Does OPTIMOX Strategy

Muhammad Wasif Saif
Yale Cancer Center, Yale University School of Medicine. New Haven, CT, USA
Summary
A recent pooled analysis and a meta-analysis
suggested a survival benefit of gemcitabine-
platinum doublets when compared with single
agent gemcitabine. Sensory neurotoxicity is a
potentially limiting toxicity associated with
oxaliplatin therapy. Because neuromodulatory
agents have shown rather disappointing
activity in the prevention of oxaliplatin-
induced neurotoxicity, the so-called
OPTIMOX (stop and go) approach offers a
reasonable strategy when oxaliplatin-based
therapy is used in the palliative setting. This
strategy seems to be successful when used as
a first-line approach, rather than being held in
reserve until chemotherapy based on another
agent fails in patients with metastatic
colorectal cancer. However, no data exists to
support OPTIMOX strategy in pancreatic
cancer. We here describe the first report of a
patient with metastatic pancreatic cancer in
whom OPTIMOX strategy allows her to
manage the toxicity as well as achieve long-
term disease control.
Dear Sir:
Since 1997, gemcitabine remains the only
standard chemotherapy approved by the US
FDA for the treatment of advanced pancreatic
cancer , which showed superior clinical
benefit to single-agent 5-fluorouracil [1].
Numerous new agents, both cytotoxic and
targeted, have been tested against and in
combination with this standard. Many
combination therapy regimens showed
encouraging results in phase II settings, which
led to more than 12 randomized phase III
trials in the last decade [2]. The combination
of gemcitabine and erlotinib is the first
combination therapy to demonstrate survival
benefits in pancreatic cancer in a phase III
study albeit a modest one [3]. Some trials
showed improved response rates or
progression-free survival, but there was no
clear improvement in survival. Among these
combinations, the combination of gemcitabine
plus platinum agents showed improved
progression-free survival or time-to-tumor
progression, but failed to demonstrate a
survival advantage over gemcitabine [4]. This
combination has regained attention after a
recent pooled analysis and a meta-analysis
suggested a survival benefit of gemcitabine-
platinum doublets when compared with single
agent gemcitabine [4, 5]. Moreover, this
regimen seems to be a reasonable option in
patients with excellent performance status [4].
Sensory neurotoxicity is a potentially limiting
factor in many patients who might otherwise
achieve good results with oxaliplatin therapy,
but it may be overcome in several ways [6].
Prevention or cure is one option, for which
glutathione, carbamazepine and gabapentin
have already been investigated [6]. Another
option is to administer a limited number of
cycles of oxaliplatin at an optimal dose

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intensity, but to suspend treatment after
delivering a total dose below that of the
oxaliplatin cumulative toxic dose and before
the development of resistance, thus enabling
later reintroduction of the drug [7, 8]. Such a
strategy is termed as optimizing oxaliplatin-
induced neuropathy (OPTIMOX: "stop-and-
go" approach). This strategy seems to be
successful when used as a first-line approach,
rather than being held in reserve until
chemotherapy based on another agent fails in
patients with metastatic colorectal cancer.
However, no data exists to support
OPTIMOX strategy in pancreatic cancer. We
here describe the first report of a patient with
metastatic pancreatic cancer in whom
OPTIMOX strategy allows her to manage the
toxicity as well as achieve long-term disease
control.
Case Report
A 69-year-old woman with unremarkable past
medical history presented in November 2006
with insidious onset of abdominal pain and
bloating. A CT scan showed a liver cyst as
large as 4.4 cm, the omentum studded with
soft tissue densities and nodules, a
leiomyomatous uterus, a right adnexal mass
versus leiomyoma. The patient was unable to
tolerate the vaginal ultrasound, but an
abdominal ultrasound revealed the presence
of the right adnexal mass. She was referred to
gynecological oncologist for possible ovarian
cancer versus a primary peritoneal carcinoma.
On January 25
th
, 2007, she underwent total
abdominal hysterectomy, bilateral salpingo-
oophorectomy, total omentectomy, tumor
debulking, lysis of adhesions, peritoneal
biopsies, right pelvic wall resection as well as
peritoneal stripping. The intraoperative report
revealed findings including 200 mL of bloody
ascites, the cul-de-sac covered with numerous
tumor nodules extending up the right
uterosacral ligament; the right pelvic sidewall
covered with tumor nodules as well as the
right side of the bladder serosa. The omentum
additionally was noted to have very large
tumor measuring 12x10 cm, and numerous
small lesions were appreciated on the dome of
the liver. Additional masses were appreciated
within the greater stomach curvature and the
lesser omentum. The tumor was strongly
positive for cytokeratin-7 (CK7) with focal
strong staining for cytokeratin-20 (CK20) and
was negative for estrogen receptor,
progesterone receptor, and CA 125. The
overall impression was that of metastatic
disease more than a primary adnexal process.
A repeat CT scan on February 5
th
, 2007
revealed an ill-defined mass within the
pancreatic tail and involving the splenic hilum
measuring 2.6x3.3 cm. Peritoneal implants
involving the greater omentum were again
demonstrated measuring in the range of 1.3-
1.8 cm. On February 8
th
, the patient
underwent an endoscopic ultrasound which
described a normal size pancreatic duct
throughout the head, uncinate process, and
body of the pancreas, and then disappearing
within a mass appreciated within the tail of
the pancreas. The mass measured 27.4x32.7
mm. Under ultrasound guidance a fine needle
aspiration was performed with the pathology
consistent with pancreatic adenocarcinoma.
Her CEA level was elevated at 8.6 U/L
(reference range: 0-3 U/L) (Table 1) and CA
19-9 was within normal limits.
She was begun on treatment with
gemcitabine/cisplatin on February 27
th
, 2007,
for two cycles. Therapy was then changed to
Table 1. Relation between chemotherapy, CEA and
administration of Ca/Mg.
Chemotherapy
regimen
CEA levela
(U/L)
Ca/Mg as
neuro-protective
Gemcitabine-cisplatinum
8.6
No
Gemcitabine-cisplatinum
8.8
No
GemOx
9.2
Yes
GemOx
6.9
Yes
GemOx
4.4
Yes
GemOx
3.3
Yes
GemOx
3.2
Yes
Gemcitabine
3.1
No
Gemcitabine
13.5
No
Gemcitabine
16.3
No
Gemcitabine
38.0
No
Gemcitabine
43.0
No
GemOx
96.1
No
GemOx
90.4
No
GemOx
110
Yes
GemOx
147
Yes
Reference range: 0-4 U/L
GemOx: gemcitabine and oxaliplatin

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GemOx consisting of gemcitabine (1,000
mg/m
2
i.v.) and oxaliplatin (85 mg/m
2
i.v.)
every two weeks on April 2
nd
, 2007. The
regimen was modified to GemOx as per
institutional practice (see discussion section)
[9]. Patient received calcium and magnesium
1 g m each before and after oxaliplatin as per
institutional practice. Oxaliplatin discontinued
in August 2007 (cumulative dose: 765 mg/m
2
)
due to cumulative thrombocytopenia/anemia
and peripheral neuropathy. Patient was
continued on single agent, gemcitabine at
dose of 1,000 mg/m
2
i.v. over 30 minutes for
two weeks out of three weeks till she
developed progressive disease in January
2008 (duration: 5.5 months) and elevated
CEA level of 38 U/L (Table 1). Since patient
has no thrombocytopenia and only grade 1
peripheral neuropathy, it was decided to
reintroduce oxaliplatin in February 2008. A
CT scan after 2 months (April 2008) showed
stable disease along with stable CEA at 43
U/L. However, a repeat CT scan in June 2008
showed progressive disease with an elevated
CEA of 110 U/L (duration: 4 months; total
dose: 260 mg/m
2
). Overall, the patient
received a total of 1,025 mg/m
2
.
Discussion
Unlike cisplatin neurotoxicity, oxaliplatin
sensory neurotoxicity is reversible, even
where it persists for several months, but
requires discontinuation of treatment. Since
oxaliplatin-related neurotoxicity is reversible,
this raises the question of whether oxaliplatin
reintroduction is beneficial in patients who
are withdrawn from treatment prior to
developing resistance to oxaliplatin. Here, we
reported our experience of reintroducing
oxaliplatin in patients with advanced
pancreatic cancer who achieved disease
control for a total of 17 months.
Because neuromodulatory agents have shown
rather disappointing activity in the prevention
of oxaliplatin-induced neurotoxicity [6], the
so-called OPTIMOX approach remains the
preferred strategy when oxaliplatin-based
therapy is used first-line in the palliative
setting. OPTIMOX-2 study, which was a
follow up to OPTIMOX-1 study, looked at
the question of giving patients who have
responded to chemotherapy and are stable a
chemotherapy-free period in patients with
metastatic colorectal cancer [7, 8].
OPTIMOX-1 evaluated the feasibility of an
oxaliplatin-free interval (not a chemotherapy-
free period) and found that patients who were
treated with this “stop-and-go” approach for
oxaliplatin fared every bit as well, in terms of
overall survival, as those individuals on
FOLFOX (oxaliplatin/5-fluorouracil (5-
FU)/leucovorin) who did not have an
oxaliplatin-free interval. So, OPTIMOX-2
took this question to the next level and asked
whether we can give a patient a
chemotherapy-free period. FOLFOX7 (a
version of FOLFOX regimen consisting of
oxaliplatin (130 mg/m
2
) infused with
leucovorin (400 mg/m
2
) over 2 h on day 1,
followed by bolus 400 mg/m
2
and a 46-h
infusion of 5-FU (2,400 g/m
2
), every 2 weeks)
was given for 6 cycles to patients in both arms,
but then patients in the experimental arm,
instead of continuing on 5-FU/leucovorin
maintenance (as in OPTIMOX-1), received
no maintenance until progression, when
chemotherapy with FOLFOX7 was
reintroduced.
The OPTIMOX-2 study was initially designed
as a 600-patient, phase 3 trial, but when
bevacizumab became available in France, the
trial was downgraded to a phase 2 study with
an accrual goal of 200 patients. The primary
Figure 1. OPTIMOX trials: the duration of disease
control (DDC) concept (modified from [7]).
PD: progressive disease
PFS: progression free survival
PR: partial response

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objective was the duration of disease control
(DDC), calculated as the sum of the duration
of the progression free survival (PFS) induced
with the initial FOLFOX therapy and with the
subsequent reintroduction of FOLFOX
(Figure 1). One important characteristic of
OPTIMOX-2 was that after induction of a
response, metastases were allowed to progress
back to baseline levels before FOLFOX was
reintroduced. In terms of efficacy, continuing
treatment with a maintenance protocol
resulted in longer progression free survival,
compared with pausing treatment altogether
(8.7 vs. 6.9 months; P=0.009). However, the
duration of disease control was almost
identical in both arms (12.9 vs. 11.7 months;
P NS).
It has to be emphasized, however, that
duration of disease control is not a validated
endpoint in clinical trials and that its
relevance for clinical practice is not yet
established, and data on overall survival are
available for OPTIMOX-2 did show
decreased over all survival in patients who
had chemotherapy free interval.
However, chemotherapy free intervals are
applicable for certain patients, especially
patients with favorable tumor biology and
especially in diseases like advanced
pancreatic cancer. Future studies are
warranted to explore OPTIMOX-2 strategy in
patients with pancreatic cancer who are
candidates for gemcitabine plus a platinum
based regimen. Moreover, the role of
maintenance therapy, not with chemotherapy,
but with targeted drugs also needs to be
explored akin to the DREAM-OPTIMOX3
study in colon cancer [10].
With these data, some patients can be given
time off treatment from drugs causing
toxicities while maintaining the other agent
(OPTIMOX-1 like strategy), allowing them to
resolve toxicities, to have time spent out of
the hospital, out of the clinic, traveling, on
vacation, allowing their normal tissue time to
recover. It is very much appreciated by
patients, and that is the bottom line.
As shown in the case report, this patient
received a simplified D1-D1 (day 1 - day 1)
GemOx regimen (S-GemOx) presented by
Andre T et al. at the ASCO 2007 annual
meeting [9]. In this study, patients with
advanced pancreatic cancer were 2:1
randomly assigned for first-line treatment to
S-GemOx (arm A: gemcitabine 1,000 mg/m
2
,
100 min infusion day 1, immediately followed
by oxaliplatin 100 mg/m
2
, 120 min infusion)
or to GemOx (arm B: gemcitabine day 1 and
oxaliplatin day 2). Treatment was repeated in
each arm every 2 weeks until disease
progression. Among 57 patients enrolled (A:
n=37; B: n=20) response rate was 27% in arm
A and 10% in arm B. Median progression free
survival was 4.0 and 2.5 months in arm A and
B, respectively. Median overall survival was
7.6 and 3.2 months in arm A and B,
respectively. S-GemOx was more toxic than
GemOx for grade 3-4 neutropenia (20% vs.
0%) and thrombocytopenia (16% vs. 10%).
Other toxicities were comparable. However,
since more cycles were administered in arm A
(median: 8.5, range: 1-29; vs. median: 5.8,
range: 2-12), grade 3 oxaliplatin-induced
neuropathy was higher in arm A (21.6% vs.
0%). Based on this study, we at the Yale
Cancer Center modified S-GemOx to
gemcitabine 1,000 mg/m
2
, 30 min infusion
day 1, immediately followed by 120 min
infusion of oxaliplatin 85 mg/m
2
, and found it
safe and efficacious (unpublished data).
This issue of OPTIMOX gains more
significance after a recent study presented at
the annual meeting of ASCO 2008. The
CONKO-003 study [11] randomized 165
patients to FF (5-FU 2 g/m
2
(24 h) plus folinic
acid or leucovorin (FA) 200 mg/m
2
(30 min)
on days 1, 8, 15, and 22) or OFF (FF plus
oxaliplatin 85 mg/m
2
, days 8 and 22). OFF
resulted in significantly longer progression
free survival (P=0.012) and overall survival
(P=0.014) vs. FF. OFF also results in
substantially greater clinical benefit in
patients with poor prognostic features. The
authors suggested that OFF should be
considered standard second-line treatment in
patients who progress on gemcitabine.
In conclusion, the results of this study suggest
that reintroduction of oxaliplatin following a

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JOP. Journal of the Pancreas - http://www.joplink.net - Vol. 9, No. 5 - September 2008. [ISSN 1590-8577]
662
break for neurotoxicity or to delay the
development of resistance is safe and proves
clinically beneficial in selected cases.
Received July 6
th
, 2008 - Accepted July 9
th
,
2008
Keywords Colorectal Neoplasms; Drug
Therapy;
gemcitabine;
gemcitabine-
oxaliplatin regimen; oxaliplatin; Pancreatic
Neoplasms; Peripheral Nervous System
Diseases
Abbreviations DDC: duration of disease
control; FF: 5-fluorouracil plus folinic acid or
leucovorin (FA); FOLFOX: oxaliplatin plus
5-fluorouracil (5-FU) plus leucovorin;
GemOx: gemcitabine and oxaliplatin; OFF: 5-
fluorouracil plus folinic acid or leucovorin
plus oxaliplatin; OPTIMOX: optimizing
oxaliplatin-induced neuropathy ("stop-and-
go" approach)
Acknowledgement I would particularly like
to thank my daughter Nawal Wasif, who has
taken time and effort to work on the
preparation of this manuscript as her summer
project, in special creating the Tables.
Conflict of interest The authors have no
potential conflicts of interest
Correspondence
Muhammad Wasif Saif
Division of Medical Oncology
333 Cedar Street, FMP 116
New Haven, CT 06520
USA
 
 
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