I. Introduction
Colorectal carcinoma is the second most common cancer
in the Western World. In Europe 90,000 patients die from this disease each year
(Black et al, 1997). In Italy each year, nearly 20,000 new patients develop
colorectal cancer with a 55% mortality rate (Bonadonna et al, 1999). In the
last 4 decades, 5-fluorouracil (5-FU) has been the most important drug in the
treatment of metastatic colorectal cancer (MCC). Modulation of 5-FU action with
leucovorin (LV) has increased response rates in the treatment of this disease,
but unfortunately the duration of response has not improved (Advanced
colorectal cancer meta-analysis project, 1992). Additional progress has been
accomplished by changing the schedule of 5-FU administration. In fact, 5-FU
when given in a bolus preferentially inhibits RNA synthesis, while as a
continuous infusion it inhibits thymidilate synthase and DNA synthesis (Sobrero
et al, 1997). Based on these principles, the introduction into clinical
practice of a bimonthly schedule combining LV with 5-FU bolus and continuous
infusion (the Òde GramontÓ regimen), has improved response rates and decreased
toxicity profiles, but has still not improved survival (de Gramont et al,
1997). Irinotecan (CPT-11) and oxaliplatin (L-OHP) are 2 new drugs that have
been recently introduced into clinical practice. The combination of CPT-11,
bolus 5-FU and LV (IFL) has been the most widely used regimen for the treatment
of patients with MCC in the United States of America and Canada (Saltz et al,
2000). The combination of L-OHP with bolus LV and 5FU and infusional 5-FU
(FOLFOX) was approved in 1999, in Europe, as first-line treatment of MCC,
following the results of a study that showed improved response compared with a
regimen containing LV and 5-FU alone (de Gramont et al, 2000). Combining CPT-11
with the de Gramont regimen (FOLFIRI) resulted also in increased response rate,
time to pregression and overall survival with respect to the de Gramont regimen
alone (Douillard et al, 2000). Recently published trials have ascertained the
superiority of FOLFOX with respect to FOLFIRI, both in the adjuvant and in
metastatic disease chemotherapy setting (Goldberg et al, 2003, 2004).
Furthermore, the FOLFOX regimen has been shown to be superior to both the
FOLFIRI and CPT-11/L-OHP combinations, both in terms of time to progression and
overall survival, with a comparable toxicity profile (Goldberg et al, 2004).
While both CPT-11 and L-OHP have contributed substantially to the improvement
of survival of patients with MCC, here we report on four studies conducted with
L-OHP- containing regimens, but with different schedules and associations,
aimed at improving response rates and decreasing the toxicity profiles in
patients with MCC.
II. Patients
and Methods
A. Patient eligibility
Patients were required to
have histologically confirmed, colorectal adenocarcinoma, a measurable lesion
>2 cm. Patients enrolled in the first phase II study were treated with a
FOLFIRI-like regimen as first-line chemotherapy, while those entered in the
second phase II study were chemotherapy na•ve. Patients exposed to radiation
therapy for rectal cancer were included, if the measurable lesion was outside
the irradiated field. Other inclusion criteria were, adequate hematological
(neutrophils >2 x 109/L, platelets >100 x 109/L, hemoglobin
>10 g/dL, hematocrit >30%), hepatic [total bilirubin level of <1.5
mg/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <
3 times the upper limit of normal (ULN)] and cardiac functions. Patients with
additional malignancies, other than curatively treated skin and cervical cancer
or with active cardiovascular disease, were excluded. All patients were
required to sign a consent form approved by the Ethical Committee of the
Civilian Hospital of Avezzano, in adherence with provisions set forth in the
Helsinki Agreement.
B.
Treatment and follow-up evaluation
Following
the initial staging procedures, a central venous line catheter was positioned
into the subclavian vein under local anaesthesia. Chemotherapy was administered
on an outpatient basis for 2 consecutive days and repeated every 2 weeks if
toxicity permitted. Treatment, preceded by administration of an
hydroxytryptamine-3 antagonist and dexamethasone, consisted of L-OHP 50 mg/m2
in 250 ml of 5% dextrose in water, LV 200 mg/m2 in a 2-hour I.V.
infusion, followed by 5-FU 400 mg/m2 bolus and 5-FU 600 mg/m2
in a 22-hour continuous infusion, over two consecutive days. Elastomeric pumps
were used for the infusion. Patients were assessed for toxicity before each
cycle of chemotherapy according to WHO Criteria. Peripheral neuropathy was
graded using the oxaliplatin-specific scale (Caussanel et al, 1990).
Chemotherapy was delayed until recovery, if
neutrophil and platelet counts were <1.5 x 109/L and <100 x 109/L,
respectively or for significant non-hematological toxicity. In case of grade 2
hematological toxicity or diarrhea the doses of all drugs were reduced by 10%.
In case of grade 3 or 4 neutropenia, mucositis or diarrhea the 5-FU dose was
reduced by 20%. The dose of L-OHP was lowered by 20% in case of grade 3
thrombocytopenia or grade 3 diarrhea and by 50% in case of grade 4
thrombocytopenia. If grade 3 neurotoxicity occurred, the doses of L-OHP were
reduced by 20% and stopped in case of grade 4.
Patients who continued to be treated with the protocol chemotherapy beyond 6
months, were allowed to prolong the interval between chemotherapy cycles from 2
to 3 weeks, in order to permit full recovery of treatment-induced toxicities.
Patients were removed from the study in case of progressive disease,
unacceptable toxicity, consent withdrawal or disease stability after 1 year.
C.
Evaluation
Prior to treatment a complete
history was taken and a physical examination was performed, weight was recorded
and complete differential blood count, serum bilirubin, creatinine, albumin,
alkaline phosphatase, transaminases, lactic dehydrogenase, and carcinoembryonic
antigen were determined. Initial radiological investigations included chest
X-ray and computed tomography of abdomen and pelvis and an electrocardiogram.
An X-ray skeletal survey was performed when abnormal areas of uptake were
observed in bone scans; CT scanning was used to evaluate hepatic lesions. Blood
counts were repeated weekly, serum biochemistry was determined before each
course of treatment and CEA and radiological investigations were repeated every
4 courses of chemotherapy (2 months). Follow-up visits were performed monthly.
Treatment endpoints were patientsÕ response rate and survival. Objective
responses were evaluated according to WHO criteria (Miller et al, 1981).
D. Statistical methods
For the response rate, exact binomial 95% confidence intervals (CI) were calculated. Survival and time to progression were calculated from the date of protocol entry to the time of progression or death, and both were assessed using the Kaplan and Meier product-limit method (Kaplan and Meier, 1958). Patients who underwent metastasectomy were not censored for progression-free survival. Logrank test was used to compare survival curves.
III. Results
A. PatientsÕ characteristics
The studies comprise 146 consecutive patients with
metastatic colorectal carcinoma evaluated and treated at the Civilian hospital
of Avezzano. The patients median age was 60 years, 77 patients had been treated
with a 5-FU/LV adjuvant chemotherapy before developing metastatic disease,
while 69 patients had metastatic disease at the diagnosis. Twenty patients were
operated for metastasectomy, and 15 patients underwent resection of metastatic
disease after administration of the FOLFOX regimen. PatientsÕ characteristics
are included in Table 1.
B. Fractionation of FOLFOX over
two days in first and second line chemotherapy for metastatic colorectal
carcinoma
In vitro and clinical studies
have shown that L-OHP as a single agent has demonstrated superior activity
compared to cisplatin or carboplatin (Raymond et al, 1997), while in a
combination with 5-FU has a greater than additive effect on colorectal cancer
cell lines (Raymond et al, 1998). Moreover, synergism in the action of L-OHP,
5-FU and LV has been demonstrated, irrespective of sequence of administration
(Fischel et al, 1998). We therefore conducted 2 phase II studies administering
this combination of drugs (FOLFOX regimen), to chemotherapy na•ve (Recchia et
al, 2004a) and to pretreated MCC patients (Recchia et al, 2003a). L-OHP doses
were fractionated over two days and administered with 5-FU/LV bolus and
continuous infusion with the aim of increasing the activity of this regimen and
decreasing toxicity. Neurotoxicity, which may occur as acute neurosensory toxicity
involving hands, feet and larynx and as chronic sensory neuropathy with loss of
Table 1.
Characteristics of patients
|
Characteristics |
No. |
% |
|
No
of patients |
146 |
100 |
|
Age, years |
|
|
|
Median |
60 |
|
|
Range |
35-79 |
|
|
Sex |
|
|
|
Males |
95 |
65 |
|
Females |
51 |
35 |
|
Performance status (ECOG) |
|
|
|
0-1 |
115 |
79 |
|
2 |
26 |
18 |
|
3 |
5 |
3 |
|
Site of primary disease |
|
|
|
Colon |
102 |
70 |
|
Rectum |
44 |
30 |
|
Metastatic disease at diagnosis |
74 |
51 |
|
Metastatic sites |
|
|
|
Liver |
92 |
42 |
|
Lung |
31 |
14 |
|
Abdomen |
51 |
23 |
|
Bone |
13 |
6 |
|
Nodes |
14 |
7 |
|
Peritoneal
carcinomatosis |
12 |
5 |
|
Brain |
6 |
3 |
35
patients had 2 metastatic sites, and 16 patients had 3 or more metastatic sites
sensation,
dysesthesias in the distal extremities and functional impairment, is one of the
most important dose-limiting toxicities of L-OHP, caused by the cumulative
effect of the doses administered and by the peak plasma concentrations of L-OHP
(Extra et al, 1998). In order to further decrease toxicity, chemotherapy was
preceded by the administration of 2400 mg of reduced gluthatione (GSH), 4 meq
Mg SO4 and 10 meq KCl. L-OHP was administered, 50 mg/m2
and LV 200 mg/m2 in a 2-hour I.V. infusion, followed by 5-FU 400 mg
m2 bolus and 5-FU 600 mg/m2 in a 22-hour continuous
infusion, on days 1 and 2 every 2 weeks (De Gramont regimen). In the first-line
chemotherapy study including 54 patients (Recchia et al, 2004a) we obtained an
overall response rate of 50% (95% CI, 36% to 64%), with a median time to
progression and overall survival of 10.3 and 19.2 months, respectively (Figure 1), whereas in the study of 46
patients pretreated with the FOLFIRI regimen (Recchia et al., 2003a), the
response rate to salvage chemotherapy was 32.6% (95% CI, 19.5% to 48,06%).
Median time to progression and overall survival were 6.4 months (range
3.1-31+), and 12.2 months (range 3.7-31.1+), respectively (Figure 2).
Overall survival for the 100 patients enrolled in
these phase-II studies, from the start of chemotherapy for metastatic disease
was 22.5 months (Figure 3). The
toxicity profile of these 2 studies was particularly favorable. In chemotherapy
na•ve patients, grade 2-3 leukopenia was observed in 31% of patients, while
only 10% of patients developed peripheral neuropathy. Grade 4 thrombocytopenia
was observed in 1 patient. Eighty-five percent of patients had no nausea or
vomiting. Grade 1-4 diarrhea occurred in 11% of patients. Treatment was delayed
in 39 courses of chemotherapy (8%) and the doses were reduced in 24 (5%).
Figure 1. --- Time to progression:
events 41 (89%), censored 5 (11%), median time to progression: 6.4 months
(range 3.1-31+)
¾ Overall survival: events 25
(54%), censored 21 (46%), median overall survival 12.2 months (range 1-31.1+)
Figure 2. --- Time to progression:
events 47 (87%), censored 7 (13%), median time to progression: 10.3 months
(range 2.8-53.2+)
¾ Overall survival: events 36
(67%), censored 18 (33%), median overall survival 19.2 months (range 1.5-53.2+)
Figure 3. Events 79 (79%), censored
21 (21%), overall median survival 22.5 months (range 1.5-100+)
In
patients pretreated with chemotherapy, grade 2-3 leukopenia was observed in 34%
of patients, while only 10% of patients developed grade 2-3 peripheral
neuropathy. Grade 4 thrombocytopenia was low and was only observed in 1
patient. Allergic cutaneous reactions were observed in 4 patients after a cumulative
median dose of oxaliplatin of 800 mg/m2 (range 450-1000 mg/m2).
In these two studies we have shown not only that
overall survival was comparable to and even better than the survival obtained
in other trials in which L-OHP was administered in one day, but the
neurotoxicity profile was particularly favorable.
C.
Alternation of fractionated FOLFOX and FOLFIRI in first line chemotherapy for
metastatic colorectal carcinoma
The high failure
rates encountered in the chemotherapy of some cancers suggest that drug
resistance is a common phenomenon. Since L-OHP and CPT-11 are non-cross
resistant their combined use may diminish emergence of resistant neoplastic
clones and may be associated with enhanced anti-neoplastic activity with a
lower toxicity profile. Based on this hypothesis, rapid cyclic alternating
chemotherapy has been suggested as a favourable treatment modality in several
cancer types (Goldie and Coldman, 1979). In
a further attempt to improve responses obtained in the 2 previously reported
multicenter phase II studies where fractionated CPT-11 had been used as first-
(Recchia et al, 2004a) or second-line chemotherapy in MCC (Recchia et al,
2004a), we performed a further study in which both regimens FOLFOX and FOLFIRI
were alternated in each patient with aim of decreasing the chances of
developing resistance to the drugs and decrease the toxicity profile.
This trial included 26 patients of whom 14 were
female; 9 patients had a median disease-free survival of 14 months, while 17
patients had stage IV disease at the diagnosis. Patients received FOLFOX as the
first course of chemotherapy, as previously described. After 14 days patients
were treated with the FOLFIRI regimen in which CPT-11, 90 mg/m2 and
LV 200 mg/m2 were administered in a 2-hour I.V. infusion, followed
by 5-FU 400 mg m2 bolus and 5-FU 600 mg/m2 in a 22-hour
continuous infusion, on days 1 and 2 every 2 weeks. A response rate of 69% was
observed, while disease stability occurred in 11% of patients, signifying that
80% of patients had a benefit from chemotherapy. After a median follow up of 12
months median time to progression had not been reached yet, while 77% of
patients were still alive. Toxicity was exceptionally low with no grade 3 or 4
hematologic or neurologic toxicity.
D. Immunotherapy for patients radically
treated with surgery and chemotherapy for metastatic recurrent colorectal
cancer
A high percentage of patients with solid
tumors achieve a complete clinical remission after initial treatment.
Unfortunately, the majority of them finally relapse due to Òminimal residual
diseaseÓ (MRD) represented by residual tumor cells detectable only by the most
sensitive methods (Math et al, 1986). The low efficiency of the immune system,
induced by surgical and chemotherapeutic treatments will prevent the
eradication of these cell clones by cell-mediated immunity (Finke et al, 1999).
Such immune dysfunction is usually worsened by cytotoxic therapy (Mackall et
al, 1994). Performance status, disease extent, weight loss and, independently
from other factors, lymphocytopenia (Riesco, 1970; Stanley, 1980; Lavin et al,
1982) are negative prognostic factors. Chemotherapy may damage interleukin-2 (IL-2) cell-mediated immune function for prolonged periods of time
(Mackall et al, 1994; Wise et al, 1988). Vascular endothelial growth factor
(VEGF), a diffusible glycoprotein produced by normal and neoplastic cells, is
an important regulator of physiologic and pathologic angyogenesis (Ferrara N et
al, 2003). Preclinical and clinical studies have shown that a murine monoclonal
anti-human antibody against VEGF can inhibit the growth of human tumor
xenofrats and an humanized variant of this antibody in combination with
irinotecan-based chemotherapy resulted in statistically significant and
clinically meaningful improvement in survival among patients with metastatic
colorectal cancer (Kim KJ et al, 1993, Hurwitz H et al., 2004). IL-2, defined
as the hormone of the immune response,
has pleiotropic activities on cell-mediated and humoral immunity. IL-2 induces
T cell proliferation, enhances the generation of cytotoxic T lymphocytes and
activates T and B cells. In addition, IL-2 amplifies the tumoricidal activity
of NK cells (Smith, 1988). The IL-2-receptor interaction (Cantrell et al, 1984)
is augmented through a paracrine route, that involves IFN-g function (Smith, 1988). The induction of endogenous
LAK cell activity and production of tumor inhibitory cytokines (Pavletic et al,
1993) may constitute the primary cytotoxic activity of IL-2. Another important
aspect is the inhibition of angiogenic activity by IL-2 through the induction
of IFN-g, which in turn, induces p-10, a protein with potent antiangiogenic activity (Keane et
al, 1999). Some chemotherapy-refractory tumors such renal cell carcinoma and
melanoma, have shown responses to high-dose IL-2 (Fyfe et al, 1995).
Nevertheless, high-dose intravenous IL-2 has been shown to have a high toxicity
through the mechanism of vascular leak syndrome with hypotension, oliguria,
respiratory distress, cardiac arrhythmias and mental status change (Fyfe et al,
1995).
Murine studies have shown that IL-2 has a higher
efficacy, when tumor burden is low (Charak et al, 1991). Consequently it may be
preferable to administer of IL-2 after surgical cytoreduction and after having
achieved the maximum response to chemotherapy (Belldegrun et al, 2000). In this
setting the action of IL-2 could be very effective on cancer cells damaged by
chemotherapy (Mitchell, 1992). IL-2 could be, indeed, the optimal cytokine to
restore the cell-mediated immune function in cancer patients after successful
chemotherapy. Unfortunately the high toxicity of I.V. IL-2 prevents its
universal adoption in this category of patients. However, this objective could
be achieved by the subcutaneous administration of lower-dose IL-2, known to be
active with a minor toxicity profile, not only in cancer patients (Lindemann et
al, 1993), but also in HIV-immunodeficient patients (Davej et al, 1997).
Another class of biological agents, capable of
enhancing IL-2 function are retinoids that share several synergistic effects
with IL-2. In fact, retinoids boost both IL-2 receptors and T-helper cells and
co-operate with IL-2 in augmenting IFN-g and IL-2 production by human peripheral mononocytes (Prabhala et al,
1991). IL-2 cultured with RA produces a synergistic increase in IFN-g
production (4 to 90 fold), while anti-IL-2 antibodies abrogate this
effect (Prabhala et al, 1991). Finally, retinoids inhibit the proliferation of
various cell lines, inducing differentiation and apoptosis. We have previously
reported that a 0.5 mg/Kg dose of 13-cis-retinoic acid (RA) on a 5-day/week
schedule was very well tolerated in patients with advanced non-small cell lung
cancer (Recchia et al, 1999; Recchia et al, 2000). In a phase 1B study, associating
IL-2 administered subcutaneously with RA administered orally for prolonged
periods of time, we determined that the optimal biological dose (OBD) for a
phase II study was 1.8 x 106 IU and 0.5 mg/Kg for 5 days/week
respectively, for 2 cycles of 3 weeks/month, for up to 2 years (Recchia et al,
2001). This regimen was easily administered, well tolerated and improved both
total lymphocyte count and CD4/CD8 ratio in patients with tumor response or
stabilization after standard chemotherapy. Moreover, it induced a complete
response in 2/18 patients treated with long-term maintenance therapy. In a
further phase II randomized study we have shown that the combination of IL-2
and RA could decrease, significantly, the VEGF in the same category of patients
(Recchia et al, 2004b).
In an attempt to apply
the aforementioned findings to clinical practice, we conducted a study in a
selected group of 20 patients with MCC (Recchia et al, 2004c), with the
objective to verify whether the combination of IL-2
and RA could improve the outcome of patients operated for colorectal cancer
recurrence (8 liver, 12 pelvis ¤ peritoneum). Twenty patients with a median age of 66
years were entered into the study from September1998 to September 2001.
Fifty-five percent of patients were males, performance status 0 in 65% of
patients and 1 in the remaining 35%. Eight patients had synchronous metastases,
while 12 patients had a median disease-free survival of 14 months and had
received a 5-FU/LV based adjuvant chemotherapy. After curative resection of metastases patients were treated for 6 months
with the fractionated FOLFOX regimen as previously described. After
chemotherapy patients received, subcutaneously, IL-2, 1.8 x 106 I.U.
plus RA 0.5 mg/Kg, orally, for 5 days/week for 2 consecutive cycles of 3 weeks,
with a 1-week rest, for 1 year.
This therapy was continued on alternate weeks for one
more year. The third year the patients continued with an alternate schedule or
as necessary according to the immune competence and to VEGF value. Patients were
monitored every 2 months by determination of VEGF, CD4/CD8 ratio, NK and tumor markers. Responses were assessed every
4 months by the CT scan or MR scan. The toxicity of IL-2 and RA was low. With a
combination of surgery and chemotherapy, a 75% response rate was obtained (95%
C.I., 51%-91%). After a median follow-up of 20 months, there was an improvement
of CD4/CD8, NK and a statistically significant decrease of VEGF (Figure 4), while median time to
progression and overall survival were not reached yet (5-year survival rate
52%. Compared with 40 patients well matched for all characteristics, IL-2
and RA therapy improved the DFS and overall survival after curative resection
of metastases from colorectal cancer (Figure
5). A phase III randomized trial has been started.
IV. Discussion
Despite the progress that has been made in the
adjuvant treatment of colorectal cancer, approximately half of the patients
develop metastatic disease (Boring et al, 1992). The low 5-year survival rate
of patients with MCC, shows that this is a relatively chemo-resistant disease;
in fact, both MDR1 and GSH S-transferase genes are hyper expressed in
colorectal carcinoma cells (Shen et al, 1997). However, with a series of
therapetical strategies it is possible to improve the clinical outcome of these
patients.
Figure 4. Vascular endothelial growth
factor
Figure 5. Overall survival of FOLFOX
alone versus FOLFOX plus interleukine-2 and 13-cis-retinoic acid
In fact, the overall response rate and overall
survival, in the aforementioned studies has been progressively increasing. From
a 32.6% of response rate and overall survival
of 12.2 months for the pretreated MCC patients, we
improved the response rate of 50% and an overall survival of 19.2 months
for patients treated with FOLFOX in first-line chemotherapy (range 3.7-31.2+).
For the entire cohort of 100 patients treated with all three drugs, the median
survival was 22.5 months with a 5-year survival rate of 18% (Figure 3). The response rate was
further increased to 69% in the protocol alternating FOLFOX and FOLFIRI
regimens. In this study median disease-free survival
and median overall survival have not been reached yet, after a median follow-up
of 12 months. A major step forward was obtained for a selected group of 20
patients that presented with metastatic, resectable,
colorectal carcinoma. In these patients after resection of metastases and
chemotherapy, the biological therapy produced a prolonged disease-free survival
and a 5-year overall survival of 52%. In this cohort of patients some
immunological parameters were monitored. With respect to baseline values, there
was a statistically significant improvement of CD4+/CD8+ ratio, NK and
lymphocyte number and a statistically significant decrease of VEGF (Figure 4). Treatment compliance
for this regimen was good, with the median relative dose-intensity delivered
for L-OHP, LV and 5-FU being 92 %, 92%, and 94% respectively. These results are
further supported by the fact that only 8% of cycles were delayed, the dose was
reduced in only 5% and treatment was maintained over a considerable length of
time with a median of 9 cycles administered (range 4-21).
One of the major toxicities encountered with the
administration of L-OHP is neurotoxicity (Table
2). Recent data indicate that L-OHP may act on specific isoforms of the
voltage gated sodium (Na+) channel to increase the excitability of
sensory neurons, an action inhibited by the Na+ channel blocker
carbamazepine (Gamelin et al, 2002). In our studies (Recchia et al, 2003a,
2004a) grade 2 or 3 neurotoxicity was observed in 10% of patients. Such a low
rate of neuropathy, as compared with the data in literature, was most likely
due to the low daily dose of L-OHP and to the prior administration of 2400 mg
of GSH, KCl (10 meq) and MgSO4 (4 meq). In fact, the mean cumulative
dose of the L-OHP administered to each patient was 900 mg (range 400-1700).
Moreover it has been demonstrated that the addition of GSH to the chemotherapy
does not reduce the clinical activity of L-OHP (Cascinu et al, 2002). All
studies employing L-OHP in the treatment of advanced colorectal cancer have
reported varying degrees of neurological toxicity with grade 3 toxicity
increasing sharply with increasing L-OHP dosage. In 2 studies where the dose of
L-OHP was 130 mg/m2, 89% of patients showed some form of
neurological toxicity (Machover et al, 1996). In the study that lead to
approval, in Europe, of L-OHP combined with LV and infusional 5-FU as
first-line treatment of MCC, L-OHP was administered on day 1 at the dose of 85
mg/m2. Grade 1,2 or 3 neurological toxicity was observed in 68% of
patients (de Gramont et al, 2000). Haematological toxicity was also reported;
however, it reached grade 4 in only 16% of patients. Stomatitis and diarrhea
were in the same range as that reported with other regimens, while severe
nausea-vomiting occurred less frequently (4% of patients) as compared to CPT-11
based regimens. Grade 3 alopecia was reported in 29% of patients.
Recently published results of
international studies have firmly established the role of a combination of
L-OHP with LV/5-FU regimen in the treatment of MCC. One study in particular has
shown the superiority of the FOLFOX regimen compared both with the
CPT-11/LV/5-FU and the CPT-11/L-OHP regimens in terms of time to progression
and overall survival, with a comparable toxicity profile (Goldberg et al,
2004). In this study, paresthesias grade 3 or greater, were observed in 18% of
patients, whereas quality of life did not vary with respect to the three
chemotherapy schedules. These data confirm that FOLFOX should be considered as
a reference regimen in the first-line treatment of MCC.
Considering the decreased toxicity profile with the
fractionated administration of L-OHP, an activity comparable to that observed
in other studies using standard regimens and an acceptable safety profile, the
fractionated bimonthly L-OHP, 5-FU/LV may be considered as an attractive
treatment for patients with MCC. In the adjuvant setting, the characteristics
of the fractionated FOLFOX regimen are very appealing, due to
