1. Controversies in Care: Using Clinical Data to Guide Treatment Selection
Cathy Eng, MD
Assistant Professor
Department of Gastrointestinal
Medical Oncology
The University of Texas
M. D. Anderson Cancer Center
Houston, Texas
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3. Controversies for Discussion
Optimal chemotherapy schedule for treating advanced colorectal cancer
Sequential vs combination therapy
Role of chemotherapy-free intervals
Continuation of anti-VEGF therapy
The future of combined biologic therapy
When is the appropriate time to incorporate anti-EGFR therapy?
EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor.
This presentation will review:
• Optimal chemotherapy schedules for treating advanced colorectal cancer, including sequential vs combination chemotherapy
• The role of chemotherapy free intervals
• Whether to continue anti VEGF therapy after disease progression
• The future of combined biologic therapies
• The appropriate time to incorporate anti EGFR therapy

4. Sequential vs Combination Therapy
In 2005, Grothey and colleagues published a study that showed the benefits of using all 3 available chemotherapeutic agents—5-fluorouracil, irinotecan, and oxaliplatin—during a patient’s treatment to improve median survival times. 4

5. Retrospective Analysis: Linking Use of 3-Drug Combo With Median OS Rates
21 arms of 11 phase III trials in advanced CRC (N = 5768)
Relationship between percentage of patients receiving all 3 active agents during course of disease (fluorouracil, irinotecan, and oxaliplatin) and median OS evaluated
Significant correlation found (P = .0001; r2 = 0.85)
Analysis suggests that combination therapy should remain the standard of care for first-line treatment of patients with advanced CRC
Multivariate analysis: only exposure to 3 drugs (P = .0001) but not use of first-line doublet (P = .69) was associated with OS
CRC, colorectal cancer; OS, overall survival.
Grothey and colleagues conducted a retrospective analysis of 21 arms from 11 phase III trials that involved slightly fewer than 6000 patients with advanced colorectal cancer. None of these trials included biologic agents. The investigators determined that treatment with all 3 active agents (5-fluorouracil, irinotecan, and oxaliplatin) was significantly correlated with overall survival, which suggests that combination therapy should remain the standard of care for first‑line treatment of patients with advanced colorectal cancer. However, a multivariate analysis revealed that only exposure to 3 drugs, and not use of first‑line doublets, was associated with an improvement in overall survival.
Grothey A, et al. J Clin Oncol. 2005;23:

6. Combination vs Sequential Therapy: CAIRO Study
First Line*
Second Line*
Third Line*
Capecitabine
(n = 397)†
Irinotecan
(n = 251), 62%
Capecitabine
+ Oxaliplatin
(n = 143), 36%
Sequential
Patients with advanced CRC and no previous treatment
(N = 803)
Capecitabine
+ Irinotecan
(n = 398)†
Capecitabine
+ Oxaliplatin
(n = 213), 53%
Combination
*All 3-week cycles.
†4 patients on each arm did not receive planned treatment.
CAIRO, Capecitabine, Irinotecan, Oxaliplatin; CRC, colorectal cancer; FOCUS, Fluorouracil, Oxaliplatin, CPT-11 Usage Study; XELIRI, capecitabine plus irinotecan; XELOX, capecitabine plus oxaliplatin.
Since the Grothey study, 2 prospective analyses have been published: CAIRO and FOCUS. The CAIRO study randomized previously untreated patients with advanced colorectal cancer to either sequential or combination treatment. In the sequential arm, patients received full-dose capecitabine (1250 mg/m2 twice daily). On progression, they were treated with second-line single‑agent irinotecan at a full dose of 350 mg/m2 every 3 weeks. Those patients older than 70 years of age received a 25% dose reduction. Patients who progressed on single‑agent irinotecan were treated with the combination of capecitabine and oxaliplatin. By the third line of therapy, only 36% of the original 397 patients remained.
In the combination arm, patients received first-line treatment with the combination of capecitabine and irinotecan (the so-called XELIRI regimen). For the combination, irinotecan was given at 250 mg/m2 and oxaliplatin at 130 mg/m2. Once the patients progressed, they were then treated with XELOX (capecitabine and oxaliplatin), with oxaliplatin given at a dosage of 130 mg/m2 and capecitabine at the full dose of 1000 mg/m2. These doses are not commonly used in combination care in the United States, where most clinicians avoid the XELIRI regimen because of the increased risk of diarrhea.
The median follow‑up time was approximately 30 months and the median number of cycles received in the sequential arm was 6 for capecitabine, 6 for irinotecan, and 4 for XELOX. The median number of cycles received in the combination arm was 7 for XELIRI and 5 for XELOX.
Patients were radiologically evaluated every 9 weeks; these data were centrally reviewed and a quality-of-life analysis was obtained.
Capecitabine: Days 1-14 twice daily
Monotherapy: 1250 mg/m2
Combination: 1000 mg/m2
Irinotecan: Day 1
Monotherapy: 350 mg/m2
Combination: 250 mg/m2
Oxaliplatin: Day 1
130 mg/m2
Koopman M, et al. Lancet. 2007;370: 6

7. Median Overall Survival
Combination vs Sequential Therapy: CAIRO Study (cont’d)
Median Overall Survival
Combination treatment did not prolong OS vs sequential therapy
PFS with first-line treatment (P = .0002)
Combination arm: 7.8 months
Sequential arm: 5.8 months
Overall RR with first-line treatment (P < .0001)
Combination arm: 41%
Sequential arm: 20% 25
P = .33 20
17.4
16.3 15
Months 10
CAIRO, Capecitabine, Irinotecan, Oxaliplatin; OS, overall survival; PFS, progression-free survival; RR, response rate.
The primary endpoint of the CAIRO study was overall survival. The study was 80% powered for an improvement in overall survival of 3.5 months for the combination. Results showed that the median survival for the patients on the combined arm was 17.4 months vs 16.3 months for the sequential arm—that is, the combination regimen did not significantly prolong overall survival vs sequential therapy. Progression‑free survival with first‑line chemotherapy was 7.8 months for the combination vs 5.8 months for the sequential arm (P = .0002). The overall response rate was more favorable in the combination arm at 41% vs 20% for the sequential arm (P < .0001). 5
Combination
treatment
Sequential treatment
Koopman M, et al. Lancet. 2007;370: 7

8. Sequential Therapy (n = 397) Combination Therapy (n = 398)
Combination vs Sequential Therapy: CAIRO Study (cont’d)
Toxicity, %
Sequential Therapy (n = 397)
Combination Therapy (n = 398)
P Value
Grade 3/4 toxicity, all lines of therapy
Diarrhea 23 27
.23
Hand-foot syndrome 13 7
.004
Thrombosis/embolism* 9 10
.48
Vomiting
.16
Nausea 8
.45
Febrile neutropenia 5
.18
Grade 3/4 toxicity, first-line therapy 11 26
< .0001 12 6
.002 .2 3
.0002 4
< 1
CAIRO, Capecitabine, Irinotecan, Oxaliplatin.
More hand-foot syndrome was noted with the combination regimen across all lines of therapy, but otherwise the toxicities were comparable between arms (P = .004). For first‑line chemotherapy specifically, the XELIRI regimen was associated with more diarrhea (P < .001), more hand-foot syndrome (P = .002), and increased vomiting (P = .0002), nausea (P = .004), and febrile neutropenia (P < .001) vs sequential therapy.
*All grades.
Koopman M, et al. Lancet. 2007;370: 8

9. Combination vs Sequential Therapy: CAIRO Study (cont’d)
Outcomes
Sequential
(n = 397)
Combination
(n = 398)
60-day mortality, %
3.0
4.5 (P = .27)
Death probably related to treatment,* n
Sepsis†
Diarrhea
Neutropenic fever 8 6 1
3 (P = .13) 2
Sudden death,‡ n 5
*In 9/11 patients, major protocol violations were detected.
†In 7/8 patients, neutropenia was present.
‡In 4/6 patients, cardiopulmonary risk factors were present.
CAIRO, Capecitabine, Irinotecan, Oxaliplatin; EORTC, European Organisation for Research and Treatment of Cancer; QLQ, quality-of-life questionnaire.
No difference was seen in the 60-day mortality rate between the combination arm and the sequential arm, and no deaths were found to be related to therapy. Six patients in the sequential arm experienced sepsis vs 2 in the combination arm. There was no increased incidence of death related to diarrhea in either arm. One patient in the sequential arm experienced neutropenic fever. Although 5 patients in the combination arm and 1 in the sequential arm experienced sudden death, 4 of these patients had cardiopulmonary risk factors. Quality-of-life scores for the first 403 (of the first 620 enrolled) evaluable patients were comparable across arms, except that more diarrhea was noted with the combined treatment regimen.
Quality-of-life analysis proposed to the first 620 patients enrolled (QLQ-C30 questionnaire of the EORTC)
403 patients were evaluable for quality of life
Quality-of-life scores comparable between the 2 arms, except for diarrhea (P = .002) which was more frequent in the combination treatment arm
Koopman M, et al. Lancet. 2007;370:

10. Conclusions From the CAIRO Study
Combination chemotherapy did not improve OS
Sequential therapy a viable option
Authors’ conclusions
Despite a higher RR and longer PFS with combination therapy, the lack of difference in OS suggests that PFS may not be the best surrogate marker
CAIRO, Capecitabine, Irinotecan, Oxaliplatin; OS, overall survival; PFS, progression-free survival; RR, response rate.
In summary, in the CAIRO study, combination chemotherapy did not improve overall survival in patients with colorectal cancer, thereby demonstrating that sequential therapy remains a viable option in this setting. The investigators also concluded that despite a higher response rate and longer progression‑free survival with combined therapy, the lack of difference in overall survival suggests that progression‑free survival may not be the best surrogate marker. However, it is important to keep in mind that patient-specific treatment goals need to be identified; for example, 1 patient may be a candidate for hepatic resection with curative intent while another may never be a surgical candidate.

11. Combination vs Sequential Therapy: FOCUS Study
Salvage Therapy
Arm A: 5-FU until it fails
(n = 710)
Switch to Ir
Ox + 5-FU (n = 153)
Arm B (Ir): 5-FU until it fails
(n = 356)
Add Ir
Ox + 5-FU (n = 76)
Patients with advanced colorectal cancer
(N = 2135)
Arm B (Ox): 5-FU until it fails
(n = 356)
Add Ox
Ir + 5-FU (n = 82)
Arm C (Ir): 5-FU + Ir until it fails
(n = 356)
Ox + 5-FU (n = 180)
Arm C (Ox): 5-FU + Ox until it fails
(n = 356)
5-FU, 5-fluorouracil; FOCUS, Fluorouracil, Oxaliplatin, and CPT11 (irinotecan)—Use and Sequencing; Ir, irinotecan; Ox, oxaliplatin; PS, performance status.
Seymour and colleagues conducted a large randomized study called the FOCUS trial wherein patients were randomized to 5 treatment strategies across 3 arms:
Arm A: 5‑FU until progression, then switch to irinotecan
Arm B (Ir): 5‑FU until progression, then add irinotecan
Arm B (Ox): 5‑FU until progression, then add oxaliplatin
Arm C (Ir): FOLFIRI until progression
Arm C (Ox): FOLFOX until progression
Overall, 35% of patients in arm A did not receive second‑line therapy because of poor performance score or death. Only 23% of patients received all 3 drugs, and treatment delays and modifications occurred in less than 40% of patients. However, 50% of patients taking oxaliplatin required a dose delay or modification, which was likely due to peripheral neuropathy.
Patient numbers declined significantly by the time salvage therapy was initiated. For instance, in arm A (the control arm), 710 patients initially started treatment, but only 153 eventually received salvage treatment. Similar decreases were observed in arms B and C.
Ir + 5-FU (n = 178)
Time to failure of first 2 drugs
Arm A: 35% of patients did not proceed to second line therapy due to death or poor PS
Only 23% of patients received all 3 drugs following amendment
Treatment delays and modifications occurred in < 40% of patients
As an exception, 50% of patients on oxaliplatin required delay or dose modification
Seymour MT, et al. Lancet. 2007;370:

12. Combination vs Sequential Therapy: FOCUS Study (cont’d)
Treatment Arm, mos OS
P Value
Arm A: 5-FU until failure, then switch to Ir
13.9 --
Arm B (Ir): 5-FU until failure, then add Ir
15.0 NS
Arm B (Ox): 5-FU until failure, then add Ox
15.2
Arm C (Ir): 5-FU + Ir until failure
16.7
A vs C (P = .02)
A vs C (Ir) (P = .01)
Arm C (Ox): 5-FU + Ox until failure
15.4
5-FU, 5-fluorouracil; FOCUS, Fluorouracil, Oxaliplatin, and CPT11 (irinotecan)—Use and Sequencing; Ir, irinotecan; Ox, oxaliplatin.
Overall survival for arm A (control) was 13.9 months. For patients receiving 5-FU until failure and then adding irinotecan (arm B [Ir]), the overall survival was 15.0 months, and for those instead adding oxaliplatin (arm B [Ox]), the overall survival was 15.2 months. As expected, no significant difference was seen in arm B vs arm A regardless of whether irinotecan or oxaliplatin was added to 5-FU on failure. In arm C, FOLFIRI until failure was associated with statistically significant overall survival improvement (P = .01) whereas FOLFOX until failure was not.
Seymour MT, et al. Lancet. 2007;370:

13. Conclusions From CAIRO and FOCUS
2 large trials (CAIRO and FOCUS) addressed sequential vs combination chemotherapy
No biologics were included
Supports an alternative to aggressive combined cytotoxic chemotherapy
Patient dependent
Unlikely that these studies will change the current US standard of combination therapy, but results are thought provoking
CAIRO, Capecitabine, Irinotecan, Oxaliplatin; FOCUS, Fluorouracil, Oxaliplatin, and CPT11 (irinotecan)—Use and Sequencing.
Both the CAIRO and FOCUS trials addressed sequential vs combined chemotherapy treatment of patients with colorectal cancer. Neither study included biologic therapies (eg, monoclonal antibodies). The results demonstrate alternatives to aggressive combined cytotoxic chemotherapy for patients seeking systemic chemotherapy for palliative reasons. However, I would not necessarily consider a sequential regimen for patients who will receive surgery with curative intent.
It is unlikely that these studies will change the current standard of combined chemotherapy in the frontline treatment of patients with colorectal cancer in the United States. However, the results indicate that a patient who may not be the best candidate for combined chemotherapy upfront can be started with a sequential regimen, and then oxaliplatin or irinotecan can be added as needed or as tolerated.

14. Aggressive Combination Therapy: When the Goal Is Curative Intent
In the next section, we will explore the use of aggressive combination therapy when the goal is curative intent. 14

15. First-line FOLFOXIRI Followed by Surgical Resection of mCRC
R0 surgery performed
(n = 37; 19%)
First-line FOLFOXIRI
Surgery revaluated
(n = 71; 36%)
Patients with unresectable metastatic colorectal cancer
(N = 196)
R1 surgery (n = 5)
Explorative surgery (n = 5)
No surgery (n = 35)
Preoperative Chemotherapy
Median cycles, n
11 (3-15)
Median duration, mos
5.5 ( )
Median time from end of CT to surgery, mos
1.9 ( )
Objective responses, n
Complete
Partial
Stable 5 28 4
Response rate
85%
CT, computed tomography; FOLFOXIRI, irinotecan, oxaliplatin, infusional 5-fluorouracil/leucovorin; mCRC, metastatic colorectal cancer; R0, complete resection; R1, resection with microscopic residual disease.
The Italian cooperative group, G. O. N. O., evaluated the FOLFOXIRI regimen in the treatment of unresectable metastatic colorectal carcinoma, demonstrating a 66% response rate in this setting.[1]
A companion study was conducted by Masi and colleagues in 196 patients with unresectable metastatic colorectal carcinoma who received FOLFOXIRI. A total of 71 (36%) patients were revaluated for surgery. Of those patients, 37 (19%) received an R0 resection, 5 patients had an R1 resection, 5 patients had exploratory surgery, and 35 patients had no surgery. A median of 11 cycles of preoperative chemotherapy were given, and the median duration of treatment was 5.5 months; this was slightly longer than commonly used in the neoadjuvant setting. However, these patients were originally considered unresectable, and only about 15% to 20% of patients who are able to convert from surgically unresectable to respectable hepatic disease.
The median time from the end of chemotherapy to surgery was just short of 2 months and the overall response rate was 85%, including 5 complete responses, 28 partial responses, and 4 patients with stable disease.
Reference
1. Falcone A, Masi G, Brunetti I, et al. The triplet combination of irinotecan, oxaliplatin and 5FU/LV (FOLFOXIRI) vs the doublet of irinotecan and 5FU/LV (FOLFIRI) as first-line treatment of metastatic colorectal cancer (MCRC): results of a randomized phase III trial by the Gruppo Oncologico Nord Ovest (G.O.N.O.). Program and abstracts of the 42nd Annual Meeting of the American Society of Clinical Oncology; June 2-6, 2006; Atlanta, Georgia. Abstract 3513.
Masi G, et al. ECCO Abstract 3022.

16. First-line FOLFOXIRI Followed by Surgical Resection of mCRC (cont’d)
100
PFS for R0 patients 75
Median PFS: months
5-year PFS: 16%
Survival (%) 50 25
100
OS for R0 patients 80 12 24 36 48 60 60
Figures used with permission from Gianluca Masi, MD.
FOLFOXIRI, irinotecan, oxaliplatin, infusional 5-fluorouracil/leucovorin; mCRC, metastatic colorectal cancer; OS, overall survival; PFS, progression-free survival; R0, complete resection.
After a median follow‑up of approximately 60 months, the progression‑free survival for patients who had an R0 resection was 17.8 months. Median survival in this group was 39 months and the 5‑year overall survival rate was 40%. These results demonstrate that despite having “unresectable” disease, if patients can have an R0 resection, they have a very favorable 5-year survival rate.
Months
Survival (%) 40
Median OS: 39+ months
5-year OS: 40% 20 12 24 36 48 60 72 84 96
Months
Masi G, et al. ECCO Abstract 3022.

17. Chemotherapy-Free Intervals: What Have We Learned?
Few data exist regarding chemotherapy‑free intervals. 17

18. Maintenance Therapy (OPTIMOX1) Chemotherapy-Free Interval (OPTIMOX2)
OPTIMOX2: Study Schema
Maintenance Therapy (OPTIMOX1)
FOLFOX7 x 6 cycles
LV5FU2 before tumor progresses to baseline size
FOLFOX7 reintroduction
(n = 99)
Patients with metastatic colorectal
cancer
(N = 202)
Chemotherapy-Free Interval (OPTIMOX2)
FOLFOX7 x 6 cycles
No maintenance until tumor
progresses to baseline size
FOLFOX7 reintroduction
(n = 103)
5FU, 5-fluorouracil; FOLFOX7, oxaliplatin, 5-fluorouracil/leucovorin; LV, leucovorin.
The OPTIMOX1 study evaluated an oxaliplatin‑free interval, whereas OPTIMOX2 assessed a full chemotherapy‑free interval.[1] Originally meant to be a phase III trial, OPTIMOX2 was amended to a phase II study of approximately 200 patients following the FDA approval of bevaciuzmab.
OPTIMOX1 used a regimen of FOLFOX for 6 cycles and then held the oxaliplatin while patients received only 5‑FU/leucovorin until their tumor had progressed to its baseline size, after which FOLFOX was then reinitiated. OPTIMOX2 also allowed patients to receive FOLFOX7 for 6 cycles, but then held all chemotherapy until the tumor had returned to its original size, after which FOLFOX was reintroduced. Many clinicians would find this schedule ethically difficult to administer because no treatment would be provided until the tumor had returned to its normal size.
For more information on this study, go online to:
Reference
1. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-go fashion in advanced colorectal cancer—a GERCOR study. J Clin Oncol. 2006;24:
Maindrault-Goebel F, et al. ASCO Abstract 4013. 18

19. OPTIMOX2 Study: PFS and OS
Trend toward improved PFS (P = .08) and OS (P = .0549) with maintenance therapy
Median PFS
Maintenance therapy (OPTIMOX1): 36 weeks
CFI (OPTIMOX 2): 29 weeks
Median OS
Maintenance therapy (OPTIMOX1): 26 months
CFI (OPTIMOX2): 19 months
No statistically significant difference in median PFS after FOLFOX7 reintroduction between OPTIMOX 2 (maintenance therapy) vs OPTIMOX 1 (chemotherapy-free interval) (17 vs 18 weeks)
CFI, chemotherapy-free interval; FOLFOX7, oxaliplatin, 5-fluorouracil/leucovorin; LV, leucovorin; OS, overall survival; PFS, progression-free survival.
Maindrault‑Goebel and colleagues noted a trend in OPTIMOX2 toward improved progression-free (P = .08) and overall survival (P = .0549) with maintenance therapy. Median progression‑free survival for patients who received maintenance therapy in OPTIMOX1 was 36  vs 29 weeks for those who had a chemotherapy‑free interval in OPTIMOX2. Median overall survival times were 26 and 19 months, respectively, but that resulted in a trend toward improved survival of only In the end, no statistically significant difference was seen in median progression‑free survival after FOLFOX7 was reintroduced between OPTIMOX2 and OPTIMOX1.
For more information on this study, go online to:
Maindrault-Goebel F, et al. ASCO Abstract 4013. 19

20. OPTIMOX2 Study: Toxicity Results
Incidence of grade 3 neuropathy similar between arms
Grade 3/4 Toxicity, %
OPTIMOX1
Maintenance Therapy
OPTIMOX2
Chemotherapy-Free Interval
FOLFOX7
Cycles 1-6
(n = 99)
LV5FU2
Maintenance
(n = 68)
Reintroduction
(n = 52)
(n = 103)
FOLFOX7 Reintroduction
(n = 62)
Neutropenia 19 6 12
Thrombocytopenia 1 4 2
Diarrhea 7
Vomiting 3
5FU, 5-fluorouracil; FOLFOX7, oxaliplatin, 5-fluorouracil/leucovorin; LV, leucovorin.
Toxicity rates were comparable between studies, including the incidence of grade 3/4 neuropathy.
For more information on this study, go online to:
Maindrault-Goebel F, et al. ASCO Abstract 4013.

21. Conclusions From OPTIMOX2 Study
Originally a phase III trial that was amended to a smaller phase II study
No statistical difference in PFS across arms
OS trend in favor of maintenance therapy
Chemotherapy was not reinitiated until the tumor had grown to its baseline size
OPTIMOX2 results did not define the utility vs futility of a chemotherapy-free interval in the reinitiation of chemotherapy at progression
Clearly does not support discontinuing treatment completely until tumor grew back to baseline dimensions
Chemo-free intervals best individualized per patient
OS, overall survival; PFS, progression-free survival.
No significant difference in progression‑free survival was seen across arms, and only a small overall survival trend was seen in favor of maintenance therapy. Chemotherapy was not reinitiated, however, until the tumor had grown back to its baseline size. Of importance, OPTIMOX2 results did not define the utility or futility of a chemotherapy‑free interval in terms of the reinitiation of chemotherapy on progression because patients were required to have tumors that returned back to their baseline size. Many clinicians do not incorporate that into their practice, and these data clearly do not support completely discontinuing treatment. In my opinion, chemotherapy‑free intervals should be individualized for specific patients. One challenging issue that remains is how to incorporate chemotherapy-free intervals into clinical trials.
For more information on this study, go online to:

22. Continuation of Therapy After Disease Progression
Continuing bevacizumab following progression remains controversial. This strategy is based on a trial, conducted by Hurwitz and colleagues, of IFL with or without bevacizumab, in which patients in the bevacizumab arm were allowed to continue treatment following progression.
Reference
Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350: 22

23. BRiTE Trial: Study Schema
Exploratory, observational, nonrandomized analysis
No treatment
(n = 253)
Grouping based on physician choice
Patients with previously untreated metastatic colorectal cancer receiving bevacizumab in combination with first-line chemotherapy
First PD
(N = 1445)
CT/EGFR inhibitor without Bevacizumab
(n = 531)
BRiTE, First-Line Bevacizumab Regimens: Investigation of Treatment Effects and Safety; CT, chemotherapy; EGFR, epidermal growth factor receptor; PD, progressive disease.
Grothey conducted an analysis of data from the observational BRiTE study, which focused on patients who continued bevacizumab following first-line progression. This analysis looked at patients who had received any bevacizumab in combination with chemotherapy; 1445 of this group had evidence of disease progression. The investigators then compared patients who received no treatment vs those who continued without bevacizumab vs those who continued bevacizumab.
For more information on this study, go online to:
CT/EGFR inhibitor with Bevacizumab
(n = 642)
Grothey A, et al. ASCO Abstract 4036.

24. BRiTE Trial: Use of Bevacizumab After First Disease Progression
Multivariate analysis indicates use of postprogression bevacizumab significantly and independently associated with better survival outcomes
Outcomes After First Disease Progression
Outcome
No Treatment
(n = 253)
CT/EGFR Inhibitor/No Bev
(n = 531)
CT/EGFR Inhibitor/Bev
(n = 642)
1-yr survival, % (95% CI)
52.5 ( )
77.3 ( )
87.7 ( )
Median OS, mos (95% CI)
12.6 ( )
19.9 ( )
31.8 (27.9-NE)
Median OS beyond first progression, mos (95% CI)
3.6 ( )
9.5 ( )
19.2 ( )
Bev, bevacizumab; BRiTE, First-Line Bevacizumab Regimens: Investigation of Treatment Effects and Safety; CI, confidence interval; CT, chemotherapy; EGFR, epidermal growth factor receptor; OS, overall survival.
Multivariate analysis indicated that the use of postprogression bevacizumab was significantly and independently associated with better survival outcomes in patients with colorectal cancer. Of patients who received no treatment, only 52.5% were alive at 1 year. Of patients who received second‑line therapy without bevacizumab, 77.3% were alive at 1 year. By contrast, 87.7% of patients who continued bevacizumab were alive at 1 year.
Of importance, the median survival time for patients who received no treatment was 12.6 months, which is comparable to historical data. Second‑line therapy increased survival to 20 months, with the addition of bevacizumab extending survival to 31.8 months. This is the longest median overall survival reported thus far.
For more information on this study, go online to:
NE, not yet estimated.
Grothey A, et al. ASCO Abstract 4036. 24

25. BRiTE Trial: Toxicity Results
No significant differences in adverse events between the bevacizumab and nonbevacizumab subgroups, before or after disease progression
New or exacerbated hypertension requiring medication: 24.6% vs 19.2%
Arterial thrombotic event: 1.2% vs 1.3%
Grade 3/4 bleeding event: 1.9% vs 2.1%
Gastrointestinal perforation: 1.6% vs 1.5%
No increase in bevacizumab-associated adverse events in group that received bevacizumab after progression
BRiTE, First-Line Bevacizumab Regimens: Investigation of Treatment Effects and Safety.
Data from BRiTE showed no significant difference in adverse event rates between the bevacizumab and nonbevacizumab subgroups. The degree of hypertension, arterial thrombotic events, bleeding, and gastrointestinal perforations was comparable to previously reported data. Additionally, no increase in bevacizumab‑associated adverse events was seen in the group that received bevacizumab after progression.
For more information on this study, go online to:
Grothey A, et al. ASCO Abstract 4036. 25

26. Conclusions of Postprogression Anti-VEGF Therapy
BRiTE provided data on what is currently occurring in the “real world”
Very high OS
However, BRiTE study only observational
Not randomized
Dose reductions left to the physicians’ discretion
No exclusion criteria
BRiTE, First-Line Bevacizumab Regimens: Investigation of Treatment Effects and Safety; OS, overall survival.
Although these are encouraging results, it should be noted that BRiTE is an observational study, not a randomized trial. The results are much better than those seen in other trials, though many of those patients received bevacizumab postprogression. The dose reductions were left to the discretion of the treating physician, and there were no exclusion criteria. Therefore, even patients with a recent myocardial infarction or a cerebrovascular accident within the past year could still be included in the study. Thus, although intriguing and thought-provoking, these data need to be considered prospectively.
For more information on this study, go online to:

27. SPIRITT: Second-line Treatment in Metastatic Colorectal Cancer
Phase II study opened November 2006
FOLFIRI q2w
+ Panitumumab 6 mg/kg
Patients with metastatic colorectal cancer who failed first-line fluoropyrimidine and oxaliplatin-based chemotherapy with at least 4 doses of bevacizumab
(recruiting 200)
FOLFIRI q2w
+ Bevacizumab 5 or 10 mg/kg
FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; q2w, every 2 weeks; SPIRITT, Second-Line Panitumumab-Irinotecan Treatment Trial.
The strategy of continuing bevacizumab following progression in colorectal cancer continues to be evaluated in clinical trials. For example, Hecht and colleagues have initiated the SPIRITT trial, in which the primary endpoint is progression-free survival. SPIRITT is enrolling patients who have failed first‑line 5‑FU– and oxaliplatin‑based therapy and who have received at least 4 doses of bevacizumab (planned N = 200). Patients will be randomized to FOLFIRI with panitumumab 6 mg/kg or FOLFIRI with additional bevacizumab at either 5 or 10 mg/kg.
ClincialTrials.gov. Available at: Accessed January 9, 2008.

28. SWOG 0600: Second-line Metastatic Colorectal Cancer
Study opened October 2007
FOLFIRI or Irinotecan
+ Cetuximab
FOLFIRI or Irinotecan
+ Cetuximab
+ Bevacizumab 5 mg/kg
Patients with metastatic colorectal cancer who progressed during first-line therapy
FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; q2w, every 2 weeks; SWOG, Southwest Oncology Group.
The phase III trial SWOG 0600 study, also known as the iBET trial, opened in October 2007 and also is enrolling patients who have failed first‑line chemotherapy. Patients are randomized to FOLFIRI or irinotecan plus standard cetuximab with the addition of bevacizumab at 5 mg/kg or 10 mg/kg (the current FDA‑approved dose in the second‑line setting).
FOLFIRI or Irinotecan
+ Cetuximab
+ Bevacizumab 10 mg/kg
ClincialTrials.gov. Available at: Accessed January 9, 2008.

29. Future of Combined Biologic Therapy
What is the future of combined biologic therapy? 29

30. PACCE: Panitumumab With CT + Bevacizumab for mCRC
Panitumumab 6 mg/kg Q2W
+ Ox-CT
+ Bevacizumab
Ox-based CT
(eg, FOLFOX)
(n = 800)
Ox-CT
+ Bevacizumab
Patients with measurable metastatic colorectal cancer per modified RECIST criteria and ECOG performance score 0 or 1
Panitumumab 6 mg/kg Q2W
+ Iri-CT
+ Bevacizumab
Iri-based CT
(eg, FOLFIRI)
(n = 200)
BOND, bowel oncology with cetuximab antibody; CT, chemotherapy; ECOG, Eastern Cooperative Oncology Group; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; FOLFOX, 5-fluorouracil, leucovorin, oxaliplatin; Iri, irinotecan; Ox, oxaliplatin; Q2W, every 2 weeks; RECIST, response evaluation criteria in solid tumors.
The BOND trial of cetuximab plus bevacizumab with or without irinotecan served as the platform for the consideration of combined biologic treatment for patients with metastatic colorectal cancer.[1] Hecht and colleagues conducted a subsequent phase III study evaluating the use of chemotherapy and bevacizumab with or without panitumumab in previously untreated patients. Patients were assigned by physician choice to either a cohort of eight hundred patients receiving an oxaliplatin‑based regimen with bevacizumab or a cohort of 200 patients receiving an irinotecan‑based regimen with bevacizumab. Each cohort was randomized to receive chemotherapy plus bevacizumab, with or without panitumumab. Our discussion will focus on the oxaliplatin arms only.
Reference
1. Cunningham D, Humblet Y, Siena S, et al. Cetuximab (C225) alone or in combination with irinotecan (CPT-11) in patients with epidermal growth factor receptor (EGFR)-positive, irinotecan-refractory metastatic colorectal cancer (MCRC). Program and abstracts of the 39th Annual Meeting of the American Society of Clinical Oncology; May 31 - June 3, 2003; Chicago, Illinois. Abstract 1012.
Iri-CT
+ Bevacizumab
Stratification factors: ECOG performance score, previous adjuvant therapy, disease site, Ox doses/Iri regimen, number of organs with metastasis
Tumor assessments: Every 12 weeks until disease progression or intolerability
Hecht JR, et al. WCGIC Abstract 273.

31. PACCE: Panitumumab With CT + Bevacizumab for mCRC (cont’d)
Adverse Event in Ox-CT Cohort
Pmab + Bev/Ox-CT (n = 401)
Bev/Ox-CT (n = 392)
Any event, %
Grade 3
Grade 4
Grade 5*
100 53 28 4 52 18 3
Any serious adverse event, % 56 37
Discontinued first-line treatment due to adverse event, % 19 20
Discontinued panitumumab due to adverse event, % 26
N/A
Panitumumab-related serious adverse event, %
Bev/Ox, bevacizumab, oxaliplatin; CT, chemotherapy; mCRC, metastatic colorectal cancer; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events.
The addition of panitumumab to bevacizumab and oxaliplatin-based chemotherapy did not significantly increase the incidences of grade 3 events, but more serious adverse events, including grade 4 and 5 (death) events, were noted. In the panitumumab arm, 19% of patients discontinued treatment because of an adverse event, which was comparable to the control arm, while 26% of patients discontinued the panitumumab component because of an adverse event.
N/A, not applicable.
*Not including disease progression (ie, neoplasms). Safety set included all patients who were dosed. Graded per NCI CTCAE v3.0.
Hecht JR, et al. WCGIC Abstract 273.

32. PACCE: Panitumumab With CT + Bevacizumab for mCRC (cont’d)
Grade 3/4 Adverse Events in
Ox-CT Cohort, %
Pmab + Bev/Ox-CT (n = 401)
Bev/Ox-CT (n = 392)
Grade 3
Grade 4
Skin toxicity 33
< 1 1
Diarrhea 21 2 12
Dehydration 14 4
Hypokalemia 8 3
Hypomagnesemia
Neutropenia 10 17 7
Neuropathy 9
Nausea
Infections* 16
Deep venous thrombosis 6
Pulmonary embolism†
Bev/Ox, bevacizumab, oxaliplatin; CT, chemotherapy; mCRC, metastatic colorectal cancer; Pmab, panitumumab.
Reported data showed more skin toxicities with the use of panitumumab, which is not surprising for an anti‑EGFR therapy. Additionally, panitumumab was associated with slightly more grade 3/4 diarrhea, dehydration, and hypokalemia. More importantly, there was an increased incidence of pulmonary embolism with panitumumab vs the control arm. There were also higher incidences of infection and nausea in the panitumumab arm.
*Grade 5 infections occurred in 2 patients (1%) on Pmab + Bev/Ox-CT and 3 patients (1%) on Bev/Ox-CT.
†Grade 5 pulmonary embolism occurred in 2 patients (1%) on Pmab + Bev/Ox-CT.
Hecht JR, et al. WCGIC Abstract 273.

33. PACCE: Panitumumab With CT + Bevacizumab for mCRC (cont’d)
Death Outcomes in Ox-CT Cohort, n (%)
Pmab + Bev/Ox-CT (n = 401)
Bev/Ox-CT (n = 392)
Deaths on study
83 (20)
58 (15)
All-cause deaths within 60 days of first dose
10 (2)
6 (2)
All-cause deaths within 30 days of last dose of first-line treatment
26 (6)
13 (3)
Safety set included all patients who were dosed
Bev, bevacizumab; CT, chemotherapy; mCRC, metastatic colorectal cancer; Ox, oxaliplatin.
Eighty-three deaths occurred in the panitumumab arm, including 10 all‑cause deaths within 60 days of the first dose and 26 deaths within 30 days of the last dose.
Hecht JR, et al. WCGIC Abstract 273.

34. Objective Response Rates
PACCE: Panitumumab With CT + Bevacizumab for mCRC (cont’d)
Objective Response Rates
< 1
100 CR PR 80 39 40 38 31 SD PD 60
Patients (%)
Not done/unevaluable 31 33 26 37 40 9 4 6 4 20
Bev, bevacizumab; CT, chemotherapy; Iri, irinotecan; mCRC, metastatic colorectal cancer; Ox, oxaliplatin; PD, progressive disease; Pmab, panitumumab; PR, partial response.
Response data showed no significant difference between the experimental and control arms. However, the patient numbers were quite small in the irinotecan arms. 24 22 26 27
Pmab + Bev/
Ox-CT
(n = 407)
Bev/
Ox-CT
(n = 405)
Pmab + Bev/
Iri-CT
(n = 68)
Bev/
Iri-CT
(n = 67)
Maximum % change in sum of longest diameter of target lesions similar between Pmab + Bev and Bev arms of Ox-CT cohort
Hecht JR, et al. WCGIC Abstract 273.

35. PACCE: Panitumumab With CT + Bevacizumab for mCRC (cont’d)
PFS Events, n (%)
Median (95%CI), mos
206 (50)
9.0 ( )
172 (42)
10.5 ( )
Pmab + Bev/Ox-CT
Bev/Ox-CT
100
ITT set 80
HR: 1.29 (95% CI: ) 60
Proportion Progression Free
Figure used with permission from J. Randolph Hecht, MD.
Bev, bevacizumab; CI, confidence interval; CT, chemotherapy; HR, hazard ratio; ITT, intent to treat; mCRC, metastatic colorectal cancer; Ox, oxaliplatin; PACCE, Panitumumab Advanced Colorectal Cancer Evaluation; PFS, progression-free survival.
The primary endpoint of the PACCE trial was progression‑free survival. This slide shows that no extra benefit was gained from the addition of panitumumab to bevacizumab and oxaliplatin; median progression-free survival times were 9 vs 10.5 months, respectively, with a hazard ratio of 1.29. 40 20 5 10 15 20
Months
Hecht JR, et al. WCGIC Abstract 273.

36. Unplanned Interim OS (Ox-CT Cohort)
PACCE: Panitumumab With CT + Bevacizumab for mCRC (cont’d)
Unplanned Interim OS (Ox-CT Cohort)
Oct 2006 Data Cutoff*
Apr 2007 Data Cutoff
OS Events, n (%)
Median, mos (95%CI)
83 (20)
18.4 (13.8-NE)
58 (14) NE
OS events, n (%)
Median, mos (95%CI)
127 (31)
18.6 ( )
95 (23) NE
100
HR: 1.56 (95% CI: )
HR: 1.44 (95% CI: )
100 80 80 60 60
Proportion Alive (%)
Figure used with permission from J. Randolph Hecht, MD.
Bev, bevacizumab; CI, confidence interval; CT, chemotherapy; HR, hazard ratio; mCRC, metastatic colorectal cancer; NE, not estimable; OS, overall survival; Ox, oxaliplatin; Pmab, panitumumab.
Results as of October 2006 showed that the median overall survival reported with the combined experimental arm was 18.4 months and had not yet been reached for the control arm. An April 2007 update continued to show no difference, with median overall survival times of 18.6 months and, again, not yet reached for the control arm. This demonstrates that the inclusion of biologic therapy in chemotherapy regimens should be considered as part of a protocol. 40 40
Pmab + bev/Ox-CT
Bev/Ox-CT 20 20 4 8 12 16 20 5 10 15 20 25
Months
Months
*Interpretation of statistical significance is limited by the lack of a prespecified significance boundary.
Hecht JR, et al. WCGIC Abstract 273.

37. CAIRO2: CAPOX-B ± Cetuximab in Advanced Colorectal Cancer
Interim analysis of randomized phase III study
Cycles 1-6 Capecitabine 1000 mg/m2 twice daily on Days Oxaliplatin 130 mg/m2 on Day 1 Bevacizumab 7.5 mg/kg on Day 1
Cycles 7 and beyond Capecitabine 1250 mg/m2 twice daily on Days Bevacizumab 7.5 mg/kg on Day 1
Stratified by previous adjuvant chemotherapy, serum LDH, number of affected organs, and institution
Patients with advanced colorectal cancer, no previous systemic treatment for advanced disease, and WHO PS 0-1
(N = 755)
CAPOX-B, capecitabine, oxaliplatin, bevacizumab; LDH, lactate dehydrogenase; OS, overall survival; PFS, progression-free survival; WHO PS, World Health Organization performance score.
Ongoing studies of biologic therapy–containing combinations include CAIRO2, a phase III study which is evaluating both anti‑EGFR and anti‑VEGF therapy in previously untreated patients (N = 755) with advanced colorectal cancer. All patients received capecitabine with oxaliplatin and bevacizumab on an every-3-week schedule for cycles 1-6; cycles 7 and beyond used full‑dose capecitabine with bevacizumab. The experimental arm also received cetuximab weekly.
Capecitabine/Oxaliplatin/Bevacizumab* as above Cetuximab 400 mg/m2 initial dose then 250 mg/m2 weekly
Primary endpoint: PFS
Secondary endpoints: OS, response rate, toxicity, quality of life
*3-week cycles.
Tol J, et al. ECCO Abstract 3000.

38. CAIRO2: CAPOX-B ± Cetuximab in Advanced Colorectal Cancer (cont’d)
Interim Safety Analysis
Adverse Event, %
CAPOX-B (n = 197)
CAPOX-B + Cetuximab (n = 192)
Any grade 3/4 event 72
81*
All grade acneiform skin rash 4
82†
Grade 3 acneiform skin rash 1
26†
Nail changes, all grades 12
31†
Grade 3 nail changes 6†
Hematologic, grade 3/4
Anemia
Neutropenia 5 2
Thrombocytopenia
CAPOX-B, capecitabine, oxaliplatin, bevacizumab.
The addition of cetuximab to chemotherapy increased the incidence of rash, but overall no significantly increased hematologic toxicities were noted.
*P =.03; difference explained by cetuximab-associated skin toxicity. †P < .001
Tol J, et al. ECCO Abstract 3000.

39. CALGB/SWOG 80405: Cetuximab and/or Bevacizumab + Combo Chemo
Cetuximab 400 mg/m2 IV on Day 1, then 250 mg/m2 once weekly
Patients with untreated metastatic colorectal cancer
(N = 2289)*
Patient/physician choice: mFOLFOX6 or FOLFIRI
Bevacizumab 5 mg/kg IV every 2 weeks
CALGB, Cancer and Leukemia Group B; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; FOLFOX, 5-fluorouracil, oxaliplatin, leucovorin.
The CALGB/SWOG study (planned N = 2289) is evaluating first-line combined biologic therapy for patients with metastatic colorectal cancer. Patients and physicians decided on FOLFOX or FOLFIRI, after which patients are randomized to cetuximab, bevacizumab, or both. The primary endpoint here is overall survival, which was mandated by the US Food and Drug Administration (FDA); progression-free survival is the secondary endpoint.
Cetuximab 400 mg/m2 IV on Day 1, then 250 mg/m2 once weekly + Bevacizumab 5 mg/kg IV every 2 weeks
Primary endpoint: OS. Secondary endpoints: PFS, response rate
*Recruitment ongoing.
ClinicalTrials.gov. Available at: Accessed January 9, 2008.

40. Summary of Combined Biologic Therapy
Interim safety analysis from PACCE indicated that combined biologic therapy may not provide added benefit in the setting of an oxaliplatin-based regimen in combination with panitumumab
Demonstrates the importance of phase II trials
Suggested combined biologic therapy is best utilized as part of a clinical trial
Preliminary results of CAIRO2 and CALGB have not demonstrated increased morbidity or decreased efficacy with addition of biologics
In summary, the interim safety analysis from PACCE indicated that combined biologic therapy (panitumumab, bevacizumab, and oxaliplatin) may not provide added benefit. However, it demonstrates the importance of phase II trials. Prior to the development of PACCE there were little data regarding panitumumab in combination with chemotherapy. Data from PACCE suggest that combined biologic therapy is best used as part of a clinical trial. Preliminary safety results from CAIRO2 have not demonstrated increased toxicities due to using 2 biologic agents in combination.

41. Results of ASCO 2007 and Anti-EGFR Therapy: Changing the Paradigm?
I will turn now to the question of anti-EGFR data presented at the 2007 ASCO meeting, and how these results may shift the treatment paradigm in colorectal cancer. 41

42. CRYSTAL Trial: FOLFIRI ± Cetuximab
FOLFIRI 5-FU bolus 400 mg/m2, infusion 2400 mg/m2 + Irinotecan 180 mg/m2 + Leucovorin 400 mg/m2 every 2 weeks
(n = 609)
Patients with previously untreated EGFR-expressing metastatic colorectal cancer, stratified by geographical region, ECOG performance score
(N = 1217)
FOLFIRI + Cetuximab 5-FU bolus 400 mg/m2, infusion 2400 mg/m2 + Irinotecan 180 mg/m2 + Leucovorin 400 mg/m2 every 2 weeks Cetuximab 400 mg/m2 initial dose, then 250 mg/m2 weekly (n = 608)
5-FU, 5-fluorouracil; CRYSTAL, Cetuximab combined with iRinotecan in first-line therapY for metaSTatic colorectAL cancer; ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan.
Van Cutsem and colleagues evaluated the role of cetuximab in the front‑line setting in the phase III CRYSTAL trial, which enrolled previously untreated patients with EGFR-expressing metastatic colorectal cancer. Patients were randomized to FOLFIRI with or without cetuximab.
For more information on this study, go online to:
Van Cutsem E, et al. ASCO Abstract 4000. 42

43. CRYSTAL Trial FOLFIRI ± Cetuximab: PFS Results
Outcome
FOLFIRI + Cetuximab (n = 599)
FOLFIRI (n = 599)
P Value
HR (95% CI)
Median PFS, mos
8.9
8.0
.0479
( )
For patients with liver metastases only
11.4
(n = 122)
9.2
(n = 134)
.023
( )
1-yr PFS, % 34 23 --
CI, confidence interval; FOLFIRI, 5-fluorouracil, leucovorin, irinotecan; HR, hazard ratio; PFS, progression-free survival.
The addition of cetuximab significantly improved progression-free survival (P = .0479), the primary endpoint of the CRYSTAL trial. Patients with liver metastases only fared the best, with median progression-free survival of 11.4 vs 9.2 months. The 1‑year progression-free survival rate was 34% vs 23% without cetuximab.
For more information on this study, go online to:
Van Cutsem E, et al. ASCO Abstract 4000. 43

44. CRYSTAL Trial FOLFIRI ± Cetuximab: Safety Results
Combination of cetuximab and FOLFIRI generally well tolerated
≥ Grade 3 Adverse Events, %
FOLFIRI + Cetuximab (n = 600)
FOLFIRI (n = 602)
Any
78.0
59.5
Neutropenia
26.7
23.3
Febrile neutropenia
2.7
2.2
Diarrhea
15.2
10.5
Vomiting
4.5
5.0
Fatigue
Skin reactions
18.7
0.2
Infusion-related reactions
2.3
FOLFIRI, 5-fluorouracil, leucovorin, irinotecan.
The safety results showed similar toxicities between study arms, although more skin reactions were noted with the use of anti‑EGFR therapy. Additionally, patients are always at risk of allergic hypersensitivity reaction.
For more information on this study, go online to:
Van Cutsem, et al. ASCO Abstract 4000. 44

45. CRYSTAL Trial: Surgery With Curative Intent
In cetuximab arm, significantly more patients undergoing surgery with curative intent had successful resection
Outcome, %
FOLFIRI + Cetuximab (n = 599)
FOLFIRI (n = 599)
Surgery with curative intent
6.0
2.5
No residual tumor after resection
4.3*
1.5
No residual tumor in patients with liver metastases only
9.8
4.5
FOLFIRI, 5-fluorouracil, leucovorin, irinotecan.
Those patients who underwent surgery with curative intent benefited from the addition of cetuximab to FOLFIRI. Those patients who received the combination and had liver metastases only had an R0 resection rate of 9.8% vs 4.5% for those who received FOLFIRI alone.
For more information on this study, go online to:
*P = .0034
Van Cutsem, et al. ASCO Abstract 4000.

46. EPIC: Cetuximab in Irinotecan-Naive Colorectal Cancer
Stratified by study site, ECOG performance score (0-1, 2)
Cetuximab† + Irinotecan‡ (n = 648)
Failure of oxaliplatin-based therapy*; EGFR positive by IHC
Irinotecan‡ (n = 650)
ECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor; IHC, immunohistochemistry; OS, overall survival; PFS, progression-free survival; RR, response rate; RT, radiotherapy.
Several studies have investigated whether it would be beneficial to use cetuximab in the treatment of patients who had not been exposed to irinotecan, the current FDA-approved regimen. The phase III EPIC trial enrolled EGFR-positive metastatic colorectal cancer patients who had failed an oxaliplatin‑based regimen and randomized them to irinotecan with or without cetuximab. The primary endpoint was overall survival.
Primary endpoint: OS Secondary endpoints: PFS, RR, disease control rate, safety, quality of life
*Failure = progression of disease or intolerance ≤ 6 months after the last dose of any agent.
†400 mg/m2 IV Week 1, then 250 mg/m2 IV weekly. ‡350 mg/m2 every 3 weeks; 300 in patients 70 years of age or older, previous RT, ECOG performance score 2.
Sobrero AF, et al. AACR Abstract LB-2.

47. EPIC: Cetuximab in Irinotecan-Naive Colorectal Cancer (cont’d)
Overall Survival 20
HR: (95.03% CI: )
Stratified log rank P = .7115 15
10.71
9.99
Months 10
CI, confidence interval; HR, hazard ratio.
Results showed that the combination of irinotecan and cetuximab was equivalent to single‑agent irinotecan in terms of overall survival. Yet, a fair amount of patients on the irinotecan-only arm proceeded to receive cetuximab. 5
Cetuximab + Irinotecan
(n = 648)
Irinotecan
(n = 650)
Sobrero AF, et al. AACR Abstract LB-2.

48. Quality of Life With Addition of Cetuximab to Irinotecan: EPIC Trial
Better quality of life observed with combination therapy despite higher incidence of select adverse effects (diarrhea and fatigue)
Patients who received cetuximab demonstrated significantly greater improvements in several quality-of-life factors vs control arm
Global health status (P = .049)
Functional scales
Physical (P = .002)
Role (P = .003)
Emotional (P = .002)
Cognitive (P < .001)
Symptom scales
Fatigue (P = .005)
Nausea/vomiting (P < .001)
Pain (P < .001)
Single items
Diarrhea (P = .017)
Insomnia (P = .035)
However, the response rate and progression-free survival data were favorable for the combination. The addition of cetuximab improved patients’ quality of life despite increased incidences of diarrhea and fatigue. Across multiple metrics, quality of life was improved with the use of cetuximab in the second‑line setting following oxaliplatin‑based therapy.
For more information on this study, go online to:
Eng C, et al. ASCO Abstract 4003. 48

49. Conclusions
Combination vs sequential: essential to identify the goals of therapy
Chemotherapy-free intervals are physician and patient dependent
OPTIMOX2 does not define our current practice of a chemotherapy-free interval
BRiTE trial provided essential information about the possible benefits of continuing anti-VEGF therapy
Must be prospectively evaluated in a controlled clinical trial—S0600
VEGF, vascular endothelial growth factor.
In conclusion, it is essential to identify the goals of combination vs sequential therapy in patients. Chemotherapy‑free intervals are physician- and patient‑dependent, and OPTIMOX2 does not define the current practice of a chemotherapy‑free interval, that is, most clinicians would not wait for a patient’s tumor to return to its baseline size. The BRiTE trial provided intriguing information about the possible benefits of continuing anti‑VEGF therapy, but should be prospectively evaluated in a controlled, randomized clinical trial, such as the S0600 or SPIRITT studies.

50. Conclusions (cont’d)
Combined biologic therapy is best given as part of a clinical trial
CALGB 80405
It is unlikely that the currently reported CRYSTAL and EPIC studies will change the paradigm of current management
CRYSTAL demonstrated that cetuximab is a reasonable alternative to bevacizumab for select patients
Combined biologic therapy continues to be evaluated in clinical trials, such as the CALGB 80405 and the CAIRO2 studies. When originally presented, it appeared unlikely that data from the CRYSTAL and EPIC studies would not change the paradigm of current first-line management. Results from the CRYSTAL trial demonstrated that cetuximab is a reasonable alternative for select patients who may not be optimal candidates for bevacizumab based therapy. Furthermore, many physicians continue to use bevacizumab following first-line progression despite the dearth of prospective data. A paradigm shift may soon be occurring with anti-EGFR therapy based on recent data demonstrating the role of KRAS as a predictive marker.

51. Go Online for Virtual Presentations and Downloadable Slides!
Download the PowerPoint slides from the symposium and listen and watch the CME-certified Virtual Presentations from:
Edward Chu, MD
Cathy Eng, MD J. Randolph Hecht, MD Eric Van Cutsem, MD, PhD
clinicaloptions.com/CRCsatellite2007