Download Improved time to treatment failure with an intermittent oxaliplatin

original articles
Annals of Oncology
Annals of Oncology 25: 1172–1178, 2014
doi:10.1093/annonc/mdu107
Published online 7 March 2014
Improved time to treatment failure with an intermittent
oxaliplatin strategy: results of CONcePT
H. S. Hochster1,†, A. Grothey2,†, L. Hart3, K. Rowland4, R. Ansari5, S. Alberts6, N. Chowhan7,
R. K. Ramanathan8, M. Keaton9, J. D. Hainsworth10 & B. H. Childs11*
1
Yale Cancer Center, Yale School of Medicine, New Haven; 2Department of Medical Oncology, Mayo Clinic Rochester, Rochester; 3Drug Development Program, Florida
Cancer Specialists, Ft. Myers; 4Cancer center, Carle Cancer Center, Urbana; 5Department of Medical Oncology, Michiana Hematology Oncology, South Bend; 6Division of
Medical Oncology, Mayo Clinic, Rochester; 7Department of Medical Oncology, Floyd Memorial Cancer Center of Indiana, New Albany; 8Clinical Trials Program, Scottsdale
Healthcare Research Institute at The Virginia B. Piper Cancer Center, Scottsdale; 9Department of Hematology and Oncology, Augusta Oncology Associates, Augusta;
10
Department of Oncology, Sarah Cannon Research Institute, Nashville; 11Department of Oncology, Sanofi US, Bridgewater, USA
Received 2 July 2013; revised 24 February 2014; accepted 25 February 2014
Background: Oxaliplatin is an integral component of colorectal cancer treatment, but its use is limited by neurotoxicity.
The Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT) tested intermittent oxaliplatin (IO) administration and
the use of concurrent calcium and magnesium salts (Ca/Mg), two modifications intended to reduce neurotoxicity and
extend the duration of treatment.
Patients and methods: In this trial involving double randomization, 140 patients were randomized to receive modified
FOLFOX7 plus bevacizumab with IO (eight-cycle blocks of oxaliplatin treatment) versus continuous oxaliplatin (CO); and
Ca/Mg versus placebo ( pre- and postoxaliplatin infusion). The primary end point was time-to-treatment failure (TTF).
Results: One hundred thirty-nine patients were entered and treated up to the point of early study termination due to concerns by the data-monitoring committee (DMC) that Ca/Mg adversely affected tumor response. Tumor response was not
a study end point. Given DMC concerns, an additional independent, blinded radiology review of all images showed no
adverse effect of treatment schedule or Ca/Mg on response by Response Evaluation Criteria In Solid Tumors. The IO
schedule was superior to CO [hazard ratio (HR) = 0.581, P = 0.0026] for both TTF and time-to-tumor progression (TTP)
(HR = 0.533, P = 0.047).
Conclusions: An IO dosing schedule had a significant benefit on both TTF and TTP versus CO dosing in this trial
despite the very attenuated sample. There was no effect of Ca/Mg on response.
Key words: bevacizumab, calcium and magnesium salts, colorectal cancer, FOLFOX, intermittent, drug-induced neurotoxicity
introduction
Oxaliplatin with infusional 5-fluorouracil (5-FU) and leucovorin (LV) (FOLFOX) is an established treatment of metastatic
colorectal cancer (CRC) [1–5]. Oxaliplatin-based therapy also
shows improved efficacy combined with bevacizumab (BEV)
[6–8]; however, neurotoxicity is a dose-limiting adverse event
(AE) for oxaliplatin [3, 4, 9, 10] and the maximal benefit
of BEV cannot be achieved without treatment to disease
progression [7]. This necessitates a strategy to ‘optimize’ use
of oxaliplatin. Intermittent oxaliplatin (IO) administration
and prophylactic calcium/magnesium salts (Ca/Mg) are two
*Correspondence to: Dr Howard S. Hochster, Yale Cancer Center, Yale School of
Medicine, 333 Cedar Street, Box 208028, New Haven, CT 06520, USA. Tel: 1+203-7856230; E-mail: [email protected]
†
HH and AG are co-first authors.
treatment modifications that may reduce neurotoxicity, allowing more extended use of oxaliplatin [11, 12].
We report the findings of Combined Oxaliplatin Neurotoxicity
Prevention Trial (CONcePT). The objective was to compare
efficacy and safety (including neurotoxicity) of IO ± Ca/Mg versus
continuous oxaliplatin (CO) ± Ca/Mg as first-line treatment in
patients with advanced CRC receiving modified FOLFOX7
(mFOLFOX) plus BEV. Patients were originally randomized to
receive either Ca/Mg or placebo combined with the IO or CO
regimen; however, a protocol amendment after 140 patients enrolled allowed Ca/Mg prophylaxis in all patients [13, 14]. An unplanned interim analysis by the data-monitoring committee
(DMC) indicated a possible negative effect of Ca/Mg on tumor response (which was not a study end point); the study was terminated, with treatment and follow-up of all patients immediately
stopped per DMC mandate. Herein, efficacy and safety data are
presented for patients randomized to the original 2 × 2 factorial
design.
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected].
original articles
Annals of Oncology
methods
patient selection
Eligible patients had histologically or cytologically documented inoperable
metastatic adenocarcinoma of the colon or rectum. Additional inclusion/exclusion criteria and ethical conduct of this study is detailed in Appendix 1.
randomization
This was a 2 × 2 parallel-group, randomized, double-blind (for Ca/Mg),
phase III trial comparing CO versus IO treatment schedules ± Ca/Mg for
neurotoxicity prophylaxis. Due to revised practice patterns as the trial enrolled, the trial was amended to a two-arm design that eliminated Ca/Mg
randomization (supplementary Figure S1, available at Annals of Oncology
online). Cohort 1 patients were randomized by the original 2 × 2 factorial
design (i.e. IO versus CO × Ca/Mg versus placebo), and patients subsequently recruited to the study (Cohort 2) all received Ca/Mg and were randomized
to either CO or IO. In the CO arms, patients received mFOLFOX plus BEV
every 2 weeks (see Appendix 1). In the IO arms, patients alternated between
eight cycles of the above regimen and eight cycles of the same regimen
without oxaliplatin until treatment failure. This design was selected as most
patients achieve maximum response within the first eight cycles and before
the onset of cumulative neurotoxicity is generally seen. We believed that
5-FU/LV plus BEV would at least hold this response until restarting oxaliplatin. Patients assigned to the Ca/Mg arms received infusional calcium gluconate (1 g) plus magnesium sulfate (1 g) in 100 ml of 5% dextrose or normal
saline over 30 min before and after oxaliplatin and LV. Placebo infusions
contained 5% dextrose or normal saline. These were assigned in a doubleblind fashion with only the local pharmacist knowing the treatment assignment. Patients with tumor regrowth to >50% of baseline at the 6-month
computed tomography scan while on IO were instructed to reintroduce oxaliplatin therapy early. Those with <50% regrowth were continued on IO.
Treatment was continued until death, disease progression, unacceptable
toxicity, patient withdrawal, or treatment delay. Criteria for treatment delays
and/or patient withdrawal are detailed in Appendix 1.
assessment of efficacy and safety
The primary end point was time-to-treatment failure (TTF) for oxaliplatin, a
composite which assessed time from randomization to discontinuation of
oxaliplatin-based treatment for any reason. TTF was measured from randomization to date of treatment discontinuation due to AEs, progression,
withdrawal of consent, or death. TTF was chosen as primary end point, since
the goal of therapy was to achieve optimal efficacy and tolerability for the
longest possible time. Secondary end points included time-to-tumor progression (TTP), incidence of AEs, and quality of life, including oxaliplatinspecific neurologic symptoms (see Appendix 1). Response was not an end
point and was not reported by investigators, but scans were carried out every
2 months using modified Response Evaluation Criteria In Solid Tumors
version 1 criteria to determine TTP. All responses and response rates
reported here were determined retrospectively by the blinded independent
radiology review committee (IRRC) when the question of interference was
raised by the DMC. Toxicities were graded according to National Cancer
Institute Common Terminology for Adverse Events Version 3.0 [15].
statistical methods
Study populations for analysis defined in Appendix 1 include the intent-totreat, as-treated, and safety populations. However, because of early trial termination, only the as-treated population in cohort 1 was used for primary
analysis. Minimal data were obtained on cohort 2 given the short interval
between initiation of the amendment and study termination. Statistical
power considerations are detailed in Appendix 1. Kaplan–Meier estimates
Volume 25 | No. 6 | June 2014
were used to calculate median TTF and TTP. Patients still on study at the
time of study termination were censored at that point. Effects of treatment
schedule and neuroprophylaxis on TTF and TTP were analyzed using Cox
regression modeling; P values were calculated via log-rank test. Effects of
treatment schedule and neuroprophylaxis on tumor response were analyzed
using exact logistic regression modeling. Analysis of the changes in oxaliplatin-induced peripheral sensory neuropathy (PSN) (Patient Neurotoxicity
Questionnaire–Oxaliplatin [PNQ-oxali] data) was carried out on the astreated population via Fisher’s exact test.
results
study conduct and termination
CONcePT was initiated (first subject enrolled) in February
2005. In August 2006, an amendment eliminated placebo
groups so all subjects would receive Ca/Mg, and removed the requirement for neurologic/neurosensory assessments. Previously
enrolled patients continued treatment as randomized (cohort 1).
Subjects enrolled after elimination of the placebo arm were
designated as cohort 2.
Results of an unplanned analysis by the independent DMC
(June 2007) of all enrolled patients, including cohort 2, indicated an apparently inferior response rate in patients receiving
Ca/Mg (based on DMC interpretation of submitted radiology
reports for 174 subjects), and prompted the DMC to recommend study termination. In this analysis, cohort 2 patients (all
of whom received Ca/Mg) were largely considered to be nonresponders, mainly because of the very short follow-up period and
paucity of scan results, which may have led to an underestimation of the response rate for Ca/Mg patients. The DMCmandated trial closure resulted in all patients immediately
stopping protocol-based therapy and affected the feasibility of
statistical analyses, including primary efficacy assessment. All
patients still on study were censored at the time of study closure.
Table 1. Treatment schedule effect on time-to-treatment failure
(TTF) and time-to-tumor progression (TTP) in intent-to-treat
patients receiving continuous oxaliplatin (CO) or intermittent
oxaliplatin (IO) and placebo or Ca/Mg
CO (N = 68)
TTF
Patients with an event, n (%)
Patients censored, n (%)
Median TTF, months (95% CI)
HR (95% CI)
TTP
Patients with an event, n (%)
Patients censored, n (%)
Median PFS, months (95% CI)
HR (95% CI)
IO (N = 71)
67 (98.5)
65 (91.5)
1 (1.5)
6 (8.5)
4.2 (3.7–5.5)
5.7 (4.7–7.1)
0.58 (0.41–0.83); P = 0.0026
24 (35.3)
21 (29.6)
44 (64.7)
50 (70.4)
7.4 (6.9–NE)
12.0 (8.3–NE)
0.53 (0.29–0.99); P = 0.047
CI, confidence interval; HR, hazard ratio; NE, not evaluable;
PFS, progression-free survival.
doi:10.1093/annonc/mdu107 | 
original articles
Annals of Oncology
disposition of patients
IO regimen compliance
One-hundred eighty patients were randomized: 140 to cohort 1
and 40 to cohort 2 (supplementary Figure S1, available at
Annals of Oncology online). All but two patients received treatment as randomized (one did not receive treatment; one
received the wrong treatment).
Seventy-one patients were treated in the IO arm (range up to 35
cycles) and 22 remained on study beyond cycle 16. Twenty-one
of the 22 patients (95%) had oxaliplatin reintroduced per protocol, including one early reintroduction at cycle 13 for regrowth.
Eight patients remained on treatment beyond cycle 24 and one
A
1.0
IO
CO
0.9
Censored data
Proportion of subjects
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Month
0.0
B
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
68
71
63
65
58
61
46
56
36
52
28
43
20
32
11
28
6
21
4
18
4
12
4
12
2
10
2
7
1
4
1
1
0
1
N at risk
:CO
:IO
1.0
CO
0.9
IO
Censored data
Proportion of subjects
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
Month
0.0
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
68
71
64
63
46
55
39
51
29
43
24
38
13
27
7
24
3
18
3
15
3
10
1
9
0
8
0
3
0
2
0
1
0
1
N at risk
:CO
:IO
Figure 1. Kaplan–Meier curves for (A) time-to-treatment failure and (B) time-to-tumor progression in the as-treated population (cohort 1) for intermittent
oxaliplatin (IO) versus continuous oxaliplatin (CO) treatment.
 | Hochster et al.
Volume 25 | No. 6 | June 2014
original articles
Annals of Oncology
IO (n = 71)
Placebo
Ca/Mg
(n = 36)
(n = 35)
longer median TTP than those receiving CO (HR = 0.53, 95%
CI 0.29–0.99; P = 0.047); the difference remained significant
when stratified (by Ca/Mg; P = 0.029). Administration of Ca/Mg
or placebo had no significant effect on TTP (HR = 0.99, 95% CI
0.55–1.79; P = 0.973); therefore, four groups were collapsed into
two (IO versus CO) for further analysis, and median TTP was
longer for the combined IO treatment group (Table 1). Kaplan–
Meier curves of TTP for IO versus CO schedule (as-treated
population, cohort 1) are shown in Figure 1B. Except for prior
chemotherapy, which showed a positive effect in delaying TTP,
no baseline prognostic factor showed a significant effect on TTP.
In view of DMC response rate analysis and the trial’s early termination, additional analyses were conducted. An IRRC, blinded
to all treatment assignments, reviewed the actual images of radiologic studies for randomized patients and scored response based
on best response (single scan), subsequently confirmed response
(second scan), and sequentially confirmed response (at least two
subsequent scans). The latter was the most stringent. No patient
achieved complete response (CR). Overall, sequentially confirmed
response rates (CR + partial response/N) for assessable patients in
the CO arm were 41% compared with 52% for the IO arm (n = 59),
with 35% stable disease in each arm. There was no effect of
treatment schedule or Ca/Mg for confirmed or subsequently
confirmed response (on the next scan). The response rate comparison of IO relative to CO, based on independent review,
favored the Ca/Mg groups (data not shown). There was also no
effect of treatment schedule or neuroprophylaxis treatment for
subsequently confirmed response or unconfirmed response.
62 (12)
adverse events
of these beyond cycle 32; all of these received IO, in eight-cycle
blocks, correctly per protocol.
efficacy
Patients with IO had a significantly longer median TTF than those
receiving CO in cohort 1. Overall hazard ratio (HR) for IO versus
CO was 0.58 [Cox regression using treatment schedule and neuroprophylaxis; 95% confidence interval (CI) 0.41–0.83; P = 0.0026].
Administration of Ca/Mg or placebo had a statistically nonsignificant effect on TTF (HR = 1.32, 95% CI 0.93–1.86; P = 0.118) and
favored Ca/Mg; therefore, four treatment groups were collapsed
into two (all IO versus all CO treatment) for further analysis.
Median TTF was longer for the combined IO group (Table 1).
Kaplan–Meier curves of TTF for IO versus CO schedule (astreated population, cohort 1) are shown in Figure 1A. There were
no imbalances in baseline prognostic factors for TTF (Table 2).
Secondary efficacy variables, including TTP, were analyzed
using the as-treated population of cohort 1; due to the large
number of censored patients, time-to-event results should be
interpreted with caution. Patients receiving IO had significantly
Table 2. Patient demographics, as-treated population (cohort 1) at
baseline
No. of patients
CO (n = 68)
Placebo
Ca/Mg
(n = 33)
(n = 35)
Mean age, years 61 (12)
(SD)
Age distribution (years)
<65
19
≥65
14
Male/female
16/17
ECOG PS
0
19a
1
13a
Stageb
0–III
12
IV
19
Unknown
2
Site of disease
Colon
25
Rectum
5
Colorectalc/
3
unknown
Prior treatment
Radiotherapy
4
Surgery
17
Adjuvant
9
therapy
a
63 (12)
67 (12)
20
15
24/11
21
15
18/18
11
24
18/17
17a
17a
22
14
16
19
12
22
1
10
25
1
14
21
0
27
6
1
31
2
3
28
6
1
5
18
6
3
19
8
4
15
7
One patient not assessed for ECOG PS.
Disease stage at initial diagnosis.
c
Not specified.
Ca/Mg, calcium/magnesium salts; CO, continuous oxaliplatin;
ECOG PS, Eastern Cooperative Oncology Group performance status;
IO, intermittent oxaliplatin; SD, standard deviation.
Overall, treatment duration was longer in cohort 1 subjects receiving IO versus CO; mean treatment duration was 7.4 and 5.5
months for IO placeco and IO Ca/mg respectively compared
with 4.7 and 4.6 months for CO pla and CO ca/mg. The most
common AE overall was PSN (76.0%), followed by fatigue
(70.9%), nausea (63.7%), diarrhea (53.6%), constipation (39.7%),
and vomiting (31.3%); other AEs occurred in <30% of subjects.
Grade 3 or 4 AEs reported by >2% and >3% of subjects for hematologic and nonhematologic AEs, respectively, in any treatment
group are shown in Table 3 for the safety population (n = 179).
The most common grade 3 or 4 AE was PSN, which was less frequently observed overall with IO versus CO (Table 3). Incidence
of grade 3 or 4 neutropenia was 17.3% in the overall study population. The most common AE leading to treatment discontinuation
in cohort 1 was PSN, which occurred in fewer patients in the IO
groups (supplementary Table S1, available at Annals of Oncology
online). Results for PNQ-oxali are presented in Appendix 2.
Overall, neurotoxicity scoring with PNQ-oxali was affected favorably by IO treatment for both chronic and acute PSN, and was
affected favorably by Ca/Mg for chronic PSN. The difference
between IO and CO was significant in favor of IO for acute PSN
(P = 0.037), but not for chronic PSN.
b
Volume 25 | No. 6 | June 2014
discussion
The primary objective of CONcePT was to investigate whether
an intermittent schedule of FOLFOX/BEV, with 4-month,
eight-cycle blocks of oxaliplatin administration alternating with
holding that drug, would allow subjects to benefit from
doi:10.1093/annonc/mdu107 | 
original articles
Annals of Oncology
Table 3. Grade 3 or 4 adverse events (AEs) reported by more than 2% of patients (hematologic AEs) or more than 3% of patients (nonhematologic
AEs) in any treatment group, safety population (n = 179), all cohorts
Grade 3 or 4 AE, n (%)
Peripheral sensory neuropathy
Peripheral motor neuropathy
Neutropenia
Thrombocytopenia
Leukopenia
Lymphopenia
Fatigue
Diarrhea
Dehydration
Hypertension
Nausea
Vomiting
Asthenia
Anorexia
Palmar–plantar erythrodysesthesia syndrome
CO (N = 88)
Placebo (N = 33)
Ca/Mg (N = 55)
IO (N = 91)
Placebo (N = 36)
Ca/Mg (N = 55)
Total (N = 179)
8 (24.2)
2 (6.1)
6 (18.2)
2 (6.1)
1 (3.0)
0
2 (6.1)
1 (3.0)
2 (6.1)
1 (3.0)
1 (3.0)
2 (6.1)
0
1 (3.0)
0
10 (18.2)
0
11 (20.0)
2 (3.6)
1 (1.8)
1 (1.8)
2 (3.6)
2 (3.6)
2 (3.6)
4 (7.3)
2 (3.6)
1 (1.8)
1 (1.8)
0
0
4 (11.1)
0
6 (16.7)
0
0
1 (2.8)
1 (2.8)
3 (8.3)
0
1 (2.8)
0
1 (2.8)
0
0
0
5 (9.1)
0
8 (14.5)
1 (1.8)
0
0
5 (9.1)
2 (3.6)
4 (7.3)
2 (3.6)
4 (7.3)
3 (5.5)
2 (3.6)
2 (3.6)
3 (5.5)
27 (15.1)
2 (1.1)
31 (17.3)
5 (2.8)
2 (1.1)
2 (1.1)
10 (5.6)
8 (4.5)
8 (4.5)
8 (4.5)
7 (3.9)
7 (3.9)
3 (1.7)
3 (1.7)
3 (1.7)
Ca/Mg, calcium/magnesium salts; CO, continuous oxaliplatin; IO, intermittent oxaliplatin.
oxaliplatin-based therapy for a longer period by reducing discontinuations (e.g. for neurotoxicity). This strategy builds on the
Optimized Leucovorin–Fluorouracil–Oxaliplatin (OPTIMOX) approach (six cycles of higher dose oxaliplatin in FOLFOX7 and 12
cycles of 5-FU/LV), but restarts treatment with oxaliplatin every
eight cycles, rather than waiting for tumor regrowth to a target
percent of baseline (as in OPTIMOX protocol, though seldom
achieved in the actual study). To further optimize treatment duration, a nonbolus 5-FU–containing regimen, mFOLFOX7, was
used as the chemotherapy backbone to reduce incidence and severity of neutropenia. The secondary objective of this trial was to
examine the effect of Ca/Mg on incidence and severity of neurotoxicity (with IO or CO treatment schedule), in a properly randomized, placebo-controlled study. The IO strategy was quite
effective in practice as 21 of 22 (95%) patients on study beyond
cycle 16 reintroduced oxaliplatin correctly, and all eight beyond
cycle 24 stopped and restarted a second or third time per protocol.
In exploratory analysis of the primary efficacy end point,
IO was associated with significantly better TTF versus CO
(HR = 0.58), and Ca/Mg prophylaxis may have improved chronic
neurotoxicity without any impact on efficacy. Analysis of other
efficacy end points showed improved TTP (HR = 0.53) favoring
the IO schedule and equivalent sequentially confirmed response.
While the response rate was lower than reported in other studies,
responses plus stable disease rates were 76% and 87% for CO and
IO, respectively, possibly reflecting stringent blinded response
evaluation; comparison with historical controls may be inaccurate
as these response rates were determined by an IRRC which retrospectively reviewed every scan in a blinded fashion. Our overall
results are also consistent with those of CAIRO2 (CApecitabine,
IRinotecan and Oxaliplatin in advanced CRC) [16], and as predicted, we found the use of mFOLFOX7 to be associated with a
low incidence of neutropenia, with efficacy outcomes comparable
with the bolus 5-FU-containing FOLFOX + BEV regimens [7].
 | Hochster et al.
Despite early termination by the DMC, subsequent IRRC
review of the actual scans (collected retrospectively) of all
treated patients for both confirmed and unconfirmed response
showed no impact of Ca/Mg on response rate [9, 17].
Furthermore, results from the initial cohort of patients randomized to Ca/Mg or placebo suggest that the efficacy of mFOLFOX
plus BEV is unaffected by co-administration of Ca/Mg.
Patient-reported outcomes assessing influence of oxaliplatin
dosing on both acute and chronic PSN also indicated a degree of
benefit for Ca/Mg over placebo in terms of alleviating chronic,
but not acute, PSN (see Appendix 2). These findings are supported by results from the ‘North Central Cancer Treatment
Group’ N04C7 adjuvant trial, which was also terminated at the
same time due to the same concerns raised by the CONcePT
DMC [18]; retrospective analysis of CAIRO2 also showed no
impact of Ca/Mg infusions on treatment efficacy, whereas
neurotoxicity was significantly reduced [19].
Current understanding of optimal palliative therapy in
advanced CRC is highlighted by a ‘continuum of care’ [20], with
exposure of patients to prolonged antitumor therapy, while limiting treatment-related toxicities. Results from CONcePT
provide a clear example of how such an approach can be realized
using an oxaliplatin/BEV-containing first-line therapy with 4
month blocks of oxaliplatin administration alternating with
breaks.
In conclusion, despite premature closure and limited sample
size, results from this study demonstrate increased efficacy and
reduced toxicity when IO is used with mFOLFOX/BEV for CRC
first-line therapy. The addition of Ca/Mg had no adverse impact
on efficacy or response. A reduction of neurotoxicity was also
suggested through patient-reported outcomes, but this question
could not be addressed definitively due to sample size limitation.
CONcePT thus signals an important direction on optimizing
oxaliplatin use in first-line treatment of CRC.
Volume 25 | No. 6 | June 2014
original articles
Annals of Oncology
acknowledgements
The authors thank Liji Shen and Marc Buyce for statistical
support and Nicholas Combates for publication support.
Editorial support in the preparation of this publication was provided by Colin Evans, PhD, Phase Five Communications, Inc.,
and sponsored by Sanofi US. The authors were responsible for
all content and editorial decisions and received no honoraria
related to the development/presentation of this publication.
funding
This work was supported by Sanofi US.
disclosure
HH has been a consultant/advisor to Sanofi US and Genentech.
AG has been a consultant/advisor to Sanofi US and Genentech,
and has received research funding from Sanofi US and
Genentech. LH’s employer, Florida Cancer Specialists, Ft. Myers,
FL, has received research funding. RKR has received honoraria
and research funding from Sanofi US. MK has been a consultant/
advisor to Celgene, and has received honoraria from Celgene and
Genentech/Roche. BHC was Vice President of Oncology at Sanofi
US during the study and at the time the manuscript was created.
All remaining authors have declared no conflicts of interest.
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appendix 1
inclusion/exclusion criteria
Eligibility criteria included age ≥18 years, measurable disease
(Response Evaluation Criteria in Solid Tumors Version 1),
Eastern Cooperative Oncology Group performance status 0–1,
no prior therapy for metastatic or recurrent disease [adjuvant
5-fluorouracil (5-FU)/leucovorin (LV) and/or irinotecan, completed >6 months before entry was allowed], life expectancy >3
months, a normal electrocardiogram, and no other serious concomitant disease. Criteria for exclusion included prior treatment
with oxaliplatin and/or bevacizumab (BEV), current digoxin
therapy, known dihydropyrimidine dehydrogenase deficiency,
peripheral neuropathy (grade >1), and current therapy to
prevent/treat neuropathy. Patients with a history of cerebrovascular event, uncontrolled hypertension, clinically significant cardiovascular or peripheral vascular disease, or history of bleeding
within 6 months of registration were also excluded.
mFOLFOX regimen
The modified FOLFOX7 regimen consisted of oxaliplatin
85 mg/m2 over 2 h, LV 200 mg/m2 over 2 h, 5-FU 2400 mg/m2
over 46 h, without a bolus; BEV was administered at a dose of
5 mg/kg.
ethical conduct of the study
The protocol complied with recommendations of the 18th
World Health Congress (Helsinki, 1964) and all applicable
doi:10.1093/annonc/mdu107 | 
original articles
amendments. The informed consent process was carried out in
accordance with Good Clinical Practice guidelines, and the
study was approved by the institutional review boards at each institution before accrual commenced.
criteria for treatment delays and/or
withdrawal
Annals of Oncology
sufficient efficacy data for a given end point; this population
could have been different for each selected end point.
safety population
All randomized subjects who received at least one dose of any of
the study drugs with treatment assignment designated according
to what was actually administered.
Treatment cycles were delayed for 1 week if any of the following
toxicities occurred during the previous cycle: absolute neutrophil count <1200/mm3, platelet count <75 000/mm3, treatmentrelated diarrhea above baseline, or any other toxicity grade >1
(except neurologic toxicity, hypertension, alopecia, and asthenia). Further 1-week treatment delays were implemented if any
of the above toxicities (except asthenia and alopecia) had not
resolved to grade ≤1. Dose modifications for 5-FU and oxaliplatin were based on the most severe toxicity observed in the previous cycle. Dose reductions were implemented for grade 3/4
neutropenia (or febrile neutropenia), thrombocytopenia, diarrhea, mucositis/stomatitis, vomiting, and grade 3 other nonhematologic toxicities. For grade ≥2 thromboembolic events,
resumption of chemotherapy was at the investigator’s discretion.
Patients were withdrawn from the study if they experienced
grade 4 nonhematologic toxicity (except neurotoxicity, alopecia,
or hypersensitivity). Patients who experienced grade 3 neurologic toxicity for >7 days had their oxaliplatin dose reduced to
65 mg/m2. Grade 3 or 4 neurologic toxicity that persisted
between treatment cycles led to the patient’s withdrawal.
quality-of-life assessments
definition of study populations
patient neurotoxicity
questionnaire–oxaliplatin
intent-to-treat population
All randomized subjects, with drug assignment per the original
randomization, regardless of whether the subject received any
study drug medication or a different drug from that to which
they were randomized.
as-treated population
All randomized subjects who had taken at least one dose of any
of the study drugs with treatment assignment designated
according to what was actually administered and who provided
 | Hochster et al.
Quality-of-life assessments related to oxaliplatin-specific neurologic symptoms were made using Patient Neurotoxicity
Questionnaire–oxaliplatin (completed at baseline, day 1 of each
therapy cycle, and end of treatment). Patients’ follow-up for survival status was conducted every 3 months from the end of treatment up to 3 years from the date of randomization, though this
was discontinued when the study was terminated.
statistical power considerations
Under the assumption that intermittent oxaliplatin (would
result in a median time-to-treatment failure of 9.4 months compared with 6 months for continuous oxaliplatin, with concurrent calcium and magnesium salts given to all patients, a sample
size of 182 assessable patients (91 for each group) would provide
80% power to detect the above difference in the primary end
point with a type I error of ≤5%.
appendix 2
Neurotoxicity scoring with Patient Neurotoxicity Questionnaire–
oxaliplatin (PNQ-oxali) was affected favorably by intermittent
oxaliplatin (IO) for both chronic and acute peripheral sensory
neuropathy (PSN), and was affected favorably by concurrent
calcium and magnesium salts (Ca/Mg) for chronic PSN.
Assessing data for all treatment cycles, the difference between Ca/
Mg and placebo was not significant for item 1 (chronic PSN; supplementary Figure S2A, available at Annals of Oncology online) or
item 2 (acute PSN; supplementary Figure S2B, available at Annals
of Oncology online) of PNQ-oxali.
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