For many years, the best administration schedule for FU has been debated, and many efforts have been made in order to improve the efficacy of FU. These include different ways of administration (e.g. bolus injection, PVI and a combination of bolus injection and PVI (Table 13.1)) as well as biochemical modulation of FU [5]. Traditionally FU was administered as a bolus injection; when using bolus regimens, a rapid intravenous injection produced higher response rates than short-time infusion of 15–30 min [6]. However, experimental data indicated that prolonged infusion time resulted in a longer exposure to FU, thereby increasing the cytotoxic effects [7, 8]. PVI has been tested in mCRC without any final conclusion; however, a meta-analysis demonstrated that PVI increased response rates (22 % vs. 14 %) and prolonged median overall survival (OS) marginally [9]. Preclinical studies showed that folinic acid (FA or leucovorin) added to FU resulted in a more stable binding to TS and improved growth inhibition in cell lines [10], which in the clinical setting was translated into a significantly improved efficacy in terms of increased response rate (from 11 to 23 %) and OS (from 10.5 to 11.7 months) [11, 12]. Therefore, FU, when given as intravenous infusion, should always be administered in combination with Lv.
Table 13.1
Most important FU/FA regimens used in patients with colorectal cancer
Regimen | Doses of 5-flourouracil | Doses of folinic acid | Cycles |
|---|---|---|---|
De Gramont | 400 mg/m2 bolus (2 h) followed by 600 mg/m2 infusion days 1–2 | 200 mg/m2 days 1–2 (2 h inf.) | 2 weeks |
Mayo | 425 mg/m2 bolus days 1–5 | 20 mg/m2 bolus days 1–5 | 4 weeks |
AIO | 2,600 mg/m2 (24 h inf.) | 500 mg/m2 (24 h inf.) | Weekly |
Roswell Park | 600 mg/m2 bolus | 500 mg/m2 bolus | Weekly |
Nordic | 500 mg/m2 bolus (3 min) days 1–2 | 60 mg/m2 days 1–2 | 2 weeks |
FU is catabolised primarily in the liver by dihydropyrimidine dehydrogenase (DPD) (Fig. 13.1), which is the rate-limiting enzyme in the catabolism [6]. However, DPD is also found in high concentrations in the gastrointestinal (GI) tract making oral administration of FU impossible.
Capecitabine is an oral prodrug of FU, which is absorbed directly from the GI tract. After absorption, capecitabine is activated to FU by three enzymatic steps (Fig. 13.1). The last step is catalysed by thymidine phosphorylase (TP), which has been shown to have a higher activity in GI cancer tissue compared to the surrounding normal tissue [13, 14] indicating a preferential activation of capecitabine in tumour tissue. This has been confirmed by the finding of higher concentration of FU in tumour compared to normal tissue after administration of capecitabine [15].
As described, the efficacy of FU is improved by modulation with FA, so naturally it has also been tested whether FA modulation of capecitabine would also improve efficacy. This was investigated in a small randomised phase II study [16], where three different regimens were tested – a continuous regimen (capecitabine 1,331 mg/m2 days 1–21), an intermittent regimen (capecitabine 2,510 mg/m2 days 1–14 every 3 weeks) and an intermittent regimen in combination with FA (capecitabine 1,657 mg/m2 and oral FA 60 mg, days 1–14 every 3 weeks). The addition of FA did not improve efficacy but increased toxicity. This resulted in the establishment of a regimen with capecitabine as single agent 2,500 mg/m2/day in 14 days followed by 1 week rest.
Capecitabine as single agent has been compared to bolus FU/FA in two randomised phase III trials. Both studies demonstrated that capecitabine was as efficient as bolus FU/FA [17, 18].
A second available oral fluoropyrimidine is UFT, which is a combination of uracil and Ftorafur, a prodrug of FU. Uracil reversibly inhibits DPD, thereby increasing the bioavailability of FU [3]. In contrast to capecitabine, UFT is most often combined with FA. UFT/FA had equivalent efficacy and was safer than bolus administration of FU/FA [19, 20]. In recent years, UFT/FA is seldom used in Europe and the USA, but UFT with or without FA or the related drug S1 is predominantly used and investigated in Japan.
Patient Preference
An obvious question is if the patients prefer oral or intravenous therapy. When chemo-naive patients were asked before they have received any treatment, the majority of patients would prefer oral therapy [21], and these results were confirmed in a randomised crossover trial [22]. However, the Mayo regimen is probably the most toxic FU regimen, and consequently side effects are not comparable to side effects of the low-toxic UFT.
Oxaliplatin
Oxaliplatin is a third-generation platinum compound, which is rapidly activated by nonenzymatic hydrolysis to form platinum derivates and oxalate. Newer studies suggest that not only the platinum derivates but also the intact oxaliplatin may exert cytotoxic effects [25]. The cytotoxicity of oxaliplatin arises from DNA damage by several mechanisms as DNA adducts formation, inter- and intra-strand DNA cross-link and DNA protein cross-links [26]. In preclinical studies oxaliplatin as single agent has been shown to have antitumour activity against colon cancer cell lines [27], and adding FU/FA to oxaliplatin has been shown to result in a synergistic cytotoxicity. A clinical study confirmed this, showing that oxaliplatin as single agent only had modest activity compared to the combination of oxaliplatin and FU/FA [28], and therefore oxaliplatin should preferably be delivered in combination with a fluoropyrimidine.
The dose-limiting toxicity of oxaliplatin is neuropathy and is seen in two forms – an acute and a chronic form.
The acute form is usually transient and resolves within days and is seen in most patients treated with oxaliplatin and is characterised by cold-induced paraesthesias and dysaesthesias during or shortly after the infusion [29]. The probability and severity of acute neuropathy are claimed to be dependent on the infusion rate so that prolongation of infusion with lower peak plasma concentrations of oxaliplatin will reduce acute neuropathy.
The chronic form of oxaliplatin-induced neuropathy is characterised by sensory paraesthesias and dysaesthesias primarily in the extremities. The most important factor for chronic persistent neuropathy is still the total cumulative dose of oxaliplatin [30].
In order to reduce neuropathy, a delivery time of 2 h of oxaliplatin is recommended; however, in the daily clinical practice with limited existing resources, a lower overall treatment time may be of importance. Therefore and inspired by a small study in patients with ovarian cancer [31], delivery of oxaliplatin as a 30 min infusion has been tested in several prospective trials in order to reduce overall treatment time. A 30-min infusion of oxaliplatin is feasible and apparently does not increase the severity of sensory neuropathy [32–37]. However, an infusion time of 30 min has never been directly compared to the standard 120 min infusion in a randomised study.
Irinotecan
Irinotecan is a derivate of camptothecin and an inactive prodrug, which is converted to the active metabolite SN-38 by carboxylesterases [38, 39]. The cytotoxicity results from inhibition of the topoisomerase [40]. The active metabolite SN-38 is primarily inactivated in the liver by the UDP-glucuronosyltransferase (UGT) – primarily by the isoenzyme 1A1 [41], which also glucuronidates bilirubin. The inactivated SN-38 is mainly excreted in the bile.
The main severe adverse events of irinotecan are diarrhoea and neutropenia. The irinotecan-induced diarrhoea is seen in two forms – an early-onset and a late-onset form – and is caused by different mechanisms. The acute form is cholinergic and occurs during or shortly after administration of irinotecan and can be prevented by administration of atropine prior to treatment.
In recent years, genetic polymorphisms in UGT1A1 have been linked to the severity of adverse events of irinotecan. Patients with reduced UGT1A1 activity – primarily caused by the UGT1A1*28 polymorphism – have more severe reactions to irinotecan, and therefore in patients who are known homozygotes for the UGT1A1*28 genotype, a reduced starting dose of irinotecan is recommended [42].
Targeted Therapy
In recent years a number of biologically active substances attacking specific signalling pathways in cancer cells (targeted therapy) have been developed and included in the treatment of patients with CRC. Three monoclonal antibodies have by now been approved for therapy in mCRC.
Angiogenesis is essential in tumour development and controlled in part by the vascular endothelial growth factor (VEGF) system. VEGF-A has the greatest impact on angiogenesis, and specifically VEGF-A is inhibited by bevacizumab (Avastin®).
Cetuximab (Erbitux®) and panitumumab (Vectibix®) block the extracellular portion of the epidermal growth factor receptor (EGFR).
Adjuvant Therapy After Radical Resection for Colon Cancer
In the adjuvant situation, patients with colon and rectal cancer are treated differently. Pre- and postoperative radiotherapy and chemoradiation for rectal cancer will be discussed in Chap. 12. The scientific support for adjuvant chemotherapy in patients with rectal cancer is much less than in colon cancer, but – similar to the situation in colon cancer – adjuvant chemotherapy may be provided. However, in the metastatic situation, patients with colon and rectal cancer are treated as one group.
Summary
Adjuvant single-agent chemotherapy increases the chance of cure by absolutely 5 % in stage II and 10 % in stage III.
Stage II patients can be divided into high and low risk of recurrence, according to the presence of at least one of the following factors: lymph nodes sampling <12, poorly differentiated tumour, vascular or lymphatic or perineural invasion, obstruction or perforation or pT4 stage.
Adjuvant chemotherapy should be offered to all medically fit patients with high-risk stage II and stage III disease, should be started as early as possible (3–8 weeks after surgery) and should be given for 6 months.
Fluoropyrimidine and oxaliplatin combinations are superior compared to single-agent 5-FU in terms of DFS and OS in stage III patients.
Fluoropyrimidine and oxaliplatin combinations might be considered in high-risk stage with multiple risk factors.
The use of targeted therapy should be avoided outside clinical trials.
Since the publication of Moertel’s study in 1990 [43] demonstrating superiority in terms of disease-free survival (DFS) and OS of FU compared to surgery alone in patients with stage III colon cancer, FU has been the cornerstone in the adjuvant treatment. The efficacy of biochemically FA-modulated FU as adjuvant therapy has subsequently been confirmed in several studies [44]. Originally, adjuvant therapy was administered for 12 months, but the duration of treatment can safely be reduced to 6 months without compromising efficacy.
Oral prodrugs of FU (capecitabine and tegafur/FA) are alternatives to intravenous treatment with FU/FA as it has been demonstrated that these oral agents have at least similar efficacy compared to intravenous FU-based regimens [45, 46].
Adjuvant FU/FA for 6 months increases the chance of cure by absolutely 5 % in stage II and 10 % in stage III [44] and was therefore the golden standard until the MOSAIC study was published in 2004 [47].
The MOSAIC trial was the first study to show that addition of oxaliplatin further improved efficacy beyond FU/FA (Table 13.2). In a recent update of MOSAIC data, it was found that in patients with stage III disease, 6-year OS was increased from 68.7 to 72.9 % [48].
Table 13.2
Single-agent fluoropyrimidines versus oxaliplatin-based adjuvant chemotherapy in patients with colon cancer stage 3
Stage | 3 year DFS (%) | 5 year OS (%) | |||||
|---|---|---|---|---|---|---|---|
Fp | +oxaliplatin | Δ | Fp | +oxaliplatin | Δ | ||
MOSAIC | 3 | 65.3 | 72.2 | 6.9* | 68.7 | 72.9 | 4.2* |
C-07 | 3 | 71.5 | 76.1 | 4.6* | 78.3 | 80.3 | 2.0 |
XELOXA | 3 | 66.5 | 70.9 | 4.5* | 74.2 | 77.6 | 3.4 |
The efficacy and tolerability of oxaliplatin (Table 13.2) have since been confirmed in NSABP C-07 [49], and recently it was demonstrated that capecitabine in combination with oxaliplatin (CapOx) increased 3-year DFS [50].
As described above, adjuvant fluoropyrimidine-based chemotherapy is the standard of care in patients with radical resected stage III colon cancer, whereas it is more controversial in patients with stage II colon cancer. Only modest but definite benefits of 4–5 % benefit in 5-year OS have been demonstrated in pooled analyses and in the Quasar study [44, 51–53] in patients treated with FU-based therapy. There is no significant benefit of adding oxaliplatin in an unselected group of patients with stage II disease. However, in the MOSAIC trial, patients with high-risk stage II had a nonsignificant reduction in the risk of relapse of 26 %, but no tendency for improvement in survival.
There is a great variability in survival within patients with stage II disease [54], and probably the choice of adjuvant therapy should be individualised and based on the risk of recurrence and the expected relative reduction in recurrence (Table 13.3).
Table 13.3
TNM 7th edition – correlation with Dukes classification and 5-year survival for patients with colon cancer based on SEER data [54]
5-year survival (%) | ||||||
|---|---|---|---|---|---|---|
Stage | T | N | Dukes | % of TxNxM0 | Relative | Absolute |
I | T1–T2 | N0 | A | 21.4 | 97.1 | 76.3 |
II | T3–T4 | N0 | B | 43.9 | 84.8 | 64.7 |
IIA | T3 | N0 | 36.6 | 87.5 | 66.7 | |
IIB | T4a | N0 | 4.5 | 79.6 | 60.6 | |
IIC | T4b | N0 | 2.8 | 58.4 | 45.7 | |
III | Any T | N1–2 | C | 34.7 | 60.3 | 47.8 |
IIIA | 3.1 | 86.8 | 70.5 | |||
T1–T2 | N1a | 1.7 | 90.7 | 73.7 | ||
T1–T2 | N1b | 1.1 | 83.0 | 67.2 | ||
T1 | N2a | 0.3 | 79.0 | 64.7 | ||
IIIB | 24.1 | 65.4 | 51.6 | |||
T3 | N1a | 8.0 | 74.2 | 58.2 | ||
T4a | N1a | 1.5 | 67.6 | 52.2 | ||
T3 | N1b | 8.3 | 65.3 | 51.7 | ||
T1–T2 | N2b | 0.1 | 62.4 | 51.8 | ||
T4a | N1b | 1.3 | 54.0 | 42.1 | ||
T3 | N2a | 4.9 | 53.4 | 42.8 | ||
IIIC | 7.5 | 32.9 | 26.5 | |||
T4a | N2a | 0.9 | 40.9 | 32.5 | ||
T3 | N2b | 3.0 | 37.3 | 30.4 | ||
T4b | N1a | 0.8 | 38.5 | 30.6 | ||
T4b | N1b | 0.9 | 31.2 | 25.4 | ||
T4b | N2a | 0.7 | 23.3 | 18.3 | ||
T4a | N2b | 0.6 | 21.8 | 17.5 | ||
T4b | N2b | 0.6 | 15.7 | 12.9 | ||
Most clinical guidelines [55, 56] recommend adjuvant chemotherapy to patients with high risk of recurrence (poorly differentiated adenocarcinoma, T4 tumour, perineural/perivenous tumour growth, perforation, acute resection due to ileus or a yield of less than 12 lymph nodes). However, still additional markers to selected patients for adjuvant therapy are warranted.
The status of the DNA mismatch repair system (MMR) is suggested to be a predictor of benefit of adjuvant therapy. Approximately 15 % of sporadic colorectal cancers have defective MMR (dMMR), and these patients have a lower risk of recurrence. Several studies have reported that FU therapy alone is of no value in dMMR patients [57]. It should be considered to assess MMR status in patients considered for FU as single-agent therapy in the adjuvant setting.
So far only few data on the effect of the MMR status in patients treated with combination chemotherapy are available [58].
The recommended treatment duration of oxaliplatin based is currently 6 months, but several ongoing international phase III studies are investigating whether treatment time can be reduced to 3 months. The purpose of IDEA (International Duration Evaluation of Adjuvant Chemotherapy) is to conduct a single, pooled analysis of all studies to test whether 3 months of oxaliplatin-based adjuvant therapy is non-inferior for disease-free survival (DFS) to 6 months of the identical therapy. The IDEA pooled analysis will consist only of stage III colon patients randomised to 3 or 6 months of a FOLFOX regimen (FOLFOX4 or mFOLFOX6) or CapOx.
In contrast to the improvement in efficacy by oxaliplatin-containing combination chemotherapy regimens, it has not been possible to demonstrate that irinotecan enhances the effect of FU/FA as adjuvant therapy [59–61].
The new targeted drugs (bevacizumab and cetuximab) have also been tested in the adjuvant setting. The first study of several studies was presented in 2009. In NSABP C-08 study, patients were randomised to adjuvant FOLFOX for 6 months with or without bevacizumab and then bevacizumab as maintenance therapy for additional 6 months. Unfortunately, preliminary data could not demonstrate an improvement in DFS by addition of bevacizumab [62].
A similar phase III study (AVANT) is also evaluating the use of adjuvant bevacizumab. A press release September 2010 stated that ‘unlike the C-08 results, preliminary efficacy data from AVANT numerically favour chemotherapy alone (the control arm)’.
N0147 assessed the potential benefit of cetuximab added to FOLFOX in patients with colon cancer stage III. The primary end point was 3-year DFS. Initially patients were enrolled regardless of KRAS status, but when the impact of KRAS status on the effect of anti-EGFR antibodies in the metastatic setting was established, the study was amended to include only patients with KRAS wild-type tumours. In patients with KRAS mutations, both 3-year DFS and OS favoured FOLFOX alone [63]. It was planned to include 2.070 patients with KRAS wild type, but NO147 closed after accrual of 1.760 patients when a pre-planned interim analysis demonstrated no benefit of addition of cetuximab – in any subgroup. Cetuximab only added to toxicity [64].
Data from ongoing or completed adjuvant trials are awaited, but currently targeted therapy should be avoided outside trials.
Systemic Treatment of Metastatic Colorectal Cancer
Summary
Systemic Therapy
The optimal strategy for every patient should be discussed in a multidisciplinary team.
FU/FA single-agent treatment prolongs median OS from 6 to 12 months.
Combination chemotherapy prolongs median OS further to around 20 months for medically fit patients.
It is important that fit patients are exposed to all active drugs.
A sequential strategy (single agent immediately followed by combination upon progression) in patients with unresectable disease and no tumour-related symptoms initially seems to be a safe strategy.
Fit elderly patients tolerate combination chemotherapy and have the same benefit as younger patients.
Targeted therapy enhances efficacy of chemotherapy, but in the general population, the benefit is not as high as anticipated from the original trials.
Surgery
The optimal strategy for every patient should be discussed in a multidisciplinary team.
Surgery first or chemotherapy first in patients with synchronous metastasis should be discussed at an MDT in each case and taking into account symptoms (primary, metastasis) and performance.
Patients with resectable metastases should receive perioperative treatment for 3 months preoperatively followed by resection followed by 3 months postoperatively.
Good prognosis patients with a single small (<2 cm) metachronous liver metastasis should be considered for upfront surgery.
If preoperative chemotherapy was not administered, adjuvant chemotherapy with fluoropyrimidines with or without oxaliplatin for 6 months should be the standard of care.
Patients with mCRC may be grouped according to the resectability of their metastases: resectable at diagnosis and initially unresectable. Patients with initially unresectable mCRC can be further subdivided into two groups: potential resectable mCRC which is defined as disease that may become resectable after tumour shrinkage and non-resectable which is defined as disease remaining unresectable despite major tumour regression [65]. Treatment strategies depend on the resectability of the disease. For patients with non-resectable mCRC, therapy is primarily of palliative character.
Monotherapy with FU/FA
For several years, FU/FA was the only available therapy in patients with mCRC producing response rates of 20 % and prolonging median OS from 6 to 12 months compared to best supportive care (BSC) [2].
Second-Line Therapy After FU/FA
Irinotecan and oxaliplatin were implemented in the treatment of CRC in the late 1990s. Irinotecan was introduced in the second-line setting in patients with mCRC resistant to FU/FA. In this setting, it was demonstrated that irinotecan significantly prolonged median OS from 6.5 to 9.2 months compared to BSC [68] and from 8.5 to 10.8 months compared to FU/FA alone [69]. A recently published study comparing oxaliplatin and FU/FA (FOLFOX) and irinotecan as single agent in patients with mCRC resistant to FU/FA demonstrated similar survival in the two treatment groups; however, the oxaliplatin-containing regimen produced significant higher response rate and longer PFS than irinotecan as single agent [70].
When oxaliplatin is given in combination with the ‘de Gramont schedule’ of FU/FA, the combination is generally is termed FOLFOX. This regimen has been modified several times, but in this review we will not distinguish between the different FOLFOX variations.
Rothenberg and colleagues performed a large study in patients resistant to irinotecan-based treatment, in which it was demonstrated that FOLFOX was superior to both oxaliplatin single agent and FU/FA in terms of response (9.9 % vs. 1.3 % vs. 0 %) and PFS (4.6 months vs. 1.6 months vs. 2.7 months); however, this benefit was not translated into a significant OS benefit (9.8 months vs. 8.7 months vs. 8.1 months) [28].
Combination Regimens as First-Line Therapy
First-line therapies with fluoropyrimidines combined with either oxaliplatin [71, 72] or irinotecan [73–75] are effective regimens (Table 13.4) producing response rates of up to 50 %, a PFS of 6–8 months and an OS of 14–16 months. Some of the studies performed failed to demonstrate a significant improvement in OS, which may be explained by crossover to the combination regimen after progressive disease to single-agent therapy.
Table 13.4
Selected phase III studies evaluating efficacy of first-line combination chemotherapy in patients with mCRC
Author, year | Regimen | No. of patients | RR (%) | Median PFS (months) | Median OS (months) |
|---|---|---|---|---|---|
5FU/FA versus combination therapy with irinotecan | |||||
Saltz et al. NEJM 2000 [75] | FU/FA | 226 | 21 | 4.3 | 12.6 |
IFL | 231 | 39* | 7.0* | 14.8* | |
Douillard et al. Lancet 2000 [73] | FU/FA | 187 | 22 | 4.4 | 14.1 |
FOLFIRI | 198 | 35* | 6.7* | 17.4* | |
Köhne et al. JCO 2005 [74] | FU/FA | 216 | 32 | 6.4 | 16.9 |
‘FOLFIRI’ | 214 | 54* | 8.5* | 20.1 | |
5FU/FA versus combination therapy with oxaliplatin | |||||
de Gramont et al. JCO 2000 [71] | FU/FA | 210 | 22 | 6.2 | 14.7 |
FOLFOX | 210 | 51* | 9.0* | 16.2 | |
Giacchetti et al. JCO 2000 [72] | FU/FA | 100 | 12 | 6.1 | 19.9 |
FOLFOX | 100 | 34* | 8.7* | 19.4 | |
Combination versus combination | |||||
Tournigand et al. JCO 2004 [80] | FOLFOX | 111 | 54 | 10.9 | 20.6 |
FOLFIRI | 111 | 56 | 14.2 | 21.5 | |
Goldberg et al. JCO 2004 [79] | IFL | 264 | 31 | 6.9 | 15.0 |
FOLFOX | 267 | 45* | 8.7* | 19.5* | |
Glimelius et al. Ann Oncol 2008 [78] | FLIRI | 281 | 35 | 9.4 | 19.4 |
FOLFIRI | 286 | 49* | 9.0 | 19.0 | |
Cassidy et al. JCO 2008 [85] | CapOx | 1,017 | 47 | 8.0 | 19.8 |
FOLFOX | 1,017 | 48 | 8.5 | 19.6 | |
Many patients maintain an excellent performance status despite progressive disease on second-line therapy. However, no chemotherapeutic has proven efficacy in the third-line settings after progression to irinotecan and oxaliplatin and FU/FA [76, 77].
Several studies have compared the different combinations head to head (summarised in Table 13.4). Efficacy of the different regimens is similar – only the US IFL regimen is definite inferior and should not be used [78–80]. It is of minor importance in which sequence the different regimens are used; however, it is important that patients are exposed to all three active drugs [81].
Different treatment strategies have been tested in two large randomised trials, either starting with single-agent capecitabine or FU/FA (sequential therapy) or initiating therapy with combination chemotherapy. It was demonstrated that there were no differences in OS between the different strategies [82, 83]; however, higher response rates were obtained with initial use of combination chemotherapy. This has led to a conclusion that in patients where response is of importance – e.g. in patients with a potentially curative resection of tumour after shrinkage or in patients with tumour-related symptoms – treatment with combination chemotherapy should be used initially. However, in patients with unresectable disease and no tumour-related symptoms, initially treatment with single-agent fluoropyrimidine (either oral or intra venous) seems to be a safe strategy.
Capecitabine in Combination with Oxaliplatin
Different schedules of CapOx have been developed, but the most widely used regimen of CapOx is the 3-week schedule with oxaliplatin 130 mg/m2 day 1 and capecitabine 2,000 mg/m2 days 1–14 every 3 weeks, even though a randomised phase II study showed that oxaliplatin in combination with dose-intensified capecitabine may be beneficial in terms of improved response rate (54.4 % vs. 42.2 %) and longer PFS (10.5 months vs. 6.0 months) compared to the ‘standard’ CapOx regimen [84]. The dose-intensified regimen did not increase the risk of toxicity.
The CapOx regimen has been compared to combination treatment with infusional FU/FA and oxaliplatin in several randomised non-inferiority phase III trials (Table 13.5). The majority of the studies conducted in the first-line setting [85–87] have demonstrated non-inferiority of CapOx compared to infusional-based regimens. However, in a study conducted by the German AIO group [88], in which an alternative CapOx regimen was used (spilt course of oxaliplatin), a slightly inferior efficacy of CapOx was found. A pooled analysis of data from studies comparing CapOx to infusional FU/FA and oxaliplatin regimens concluded that CapOx had similar PFS and OS compared to infusional regimens; however, CapOx resulted in significant lower response rates with an absolute difference of 6.6 % [89]. In second-line efficacy, CapOx is comparable to FOLFOX [90].
Table 13.5
Phase III trials comparing CapOx to infusional FU/FA + oxaliplatin
Author | No | Regimen | mPFS (months) | mOS (months) | RR (%) |
|---|---|---|---|---|---|
First-line therapy | |||||
Porschen et al. JCO 2007 [88] | 474 | CapOx | 7.1 | 16.8 | 48 |
FUFOX | 8.0 | 18.8 | 54 | ||
Diaz-Rubio et al. JCO 2007 [86] | 348 | CapOx | 8.9 | 18.1 | 37 |
FUOX | 9.5 | 20.8 | 46 | ||
Cassidy et al. JCO 2008 [85] | 2,034 | CapOx | 8.0 | 19.8 | 47 |
FOLFOX | 8.5 | 19.6 | 48 | ||
Ducreux et al. IJC 2011 [87] | 306 | CapOx | 8.8 | 19.9 | 42 |
FOLFOX6 | 9.3 | 20.5 | 46 | ||
Second-line therapy | |||||
Rothenberg et al. Ann Oncol 2008 [90] | 627 | CapOx | 4.7 | 11.9 | 20 |
FOLFOX | 4.8 | 12.5 | 18 | ||
Duration of Combination Chemotherapy and Complete Chemotherapy-Free Intervals
When FU/FA was the only available drug, median PFS – and thus median duration of treatment – was around 4–5 months. Chemotherapy was regularly maintained until progression of disease, because there is no cumulative dose-limiting toxicity. This approach was frequently carried on with the introduction of modern combination chemotherapy. However, this policy must be revised as recent studies have shown that different stop-and-go strategies compared with continuous use of chemotherapy until progression do not necessarily reduce efficacy [91].
In a Medical Research Council trial, patients with mCRC started monotherapy (de Gramont, continuous infusional 5-FU or raltitrexed), and patients without progression at 12 weeks were randomised to continue therapy or to stop. There was no evidence of a difference in OS between the intermittent or the continuous group, and furthermore patients on intermittent chemotherapy had significantly less toxicity [92].
The major issue with continuous oxaliplatin regimens is the risk of chronic neuropathy, and as a consequence the majority of patients will discontinue therapy before progression. The French GERCOR group has evaluated different stop-and-go strategies to optimise the use of oxaliplatin. First a ‘stop-and-go strategy with dose-intensive FOLFOX for 6 cycles followed by maintenance therapy with FU/FA alone until progression and reintroduction of oxaliplatin at progression’ (OPTIMOX approach) was compared with ‘standard FOLFOX until progression’ strategy. Patients receiving the OPTIMOX approach experienced less neurotoxicity and without any loss of efficacy (Table 13.6) [93].
Table 13.6
Selected randomised studies evaluating a stop-and-go strategy in patients with mCRC
Author, year | Regimen | No. of patients | RR (%) | Median PFS (months) | Median OS (months) |
|---|---|---|---|---|---|
Continuous FOLFOX versus stop-and-go strategy | |||||
Tournigand et al. JCO 2006 [93] | FOLFOX | 311 | 58.5 | 9.0 | 19.3 |
Stop-and-goa | 309 | 59.2 | 8.7 | 21.2 | |
Chibaudel et al. JCO 2009 [94] | FOLFOX | 98 | 59.2 | 8.6 | 23.8 |
CFIb | 104 | 59.6 | 6.6* | 19.5 | |
Continuous Ox-Fp | 815 | – | – | 15.6 | |
Intermittent Ox-Fp CFIb | 815 | – | – | 14.3 | |
Labianca et al. ASCO 2006 [91] | Continuous FOLFIRI | 168 | 36.5 | 6.5 | 17.6 |
Intermittent FOLFIRI b | 163 | 33.6.5 | 6.2 | 16.9 | |
Subsequently it was therefore natural to investigate whether patients could stay away from maintenance therapy with FU/FA, but a chemotherapy-free interval (CFI) after just 3 months of FOLFOX and reintroduction after progression resulted in loss of efficacy [94, 95].
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