Chemotherapy Intensification Gianluca Masi, MD, and Alfredo Falcone, MD

Corresponding author Alfredo Falcone, MD Department of Oncology, Azienda USL-6 of Livorno Viale Alfieri, 36, 57124 Livorno, Italy. E-mail: [email protected] Current Colorectal Cancer Reports 2007, 3:116–122 Current Medicine Group LLC ISSN 1556-3790 Copyright © 2007 by Current Medicine Group LLC

Today the treatment of metastatic colorectal cancer is based on several treatment options incorporating chemotherapy, targeted agents, and the surgery of metastases, and a median survival of almost 2 years has been reached. Despite these advances and the availability of multiple lines of treatment, the choice of the first-line chemotherapy indeed still matters, and the development of chemotherapy regimens associated with improved efficacy is a key question in the “biologics era.” This review discusses the development of the triple drug combination FOLFOXIRI (irinotecan [CPT11], oxaliplatin, and 5-fluorouracil [5FU]/leucovorin [LV]). Several phase II trials demonstrated the feasibility of this combination and, more importantly, a phase III trial demonstrated that the triplet FOLFOXIRI is the first studied combination that significantly increases response rate, complete tumor resection of metastases, progression-free survival, and overall survival compared with an infusional 5FU containing doublet, such as FOLFIRI (5FU/LV and CPT-11). Therefore, FOLFOXIRI represents a new first-line option of care for patients with metastatic colorectal cancer.

Introduction During these past years, the treatment of metastatic colorectal cancer (MCRC) has achieved considerable progress and the median survival of patients has been improved from less than 6 months to almost 2 years [1]. These results have been reached mainly because of improvements in the efficacy of chemotherapy, increased use of surgery of metastases, and, more recently, with the integration of targeted agents. Chemotherapy is the cornerstone of treatment of MCRC, and the optimal use of the active cytotoxic agents is a key issue for the management of this disease. For decades, 5-fluorouracil (5FU) has been the only available treatment for patients with MCRC [2]. Irinotecan

(CPT-11) and oxaliplatin (LOHP) are newer agents with antitumor activity in this disease. The combinations of CPT-11 + 5FU/leucovorin (LV) and LOPH + 5FU/LV have demonstrated increased antitumor activity and efficacy compared with 5FU/LV alone in phase III randomized studies [3–7]. These data have confirmed that in MCRC, as also previously indicated by a meta-analysis of 25 randomized trials with 5FU-based regimens, a more active first-line treatment can be more effective in terms of improved progression-free survival (PFS) and overall survival (OS) [8]. The randomized study conducted by the Groupe Cooperateur Multidisciplinaire en Oncologie [9••] demonstrated that a strategy incorporating two sequential doublets (first-line simplified FOLFIRI followed by FOLFOX 6 at progression or the reverse sequence) achieved considerable activity and efficacy; of interest, median survival was approximately 21 months. These results suggested that the exposure of MCRC patients to all of the three most active agents, irrespective of their sequence, is associated with promising survival. Moreover, a pooled analysis of seven phase III trials in MCRC demonstrated that survival is correlated with the proportion of patients who received all of the three active drugs in the course of their disease, but not with the proportion of patients who received any second-line therapy [10••]. In addition, this analysis also showed that, in a sequential strategy, not all patients who progress after first-line chemotherapy are able to receive second-line treatment and, therefore, cannot be exposed to the three active agents. In fact, approximately 20% to 50% of patients, mainly because of deterioration of their performance status and liver function, will not be fit enough to undergo further chemotherapy. Therefore, a way to further improve the outcome of MCRC patients could be to administer an intensified chemotherapy consisting of a first-line regimen containing all three of the active agents (LOHP, CPT-11, and 5FU/LV). This regimen, if feasible, could expose 100% of patients to these three drugs. More importantly, if this regimen proved to be more active than a standard two-drug combination, it could also increase the post-chemotherapy resection-rate of metastases and, therefore, improve the long-term control of disease. In fact, studies initially conducted with LOHP- and 5FU-based regimens [11,12] and, more recently, also with different combinations [13] indicate that an active first-line chemotherapy in initially unresectable patients can allow, after response, a radical

Chemotherapy Intensification Masi and Falcone

resection of metastatic disease in a subgroup of patients, of which 20% to 40% are long-term survivors. In particular, a pooled analysis conducted by Folprecht et al. [14••] demonstrated a strong correlation between the response rate (RR) to first-line chemotherapy and the post-chemotherapy radical resection rate of metastatic disease. This paper critically reviews the main trials evaluating the triple-drug combination 5FU/LV + CPT-11 + LOHP and the development of this regimen from phase I to phase III.

117

Table 1. Simplified FOLFOXIRI: treatment schedule* Drug

Day 1

CPT-11

165 mg/m2, 1 h

LOHP

85 mg/m2, 2 h

l-LV

200 mg/m2, 2 h

5FU

3200 mg/m2, 48-h continuous infusion

*Repeated every 2 weeks. 5FU—5-fluorouracil; CPT-11—irinotecan; FOLFOXIRI—irinotecan, oxaliplatin, and 5-fluorouracil/leucovorin; l-LV—l-leucovorin; LOHP—oxaliplatin.

Phase I to II Trials On the basis of the earlier-mentioned considerations and of the results of an in vitro study on two human colon cancer cell lines showing a synergism when CPT-11 precedes LOHP/ 5FU exposure [15], several groups have developed triple-drug combinations including 5FU, CPT-11, and LOHP. All of these studies have demonstrated the feasibility of these combinations, with neutropenia and diarrhea being the dose-limiting toxicities, and showed a promising antitumor activity in MCRC patients. In detail, Souglakos et al. [16] treated 31 MCRC patients with 150 mg/m2 of first-line CPT-11 on day 1, 65 mg/m2 of LOHP on day 2, followed by standard “de Gramont” LV-modulated bolus + infusional 5FU on days 2 and 3, repeated every 2 weeks, achieving an overall RR of 58% and reporting grade 3 to 4 diarrhea and neutropenia in 32% and 45% of patients, respectively. Ychou et al. [17] associated escalating doses of CPT-11 and LOHP given at day 1 with the standard “de Gramont” regimen (LV5FU2) or with the simplified LV5FU schedule given at day 1 and 2, repeated every 2 weeks in patients with advanced solid tumors. The recommend doses of CPT-11 and LOHP were 180 mg/m2 and 85 mg/m2, respectively; grade 3 to 4 diarrhea affected 27% of patients and 78% had grade 3 to 4 neutropenia. Calvo et al. [18] reported a 69% RR in 26 patients treated with 250 mg/m2 of CPT-11 on day 1, 120 mg/m2 of LOHP on day 1, and 500 mg/m2 of LV + 2600 mg/m2 of 5FU over 24 hours on days 1 and 15, repeated every 4 weeks. The authors observed grade 3 to 4 diarrhea in 34% of patients and grade 3 to 4 neutropenia in 38% of patients. Moreover, Garufi et al. [19] demonstrated the feasibility of this triple-drug combination using a chronomodulated infusion of 5FU and LOHP, whereas Comella et al. [20] and Goetz et al. [21] used 5FU bolus. On behalf of the Italian collaborative group, Gruppo Oncologico Nord Ovest (GONO), our group studied a three-drug combination including CPT-11, LOHP, and 5FU/LV (FOLFOXIRI) using the treatment sequence CPT-11nLOHPn5FU. A biweekly schedule was chosen because previous studies had demonstrated that, for the agents we used, it had a favorable toxicity profile, was active, and was convenient in an outpatient setting. In addition, 5FU was administered as a 48-hour continuous infusion without any bolus to reduce its related toxicities, thus favoring its combination with optimal doses of CPT11 and LOHP.

In our initial phase I to II study [22], we demonstrated that biweekly CPT-11, LOHP, and chronoinfusional 5FU modulated by LV (CPT-11, 175 mg/m 2 , 1-hour intravenous [IV] infusion on day 1; LOHP, 100 mg/m 2 , 2-hour IV infusion on day 1; l-LV, 200 mg/m 2 , 2-hour IV infusion on day 1; 5FU, 3800 mg/m 2 , 48-hour IV chronomodulated continuous infusion starting on day 1; repeated every 2 weeks) can be combined at significant doses of each single agent with acceptable toxicities. Of interest, this combination was associated with a high degree of antitumor activity with a RR of 71% and a complete RR of 12%. This allowed us to perform radical surgery on residual metastases in 11 patients (26%) that were initially unresectable. Median PFS and OS statistics (10.4 months and 26.5 months, respectively) were also very promising. On the basis of these results, we conducted a subsequent phase II [23•] study in the attempt to develop a simplified FOLFOXIRI regimen that could be more easily feasible in clinical practice as well as in multicenter settings. To obtain this, we planned the administration of slightly reduced doses of CPT-11, LOHP, and 5FU and the delivery of 5FU as a flat, continuous, not chronomodulated, 48-hour infusion (CPT-11, 165 mg/ m 2 , 1-hour IV infusion on day 1; LOHP, 85 mg/m 2 , 2hour IV infusion on day 1; l-LV, 200 mg/m 2 , 2-hour IV infusion on day 1; 5FU, 3200 mg/m 2 , 48-hour IV flat continuous infusion starting on day 1; repeated every 2 weeks) as reported in Table 1. This simplified regimen produced a lower incidence of both hematologic and nonhematologic toxicities. In particular, the incidence of grade 3 diarrhea and grade 3 stomatitis were reduced from 21% to 16% and from 10% to 6% of patients, respectively. Grade 4 neutropenia was observed in 34% of patients compared with 55% as seen in the previous study. Of interest, results in terms of antitumor activity (overall RR of 72% and a post-chemotherapy, complete tumor resection [R0] surgical rate of 25%) and in terms of efficacy (median PFS of 10.8 months and a median survival of 28.4 months) were similar with those previously reported and still are very promising. The combined analysis of the 74 patients enrolled in these two previously mentioned studies also demonstrated that a radical resection of residual metastatic disease,

118 Therapeutic Approaches to Metastatic Colorectal Cancers

Table 2. FOLFOXIRI versus FOLFIRI: results of the GONO phase III trial FOLFOXIRI

FOLFIRI

P value

122

122

NA

Patient characteristics Number Age, median Age, range ECOG PS 1–2

62 y

64 y

NA

27–75 y

21–75 y

NA

39%

40%

NS

Previous adjuvant chemotherapy

24%

24%

NS

Multiple sites of metastases

47%

45%

NS

Liver-only metastases

32%

34%

NS

Neurotoxicity, grade 2–3

19%

0%

< 0.0001

Diarrhea, grade 3–4

20%

12%

NS

Neutropenia, grade 3–4

50%

28%

0.0006

Febrile neutropenia

5%

3%

NS

Response rate, investigators

66%

41%

0.0002

Response rate, confirmed

60%

34%

< 0.0001

R0-surgery, ITT

15%

6%

0.033

R0-surgery, liver-only metastases

36%

12%

0.017

Main observed toxicities

Activity and efficacy

PFS, median

9.9 mo

6.9 mo

0.0009

OS, median

23.6 mo

16.7 mo

0.042

ECOG PS—Eastern Cooperative Oncology Group Performance Status; FOLFIRI—5-fluorouracil/leucovorin and irinotecan; FOLFOXIRI—irinotecan, oxaliplatin, and 5-fluorouracil/leucovorin; GONO—Gruppo Oncologico Nord Ovest; ITT—intention to treat; NA—not applicable; NS—not significant; OS—overall survival; PFS—progression-free survival.

after response to chemotherapy, could be performed in 19 initially unresectable patients (26%). The outcome of these resected patients was also promising with a 4-year survival of 37% [24•]. In summary, this simplified FOLFOXIRI combination had manageable toxicities and very promising antitumor activity. On the basis of these results, the GONO decided to compare, in a phase III multicenter randomized trial, the simplified FOLFOXIRI regimen to a standard doublet combination with 5FU/LV and CPT-11 (FOLFIRI) that had demonstrated in a previous phase III study improved RR, PFS, and OS in comparison to the 5FU/LV (“de Gramont” schedule) [3].

Phase III Trials From November 2001 to April 2005, the GONO group enrolled MCRC patients [25••] with unresectable metastatic disease, aged 18 to 75 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 or less for patients aged 70 years or less, ECOG PS equivalent to 0 for patients aged 71 to 75 years, and adequate organ function. Previous fluoropyrimidine-based adjuvant chemotherapy was allowed if the treatment had ended more than 6 months before randomization. Patients

were stratified according to center, based on ECOG PS (0 vs 1 or 2) and history of adjuvant therapy (yes vs no), and then were randomly assigned to FOLFIRI (irinotecan, 180 mg/m 2 , given over 1 hour in 250 mL of normal saline on day 1, 5FU 400 mg/m 2 bolus and 600 mg/m 2 by 22-hour infusion + l-LV 200 mg/m 2 on days 1 and 2) or FOLFOXIRI (CPT-11, 165 mg/m 2 , in 250 mL of normal saline over 1 hour immediately followed by LOHP, 85 mg/m 2 , in 250 mL dextrose 5% and l-LV, 200 mg/m 2 , in 250 mL dextrose 5% infused concomitantly over 2 hours via a Y-connector, immediately followed by 5FU, 3200 mg/m 2 , as a 48-hour continuous infusion). Both regimens were repeated every 2 weeks. Treatment was administered biweekly until there was evidence of progression, unacceptable toxicity, patient refusal, or for a maximum of 12 cycles. Prophylactic treatment for neutropenia with cytokines was not recommended. Trial results are summarized in Table 2. The primary study endpoint was the externally reviewed RR. Secondary endpoints were PFS, OS, post-chemotherapy R0 surgical resections, safety, and quality of life. A total of 244 patients from 15 Italian centers were enrolled into the study and randomly assigned to FOLFIRI (n = 122) or FOLFOXIRI (n = 122). The baseline characteristics of the patients were balanced among the

Chemotherapy Intensification Masi and Falcone

100

60 40

60 40

20

20

0

0 0

6

12

18

24

30

36

FOLFOXIRI (median, 23.6 months) FOLFIRI (median, 16.7 months) HR = 0.74 P = 0.042

80 Alive, %

Progression free, %

80

A

100

FOLFOXIRI (median, 9.9 months) FOLFIRI (median, 6.9 months) HR = 0.65 P = 0.0009

42

Months

0

B

119

6

12

18

24

30

36 42

48

54

60

Months

Figure 1. GONO phase III trial. A, Kaplan-Meier estimates of progression-free survival. B, Kaplan-Meier estimates of overall survival. FOLFIRI—5-fluorouracil/leucovorin and irinotecan; FOLFOXIRI—irinotecan, oxaliplatin, and 5-fluorouracil/leucovorin; GONO—Gruppo Oncologico Nord Ovest; HR—hazard ratio.

treatment groups. Overall, the study population was relatively unselected; median age was 64 years (range, 21–75) for FOLFIRI and 62 years (range, 27–75) for FOLFOXIRI. ECOG PS was 1 or 2 in 40% and 39% of patients, respectively, 24% of patients in both arms had received a previous adjuvant chemotherapy, 45% and 47% of patients, respectively, had multiple organ involvement, and only 34% and 32% of patients had metastases confined to the liver (Table 2). All randomized patients received at least 1 cycle of study treatment and, therefore, were evaluated for safety. Both treatments were relatively well tolerated and associated with manageable toxicities. The median number of administered cycles was 10 (range, 1–16) in the FOLFIRI arm and 11 (range, 1–16) in the FOLFOXIRI arm. The relative dose-intensity administered of 5FU, CPT-11, and LOHP ranged between 82% and 87%, as planned for all agents in both arms. No toxic deaths occurred, and only two patients (1.6%) in each arm died within 60 days from the treatment start, all because of rapidly progressive disease. Most commonly observed toxicities were neutropenia, diarrhea, nausea and vomiting, stomatitis, peripheral neurotoxicity, alopecia, and thrombocytopenia (Table 2). However, grade 3 to 4 toxicities were uncommon, except for neutropenia. In particular, the adverse effect that occurred significantly more often in patients who received FOLFOXIRI were grade 2 to 3 peripheral neurotoxicity (0% vs 19%, P < 0.0001) and grade 3 to 4 neutropenia (28% vs 50%, P = 0.0006). Nevertheless, the incidence of febrile neutropenia was comparable between FOLFIRI and FOLFOXIRI (3% vs 5% of patients, P = 0.75), and there were no episodes of documented infections. Although the use of granulocyte colony–stimulating factor (G-CSF) was not planned, it was used in 2% of FOLFIRI cycles and in 6% of FOLFOXIRI cycles.

With respect to the evaluation of antitumor activity and according to an intention to treat analysis, all patients were considered evaluable (Table 2). As assessed by investigators, the RR was 66% in the FOLFOXIRI arm compared with 41% in the FOLFIRI arm, and this difference was significant (P = 0.0002). The externally reviewed RR was also significantly higher in the FOLFOXIRI group compared with FOLFIRI (60% vs 34%, P < 0.0001). Moreover, the rate of progression was significantly lower for patients treated with FOLFOXIRI (11% vs 24%, P = 0.02). The superior tumor shrinkage achieved with FOLFOXIRI allowed an increased rate of post-chemotherapy radical surgery to remove residual metastases. In particular, among all study population, 18 (15%) patients underwent radical R0 surgery of metastases in the FOLFOXIRI arm versus seven (6%) patients in the FOLFIRI arm (P = 0.033). Taking into consideration only patients with metastases initially confined to the liver, the rate of secondary R0 surgery of metastases was 36% for FOLFOXIRI compared with 12% for FOLFIRI (P = 0.017). The improved activity of FOLFOXIRI resulted in an increased PFS. In particular, after a median follow-up of 36.3 months, 111 patients in the experimental arm versus 114 patients in the reference arm have progressed, and the median PFS is 9.9 months versus 6.9 months (P = 0.0009) with a hazard ratio for progression of 0.65 in favor of FOLFOXIRI (95% CI, 0.47 to 0.83; Fig. 1). In addition, the rate of early progressions, which was based upon the number of patients who progressed within 6 months from the treatment onset, was significantly lower in the FOLFOXIRI arm (18% vs 45%, P < 0.0001). Overall, the rate of patients who received a second-line treatment was 78% for the FOLFIRI group and 73% for the FOLFOXIRI group. In particular, as recommended by the

120 Therapeutic Approaches to Metastatic Colorectal Cancers

protocol, 68% of patients who received FOLFIRI in first-line treatment received FOLFOX in second-line treatment. After a median follow up of 36.3 months, 84 patients in the experimental arm versus 96 patients in the reference arm had died, and the median OS was significantly longer in the FOLFOXIRI group than in the FOLFIRI group (23.6 months vs 16.7 months, P = 0.042) corresponding to a hazard ratio for death of 0.74 (95% CI, 0.55–0.99; Fig. 1). Eighty-nine patients (36% in the FOLFIRI arm and 37% in the FOLFOXIRI arm) participated in the quality-of-life assessment and could be evaluated. The two groups did not differ significantly at baseline. Analyses evaluating the worsening of the quality of life from baseline according to global health status, role functioning, physical activity, social activity, emotional status, fatigue, anorexia, pain, diarrhea, nausea, and vomiting showed no significant differences between the two arms. The Hellenic Oncology Research Group (HORG) has reported the results of another phase III study [26] comparing FOLFIRI to a triplet combination of 5FU, CPT-11, and LOHP (CPT-11, 150 mg/mq, given on day 1; LOHP, 65 mg/mq, on day 2; LV, 200 mg/mq, on days 2 and 3; and 400 mg/mq of 5 FU as an IV bolus and 600 mg/mq as 22hour IV continuous infusion on days 2 and 3). This study, although it suggested some improvements for the triplet combination in terms of RR (33.6% vs 43%), surgical R0 resections (4% vs 10%), PFS (median, 6.9 months vs 8.4 months), and OS (median, 19.5 months vs 21.5 months), failed to demonstrate statistically significant benefits in favor of the experimental arm. Two substantial differences exist between the earliermentioned GONO study and the present HORG study. First is the schedule used by the HORG. A 5FU bolus was given (400 mg/m 2 on days 1 and 2) and this required, to make the regimen feasible, the use of a planned dose of LOHP and CPT-11 significantly lower than in our study (65 vs 85 mg/m 2 for LOHP and 150 vs 165 mg/m 2 for CPT-11). Despite this reduced planned dose intensity, diarrhea was substantial (grade 3–4: 28%) and apparently more frequent than with our combination without bolus 5FU (20%). The second relevant difference is the study population, which was older and with a poorer performance status than studied by the HORG. In fact, this study differs from ours in that patients older than 75 years or between 71 and 75 years with an ECOG PS of 1 or greater were not excluded. Instead, patients up to 84 years of age, also with an impaired PS, were included. In particular, median age in the triplet arm was 66 years versus 62 years in the GONO study. In addition, only 36% of patients in the HORG study had an ECOG PS of 0 (61% in our study), and more patients had an ECOG PS of 2 (11% vs 2%). Indeed, Souglakos et al. [26] report a significantly higher incidence of toxicity in older and PS 2 patients, and the clinical consequences of this increase in toxicity should have been more relevant for the more toxic triplet combination.

Conclusions Despite the considerable improvements in the results recently obtained, MCRC is still a major health problem, and almost 50% of newly diagnosed patients die of their disease. Compared with the limited survival impact achieved when 5FU was the only existing therapy, the treatment of MCRC today can be based on several treatment options incorporating chemotherapy, targeted agents, and surgery of metastases. Despite these advances and the availability of multiple lines of treatment, the choice of the first-line chemotherapy does indeed still matter, and the development of chemotherapy regimens associated with improved efficacy is a key question also in the “biologics era.” The results of the above-mentioned GONO studies clearly support the hypothesis that, as a strategy, upfront exposure to a three-drug combination is associated with remarkable activity and is more effective than the initial use of a doublet, such as FOLFIRI. In particular, the GONO phase III study demonstrated a statistically significant improved RR, secondary R0 surgery rate, time to disease progression, and OS for patients treated with the FOLFOXIRI regimen as compared with FOLFIRI. Although this is obtained at the cost of a modest increase in toxicity, the use of this triplet is not detrimental in terms of quality of life. FOLFOXIRI represents the first studied combination that was demonstrated to be superior to an infusional 5FU containing doublet, such as FOLFIRI, and this improvement in efficacy, coupled with a manageable toxicity profile, supports its use as a first-line option of care for patients with MCRC. No conclusion can be drawn from this study in regard to the comparison with the other frequently used doublet, FOLFOX. Although FOLFOX has more consistent data in regard to the capacity to induce resectability in previously unresectable patients, similar results have been reported also with FOLFIRI [13]. Comparisons of FOLFOX with FOLFIRI in randomized studies have always reported equivalent activity and efficacy between these two regimens [9,27••]. Therefore, we can speculate that, if compared with FOLFOX, FOLFOXIRI would be expected to be more active and effective. It must be stressed that patient candidates to FOLFOXIRI should have characteristics similar to those included in the GONO study. Therefore, patients older than 75 years of age, patients aged 71 to 75 years but with an ECOG PS of 1 or greater, or patients with expected, increased risks of toxicity should not receive this triplet. We believe that the use of FOLFOXIRI is of particular interest in a neoadjuvant strategy, in initially unresectable patients, and in patients with few chances to achieve a three-drug exposure in a sequential strategy. Future developments should evaluate the integration of FOLFOXIRI with targeted agents, and a phase II study evaluating the combination of FOLFOXIRI and Bevacizumab is being activated by the Gruppo Oncologico Nord Ovest.

Chemotherapy Intensification Masi and Falcone

Acknowledgments The authors thank Mr. Michele Andreuccetti and Mrs. Cinzia Orlandini.

References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.

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