

II (48%) & III (52%)

A: 5-FU (450 mg/m2)/LEV Days 1–5 every 4 weeks B: 5-FU (370 mg/m2)/ LV (100 mg/m2)/LEV Days 1–5 every 4 weeks

71.0%

0.16 (C vs. D)

69.4%

0.06 (C vs. D)

2·2 factorial design with patients randomly assigned to 5-FU with high or low-dose LV and either active or placebo LEV. LEV/placebo randomisation closed early, therefore 64 fewer patients in the LEV/placebo comparison. Both colonic and rectal cases are included

71.5%

0.94

68% (5-year)

0.68

71%

review

doi:10.1093/annonc/mdl029 | 1349

INTACC-1 [23] Italy 1992–1995

II (T4 tumours only; 8%) & III (92%)

72.8%

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

FOGT [24] Germany 1992–1999

Annals of Oncology

Volume 17 | No. 9 | September 2006

Table 1. Recent European adjuvant therapy studies assessing bolus fluorouracil/leucovorin

Study [Author]

Stage of disease

Treatment arms

Treatment duration

No. of eligible patients (total)

3–5 year disease/relapse free survival

P

3–5 year overall survival

P

II (55%) & III (45%)

A: 5-FU (370 mg/m2)/ LV (100 mg/m2)/LEV Days 1–5 every 4 weeks B: 5-FU (600 mg/m2) days 2 and 16/methotrexate (200 mg/m2) days 1 and 15/LEV Repeated every 28 days

6 months

985

63% (5-year)

0.44

77%

0.90

6 months

960 (Total: 1945)

67%

A: 5-FU (450 mg/m2) Days 1–5 then weekly from day 29 B: 5-FU (450 mg/m2)/LEV days 1–5 then weekly from day 29 C: 5-FU (450 mg/m2) days 1–5 then weekly from day 29/IFN (3.5·106IU thrice weekly) D: 5-FU (450 mg/m2) days 1–5 then weekly from day 29/IFN (3.5·106IU thrice weekly)/LEV

52 weeks 52 weeks

140 140

NR NR

52 weeks

142

NR

52 weeks

145 (Total: 567)

NR

Comments

Country Period of study INTACC-2 [28] Italy 1995–1998

ABCSG [27] Austria 1991–1999

III

review

77%

0.0028 (Arms B+D vs. A+C) in favour of no levamisole 0.8826 (Arms A+B vs. C+D)

NR NR

0.0027(Arms B+D vs. A+C) 0.738(Arms A+B vs. C+D)

DFS and OS in favour of no levamisole. No differences in DFS and OS with addition of interferon.

NR

NR

Annals of Oncology

Volume 17 | No. 9 | September 2006

NACCP: Netherlands Adjuvant Colon Cancer Project. AGO: Arbeitsgemeinschaft Gastrointestinale Onkologie. FOGT: Forschungsgruppe Onkologie Gastrointestinaler Tumoren. INTACC: Italian National Intergroup of Adjuvant Chemotherapy in Colon Cancer. ABCSG: Austrian Breast and Colorectal Cancer Study Group. LEV: levamisole given 50 mg 8 hourly for 3 days every 2 weeks. LV: leucovorin. DFS: disease free survival. NR: not reported in publication. OS: overall survival. IFN: interferon a-2a.

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

1350 | Chau & Cunningham

Table 1. (Continued)

Annals of Oncology

Volume 17 | No. 9 | September 2006

Table 2. Randomised studies comparing bolus vs. continuous infusion 5-FU as adjuvant treatment for colon cancer Study [Author]

Stage of disease

Treatment arms

Treatment duration

No. of eligible patients (total)

5 year disease/relapse free survival

P

5 year overall survival

P

Comments

II (43%) and III (57%)

A: Bolus 5-FU (400 mg/m2)/LV (200 mg/m2) Days 1–5 every 4 weeks B: LV5FU2 Bolus 5-FU (400 mg/m2) days 1 + 2 Infused 5-FU (600 mg/m2) days 1 + 2 LV (200 mg/m2) days 1 + 2 Repeated every 2 weeks

24 or 36 weeks

453

67.7%

NS

80%

NS

24 or 36 weeks

452 (Total: 905)

67.2%

2·2 factorial design comparing treatment arms and treatment durations Both colon and high rectal cancer patients wre included

A: Bolus 5-FU (425 mg/m2)/LV (20 mg/m2) Days 1–5 every 4 weeks for 3 cycles, then every 5 weeks for 3 cycles/LEV B: Infused 5-FU (250 mg/m2/day) weeks 1–7 then 1 week’s rest/LEV

6 months

463

61%

6 months

477 (Total: 940)

63%

A: Bolus 5-FU (425 mg/m2)/LV (20 mg/m2) Days 1–5 every 4 weeks B: Infused 5-FU (300 mg/m2/day) continuously

6 months

404

66.7%

3 months

397 (Total: 801)

73.3%

Period of study Country GERCOR [31] 1996–1999 France

Intergroup 0153 [33] 1994–1999 USA

SAFFA [32] 1993–2003 UK

II (15%) and III (85%)

II (41%) and III (59%)

80%

0.59

70%

0.20

69%

0.10

71.5%

0.08

Both colon and rectal cancer patients were included

GERCOR: Groupe Co operateur multidisciplinaire en oncology LEV: levamisole given 50mg 8 hourly for 3 days every 2 weeks. SAFFA: Short Adjuvant Fluorouracil and Folinic Acid Study LV: leucovorin NS: non significant.

review

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

doi:10.1093/annonc/mdl029 | 1351

75.7%

Study [Author]

Treatment arms

Treatment duration

No. of eligible patients (total)

3–5 year disease/relapse free survival

P

3–5 year overall survival

P

Comments

III

A: Bolus 5-FU (425 mg/m2)/ LV (20 mg/m2) Days 1–5 every 4 weeks B: Capecitabine 2500 mg/m2/day Days 1–14 every 3 weeks

6 months

983

60.6% (3-year)

0.05

77.6% (3-year)

0.07

6 months

1004 (Total: 1987)

64.2%

Study designed for non-inferiority and the primary endpoint was met

A: 5-FU (500 mg/m2)/LV (500 mg/m2) Weekly · 6 every 8 weeks B: UFT (300 mg/m2/day)/LV (90 mg/day) days 1–28 every 5 weeks

6 months

777

76.4% (5-year)

6 months

784 (Total: 1561)

74.5%

A: LV5FU2 Bolus 5-FU (400 mg/m2) days 1 + 2 Infused 5-FU (600 mg/m2) days 1 + 2 LV (200 mg/m2) days 1 + 2 Repeated every 2 weeks B: FOLFOX Oxaliplatin (85 mg/m2) day 1 Bolus 5-FU (400 mg/m2) days 1 + 2 Infused 5-FU (600 mg/m2) days 1 + 2 LV (200 mg/m2) days 1 + 2 Repeated every 2 weeks

6 months

1,123

72.9% (3-year)

6 months

1,123 (Total: 2,246)

78.2%

A: 5-FU (500 mg/m2)/LV (500 mg/m2) Weekly · 6 every 8 weeks B: Oxaliplatin (85 mg/m2) every 2 weeks for 6 weeks, then 2 weeks’ rest 5-FU (500 mg/m2)/LV (500 mg/m2) Weekly · 6 every 8 weeks

6 months

1,207

71.6% (3-year)

6 months

1,200 (Total: 2,407)

76.5%

A: LV5FU2 Bolus 5-FU (400 mg/m2) days 1 + 2 Infused 5-FU (600 mg/m2) days 1 + 2 LV (200 mg/m2) days 1 + 2 Repeated every 2 weeks B: FOLFIRI Irinotecan (180 mg/m2) day 1 Bolus 5-FU (400 mg/m2) days 1 + 2 Infused 5-FU (600 mg/m2) days 1 + 2 LV (200 mg/m2) days 1 + 2 Repeated every 2 weeks

6 months

200

60% (3-year)

6 months

200 (Total: 400)

51%

Period of study Country

Oxaliplatin MOSAIC [3] 1998–2001 Global

NSABP C-07 [5] 2000–2002 USA

II (40%) and III (60%)

II (29%) and III (71%)

High risk stage III N2 or occlusion/ perforation

0.62

78.7%

0.88

78.7%

0.002

86.6% (3-year)

NS

87.7%

<0.004

NR

NR

NR

0.22

NR

NR

NR

Annals of Oncology

Irinotecan FNCLCC ACCORD-02/FFCD 9802 [6] 1998–2002 France

II (47%) and III (53%)

81.3%

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

Oral fluoropyrimidines X-ACT [35] 1998–2001 Global

NSABP C-06 [36] 1997–1999 USA

Volume 17 | No. 9 | September 2006

Stage of disease

review

1352 | Chau & Cunningham

Table 3. Randomised studies evaluating oral fluoropyrimidines, oxaliplatin and irinotecan as adjuvant treatment for colon cancer

CALGB 89803 [38] 1999–2001 USA

III

III

A: LV5FU2 Bolus 5-FU (400 mg/m2) days 1 + 2 Infused 5-FU (600 mg/m2) days 1 + 2 LV (200 mg/m2) days 1 + 2 Repeated every 2 weeks B: FOLFIRI Irinotecan (180 mg/m2) day 1 Bolus 5-FU (400 mg/m2) days 1 + 2 Infused 5-FU (600 mg/m2) days 1 + 2 LV (200 mg/m2) days 1 + 2 Repeated every 2 weeks

6 months

1,058

60.3% (3-year)

6 months

1,053 (Total: 2,111)

63.3%

A: 5-FU (500 mg/m2)/LV (500 mg/m2) Weekly · 6 every 8 weeks B: Irinotecan (125 mg/m2)/ 5-FU (500 mg/m2)/LV (20 mg/m2) given weekly · 4 every 6 weeks for 5 cycles

32 weeks

629

NR

30 weeks

635 (Total: 1,264)

NR

0.091

NR

NR

NR

0.80

NR

Results were for stage III only. 894 stage II patients also randomized.

Annals of Oncology

Volume 17 | No. 9 | September 2006

PETACC-3 [4] 2000–2002 Global

0.81

NR

X-ACT: Xeloda in Adjuvant Colon Cancer Therapy. NSABP: National Surgical Adjuvant Breast and Bowel Project. MOSAIC: The Multicenter International Study of Oxaliplatin, Fluorouracil, Leucovorin in the Adjuvant Treatment of Colon Cancer. FNCLCC: Federation Nationale des Centres de Lutte Contre le Cancer. FFCD: Federation Francaise de Cancerologie Digestive. PETACC: Pan-European Trials in Adjuvant Colon Cancer. CALGB: Cancer and Leukaemia Group B. LV: leucovorin. NS: non significant. NR: not reported.

review

doi:10.1093/annonc/mdl029 | 1353 Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

review resulted in an improvement in overall survival over surgery alone (HR: 0.89; 95% CI: 0.80–0.99; P = 0.04). However, since UFT is neither licensed nor routinely used in many countries including the USA, probably only capecitabine will be integrated into the adjuvant therapy of colon cancer in routine clinical practice.

1354 | Chau & Cunningham

it is debatable of whether any formal statistical testing should be performed at all on baseline characteristics in large RCTs. However, T-staging was included as a stratification factor in the MOSAIC study. CALGB C89803 study used irinotecan/bolus 5-FU/LV (IFL) regimen which had a considerable safety issue [41] and IFL was inferior in efficacy to FOLFOX in advanced CRC [42]. Therefore one may conclude that irinotecan adjuvant studies performed thus far were not adequately designed and the value of irinotecan is still to be proven. With over 3700 patients recruited into these three studies with no apparent benefit, further large scale RCTs evaluating irinotecan as adjuvant treatment will be unlikely to be performed. However, this also illustrated the importance of not extrapolating efficacy data in advanced CRC into adjuvant setting without randomised confirmatory data, especially with the advent of monoclonoal antibodies in CRC.

how safe is adjuvant chemotherapy? Whereas continuous infusion schedules of 5-FU/LV has shown equivalent efficacy to bolus schedules, continuous infusion 5-FU had a much more favourable toxicity profile. Neutropenia, diarrhoea and stomatitis all occurred significantly less frequently. However, hand foot syndrome was observed more often with the continuous infusion schedule. Table 4 shows comparisons of grade 3/4 toxicities [30, 32, 33]. Capecitabine was also associated with similar favourable toxicity profile to continuous infusion 5-FU [35]. Interestingly, despite objective toxicity, as assessed by health care professionals, was less with capecitabine, there was no difference in global quality of life (QoL) between capecitabine and bolus 5-FU/LV [35]. This might be related to the timing of self reported QoL assessment, as this improvement in QoL was seen with continuous infusion 5-FU, when compared with bolus 5-FU/LV, if assessment was performed weekly in the first course of chemotherapy [43]. In the NSABP C-06 study, oral treatment with UFT/LV was perceived by patients as more convenient than standard intravenous bolus 5-FU/LV. While the pattern of symptoms associated with each regimen was different, the impact on QoL in general, and within the categories of colon-specific, physical, emotional, social, and functional health, was similar [44]. Despite oxaliplatin has shown improved efficacy to LV5FU2, this improvement came at a price of added toxicity. Table 5 shows comparisons of grade 3/4 toxicities between continuous infusion 5-FU alone or in combination with oxaliplatin or irinotecan. Most notably, nausea and vomiting, neutropenia and parathesia were more commonly seen with FOLFOX, than with LV5FU2. Although neutropenia was more frequent with FOLFOX, the incidence of febrile neutropenia was 1.8% which was statistically significantly higher than LV5FU2 at 0.2% (P < 0.001) [3], but this might not be important clinically. Nevertheless 44% of patients developed grades 2–3 peripheral neuropathy during treatment, which decreased to 5.9% one year post-treatment and 3.9% at 18 months of follow-up. Residual functional neuropathy is much less acceptable in patients who have had a potentially curative resection. Another large phase III XELOX-A study randomised patients between oxaliplatin/ capecitabine (XELOX n = 937) or bolus 5-FU/LV (n = 924) in stage III colon cancer. Efficacy data are expected in late 2007.

Volume 17 | No. 9 | September 2006

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

Combination chemotherapy in adjuvant treatment Irinotecan and oxaliplatin had made a significant impact in metastatic CRC in recent years. Evaluating these two agents in the adjuvant setting was therefore logical. Table 3 shows five randomised controlled trails performed to evaluate these agents [3–6, 38]. The European Multicenter International study of Oxaliplatin/infused 5-FU/LV [FOLFOX 4] in the Adjuvant treatment of Colon Cancer (MOSAIC) study recruited 2248 stage II and III colon cancer patients. FOLFOX 4 significantly improved DFS compared with LV5FU2 [3]. Furthermore, the recently reported NSABP C-07 study has shown that the addition of oxaliplatin to bolus 5-FU/LV also significantly improved DFS compared to bolus 5-FU/LV alone [5]. Therefore oxaliplatin-containing regimen should be considered for all stage III colon cancer patients. However, one should bear in mind that no overall survival advantage has yet been demonstrated in either MOSAIC [39] or NSABP C-07 studies, as data are still maturing. In MOSAIC study, with a median follow-up of 56 months, there was an absolute 4-year OS difference of 2.1% (FOXFOX: 84.9% versus LV5FU2: 82.8%; HR: 0.91; 95% CI: 0.75–1.11) [39]. A larger proportion of patients in the LV5FU2 arm (42.7%) received oxaliplatin-based regimens at the time of recurrence compared to those in the FOLFOX arm (15.5%). Similar proportions of patient received irinotecan-based regimens (49.5% versus 51.9% respectively). Considering the survival benefit of having access to all three active drugs – fluoropyrimidines, irinotecan, oxaliplatin in recurrent or metastatic CRC [40], the use of oxaliplatin-based salvage at the time of recurrence in the LV5FU2 arm may dilute the benefit of FOLFOX in improving DFS. In contrast, all three RCTs evaluating irinotecan had failed to show a benefit of adding irinotecan to bolus or continuous infusion 5-FU/LV in improving the DFS, therefore irinotecan should not be used routinely in the adjuvant setting [4, 6, 38]. As discussed before, the definition of DFS could be critical in the conclusions of a study. PETACC-3 included second noncolorectal cancer as an event in DFS [4], where this was not included in the MOSAIC study [3]. The relapse free survival (RFS) excluded second non-colorectal cancer and was used as a secondary endpoint in the PETACC 3 study. Therefore RFS in PETACC 3 was identical to DFS in MOSAIC study. There was indeed a statistically significant improvement in RFS in favour of FOLFIRI (irinotecan/bolus and continuous infusion 5-FU/ LV) in PETACC 3 study. The ACCORD study targeted high risk stage III colon cancer, but the expected 15% difference in 3-year DFS (from 45% with LV5FU2 to 60% with FOLFIRI) was far too optimistic [6]. Thus the study was underpowered to show any smaller but clinically meaningful differences. Secondly, similar to PETACC 3, T-staging was not a stratification factor in the randomisation process leading to a statistically significant imbalance of T4 versus T1–3 tumours in both studies, although

Annals of Oncology

review

Annals of Oncology

Table 4. Comparisons of grade 3/4 toxicities between bolus and continuous administration of fluoropyrimidines Toxicities Diarrhoea Stomatitis Nausea and vomiting Hand foot syndrome Neutropenia All toxicities

GERCOR Bolus Continuous infusion

Intergroup 0153 Bolus Continuous infusion

SAFFA Bolus

Continuous infusion

X-ACT Bolus Capecitabine

9% 7% 3% 0% 16% 26%

19% 18% 13% 0.4% 51% 71%

15% 18% 2% 3% 55% 68%

5%* 4%* 1.5% 7.1%* 1%* 21%*

13% 14% 3% <1% 26% NR

4%* 2%* 1% 0% 7%* 11%*

7% 8% 3% 4% 0.7% 35%

11% 2%* 3% 17%* 2%* NR

Table 5. Comparisons of grade 3/4 toxicities between continuous infusion 5-FU alone or in combination with oxaliplatin or irinotecan Toxicities Diarrhoea Stomatitis Nausea and vomiting Hand foot syndrome Neutropenia Parathesia

GERCOR LV5FU2

SAFFA PVI 5-FU

MOSAIC LV5FU2

FOLFOX

PETACC LV5FU2

FOLFIRI

ACCORD 02 LV5FU2

FOLFIRI

4% 2% 1% 0% 7% 0.4%

5% 4% 1.5% 7.1% 1% 0.3%

6.6% 2.2% 3.2% 2.4% 4.7% 0.2%

10.8% 2.7% 10.9% 2.0% 40.6% 12.4%

5.6% 2.4% 2% NR 6% NR

11.9% 1.4% 10.9% NR 28.2% NR

6.1% NR 1.5%# NR 4.1% NR

11.6% NR 12.6%# NR 28.3% NR

# Only incidences of nausea were reported. GERCOR: Groupe Co operateur multidisciplinaire en oncology. SAFFA: Short Adjuvant Fluorouracil and Folinic Acid Study. MOSAIC: The Multicenter International Study of Oxaliplatin, Fluorouracil, Leucovorin in the Adjuvant Treatment of Colon Cancer. PETACC : Pan-European Trials in Adjuvant Colon Cancer. PVI 5-FU: Protracted venous infusion 5-FU. LV5FU2 : Bolus and continuous infusion 5-FU / leucovorin. FOLFOX: Oxaliplatin/Bolus and continuous infusion 5-FU/leucovorin. FOLFIRI: Irinotecan/Bolus and continuous infusion 5-FU/leucovorin.

Early safety data of XELOX were comparable to FOLFOX except neutropenia which appears to occur at lower frequency (8%) with XELOX [45]. This has led to the acceptance of using adjuvant XELOX in some patients with contra-indications to pumps and central venous catheters. Concerns have been raised over the safety of irinotecan when given in combination to bolus 5-FU/LV (IFL regimen). Higher than expected 60-day all cause mortality rates were noted in the CALGB C89803 study (2.2% in IFL versus 0.8% in control arms) [41]. This was attributed to a gastrointestinal syndrome characterised by diarrhoea, nausea and vomiting, dehydration coupled with febrile neutropenia and electrolyte imbalances and a vascular syndrome characterised by acute, fatal myocardial infarction, cerebrovascular accident and pulmonary embolism. Treatment related mortality with IFL was concerning and not acceptable in adjuvant settings. The nearly three-fold increase in early mortality in a relatively underpowered study may be contributory to the lack of survival benefit over bolus 5-FU/LV in the C89803 trial. However, when irinotecan was combined

Volume 17 | No. 9 | September 2006

with continuous infusion 5-FU, mortality rate was 0.9% in the PETACC [4] and 0.5% in the ACCORD 2 [6] studies, much more in line to that with continuous infusion 5-FU alone. Table 5 shows grades 3/4 toxicities with irinotecan- based adjuvant treatment studies. Interestingly FOLFIRI showed very similar incidences of grades 3 or 4 diarrhoea, stomatitis and nausea/ vomiting to FOLFOX in adjuvant setting. However, neutropenia was much less common with FOLFIRI than FOLFOX.

is adjuvant treatment indicated in stage II colon cancer? Whereas the role of adjuvant treatment is well established in stage III disease, there is no international consensus in stage II disease. The lower rate of recurrence and better survival in stage II versus stage III disease render benefits of adjuvant chemotherapy less clear cut. Most of studies performed in the past were generally too small and under-powered. The

doi:10.1093/annonc/mdl029 | 1355

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

No formal statistical comparisons were made between treatment arms in the Intergroup 0153 study. *P < 0.001. NR: not reported. GERCOR: Groupe Co operateur multidisciplinaire en oncology. SAFFA: Short Adjuvant Fluorouracil and Folinic Acid Study. X-ACT: Xeloda in Adjuvant Colon Cancer Therapy.

review

Annals of Oncology

were 80.3% for chemotherapy arm and 77.4% for observation arm. Among the patients with stage II colon cancer, the survival benefit for chemotherapy was also significant (P = 0.04). In the MOSAIC study, FOLFOX was also associated with a nonsignificant improvement in DFS compared to LV5FU2, but the study was not powered to detect differences between treatment arms by disease stage. However, one should emphasise that there is no universal consensus on the definition of high risk stage II colon cancer, but the ASCO guidelines could serve as a reasonable guide [46]. Additional molecular markers such as microsatellite instability (MSI) are being incorporated into the currently recruiting ECOG E5202 trial. Patients are stratified according to disease stage (IIA versus IIB) and microsatellite stability (MSS) (stable versus low-grade instability [MSI-L]). Patients with high-risk disease are randomised to either FOLFOX or FOLFOX + bevacizumab. Patients with low-risk disease are assigned to observation alone after surgery.

what is the optimal duration of chemotherapy? Although the results from the Intergroup-0035 study led to the adoption of 5-FU and levamisole given for 12 months as standard adjuvant therapy, 30% of patients discontinued treatment prematurely because of toxicity with a median of 5months’ treatment [50]. Further US Intergroup studies (INT0089 and INT 0089-46-51) established 6 months as the standard duration of 5-FU/LV [22, 51]. In the GERCOR study comparing LV5FU2 with bolus 5-FU/LV, a second randomisation was performed between 24 and 36 weeks of treatment, no DFS or OS differences were seen [30, 31]. In the SAFFA study, 12 weeks of PVI 5-FU resulted in equivalent efficacy compared to 6 months of bolus 5-FU/LV [32]. Table 6 shows selected randomised studies where the duration of

Table 6. Randomised trials evaluating duration of adjuvant treatment Study

Treatment arms

Duration

5-year DFS

5-year OS

Intergroup 0089 [22] n = 3759

5-FU/LEV 5-FU/LV (Mayo) 5-FU/LV (Roswell) 5-FU/LV/LEV 5-FU/LEV 5-FU/LEV 5-FU/LEV/LV 5-FU/LEV/LV 5-FU/LV (bolus or continuous infusion) 5-FU/LV (bolus or continuous infusion) 5-FU/LV PVI 5-FU

12 6 8 6 6 12 6 12 6 9 6 3

55% 60% 58% 49% 58% 63% 63% 57% 68% 67% 67% 73%

64% 66% 66% 54% 60% 68% 70% 65% 81% 78% 72% 76%

Intergroup 0089–46–51 [51] n = 891

GERCOR [31] n = 905 SAFFA [32] n = 801

months months months months months months months months months months months months

GERCOR: Groupe Co operateur multidisciplinaire en oncology. SAFFA: Short Adjuvant Fluorouracil and Folinic Acid Study. DFS: disease free survival. OS: overall survival. LEV: levamisole. LV: leucovorin. PVI: protracted venous infusion.

1356 | Chau & Cunningham

Volume 17 | No. 9 | September 2006

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

American Society of Clinical Oncology (ASCO) guidelines currently recommend that routine use of adjuvant chemotherapy is not indicated for medically fit stage II colon cancer patients [46]. However, ASCO guidelines suggested that several subsets of patients could be considered for adjuvant therapy. These include patients with poorly differentiated histology, T4 lesions, bowel perforation presentation and inadequately sampled lymph nodes (n < 13) [46, 47]. In an analysis of 35 787 cases of T3N0 colon cancer from the USA National Cancer Database, patients were stratified by the number of lymph nodes undergoing pathological examination [47]. The 5-year survival rates for 1–7 nodes examined was 49.8%, 8–12 nodes 56.2% and ‡13 lymph nodes 63.4% (P < 0.0001). The average yield of positive nodes did not significantly increase once 13 nodes were examined and this might represent the number of examined nodes necessary to adequately stage T3N0 tumour. A meta-analysis performed by a Canadian group based on 4187 patients found no significant survival benefit for adjuvant chemotherapy (risk ratio [RR]: 0.87; 95% CI: 0.75–1.01; P = 0.07) [48]. ASCO selected 12 trials based on the more stringent criteria requiring inclusion of a surgery-alone control arm and at least one 5-FU based chemotherapy arm. A meta-analysis based on these 12 trials again found no significant survival advantage (RR: 0.86; 95% CI: 0.73–1.02) [46]. However, the largest randomised trial addressing this issue was recently reported. In the QUASAR uncertain study [49], 3239 patients were randomised between observation (n = 1617) or 5-FU/LV (n = 1622). 92% of patients in this study had stage II colon cancer. With a median follow-up of 4.6 years, adjuvant chemotherapy was associated with significantly reduced recurrence (RR: 0.78; 95% CI: 0.67–0.91; P = 0.001) and improved survival (RR: 0.83; 95% CI: 0.71–0.97; P = 0.02). The 5-year recurrence rates were 22.2% for chemotherapy arm and 26.2% for observation arm. The 5-year overall survival rates

review

Annals of Oncology

chemotherapy was addressed [22, 31, 32, 51]. These data were relevant as patients’ quality of life would improve earlier if the duration of chemotherapy was shorter since 5-FU did not have long term side effects [43]. Moreover, as oxaliplatin induced neurotoxocity is related to its cumulative dose, shorter duration of treatment would translate into less disabling neurotoxicity for patients.

when should one start adjuvant chemotherapy after surgery?

future directions in adjuvant therapy With the advent of monoclonal antibodies in metastatic CRC, the next wave of adjuvant therapy trials is focusing on the use of these new targeted agents. Antibodies targeting against epidermal growth factor receptor such as cetuximab [53] and vascular endothelial growth factor such as bevacizumab [54] have both shown efficacy in the metastatic setting. Large scale phase III trials are now underway recruiting 14 000 patients. Table 7 shows on-going studies evaluating cetuximab and bevacizumab in the adjuvant setting. As these monoclonal antibodies have relatively mild side-effect profile compared to cytotoxic drugs, aside from assessing the additional benefit of these monoclonal antibodies over cytotoxic agents, the long

conclusions Disease free survival has been increasingly used as a surrogate efficacy endpoint and its definition will require international agreement to interpret results from RCTs appropriately. Equivalent efficacy has been shown between continuous infusion 5-FU and bolus 5-FU. Oxaliplatin-based adjuvant chemotherapy is becoming the standard of care as adjuvant chemotherapy (at least in stage III colon cancer), whereas irinotecan should not be routinely used in adjuvant setting. Oral

Table 7. Ongoing adjuvant therapy studies evaluating bevacizumab and cetuximab Trials

Stages of disease

Treatment arms

Number of patients to be recruited

NSABP C-08 AVANT PETACC-8 Intergroup 0147 (ECOG/NCCTG) ECOG E5202*

II and III II and III III III II

FOLFOX Vs. FOLFOX + bevacizumab FOLFOX Vs. FOLFOX + bevacizumab Vs. XELOX + bevacizumab FOLFOX Vs. FOLFOX + cetuximab FOLFOX Vs. FOLFOX + cetuximab Observation Vs. FOLFOX Vs. FOLFOX + bevacizumab

2632 3450 2000 2300 3610

*Patients are stratified according to disease stage (IIA vs IIB) and microsatellite stability (MSS) (stable vs low-grade instability [MSI-L]). Patients with high-risk disease are randomized to either FOLFOX or FOLFOX + bevacizumab. Patients with low-risk disease are assigned to observation alone after surgery. NSABP: National Surgical Adjuvant Breast and Bowel Project. AVANT: Avastin adjuvant. PETACC: Pan-European Trials in Adjuvant Colon Cancer. ECOG: Eastern Co-operative Group. NCCTG: North Central Cancer Treatment Group. FOLFOX: Oxaliplatin/bolus and continuous infusion fluorouracil/leucovorin. XELOX: Oxaliplatin/capecitabine.

Volume 17 | No. 9 | September 2006

doi:10.1093/annonc/mdl029 | 1357

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

Most clinical trials stipulated that adjuvant treatment to be started within 6–7 weeks of surgery. However, in real life situations there are often delays in commencing treatment. It is unclear whether delay in starting adjuvant chemotherapy would be detrimental to patients’ survival. In a Swedish adjuvant therapy study in stage III colon cancer, patients who started treatment more than 8 weeks after surgery had worse survival compared to those who started within 8 weeks, and indeed survival was the same to those on observation alone [52]. Similarly, in the SAFFA study, significantly inferior survival was found for patients starting adjuvant therapy beyond 8 weeks after surgery [32].

term effects of these agents on cancer survivors and the optimal duration of these agents would be very important issues to address, bearing in mind the costs associated with these treatments. Another important issue to address is the choice of first line regimen for recurrent or metastatic disease after FOLFOX adjuvant therapy. In breast cancer, once a patient has relapsed from an anthracycline-based adjuvant chemotherapy, a noncross resistant taxane-based regimen is usually preferred. Patients are seldom rechallenged with another anthracyclinebased chemotherapy as first line treatment for recurrent breast cancer. However, in advanced CRC, patients are only considered to be truly 5-FU refractory if they progress on or within 3 months of fluoropyrimidines-based treatment. Fluorouracil rechallenge ‡6 months after initial treatment is a reasonable treatment approach [55], considering that first line combination treatment is not always necessary in advanced CRC [40, 56]. Therefore if patients do not have any residual neuropathy and there has been >6 months of disease free interval after adjuvant FOLFOX therapy, the choice between oxaliplatin and irinotecan-based chemotherapy should be individually tailored taking into account previous oxaliplatin-related toxicity. However, oxaliplatin-based therapy may be preferable if liver or pulmonary metastectomy is a primary treatment aim. Ultimately, only prospective RCTs can provide the answers, but focus should be on the partnership between cytotoxic and targeted therapy in this scenario rather than choosing between oxaliplatin or irinotecan-based therapy.

review

potential conflict of interests Ian Chau has received an honorarium and consultancy fee from Sanofi-Aventis and Roche. David Cunningham has received an honorarium, consultancy fees and research support from Sanofi-Aventis, Roche, Pfizer and Merck.

references 1. Parkin DM, Bray F, Ferlay J et al. Global cancer statistics, 2002. CA Cancer J Clin 2005; 55: 74–108. 2. Martenson JA, Jr., Willett CG, Sargent DJ et al. Phase III study of adjuvant chemotherapy and radiation therapy compared with chemotherapy alone in the surgical adjuvant treatment of colon cancer: results of intergroup protocol 0130. J Clin Oncol 2004; 22: 3277–3283. 3. Andre T, Boni C, Mounedji-Boudiaf L et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 2004; 350: 2343–2351. 4. Van Cutsem E, Labianca R, Hossfeld D et al. Randomized phase III trial comparing infused irinotecan/5-fluorouracil (5-FU)/folinic acid (IF) versus 5-FU/FA (F) in stage III colon cancer patients (pts). (PETACC 3). J Clin Oncol (Meeting Abstracts) 2005; 23: LBA8. 5. Wolmark N, Wieand S, Kuebler JP et al. A phase III trial comparing FULV to FULV + oxaliplatin in stage II or III carcinoma of the colon: Results of NSABP Protocol C-07. J Clin Oncol (Meeting Abstracts) 2005; 23: LBA3500. 6. Ychou M, Raoul JL, Douillard JY et al. A phase III randomized trial of LV5FU2+CPT-11 vs. LV5FU2 alone in adjuvant high risk colon cancer (FNCLCC Accord02/FFCD9802). J Clin Oncol (Meeting Abstracts) 2005; 23: 3502 7. Romond EH, Perez EA, Bryant J et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353: 1673–1684. 8. Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005; 353: 1659–1672.

1358 | Chau & Cunningham

9. Thurlimann B, Keshaviah A, Coates AS et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353: 2747–2757. 10. Coombes RC, Hall E, Gibson LJ et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350: 1081–1092. 11. Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349: 1793–1802. 12. Baum M, Budzar AU, Cuzick J et al. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 2002; 359: 2131–2139. 13. Winton T, Livingston R, Johnson D et al. Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 2005; 352: 2589–2597. 14. Arriagada R, Bergman B, Dunant A et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 2004; 350: 351–360. 15. Neoptolemos JP, Stocken DD, Friess H et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350: 1200–1210. 16. Sargent DJ, Wieand HS, Haller DG et al. Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 2005; 23: 8664–8670. 17. Howell A, Cuzick J, Baum M et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 2005; 365: 60–62. 18. Chua YJ, Sargent D, Cunningham D. Definition of disease-free survival: this is my truth-show me yours. Ann Oncol 2005; 16: 1719–1721. 19. Buyse M, Zeleniuch-Jacquotte A, Chalmers TC. Adjuvant therapy of colorectal cancer. Why we still don’t know. JAMA 1988; 259: 3571–3578. 20. Wolmark N, Fisher B, Rockette H et al. Postoperative adjuvant chemotherapy or BCG for colon cancer: results from NSABP protocol C-01. J Natl Cancer Inst 1988; 80: 30–36. 21. Smith RE, Colangelo L, Wieand HS et al. Randomized trial of adjuvant therapy in colon carcinoma: 10-year results of NSABP protocol C-01. J Natl Cancer Inst 2004; 96: 1128–1132. 22. Haller DG, Catalano PJ, Macdonald JS et al. Phase III Study of Fluorouracil, Leucovorin, and Levamisole in High-Risk Stage II and III Colon Cancer: Final Report of Intergroup 0089. J Clin Oncol 2005; 23: 8671–8678. 23. Di Costanzo F, Sobrero A, Gasperoni S et al. Adjuvant chemotherapy in the treatment of colon cancer: randomized multicenter trial of the Italian National Intergroup of Adjuvant Chemotherapy in Colon Cancer (INTACC). Ann Oncol 2003; 14: 1365–1372. 24. Link KH, Kornmann M, Staib L et al. Increase of survival benefit in advanced resectable colon cancer by extent of adjuvant treatment: results of a randomized trial comparing modulation of 5-FU + levamisole with folinic acid or with interferon-alpha. Ann Surg 2005; 242: 178–187. 25. Porschen R, Bermann A, Loffler T et al. Fluorouracil plus leucovorin as effective adjuvant chemotherapy in curatively resected stage III colon cancer: results of the trial adjCCA-01. J Clin Oncol 2001; 19: 1787–1794. 26. QUASAR Collaborative Group. Comparison of flourouracil with additional levamisole, higher-dose folinic acid, or both, as adjuvant chemotherapy for colorectal cancer: a randomised trial. Lancet 2000; 355: 1588–1596. 27. Schippinger W, Jagoditsch M, Sorre C et al. A prospective randomised trial to study the role of levamisole and interferon alfa in an adjuvant therapy with 5-FU for stage III colon cancer. Br J Cancer 2005; 92: 1655–1662. 28. Sobrero A, Frassineti G, Falcone A et al. Adjuvant sequential methotrexate –> 5fluorouracil vs 5-fluorouracil plus leucovorin in radically resected stage III and high-risk stage II colon cancer. Br J Cancer 2005; 92: 24–29. 29. Taal BG, Van Tinteren H, Zoetmulder FA. Adjuvant 5FU plus levamisole in colonic or rectal cancer: improved survival in stage II and III. Br J Cancer 2001; 85: 1437–1443.

Volume 17 | No. 9 | September 2006

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

fluoropyrimidines had demonstrated equivalent efficacy to bolus 5-FU/LV as adjuvant treatment—its combination with oxaliplatin and monoclonal antibodies is currently being evaluated in randomised phase III studies. In terms of safety, a continuous infusion schedule has a more favourable safety profile than bolus schedule and capecitabine is similar to continuous infusion 5-FU/LV. Both continuous infusion 5-FU/ LV and capecitabine represent more optimal partners to oxaliplatin and irinotecan. However, the addition of oxaliplatin and irinotecan to fluoropyrimidines increases the toxicity and, in the case of IFL, compromised the efficacy due to excessive treatment-related deaths. For stage II colon cancer, adjuvant therapy remains an area of controversy. In medically fit patients, chemotherapy with 5-FU/LV can be offered, especially in those with high-risk characteristics such as intestinal perforation, T4 tumours, poorly differentiated tumours, inadequately pathologically examined (<13) lymph node and extramural venous or lymphatic invasion. For average risk patients, a discussion of the small benefit of chemotherapy should be made and the patient should be involved in the decision-making process. Oxaliplatin-based combination chemotherapy may be over-treatment in stage II colon cancer, as neurotoxicity can be prolonged and disabling. Six months of adjuvant treatment is the current standard duration and treatment should start within 8 weeks post surgery. However, 3 months of treatment may be enough and should be explored further.

Annals of Oncology

review

Annals of Oncology

Volume 17 | No. 9 | September 2006

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

as adjuvant chemotherapy for colorectal cancer. Eur J Cancer 2005; 41: 1551–1559. Yothers G, Kopec JA, Ganz PA et al. A comparison of quality of life in colon cancer patients receiving adjuvant uracil/ftorafur + leucovorin versus 5fluorouracil + leucovorin in NSABP C-06. J Clin Oncol (Meeting Abstracts) 2005; 23: 8080. Schmoll HJ, Tabernero J, Nowacki M et al. Early safety findings from a phase III trial of capecitabine plus oxaliplatin (XELOX) vs. bolus 5-FU/LV as adjuvant therapy for patients (pts) with stage III colon cancer. J Clin Oncol (Meeting Abstracts) 2005; 23: 3523. Benson AB, III, Schrag D, Somerfield MR et al. American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 2004; 22: 3408–3419. Swanson RS, Compton CC, Stewart AK et al. The prognosis of T3N0 colon cancer is dependent on the number of lymph nodes examined. Ann Surg Oncol 2003; 10: 65–71. Figueredo A, Charette ML, Maroun J et al. Adjuvant therapy for stage II colon cancer: a systematic review from the Cancer Care Ontario Program in evidencebased care’s gastrointestinal cancer disease site group. J Clin Oncol 2004; 22: 3395–3407. Gray RG, Barnwell J, Hills R et al. QUASAR: A randomized study of adjuvant chemotherapy (CT) vs observation including 3238 colorectal cancer patients. J Clin Oncol (Meeting Abstracts) 2004; 22: 3501. Moertel CG, Fleming TR, Macdonald JS et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 1990; 322: 352–358. O’Connell MJ, Laurie JA, Kahn M et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998; 16: 295–300. Glimelius B, Cedermark B, Dahl O et al. Adjuvant chemotherapy in colorectal cancer: joint analyses of randomised trials by the Nordic Gastrointestinal Tumour Adjuvant Therapy Group. Eur J Cancer 2003; 1: S318. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337–345. Hurwitz H, Fehrenbacher L, Novotny W et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004; 350: 2335–2342. Yeoh C, Chau I, Cunningham D et al. Impact of 5-fluorouracil rechallenge on subsequent response and survival in advanced colorectal cancer: pooled analysis from three consecutive randomized controlled trials. Clin Colorectal Cancer 2003; 3: 102–107. Seymour MT, UK NCRI Colorectal Clinical Studies Group. Fluorouracil, oxaliplatin and CPT-11 (irinotecan), use and sequencing (MRC FOCUS): A 2135-patient randomized trial in advanced colorectal cancer (ACRC). J Clin Oncol (Meeting Abstracts) 2005; 23: 3518.

doi:10.1093/annonc/mdl029 | 1359

Downloaded from http://annonc.oxfordjournals.org/ at Karolinska Institutet University Library on June 1, 2015

30. Andre T, Colin P, Louvet C et al. Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 2003; 21: 2896–2903. 31. Andre T, Quinaux E, Louvet C et al. Updated results at 6 year of the GERCOR C96.1 phase III study comparing LV5FU2 to monthly 5FU-leucovorin (mFufol) as adjuvant treatment for Dukes B2 and C colon cancer patients. J Clin Oncol (Meeting Abstracts) 2005; 23: 3522. 32. Chau I, Norman AR, Cunningham D et al. A randomised comparison between 6 months of bolus fluorouracil/leucovorin and 12 weeks of protracted venous infusion fluorouracil as adjuvant treatment in colorectal cancer. Ann Oncol 2005; 16: 549–557. 33. Poplin EA, Benedetti JK, Estes NC et al. Phase III Southwest Oncology Group 9415/Intergroup 0153 randomized trial of fluorouracil, leucovorin, and levamisole versus fluorouracil continuous infusion and levamisole for adjuvant treatment of stage III and high-risk stage II colon cancer. J Clin Oncol 2005; 23: 1819–1825. 34. Van Cutsem E, Hoff PM, Harper P et al. Oral capecitabine vs intravenous 5fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials. Br J Cancer 2004; 90: 1190–1197. 35. Twelves C, Wong A, Nowacki MP et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005; 352: 2696–2704. 36. Wolmark N, Wieand S, Lembersky B et al. A phase III trial comparing oral UFT to FULV in stage II and III carcinoma of the colon: Results of NSABP Protocol C-06. J Clin Oncol (Meeting Abstracts) 2004; 22: 3508. 37. Sakamoto J, Ohashi Y, Hamada C et al. Efficacy of oral adjuvant therapy after resection of colorectal cancer: 5-year results from three randomized trials. J Clin Oncol 2004; 22: 484–492. 38. Saltz LB, Niedzwiecki D, Hollis D et al. Irinotecan plus fluorouracil/leucovorin (IFL) versus fluorouracil/leucovorin alone (FL) in stage III colon cancer (intergroup trial CALGB C89803). J Clin Oncol (Meeting Abstracts) 2004; 22: 3500. 39. de Gramont A, Boni C, Navarro M et al. Oxaliplatin/5FU/LV in the adjuvant treatment of stage II and stage III colon cancer: Efficacy results with a median follow-up of 4 years. J Clin Oncol (Meeting Abstracts) 2005; 23: 3501. 40. Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 2005; 23: 9441–9442. 41. Rothenberg ML, Meropol NJ, Poplin EA et al. Mortality Associated With Irinotecan Plus Bolus Fluorouracil/Leucovorin: Summary Findings of an Independent Panel. J Clin Oncol 2001; 19: 3801–3807. 42. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22: 23–30. 43. Chau I, Norman AR, Cunningham D et al. Longitudinal quality of life and quality adjusted survival in a randomised controlled trial comparing six months of bolus fluorouracil/leucovorin vs. twelve weeks of protracted venous infusion fluorouracil