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Department of Hematology and Oncology, Institut du Cancer et d'Immunogénétique (ICIG), Hôpital Paul Brousse, Assistance Publique Hôpital de Paris, Villejuif, and University Paris XI, Paris, France
Herein we present a historical review of the development of systemic chemotherapy for colorectal cancer (CRC) in the metastatic and adjuvant treatment settings. We describe the discovery of 5-fluorouracil (5-FU) by Heidelberger and colleagues in 1957, the potentiation of 5-FU cytotoxicity by the reduced folate leucovorin, and the advent of novel cytotoxic agents, including the topoisomerase I inhibitor irinotecan, the platinum-containing agent oxaliplatin, and the 5-FU prodrug capecitabine. The combination therapies, FOLFOX (5-FU/leucovorin and oxaliplatin) and FOLFIRI (5-FU/leucovorin and irinotecan), have become established as efficacious cytotoxic regimens for the treatment of metastatic CRC, resulting in overall survival times of approximately 2 years. When used as adjuvant therapy, FOLFOX also improves survival and is now the gold standard of care in this setting. Biological agents have been discovered that enhance the effect of cytotoxic therapy, including bevacizumab (a humanized monoclonal antibody that targets vascular endothelial growth factor, a central regulator of angiogenesis) and cetuximab/panitumumab (monoclonal antibodies directed against the epidermal growth factor receptor). Despite the ongoing development of novel antitumor agents and therapeutic principles as we enter the era of personalized cancer medicine, systemic chemotherapy involving infusional 5-FU/leucovorin continues to be the cornerstone of treatment for patients with CRC.
The most recent estimates of the worldwide burden of cancer (GLOBOCAN 2012) indicate that colorectal cancer (CRC) is the third most commonly diagnosed cancer (1.36 million cases; 9.7%) after lung (1.83 million; 13.0%) and breast cancer (1.68 million; 11.9%), and the fourth highest cause of cancer death (694,000 deaths; 8.5%) after lung (1.59 million; 19.4%), liver (746,000; 9.1%), and stomach cancer (723,000; 8.8%).
Despite these statistics, most patients (70%-80%) newly diagnosed with CRC have localized disease that is amenable to curative (R0) surgical resection.
Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05. A baseline from which to compare modern adjuvant trials.
which demonstrated significantly improved survival outcomes after surgery and chemotherapy compared with surgery alone (P < .0001).
The remaining 20% to 30% of newly diagnosed patients present with unresectable metastatic disease. In addition, a considerable proportion of patients (40%–50%) experience disease recurrence after surgical resection or develop metastatic disease, typically in the liver or lungs.
Patients with unresectable mCRC who receive supportive care alone have been shown to have a poor prognosis, with a median overall survival (OS) of 5 months.
Herein, we present a historical review of systemic chemotherapy in the adjuvant and metastatic settings, highlighting the key studies that have driven the development of chemotherapy for patients with CRC (Figure 1).
Figure 1Landmark Advances in the Evolution of Systemic Chemotherapy for Patients With CRC
Abbreviations: 5-FU = 5-Fluorouracil; FOLFIRI = Infusional 5-FU/LV With Irinotecan; FOLFOX = 5-FU/LV With Oxaliplatin; LV = Leucovorin; mCRC = Metastatic Colorectal Cancer; MOSAIC = Multicenter International Study of Oxaliplatin/5-FU/Leucovorin in the Adjuvant Treatment of Colon Cancer.
The German chemist Paul Ehrlich was the first person to coin the term ‘chemotherapy’ during his work on the use of chemical agents to treat infectious diseases in the early 1900s.
Charles Heidelberger and colleagues at the University of Wisconsin observed that tumor tissues preferentially used uracil for nucleic acid biosynthesis, and correctly postulated that a fluorouracil analogue would inhibit tumor cell division by blocking the conversion of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (thymidylate). Biochemical studies demonstrated that the main route of 5-FU activation proceeds via complex metabolic pathways that result in the formation of 5-fluorodeoxyuridine monophosphate (FdUMP), a potent inhibitor of thymidylate synthase (Figure 2).
The level of inhibition of thymidylate synthase achieved with FdUMP in patient tumors was shown to correlate with the clinical response to 5-FU treatment.
Studies of the molecular mechanism of thymidylate formation identified the transient formation of a ternary complex consisting of the substrate dUMP, the folate cofactor 5,10-methylenetetrahydrofolate (MTHF), and thymidylate synthase.
The next key advance in the development of 5-FU-based chemotherapy was the finding that inhibition of thymidylate synthase by 5-FU could be potentiated by increased intracellular levels of reduced folates.
At this juncture, it is interesting to note that the antitumor activity of folic acid analogues, including aminopterin and amethopterin (methotrexate), was first demonstrated in 1948 by Sidney Farber and Louis Diamond in children with leukemia.
The potentiation of 5-FU activity was shown to be mediated by the formation of a stable ternary complex consisting of FdUMP, MTHF, and thymidylate synthase.
Polyglutamate derivatives of MTHF were shown to substantially increase the efficiency of binding of FdUMP to thymidylate synthase compared with monoglutamate derivatives, in a human colon adenocarcinoma xenograft
Effect of polyglutamylation of 5,10-methylenetetrahydrofolate on the binding of 5-fluoro-2'-deoxyuridylate to thymidylate synthase purified from a human colon adenocarcinoma xenograft.
reported that 20 μM leucovorin enhanced 5-FU cytotoxicity approximately fivefold in cultured leukemia cells. Following on from this study, the antitumor activity of 5-FU/leucovorin and 5-FU/methyl THF was established in a number of studies of tumor cell lines, including those of human origin.
In a pooled analysis of 21 phase II studies of patients with advanced CRC, conducted by Poon et al in 1989, the response rate (RR) of tumors to 5-FU/leucovorin was reported to be 23%.
Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.
Machover et al administered 200 mg/m2 leucovorin using intravenous (I.V.) bolus and 370 mg/m2 5-FU in a 15-minute I.V. infusion daily for 5 days to patients with gastric cancer and mCRC, with courses repeated at 28-day intervals.
Madajewicz et al administered 500 mg/m2 leucovorin as a 2-hour infusion to patients with mCRC, with escalating bolus doses of 5-FU up to a maximum of 750 mg/m2 given 1 hour after the leucovorin infusion; this schedule was repeated weekly for 6 weeks, followed by a 2-week rest period.
Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.
showed that there was only a trend toward increased OS with I.V. bolus 5-FU/leucovorin, but RR and progression-free survival (PFS) were significantly increased, compared with 5-FU alone in patients with mCRC. Median OS was 12.2 months for patients who received 5-FU with high-dose (200 mg/m2) leucovorin and 12.0 months for those receiving 5-FU with low-dose (20 mg/m2) leucovorin, compared with 7.7 months for 5-FU alone (P = .05, both leucovorin doses). RRs for 5-FU with high-dose or low-dose leucovorin were 26% (P = .04) and 37% (P < .001), respectively, compared with 10% for 5-FU alone. The time to progression (TTP) rates for 5-FU with high-dose or low-dose leucovorin were also significantly improved compared with 5-FU alone (P = .015 and P = .007, respectively).
Another important study, carried out by Petrelli et al,
A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma.
demonstrated that the RR for 5-FU with high-dose leucovorin (48%) was significantly greater than that with 5-FU alone (11%) or 5-FU with methotrexate (5%; overall P = .0009). In a subsequent phase III study that compared 5-FU with high-dose or low-dose leucovorin with 5-FU alone, Petrelli et al
The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group.
reported RRs of 12% for 5-FU alone, 30% for 5-FU with high-dose leucovorin (P < .01), and 18.8% for 5-FU with low-dose leucovorin (P = not significant [NS]).
involving 3338 patients, reported a twofold increase in RR with 5-FU/leucovorin (21%) compared with 5-FU alone (11%; P < .0001) and a small but statistically significant OS benefit for 5-FU/leucovorin over 5-FU alone (11.7 vs. 10.5 months, respectively; P = .004).
Key developments in the early 2000s included the introduction of the topoisomerase I inhibitor irinotecan and the platinum-containing agent oxaliplatin as components of cytotoxic combination therapy for mCRC. Irinotecan was first discovered and synthesized in Japan by Yakult Honsha Ltd in 1983.
Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors.
It is a prodrug analogue (7-ethyl-10-piperidino-piperidino-carbonyloxy derivative) of the alkaloid camptothecin that is converted to the active metabolite SN-38 by liver carboxylesterases.
Oxaliplatin was also discovered in Japan at Nagoya City University by Yoshinori Kidani in 1976 by testing the antitumor activity of various platinum (II) complexes of 1,2-diaminocyclohexane isomers.
found that treatment with bolus 5-FU/leucovorin and irinotecan (IFL) resulted in significantly longer PFS (7.0 vs. 4.3 months; P = .004), greater RR (39% vs. 21%; P < .001), and longer OS (14.8 vs. 12.6 months; P = .04) than 5-FU/leucovorin alone as first-line therapy for patients with mCRC. In the Intergroup trial N9741,
A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.
the efficacy of FOLFOX (5-FU/leucovorin with oxaliplatin) was significantly better than that of IFL with regard to OS (19.5 vs. 15.0 months, respectively; P < .0001), TTP (8.7 vs. 6.9 months; P = .0014), and RR (45% vs. 31%; P = .002). The FOLFOX regimen was also associated with significantly lower rates of severe nausea, vomiting, diarrhea, and febrile neutropenia than was the IFL regimen (all P < .001). The unfavorable toxicity profile of the IFL regimen led to the development of a regimen comprised of infusional IFL (FOLFIRI). The GOIM (Gruppo Oncologico Dell'Italia Meridionale) study
Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale.
each showed similar efficacy for the FOLFIRI and FOLFOX regimens. The GOIM study reported RRs of 31% and 34% (P = NS), OS rates of 14 and 15 months (P = NS), and median TTPs of 7 months (both, P = NS) for FOLFIRI and FOLFOX, respectively. The GERCOR study demonstrated OS rates of 21.5 months in patients allocated to FOLFIRI then FOLFOX, and 20.6 months in those treated with FOLFOX then FOLFIRI (P = NS). As first-line therapy, FOLFIRI achieved an RR of 56% and PFS of 8.5 months, and for FOLFOX the RR was 54% (P = NS) and the PFS was 8.0 months (P = NS).
The combination of infusional 5-FU/leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) was compared with FOLFIRI in 2 randomized, phase III trials. Souglakos et al
FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG).
Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.
showed a significantly greater RR for patients treated with FOLFOXIRI than for those treated with a modified FOLFIRI regimen containing 400 to 600 mg/m2 5-FU (60% vs. 34%, respectively; P < .0001). PFS (9.8 vs. 6.9 months; P = .0006) and OS (22.6 vs. 16.7 months; P = .032) were also significantly improved in the FOLFOXIRI arm compared with in the modified FOLFIRI arm, but at the cost of a significant (P < .001) increase in toxicity, in terms of increased grades of peripheral neurotoxicity (P < .001) and neutropenia (P < .001).
The idea of targeting angiogenesis as an anticancer therapy was first proposed by Judah Folkman and colleagues in 1971.
evaluated the humanized monoclonal antibody bevacizumab, which inhibits the action of vascular endothelial growth factor. In this trial, patients were randomized to IFL with bevacizumab or IFL alone. The addition of bevacizumab significantly improved OS (20.3 vs. 15.6 months, respectively; P < .001), PFS (10.6 vs. 6.2 months; P < .001), and RR (44.8% vs. 34.8%; P = .004) compared with IFL alone. In another key trial, the Eastern Cooperative Oncology Group 3200 study
Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.
enrolled patients previously treated with IFL and found that OS (12.9 vs. 10.8 months, respectively; P < .0011), PFS (7.3 vs. 4.7 months; P < .0001), and RR (22.7% vs. 8.6%; P < .0001) were all significantly improved with bevacizumab and FOLFOX treatment compared with FOLFOX alone.
In 1983 and 1984, John Mendelsohn and Gordon Sato and colleagues proposed epidermal growth factor receptor (EGFR) as a novel target for cancer therapy, based on observations that EGFR was frequently overexpressed in epithelial tumors and that monoclonal antibodies directed against EGFR inhibited the growth of cancer cells.
Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody.
Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity.
The anti-EGFR monoclonal antibodies cetuximab and panitumumab were the first therapeutic agents targeted at a specific molecular pathology: EGFR-positive tumors expressing wild type Kirsten rat sarcoma viral oncogene homolog (KRAS).
The efficacy of cetuximab in the treatment of patients with mCRC was evaluated in the CRYSTAL (Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer) study,
Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.
in which patients with EGFR-positive tumors were randomized to receive FOLFIRI alone or FOLFIRI with cetuximab. FOLFIRI with cetuximab marginally improved PFS compared with FOLFIRI alone (8.9 vs. 8.0 months, respectively; P = .048), but there was no significant difference in OS between the 2 treatments (19.9 vs. 18.6 months; P = NS). In a subset analysis of patients with wild type KRAS (63%), FOLFIRI with cetuximab significantly improved OS (23.5 vs. 20.0 months; P = .01), PFS (9.9 vs. 8.4 months; P = .001), and RR (57.3% vs. 39.7%; P = .001) compared with FOLFIRI alone. No significant difference in efficacy was evident in patients with mutant KRAS.
In the PRIME (Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy) trial,
Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.
patients were randomized to treatment with FOLFOX with or without panitumumab, regardless of EGFR or KRAS status. In the subset with wild type KRAS (60% of the study population), panitumumab with FOLFOX significantly improved PFS compared with FOLFOX alone (9.6 vs. 8.0 months, respectively; P = .02), but did not lead to a significant improvement in OS (23.9 vs. 19.7 months; P = NS).
The UK Medical Research Council (MRC) Continuous Chemotherapy Plus Cetuximab or Intermittent Chemotherapy trial was a 3-arm randomized controlled trial in which patients were randomized to receive continuous FOLFOX, continuous FOLFOX with cetuximab, or intermittent FOLFOX alone. Maughan et al
Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.
reported the results for 2 of these regimens: FOLFOX with cetuximab increased RR compared with FOLFOX alone (59% vs. 50%, respectively; P = .015), but there was no evidence of improved PFS or OS in patients with wild type KRAS.
Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study.
were randomized to receive Nordic FLOX (bolus FOLFOX), Nordic FLOX with cetuximab, or intermittent Nordic FLOX with cetuximab. OS, PFS, and RR were similar in the 3 treatment arms (OS: 20.4, 19.7, and 20.3 months, respectively [P = NS]; PFS: 7.9, 8.3, and 7.3 months [P = NS]; and RR: 41%, 49%, and 47% [P = NS]). In patients with wild type KRAS, cetuximab did not provide any additional benefit compared with Nordic FLOX alone for PFS, OS, or RR.
Findings of several key studies presented at the 2013 Annual Meeting of the American Society of Clinical Oncology (ASCO) provided important updates to the current picture. In the FIRE-3 (FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer) trial,
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.
patients with wild type KRAS were randomized to receive first-line FOLFIRI with cetuximab or FOLFIRI with bevacizumab. The primary end points of overall RR (62% vs. 58%, respectively) and PFS (10.0 vs. 10.3 months, respectively) were not significantly different in the 2 treatments arms. However, FOLFIRI with cetuximab provided a statistically significant improvement in OS compared with FOLFIRI with bevacizumab (28.7 vs. 25.0 months, respectively; P = .017). A further important contribution to the ongoing first-line therapy debate in mCRC was the TRIBE (Combination Chemotherapy and Bevacizumab as First-line Therapy in Treating Patients with Metastatic Colorectal Cancer) trial.
FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): results of the phase III TRIBE trial by GONO group (abstract 3505).
This trial, which evaluated FOLFOXIRI and bevacizumab versus FOLFIRI and bevacizumab, showed a significant difference in the primary end point of PFS (12.1 vs. 9.7 months, respectively; P = .006). The phase II PEAK (Panitumumab Efficacy in Combination with mFOLFOX6 Against Bevacizumab plus mFOLFOX6 in mCRC Subjects with Wild-Type KRAS Tumors) trial
Analysis of KRAS/NRAS mutations in PEAK: a randomized study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) (abstract 3631).
randomized patients with wild type rat sarcoma (KRAS or neuroblastoma rat sarcoma) to first-line panitumumab with FOLFOX or bevacizumab with FOLFOX. PFS for panitumumab with FOLFOX was 13.1 months, compared with 9.5 months for bevacizumab with FOLFOX (P = .02). OS for the panitumumab arm was not reached at the time of reporting, but was 29 months for the bevacizumab arm. At ASCO 2012, PEAK data were reported, which suggested that the panitumumab regimen had an adverse effect on PFS in patients with mutated compared with wild type KRAS, although the effect was not significant (15.5 vs. 19.3 months, respectively; P = NS).
PEAK (study 20070509): a randomized phase II study of mFOLFOX6 with either panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) in patients (pts) with unresectable wild-type (WT) KRAS metastatic colorectal cancer (mCRC) (abstract 446).
Although not validated, the PEAK results suggest that panitumumab should not be used for the treatment of mCRC in patients with KRAS mutations or in whom the KRAS status is unknown.
Orally administered 5-FU prodrugs were developed to provide a convenient alternative to treatment regimens requiring I.V. infusion of 5-FU. An example of such an oral regimen is the combination of uracil and the 5-FU prodrug tegafur in a 4:1 molar ratio (UFT). Uracil competitively inhibits dihydropyrimidine dehydrogenase, the main catabolic enzyme of 5-FU (Figure 2). In a meta-analysis of 5 randomized controlled trials that compared UFT/leucovorin with bolus 5-FU/leucovorin, Bin et al
Oral uracil-tegafur plus leucovorin vs fluorouracil bolus plus leucovorin for advanced colorectal cancer: a meta-analysis of five randomized controlled trials.
reported that there were no significant differences in OS and RR between the 2 regimens; however, UFT/leucovorin had a significantly lower toxicity rate than bolus 5-FU/leucovorin (P < .001 for stomatitis/mucositis, Grade 1-4 leukopenia, febrile neutropenia, and infection). These findings are consistent with a pooled efficacy analysis from 2 phase III studies that compared capecitabine (another oral 5-FU prodrug) with bolus 5-FU/leucovorin.
Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials.
A statistically significant difference in RR was reported for capecitabine compared with 5-FU and leucovorin (26% vs. 17%, respectively; P < .0002), whereas OS (12.9 vs. 12.8 months; P = NS) and TTP (4.6 vs. 4.7 months; P = NS) were equivalent in the 2 treatment groups. In Table 1 the findings of the key mCRC studies described in this section are summarized.
Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.
A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma.
The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group.
A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.
Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale.
FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG).
Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.
Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.
Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.
Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.
Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.
Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study.
Figure 3 shows the temporal trend of OS in these studies. It can be seen that median OS increased sharply from 12.0 months in the early studies of Petrelli et al
A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma.
Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.
Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale.
A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma.
The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group.
Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.
A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.
Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale.
FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG).
Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.
Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.
Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.
To investigate the efficacy of cetuximab with FOLFIRI versus FOLFIRI alone; and the association between tumor KRAS mutation status and clinical response to cetuximab
1198
OS: 19.9 versus 18.6 months (P = NS) PFS: 8.9 versus 8.0 months (P = .048). In patients with wild type KRAS (63%), OS: 23.5 versus 20.0 months (P = .01) PFS: 9.9 versus 8.4 months (P = .001) RR: 57.3% versus 39.7% (P = .001) No significant difference in efficacy was evident in patients with mutant KRAS
Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.
Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.
Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study.
Figure 3Temporal Trend of Median Overall (OS) Survival in Key Metastatic Colorectal Cancer Clinical Trials. The OS Values Shown for Each Study Represent the Treatment Arm With the Longest Median Survival
Abbreviations: AFV = Avastin/Fluorouracil; COIN = Continuous Chemotherapy With Cetuximab or Intermittent Chemotherapy; 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; PRIME = Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy.
In the 1970s and 1980s, the antihelminthic drug levamisole attracted interest as a possible chemotherapeutic agent because of its putative immunomodulatory activity.
In 1989, the North Central Cancer Treatment Group (NCCTG) reported that treatment with levamisole with 5-FU led to a significant reduction in cancer recurrence (P = .003) and a significant increase in OS (P = .03) when compared with no adjuvant therapy.
Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic.
published the results of their seminal study of the efficacy of 5-FU with levamisole versus no adjuvant therapy in patients with stage II or III CRC. 5-FU with levamisole reduced the risk of cancer recurrence by 41% (P < .0001) and the overall death rate by 33% (P = .006) compared with observation alone. Interestingly, treatment with levamisole alone had no effect. These findings led to the acceptance of 5-FU with levamisole as the standard adjuvant therapy in the 1990s.
The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03.
reported a 3-year disease-free survival (DFS) rate of 73% for patients receiving 5-FU/leucovorin, compared with a rate of 64% for those who received a combination of the alkylating nitrosourea lomustine, the alkaloid vincristine, and 5-FU (MOF; P = .0004). The IMPACT (International Multicenter Pooled Analysis of Colorectal Cancer Trials)
Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators.
pooled data from 3 randomized trials that investigated high-dose 5-FU/leucovorin compared with no adjuvant therapy. 5-FU/leucovorin reduced mortality by 22% (P = .029) and CRC events by 35% (P < .0001) compared with no adjuvant therapy.
A number of randomized trials evaluated the efficacy and safety of the most commonly used 5-FU/leucovorin treatment regimens in the adjuvant setting. The intergroup-0089 study
set out to evaluate 4 regimens: (1) the Mayo Clinic regimen, comprised of a daily 20 mg/m2 (low-dose) I.V. bolus of leucovorin and 425 mg/m2 I.V. bolus of 5-FU for 5 consecutive days, repeated every 4 to 5 weeks; (2) the Roswell Park regimen, consisting of a weekly 500 mg/m2 (high-dose) I.V. bolus of leucovorin and 500 mg/m2 I.V. bolus of 5-FU for 6 weeks, repeated every 8 weeks; (3) low-dose 5-FU/leucovorin with levamisole; and (4) levamisole alone. The main finding was that there were no statistically significant differences among the treatment arms in DFS (9.4, 7.9, 9.2, and 7.1 months, respectively) or OS (11.5, 10.7, 11.4, and 10.3 months, respectively). The MRC study
Twelve weeks of protracted venous infusion of fluorouracil (5-FU) is as effective as 6 months of bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer.
evaluated 3 months of continuous infusion of 5-FU and a 6-month course of the Mayo Clinic regimen. There was no statistically significant difference between the 2 arms in terms of OS (87.9% vs. 83.2%, respectively; P = NS). However, patients in the Mayo Clinic regimen arm had significantly lower rates of PFS compared with those who received continuous infusion 5-FU (69% vs. 80%, respectively; P = .02). In terms of safety, the frequency of Grade 3 or 4 neutropenia, diarrhea, stomatitis, and severe alopecia were significantly lower (P < .0001), and global quality of life scores significantly better (P < .001), for patients in the continuous infusion arm compared with the Mayo Clinic regimen arm. The GERCOR C96.1 study
Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1.
Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study.
). There were no statistically significant differences between the 2 arms in terms of DFS (P = NS) or OS (P = NS), but the de Gramont regimen was significantly less toxic than the Mayo Clinic regimen (P = .001).
In the X-ACT (Xeloda in Adjuvant Colon Cancer Therapy) trial,
patients were randomized to capecitabine or the Mayo Clinic regimen. There were no statistically significant differences between the 2 arms in terms of DFS (64.2% vs. 60.6%, respectively; P = NS) or OS (81.3% and 77.6%; P = .05). However, capecitabine was associated with significantly fewer adverse events than the Mayo Clinic regimen (P < .001). The NSABP C-06 study,
Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06.
which compared tegafur with leucovorin versus the Roswell Park regimen, reported that 5-year DFS (68.2% vs. 67.0%, respectively; P = NS) and OS (78.7% vs. 78.5%; P = NS) were similar for the 2 treatments.
In 2004, an interim analysis of data from the pivotal MOSAIC (Multicenter International Study of Oxaliplatin/5-FU/Leucovorin in the Adjuvant Treatment of Colon Cancer) trial
showed that FOLFOX significantly improved 3-year DFS compared with 5-FU/leucovorin (FL regimen: 2-hour I.V. infusion of 200 mg/m2 of leucovorin followed by an I.V. bolus of 400 mg/m2 of 5-FU and then a 22-hour I.V. infusion of 600 mg/m2 of 5-FU given on 2 consecutive days every 14 days); FOLFOX, 78.2% versus FL, 72.9%, respectively (P = .002) in patients with stage III CRC, although neutropenia (Grades 3 and 4) was significantly more frequent with FOLFOX than with FL (41.1% vs. 4.7%; P < .001). The final analysis of data from MOSAIC in 2009
confirmed statistically significant improvements in DFS and OS for FOLFOX compared with FL (5-year DFS: 73.3% vs. 67.4%, respectively [P = .003] and 6-year OS: 78.5% vs. 76.0% [P = .046]). No survival benefit was detected in patients with stage II disease. The MOSAIC findings established FOLFOX as the standard adjuvant therapy for resected stage III CRC, and, in so doing, suggested that treatments with proven efficacy in the management of mCRC could also be effective in the adjuvant setting. Unfortunately, negative results from a number of large multicenter trials have shown these hopes to be unfounded.
The PETACC (Pan-European Trial in Adjuvant Colorectal Cancer)-3
Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3.
compared FOLFIRI and 5-FU/leucovorin (de Gramont regimen) in patients with stage III disease. FOLFIRI did not produce significant improvements compared with 5-FU/leucovorin in either DFS (56.7% vs. 54.3%, respectively; P = NS) or OS (73.6% vs. 71.3%; P = NS). These findings corroborated those of the Cancer and Leukemia Group B (CALGB) 89803
Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803.
trials. The CALGB study reported that there was no significant difference in 3-year DFS, the primary end point of the trial, between 5-FU/leucovorin and IFL (60% vs. 63%, respectively; P = NS). The main ACCORD02 findings were that 5-year OS rates for 5-FU/leucovorin and FOLFIRI were 67% and 61%, respectively (P = NS), and 3-year DFS rates were 60% and 51% (P = NS).
Much effort has been expended in investigating the efficacy of bevacizumab and cetuximab in the adjuvant setting. In the NSABP C-08 trial,
carried out in patients with stage II or III CRC, treatment with FOLFOX with bevacizumab showed no significant improvement in 3-year DFS compared with FOLFOX alone (77.4% vs. 75.5%, respectively; P = NS). In the NCCTG/Intergroup N0147 trial,
Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.
patients with resected stage III CRC and wild type KRAS were randomly assigned to receive mFOLFOX6 (modified FOLFOX) with cetuximab or mFOLFOX6 alone. The trial was terminated when the prespecified interim analysis demonstrated that there was no benefit in terms of the primary end point of 3-year DFS from the addition of cetuximab to mFOLFOX6 (74.6% with mFOLFOX6 alone vs. 71.5% with mFOLFOX6 with cetuximab; P = NS). In Table 2 the findings of the key adjuvant studies described in this section are summarized.
Table 2Key Clinical Studies in the Development of Adjuvant Therapy for Patients With CRC
The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03.
Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators.
Pooled analysis of 3 randomized trials to investigate the efficacy of high-dose 5-FU/LV versus no adjuvant therapy in patients with stage II or III CRC
1493
3-Year OS: 83% versus 78% Overall death rate: −22% (P = .029) CRC events: −35% (P < .0001)
To assess the relative efficacy of 5-FU/LV (Mayo Clinic regimen), 5-FU/LV (Roswell Park regimen), Mayo Clinic regimen with levamisole, and 5-FU with levamisole in patients with stage II or III CRC
Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06.
Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1.
Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3.
Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.
To assess the benefit of cetuximab with mFOLFOX6 versus mFOLFOX6 in wild type KRAS patients with stage III CRC
2686
3-Year OS: 87% versus 86% (P = NS) 3-Year DFS: 75% versus 72% (P = NS) (prespecified interim analysis)
Abbreviations: CRC = colorectal cancer; DFS = disease-free survival; FOLFIRI = infusional 5-FU/LV with irinotecan; FOLFOX = 5-FU/LV with oxaliplatin; 5-FU = 5-fluorouracil; GERCOR = Groupe Coopérateur Multidisciplinaire en Oncologie; IMPACT = International Multicentre Pooled Analysis of Colorectal Cancer Trials; INT = intergroup; KRAS = Kirsten rat sarcoma viral oncogene homolog; LV = leucovorin; mFOLFOX6 = modified FOLFOX; MOF = 5-FU with lomustine and vincristine; MOSAIC = Multicenter International Study of Oxaliplatin/5-FU/Leucovorin in the Adjuvant Treatment of Colon Cancer; NCCTG = North Central Cancer Treatment Group; NS = nonsignificant; NSABP = National Surgical Adjuvant Breast and Bowel Project; OS = overall survival; PETACC = Pan-European Trial in Adjuvant Colorectal Cancer; X-ACT = Xeloda in Adjuvant Colon Cancer Therapy.
The evolution of chemotherapy for patients with CRC has involved a series of landmark advances, including the discovery of 5-FU, the identification of the reduced folate leucovorin as a clinical potentiator of 5-FU cytotoxicity, and the advent of novel cytotoxic and biological agents. As we move into the era of personalized cancer medicine, systemic chemotherapy involving infusional 5-FU/leucovorin remains the cornerstone of treatment for patients with CRC, but there is a need for empirical studies to explore how current treatment regimens can be optimized for individual patients.
Disclosure
Isofol Medical AB, Gothenburg, Sweden, is currently evaluating a reduced folate (Modufolin) together with 5-FU or methotrexate as a treatment for CRC in clinical trials. Bengt Gustavsson is a director of Isofol Medical AB. Fernando Gibson is an employee of PharmaGenesis London, which received payment from Isofol Medical AB for this work. The remaining authors have stated that they have no conflicts of interest.
References
Ferlay J.
Soerjomataram I.
Ervik M.
et al.
GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11.
International Agency for Research on Cancer,
Lyon, France2013
Long-term survival results of surgery alone versus surgery plus 5-fluorouracil and leucovorin for stage II and stage III colon cancer: pooled analysis of NSABP C-01 through C-05. A baseline from which to compare modern adjuvant trials.
Effect of polyglutamylation of 5,10-methylenetetrahydrofolate on the binding of 5-fluoro-2'-deoxyuridylate to thymidylate synthase purified from a human colon adenocarcinoma xenograft.
Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.
A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma.
The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. Gastrointestinal Tumor Study Group.
Antitumor activity of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptothecin, a novel water-soluble derivative of camptothecin, against murine tumors.
A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.
Phase III randomized trial of FOLFIRI versus FOLFOX4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell'Italia Meridionale.
FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin and irinotecan) vs FOLFIRI (folinic acid, 5-fluorouracil and irinotecan) as first-line treatment in metastatic colorectal cancer (MCC): a multicentre randomised phase III trial from the Hellenic Oncology Research Group (HORG).
Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest.
Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200.
Growth stimulation of A431 cells by epidermal growth factor: identification of high-affinity receptors for epidermal growth factor by an anti-receptor monoclonal antibody.
Monoclonal anti-epidermal growth factor receptor antibodies which are inhibitors of epidermal growth factor binding and antagonists of epidermal growth factor binding and antagonists of epidermal growth factor-stimulated tyrosine protein kinase activity.
Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status.
Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.
Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial.
Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: the NORDIC-VII study.
FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial.
FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): results of the phase III TRIBE trial by GONO group (abstract 3505).
Analysis of KRAS/NRAS mutations in PEAK: a randomized study of FOLFOX6 plus panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) (abstract 3631).
PEAK (study 20070509): a randomized phase II study of mFOLFOX6 with either panitumumab (pmab) or bevacizumab (bev) as first-line treatment (tx) in patients (pts) with unresectable wild-type (WT) KRAS metastatic colorectal cancer (mCRC) (abstract 446).
Oral uracil-tegafur plus leucovorin vs fluorouracil bolus plus leucovorin for advanced colorectal cancer: a meta-analysis of five randomized controlled trials.
Oral capecitabine vs intravenous 5-fluorouracil and leucovorin: integrated efficacy data and novel analyses from two large, randomised, phase III trials.
Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic.
The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project protocol C-03.
Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators.
Twelve weeks of protracted venous infusion of fluorouracil (5-FU) is as effective as 6 months of bolus 5-FU and folinic acid as adjuvant treatment in colorectal cancer.
Phase III study comparing a semimonthly with a monthly regimen of fluorouracil and leucovorin as adjuvant treatment for stage II and III colon cancer patients: final results of GERCOR C96.1.
Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French intergroup study.
Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06.
Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3.
Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803.
Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial.
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