The treatment of colorectal cancer has evolved dramatically in recent years with the availability of new chemotherapeutic agents and inhibitors of the vascular endothelial growth factor- and epidermal growth factor-signaling pathways. The incremental benefit of each individual line of therapy for advanced disease is relatively small. Advances in our ability to select patients should improve the cost-effectiveness of our treatment strategies (avoiding unnecessary toxicity in the patients who are unlikely to benefit and accepting the potential for adverse events in the patients who stand to benefit the most from a given regimen).
Key points
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The availability of new chemotherapeutic agents (oxaliplatin, irinotecan, capecitabine) as well as vascular endothelial growth factor and epidermal growth factor receptor inhibitors has translated into improved outcomes in colorectal cancer (CRC).
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With respect to combination therapy for CRC, more is often better, but at the expense of increased toxicity and cost. It also has the potential to lead to worse outcomes, underscoring the importance of randomized clinical trials and appropriate patient selection.
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The addition of oxaliplatin improves outcomes in stage III colon cancer, but the data do not support its use in stage II colon cancer, patients older than 70 years, or as a radiosensitizer in rectal cancer. Furthermore, targeted agents have no role in adjuvant therapy for colon cancer.
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Choice of therapy for metastatic disease is governed by several factors, including previous therapy, comorbidities, goals of therapy, tumor mutational status, and personal preference.
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The small incremental benefits observed with individual lines of therapy will hopefully be enhanced by better patient selection (ie, avoiding unnecessary toxicity in patients who are unlikely to benefit and accepting toxicity in patients who stand to benefit the most from combination therapy).
Introduction
The treatment of colorectal cancer has evolved dramatically over the last decade, as shown by the availability of additional chemotherapeutic agents as well as agents targeting the vascular endothelial growth factor (VEGF)–signaling and epidermal growth factor receptor (EGFR)-signaling pathways. The most striking impact has been in patients with metastatic disease, in whom access to these new therapeutic strategies has been associated with a more than doubling of overall survival (OS). Although more has often translated into better (eg, higher response rates [RRs] with combination chemotherapy), more has also typically come at a price, both literally and figuratively, leading one to question if more is always better, and if some patients stand to benefit more than others. This issue is perhaps best exemplified by the lack of incremental benefit of greater than 6 months of adjuvant chemotherapy for stage III colon cancer, the lack of benefit from targeted agents in the adjuvant setting, and the potential for harm when EGFR inhibitors are used in patients with RAS mutant tumors or when combining targeted agents for first-line treatment of metastatic disease. Furthermore, less may be acceptable in the setting of maintenance therapy for advanced disease, but giving something may be better than nothing. Additional information is needed to optimize patient selection and choice of therapy in treating colorectal cancer.
Introduction
The treatment of colorectal cancer has evolved dramatically over the last decade, as shown by the availability of additional chemotherapeutic agents as well as agents targeting the vascular endothelial growth factor (VEGF)–signaling and epidermal growth factor receptor (EGFR)-signaling pathways. The most striking impact has been in patients with metastatic disease, in whom access to these new therapeutic strategies has been associated with a more than doubling of overall survival (OS). Although more has often translated into better (eg, higher response rates [RRs] with combination chemotherapy), more has also typically come at a price, both literally and figuratively, leading one to question if more is always better, and if some patients stand to benefit more than others. This issue is perhaps best exemplified by the lack of incremental benefit of greater than 6 months of adjuvant chemotherapy for stage III colon cancer, the lack of benefit from targeted agents in the adjuvant setting, and the potential for harm when EGFR inhibitors are used in patients with RAS mutant tumors or when combining targeted agents for first-line treatment of metastatic disease. Furthermore, less may be acceptable in the setting of maintenance therapy for advanced disease, but giving something may be better than nothing. Additional information is needed to optimize patient selection and choice of therapy in treating colorectal cancer.
Adjuvant combination therapy for resectable colon cancer
Stage III Colon Cancer
Given a significant risk of recurrence, the use of adjuvant fluoropyrimidine (FP)-based treatment is standard in stage III colon cancer. This treatment was initially given for 12 months, and subsequent studies proved that more was not superior to less. The optimal duration of therapy is unknown, but the data suggest that adjuvant therapy should not be given for more than 6 months. Most of the current phase 3 trials in adjuvant therapy are focused on the optimal duration of therapy ( Table 1 ), many of which are encompassed by the IDEA (International Duration Evaluation of Adjuvant Chemotherapy) collaboration. In terms of combination chemotherapy ( Table 2 ), the addition of oxaliplatin (OX) (eg, FOLFOX [infusional/bolus 5-fluorouracil, leucovorin, OX], XELOX [capecitabine (CAPE)/OX], FLOX [OX, bolus 5-fluorouracil, leucovorin]) improves disease-free survival (DFS) in patients with stage III disease. In addition, in the Multicenter International Study of Oxaliplatin, 5-Fluorouracil, Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) study, treatment with FOLFOX improved OS at 6 years in stage III patients (72.9% vs 68.7%; hazard ratio [HR] = 0.8; 95% confidence interval [CI], 0.65–0.97; P = .023). The incremental benefit of OX-based therapy comes at a price (eg, hand-foot syndrome, neuropathy, neutropenia), without increasing treatment-related mortality. Although OX-related neuropathy typically improves with discontinuation of drug, 15% of patients have at least grade 1 residual neuropathy at 4 years. Despite showing a DFS benefit, the value of the weekly FLOX regimen is limited because it causes more grade 3/4 diarrhea than FOLFOX, does not affect OS, and was associated with shorter survival after recurrence in NSABP C-07. As to whether all patients with stage III disease stand to benefit from the addition of OX, guidelines suggest restricting the use of OX to patients younger than 70 years based on data suggesting that elderly patients do not benefit from the addition of OX to leucovorin infusional/bolus 5-fluorouracil (LV5FU2).
| Study ID | Stage | Study Arms | Location |
|---|---|---|---|
| CALGB/SWOG 80702 | III | FOLFOX (3 vs 6 mo) with or without celecoxib | United States |
| ICOG-CC01 | IIIA/B | UFT/LV with or without polysaccharide-K | Japan |
| 2007-000354-31 | II/III | FOLFOX (3 vs 6 mo) with or without bevacizumab | Italy |
| CDR0000613042 | II/III | 12 vs 6 cycles OxMdG or XELOX | UK |
| CDR0000647466 | III | 3 vs 6 mo FOLFOX or XELOX | France |
| 2009-11-008 | II/III | 3 vs 6 mo of oxaliplatin in patients receiving 6 mo adjuvant FOLFOX/CAPOX | Korea |
| CT/09.12 | II/III | 3 vs 6 mo FOLFOX/CAPOX | Greece |
| NeoCol | T3,4 | Neoadjuvant chemo × 3 followed by surgery vs surgery + adjuvant chemo × 8 | Denmark |
| Study | Stage | Study Arms | N | Primary Endpoint | DFS (%) | OS (%) | Reference |
|---|---|---|---|---|---|---|---|
| Oxaliplatin-Based | |||||||
| MOSAIC | II/III | FOLFOX4 LV5FU2 | 2246 | DFS | 73.3 67.4 at 5 y; HR = 0.80; 95% CI, 0.68–0.93; P = .003 | 78.5 76 at 6 y; HR = 0.84; 95% CI, 0.71 to 1.00; P = .046 | Andre et al, 2009 |
| II/III | No Change 68.7/72.9, HR = 0.80; 95% CI, 0.65 to 0.97; P = .023 | Andre et al, 2009 | |||||
| NSABP C07 | II/III | FLOX FU/LV | 2407 | DFS | 73.2 67.0 at 4 y; HR = 0.80; 95% CI, 0.69–0.93; P <.004 | No change | Kuebler et al, 2007 |
| NO16968 | III | XELOX FU/LV | 1886 | DFS | 70.9 66.5 at 3 y; HR = 0.80; 95% CI, 0.69–0.93; P = .0045 | No change (77.6/74.2 at 5 y) | Haller et al, 2011 |
| Irinotecan-Based | |||||||
| FNCLCC Accord02/FFCD9802 | III | FOLFIRI LV5FU2 | 400 | DFS | No change | No change | Ychou et al, 2009 |
| CALGB 89803 | III | IFL FU/LV | 1264 | OS, DFS | No change | No change | Saltz et al, 2007 |
| PETACC-3 | III | FOLFIRI LV5FU2 | 2094 | DFS | No change at 5 y | No change at 5 y (73.6/71.3) | Van Cutsem et al, 2009 |
Despite proven benefits in the metastatic setting, the addition of irinotecan (IRI) is not indicated in the adjuvant study. The results of Pan European Trial Adjuvant Colon Cancer (PETACC)-3, FNCLCC Accord02/FFCD9802, and Cancer and Leukemia Group B (CALGB) 89803 failed to show an incremental benefit from addition of IRI to standard infusional LV5FU2 or bolus FU/LV (see Table 2 ). Combination therapy was associated with greater toxicity, and in combination with bolus FU/LV, IRI increased treatment mortality in the adjuvant setting.
Targeted agents have been similarly ineffective in the adjuvant setting ( Table 3 ). The addition of bevacizumab (BEV), a humanized monoclonal antibody directed against VEGF, to OX-based chemotherapy increased toxicity (eg, grade 3/4 hypertension, serious adverse events) without an improvement in DFS. Furthermore, the results of the AVANT trial suggested a potential detrimental effect on OS with BEV in patients with stage II/III colon cancer. Similarly, regardless of KRAS (Kirsten rat sarcoma viral oncogene homolog) mutational status, the addition of cetuximab, an antibody to the EGFR to mFOLFOX6 increased toxicity (particularly in older patients), without improving DFS in patients with stage III disease. A trend toward improved DFS and OS was observed with cetuximab in a small subgroup of patients treated with infusional/bolus FU, LV, IRI (FOLFIRI).
| Study | Stage | Study Arms | N | Primary Endpoint | DFS (%) | OS (%) | Reference |
|---|---|---|---|---|---|---|---|
| BEV-Based | |||||||
| NSABP C-08 | II/III | FOLFOX6+BEV | 2673 | DFS in stage III | No change at 3 or 5 y | No change at 5 y | Allegra et al, 2011 |
| II/III | FOLFOX6 | ||||||
| AVANT | II/III | FOLFOX4 BEV+FOLFOX4 BEV+XELOX | 3451 | DFS in stage III | No change at 4 y | BEV+FOLFOX/FOLFOX HR = 1.27; 95% CI, 1.03 to 1.57; P = .02 | de Gramont et al, 2012 |
| BEV+XELOX/FOLFOX HR = 1.15; 95% CI, 0.93 to 1.42; P = .21 | |||||||
| Cetuximab-Based | |||||||
| N0147 | III | FOLFOX6+cetuximab FOLFOX6 | 2686 | DFS | No change at 3 y (regardless of KRAS status) | No change | Alberts et al, 2012 |
Stage II Colon Cancer
The optimal therapy for stage II disease remains controversial given an expected 5-year OS of 75% or greater. At a minimum, the available evidence suggests that less is more in patients without high-risk features. The results of 2 meta-analyses suggest that nearly all of the benefit of adjuvant therapy with FP-based therapy is in patients with stage III disease. A small, but statistically significant, improvement in OS was noted in the QUASAR (Quick and Simple and Reliable) trial with adjuvant FU/LV, but the results may have been confounded because many patients were high risk by virtue of having fewer than 12 lymph nodes sampled. Another meta-analysis yielded similarly conflicting results, possibly stemming from inclusion of nontraditional chemotherapy regimens and lack of surgical quality control. A post hoc exploratory analysis of DFS and OS in the MOSAIC study showed that the addition of OX is also without obvious benefit (compared with FU/LV alone) in patients with stage II disease. Taken together, the data suggest that less is more in patients with low-risk stage II colon cancer. The incremental benefit of adjuvant FU/LV is modest at best, and the benefits of adding OX unclear. In low-risk stage II patients, current recommendations are to use an FP alone if chemotherapy is considered.
In patients with high-risk stage II disease (defined as harboring poor prognostic features), adjuvant chemotherapy is often considered based on subset analyses, suggesting a higher likelihood of recurrence in this population. However, neither FLOX nor FOLFOX has been shown to be associated with improved OS over FP treatment alone in stage II patients with high-risk features.
Ongoing studies are aimed at validating predictive markers that may be used to prospectively select the patients most likely to benefit from adjuvant therapy in stage II disease. Microsatellite instability (MSI) is a marker of more favorable outcome and may be a predictor of decreased benefit from adjuvant therapy with FP alone in stage II disease. The available data suggest that patients with resected MSI-high stage II colon cancers have an excellent prognosis and are unlikely to benefit from FP alone in the adjuvant setting. Several multigene assays have also been developed that may help to identify the stage II patients most likely to benefit. However, although the panels seem to have prognostic value, their predictive value in terms of response to chemotherapy remains to be established.
Adjuvant/neoadjuvant combination therapy for resectable rectal cancer
Chemoradiation
The treatment of rectal cancer is based on the stage of the tumor, goals of care, patient preference, and the likely functional result (eg, bowel, urinary, sexual function). Patients with stage I disease are treated with surgery alone. The treatment of patients with stage II/III disease involves chemoradiation (CRT), surgery, and adjuvant chemotherapy. However, the relative value of the individual treatment components of multimodality therapy remains unclear, particularly in the context of patients experiencing a complete response to neoadjuvant therapy and in patients with T3N0 proximal rectal cancers (in whom the incremental value of radiation (RT) is uncertain).
The usefulness of infusional 5FU as a radiosensitizer in stage II/III rectal cancer was established 20 years ago and has been shown to reduce the risk of relapse and improve OS compared with bolus 5FU/RT. CAPE is noninferior to infusional FU. Modern CRT is typically delivered in the neoadjuvant setting based on data suggesting improved outcomes (eg, reduction in local recurrence) compared with postoperative treatment. However, a key limitation of neoadjuvant therapy is the risk of overtreatment, particularly because overstaging with preoperative imaging occurs. On the other hand, roughly 20% of preoperatively staged cT3N0 tumors treated with neoadjuvant CRT are understaged (ie, positive lymph node involvement at surgery), suggesting potential value to overtreating cT3N0 disease. Modern surgical techniques, such as total mesorectal excision, may reduce the incidence of a positive circumferential radial margin (an important pathologic staging parameter in rectal cancer), thus reducing the risk of local recurrence and potentially circumventing the need for RT in selected patients.
Approximately 20% of patients treated with neoadjuvant CRT experience a pathologic complete response (pCR), a feature that portends a good prognosis. Considerable effort has gone into enhancing the response to neoadjuvant treatment, either by adding radiosensitizers, incorporating preoperative chemotherapy or increasing the interval between completion of CRT and resection. The value of adding OX to traditional CRT has been assessed in several trials ( Table 4 ). Toxicity is increased without a reproducible increase in pCR rate. Many of the efficacy end points are not yet mature or have yielded conflicting results. Thus, the value of OX when added to concurrent RT for the treatment of rectal cancer remains controversial. Differences in trial design (including adjuvant chemotherapy, RT dose, and FP backbone) make cross-trial comparisons difficult. In the German CAO/ARO/AIO-04 study, improved pCR and DFS (but not OS) were observed with OX, but study patients received a more protracted schedule of infusional FU during CRT and FOLFOX instead of bolus FU/LV in the adjuvant setting. These features raise the possibility that more might not have been better had control patients received protracted FU infusion during CRT and adjuvant infusional LV5FU2. Additional trials assessing the optimal treatment of localized rectal cancer are ongoing ( Table 5 ).
| Study | Study Arms | N | First End Point | DFS (%) | OS (%) | Local Recurrence (%) | pCR Rate (%) | Reference |
|---|---|---|---|---|---|---|---|---|
| ACCORD 12 | CAPE-RT+OX/CAPE-RT (preoperative) | 598 | pCR | No change at 3 y | No change at 3 y | No change at 3 y | 19.2/13.9 No change | Gerard et al, 2012 |
| STAR-01 | FU-RT+OX/FU-RT (preoperative) | 747 | OS | TBD | TBD | 16/16 No change | Aschele et al, 2011 | |
| R-04 | Continuous infusion FU-RT ± OX CAPE-RT ± OX preoperative | 2407 | Local recurrence | TBD | TBD | TBD | No change a | O’Connell et al, 2014 |
| CAO/ARO/AIO-04 | CRT+OX-S-FOLFOX/CRT-S-bolus FU/LV | 1265 | DFS | 75.9/71.2 at 3 y 68.8/64.3at 5 y HR = 0.79, 95% CI .64-.98; P = .030 | No change | TBD | 17/13 HR = 1.40, 95% CI 1.02–1.92; P = .038 (exploratory) | Rodel et al, 2012 Rodel et al, 2014 |
| PETACC-6 | CAPE, OX, RT-S-CAPOX/CAPE, RT-S-CAPE | 1094 | DFS | No change at 3 y (interim) | TBD | TBD | TBD | Schmoll et al, 2014 |
a Also no change in sphincter-sparing procedures or surgical downstaging.
| Study ID | Stage | Study Arms | Location |
|---|---|---|---|
| Role of RT | |||
| FDRT-002 | II/III | High-intensity vs low-intensity neoadjuvant CRT | China |
| BE-2-48 | II/III | Short course RT vs conventional CRT followed by surgery | Lithuania |
| NL36315.042.11 | T4 or N2 tumors | Short course RT followed by CAPOX × 6 vs conventional CRT | Netherlands + others |
| FDRT-002 | II/III | Neoadjuvant FU/RT vs FOLFOX × 4 followed by FU/RT vs FOLFOX × 4 without RT | China |
| N1048 | II/III | Neoadjuvant FOLFOX × 6 followed by selective use of CRT vs standard CRT | NCCTG, United States |
| CRCCZ-R01 | II/III with (-) CRM by MRI | Neoadjuvant CRT followed by surgery vs surgery followed by selective use of CRT | China b |
| 9100013841 | III | CRT vs wide pelvic lymphadenectomy | Taiwan |
| 4-2014-0239 | II/III with (-) CRM by MRI | TME ± adjuvant FOLFOX in patient with (-) CRM | China b |
| Role of Chemotherapy | |||
| AERO-R98 | II/III | Adjuvant FU/LV vs LV5FU2+IRI | France |
| CAMS_rectal cancer_01 | II/III | Adjuvant CRT with capecitabine vs OX plus capecitabine | China |
| 515(A1144)/2005 | II/III | Neoadjuvant RT with chronomodulated capecitabine with or without OX | Italy |
| PRODIGE 23 | II/II | Neoadjuvant mFOLFIRINOX then CRT vs CRT alone | France |
| NP-113/2011 | T3,4N0,1M0 | Adjuvant 5FU/OX × 4 mo vs observation | Brazil |
| CDR0000613042 | II/III | 12 vs 6 cycles OxMdG or XELOX | UK |
| Timing of Surgery | |||
| P 110125 | II/III | Surgery after 7 vs 11 wk delay after CRT | France |
a http://www.clinicaltrials.gov .
Phase 2 studies exploring the value of IRI, EGFR inhibitors, or BEV to improve the response to neoadjuvant CRT have been performed; however, phase 3 data are not yet available. Use of these agents is not recommended outside a clinical trial.
Adjuvant Chemotherapy for Rectal Cancer
The treatment of stage II/III rectal cancer typically includes adjuvant chemotherapy with FU/LV. The role of adjuvant chemotherapy relative to CRT has been difficult to ascertain, although 1 meta-analysis suggested that adjuvant chemotherapy improves DFS and OS. Other regimens (eg, FOLFOX, CAPOX [capecitabine/OX], and CAPE) have been used by extrapolation from colon cancer (see Table 4 ). The PETACC-6 and AIO/ARO/AI-04 trials both evaluated OX-based chemotherapy for rectal cancer, but yielded conflicting results. Ongoing studies are designed to further optimize chemotherapy for localized rectal cancer, including addressing the potential for preoperative chemotherapy to replace the need for CRT entirely (see Table 5 ).
First-line therapy for metastatic colorectal cancer
Single-Agent Chemotherapy
The treatment of metastatic colorectal cancer (mCRC) has evolved dramatically over the past 15 years ( Tables 6 and 7 ). Several agents (FU/LVCAPE, OX, and IRI) are routinely used in a variety of single-agent and combination chemotherapy regimens. Infusional FU is better tolerated (less granulocytopenia, diarrhea, and mucositis) and more efficacious than bolus FU. CAPE is superior to bolus FU in the first-line setting (improved RR, with less diarrhea, nausea, stomatitis, and alopecia, and fewer hospitalizations) but is associated with a higher rate of hyperbilirubinemia and hand-foot syndrome. As in the adjuvant setting, CAPE seems to be equivalent to infusional FU in the treatment of metastatic disease. In combination with bolus FU, the addition of LV improves OS, but use of more (eg, high-dose) LV does not seem to be superior to low-dose drug. There is no obvious benefit to adding LV to protracted 5FU infusions. Historically, patients treated with an FP alone could expect a 15% to 20% RR, median progression-free survival (PFS) 5 to 6 months and OS 10 to 14 months. By themselves, OX and IRI have limited activity in the first-line setting.
| Regimen | First End Point | Study Arms | N | RR (%) | PFS | OS | Reference |
|---|---|---|---|---|---|---|---|
| FP alone | RR | Bolus FU + high-dose LV | 148 | 21.6 | 39.3 wk | 55 wk | Jager et al, 1996 |
| Bolus FU + low-dose LV | 143 | 17.5 | 30 wk | 54 wk | |||
| OS | Bolus FU/LV | 173 | 14.5 | 22 wk | 56.8 wk | de Gramont et al, 1997 | |
| LV5FU2 | 175 | 32.6, P = .0004 | 27.6 wk, P = .001 | 62 wk | |||
| b | CAPE | 603 | 26, P = .002 | 4.6 mo | 12.9 mo | Van Cutsem et al, 2004 | |
| Bolus FU/LV | 604 | 17 | 4.7 mo | 12.8 mo | |||
| Doublet chemotherapy | PFS | LV5FU2 | 210 | 22.3 | 6.2 | 14.7 mo | de Gramont et al, 2000 |
| LV5FU2+OX | 210 | 50.7, P = .0001 | 9.0, P = .0003 | 16.2 mo | |||
| PFS | CAPOX | 242 | 48 | 7.1 | 16.8 mo | Porschen et al, 2007 | |
| FUFOX | 234 | 54 | 8.0 | 18.8 mo | |||
| PFS | XELOX (± placebo or BEV) | 1017 | 47 | 8.0 | 19.8 mo | Cassidy et al, 2011 | |
| FOLFOX4 (± placebo or BEV) | 1017 | 48 | 8.5 | 19.6 mo | |||
| PFS | FOLFIRI | 144 | 47.2 | 7.6 | 23.1 mo | Fuchs et al, 2007 | |
| mIFL | 141 | 43.3 | 5.9; P = .004 | 17.6 mo | |||
| CAPIRI | 145 | 38.6 | 5.8; P = .015 | 18.9 mo | |||
| TTP | mIFL | 151 | 32 | 5.5 | 16.4 mo | Goldberg et al, 2006 Ashley et al, 2007 | |
| FOLFOX | 154 | 48, P = .006 | 9.7, P <.0001 | 19.0 mo, P <.026 | |||
| IROX | 383 | 36.4, P = .002 | 6.7, P <.001 | 17.3 mo, P = .001 | |||
| PFS | FOLFIRI→FOLFOX | 109 | 56 | 8.5 | 21.5 mo | Tournigand, et al, 2004 | |
| FOLFOX→FOLFIRI | 111 | 54 | 8.0 | 20.6 mo | |||
| RR | FOLFIRI | 164′ | 31 | 9 | 14 mo | Colucci et al, 2005 | |
| FOLFOX4 | 172 | 34 | 10 | 15 mo | |||
| Triplet chemotherapy | RR | FOLFOXIRI | 122 | 60 | 9.8 | 22.6 | Falcone et al, 2007 |
| FOLFIRI | 122 | 34, P <.0001 | 6.9, P = .0006 | 16.7, P = .032 | |||
| OS | FOLFOXIRI | 137 | 43 | 8.4 | 21.5 | Souglakos et al, 2006 | |
| FOLFIRI | 146 | 33.6 | 6.9 | 19.5 |
a No significant change unless P value provided.
| Study Arms | N | Neutropenia | Febrile Neutropenia/Infection | Diarrhea | Somatitis | Neurotoxicity | Fatigue/Asthenia | Skin Toxicity (+HFS) | Hypertension | Reference |
|---|---|---|---|---|---|---|---|---|---|---|
| LV5FU2 | 210 | 5.3 | NR/1.5 | 5.3 | 1.5 | 0 | 5 | NR | NR | de Gramont et al, 2000 |
| FOLFOX | 210 | 42 a | NR/1.5 | 12 a | 6 a | 18 a | 5.6 | NR | ||
| FOLFOX4 | 649 | 44 a | 4.8 a /NR | 11 | 2 | 4 | 9/4 | 1 | NR | Cassidy et al, 2008 |
| CAPOX | 655 | 7 | 0.9/NR | 19 a | 1 | 4 | 6/5 | 6 a | ||
| FOLFIRI | 137 | 43 | 3.6/NR | 14 | NR | NR | NR | 0 | NR | Fuchs et al, 2007 |
| IFL | 137 | 41 | 12/NR | 19 | NR | NR | NR | 0 | ||
| CAPIRI | 141 | 32 | 7/NR | 48 a | NR | NR | NR | 10 a | ||
| FOLFIRI | 164 | 10 | NR | 10 | 1 | 0 | 0 | 0 | NR | Colucci et al, 2005 |
| FOLFOX | 172 | 10 | NR | 5 | 1 | 4 | 0 | 0 | ||
| FOLFIRI | 602 | 25 | NR | 11 | NR | NR | 5 | 0 | NR | Van Cutsem et al, 2009 |
| FOLFIRI+cetux | 600 | 28 | NR | 16 | NR | NR | 5 | 20 | ||
| FOLFOX | 327 | 42 | 2 | 9 | <1 | 16 | 3 | 2 | NR | Douillard et al, 2010 |
| FOLFOX+Pmab | 322 | 43 | 2 | 18 | 9 | 16 | 10 | 37 | ||
| FOLFOX4 | 168 | 34 | NR | 7 | 1 | 7 | 3 | 1 | NR | Bokemeyer et al, 2010 |
| FOLFOX4+cetux | 170 | 30 | NR | 8 | 3 | 4 | 5 | 18 | ||
| FOLFIRI-cetux | 297 | 12.8 | 1.7/NR | 11.5 | 3.7 | NR | 0.7/NR | 17 | 6.4 | Heinemann et al, 2013 |
| FOLFIRI-BEV | 295 | 11.2 | 1/NR | 13.6 | 4.1 | NR | 1.4/NR | 0 | 6.8 | |
| Chemo-cetux | 547 | NR | NR | NR | NR | 12 | NR | 7 | 1 | Venook et al, 2014 |
| Chemo-BEV | 534 | NR | NR | NR | NR | 14 | NR | 0 | 7 |
Doublet Chemotherapy
Combination therapy with an FP plus IRI or OX is associated with improved RRs, PFS, and OS compared with treatment with an FP alone, but at the expense of added toxicity (see Tables 6 and 7 ). CAPOX has similar efficacy to FOLFOX and an acceptable safety profile. FOLFOX is associated with more grade 3/4 neutropenia, febrile neutropenia, and venous thromboembolic events; CAPOX is associated with more grade 3 diarrhea (19% vs 11%) and grade 3 hand-foot syndrome (6% vs 1%). In terms of IRI-based combinations, FOLFIRI is associated with a longer PFS than irinotecan, 5-fluorouracil, and leucovorin (IFL), a less tolerable bolus regimen that is no longer used. The results with CAPIRI have been mixed. Several European studies have shown promising results and good tolerability with CAPIRI-based treatment; others have been stopped prematurely because of serious toxicity concerns. The BICC-C study showed that CAPIRI was less active than FOLFIRI (PFS), and associated with more grade 3 or higher nausea, vomiting, dehydration, diarrhea, dehydration, and hand-foot syndrome. CAPIRI is not a routinely recommended regimen in the United States.
FOLFOX, FOLFIRI, and CAPOX have similar efficacy in the first-line setting. With doublet chemotherapy, patients can expect 40% to 50% RR, median PFS 8 to 9 months, and median OS 16 to 19 months, which compares favorably with historical data with an FP alone. In the absence of obvious contraindication, patients are routinely treated with at least doublet combination chemotherapy in the first-line setting. The results of a meta-analysis including more than 6000 patients suggested that the risk/benefit ratio of doublet therapy in the first-line setting is preserved in patients with performance status (PS) 2 or 1 or less, although the risks of some gastrointestinal toxicities were increased in PS 2 patients.
The optimal sequence for the various doublet chemotherapy regimens remains uncertain, as is the need for up-front combination therapy in all patients. Tournigand and colleagues reported that FOLFIRI and FOLFOX are equally viable options in the first-line setting (when opposite regimen used second-line). Three other studies have explored whether combination therapy up-front is essential, recognizing that improvements in OS with doublet therapy may reflect subsequent lines of therapy. In the absence of targeted therapy, there is little difference in outcome whether a patient starts with combination therapy or a less intensive regimen. The French group compared mLV5FU2, then FOLFOX, then FOLFIRI versus FOLFOX, then FOLFIRI in patients with unresectable mCRC. Median PFS after 2 lines of therapy was similar in the 2 groups (around 10 months) but grade 3/4 events and toxic deaths were more common in patients treated with up-front combination therapy. The CAIRO study examined sequential treatment (CAPE, then IRI, then CAPOX) or combination therapy (CAPIRI, then CAPOX) in 820 patients. There was no difference in OS (16.3 months vs 17.4 months; HR = 0.92 (95% CI, 0.79–1.08; P = .3281)). Grade 3/4 toxicity was similar between groups except for more hand-foot syndrome in the sequential group. The MRC FOCUS study was designed to compare (1) LV5FU2, then (2) IRI LV5FU2, then combination therapy (FOLFOX or FOLFIRI); and (3) combination therapy up-front. The median OS was similar in all groups (13.9 months in control), with the exception of patients assigned to up-front FOLFIRI (median OS 17.7; P = .01). Taken together, these data are consistent with the hypothesis that exposure to IRI OX, FP at some point in the disease course is more important than the specific sequence. Although compelling, the studies on sequencing chemotherapy regimens in mCRC should be interpreted with caution in the era of targeted therapy.
Doublet Chemotherapy Regimen Plus a Vascular Endothelial Growth Factor Inhibitor
BEV has been shown to improve OS compared with chemotherapy in numerous trials in patients with mCRC (see Table7 ; Tables 8 and 9 ). The first study was performed in patients receiving a now antiquated regimen (IFL) and was associated with a nearly 5-month improvement in OS (20.3 months vs 15.6 months; HR, 0.66; P <.001). Similarly, a combined analysis of several trials showed a 3-month benefit of BEV combined with FU/LV compared with FU/LV (with or without IRI).
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Is More Not Better?
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