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in vivo 19:1077-1080
(2005) -
Lissoni et al.
Enhancement of the Efficacy of Chemotherapy with Oxaliplatin Plus
5-Fluorouracil by Pretreatment with IL-2 Subcutaneous Immunotherapy in
Metastatic Colorectal Cancer Patients with Lymphocytopenia Prior to Therapy
P. LISSONI1, F.
BRIVIO2, L. FUMAGALLI2, G. DI FEDE3 and G.
BRERA4
1Division
of Radiation Oncology and 2Division of Surgery, S. Gerardo
Hospital, Monza, Milan; 3Institute of Biological Medicine, Milan;
4Ambrosian University, Milan, Italy
Abstract. The present study was carried out to evaluate the
influence of a short-period IL-2 administration on the efficacy of
chemotherapy in rnetastatic colorectal cancer patients with pretreatment
lymphocytopenia, which was defined as a lymphocyte count of less than
1500/mm3. The study included 144 consecutive metastatic
colorectal cancer patients, who underwent chemotherapy with oxaliplatin
plus 5-fluorouracil. Lymphocytopenia was seen in 4l/144 (28%) patients, who
were randomized to receive chemotherapy alone or chemotherapy after a
prechemoimmunotherapy with IL-2 (3 MIU twice/day for 3 consecutive days),
whereas patients with a normal pretreatment lymphocyte count received only
chemotherapy. A normalization of the lymphocyte number was achieved in
12/19 lymphocytopenic patients pretreated with IL-2.
The objective tumor regression rate achieved in patients with a normal
lymphocyte count prior to chemotherapy was significantly higher compared to
that obtained in lymphocytopenic patients treated with chemotherapy alone
(54/103 vs. 3/22, p<0.01), whereas no significant difference occurred
between patients with normal lymphocyte count and lymphocytopenic patients
pretreated with IL-2 (54/103 vs. 8/19). This study confirms that
pretreatment lymphocytopenia is associated with reduced efficacy of
chemotherapy in metastatic colorectal cancer patients. Moreover, it
suggests that pretreatment with IL-2 before the onset of chemotherapy may
enhance the efficacy of chemotherapy in lymphocytopenic patients. Therefore,
the administration of IL-2 before the onset of chemotherapy to improve the
immune status of cancer patients may be considered as a new
chemoimmunotherapeutic combination, which may be recommended in the
treatment of advanced cancer patients, particularly in those with
cancer-related immune alterations.
Despite great advances in the
understanding of the immunobiology of tumors (1-3), their clinical
management still remains founded on the biological characteristics of the
tumor, namely of histology, stage, genetic profile and eventual expression
of receptors for hormones and growth factors. Recent immunobiological
discoveries have generally been limited to experimental studies. In
particular, there is little data on the possible influence of the host
immunobiological status on the efficacy of cancer chemotherapy for
metastatic solid tumors.
However, preliminary clinical studies suggest that the evidence of
lymphocytopenia, prior to the onset of chemotherapy, is associated with a
reduced efficacy of the treatment, confirming the importance of the
biological response of the patients in the prognosis of their neoplastic
disease and in conditioning the efficacy of chemotherapy itself (4).
Previous clinical studies had already demonstrated that the occurrence of
lymphocytopenia represents a negative biological prognostic factor, because
of its association with a lower survival time (5). Cancer-related
lymphocytopenia is the expression of the immunosuppressive status, which
characterizes the progression of the neoplastic disease, and depends, at
least in part, on the production of immunosuppressant substances by cancer
cells (6). In particular, lymphocytopenia appears to be associated with a
progressive decline in the blood concentrations of IL-2 (7), produced by T
helper-type 1 lymphocytes (8). Since IL-2 represents the main growth factor
for lymphocytes (9), at least from a theoretical point of view the
lymphocytopenic status of advanced cancer patients could potentially be
corrected and modified by the administration of IL-2 before starting the
chemotherapeutic approach.
To date, several
chemoimmunotherapeutic combinations with IL-2 plus chemotherapy have been
proposed (10-12). However, all chemoimmunotherapeutic combinations so far
elaborated have simply used the chemotherapeutic agents to induce damage to
cancer cells, in an attempt to enhance their antigenicity, with the ensuing
potential increased efficacy of IL-2 immunotherapy (10-12). However, there
are no data about administering IL-2 in an attempt to enhance the efficacy
of the commonly used chemotherapeutic regimens.
The present study was carried out to evaluate the influence of a
short-period IL-2 subcutaneous (s.c.) immunotherapy on cancer-related
lymphocytopenia, with the aim of increasing the efficacy of cancer
chemotherapy in metastatic solid tumor patients.
Materials and Methods
The study included 144
metastatic colorectal cancer patients (M/F: 92/52; median age: years, range
41-75). The eligibility criteria were as follows: histologically proven
metastatic colorectal cancer, measurable lesions, no double tumor, no brain
metastases, no more than one previous chemotherapeutic line with
5-fluorouracil (5-FU) for the metastatic disease, and no concomitant
chronic therapy with corticosteroids or other immunosuppressive drugs.
Lymphocytopenia was defined as the presence of a total lymphocyte number
less than 1500/mm3 prior to the onset of chemotherapy and was observed in
41/144 (28%) patients prior to chemotherapy.
According to the metastatic locations, patients with pretreatment
lymphocytopenia were randomized to receive chemotherapy alone, or to be
treated with a short-period IL-2 s.c. immunotherapy before the onset of
chemotherapy. The experimental protocol was explained to each patient and
written consent was obtained.
According to the schedule proposed by Hochster et al. (13), the
chemotherapeutic regimen consisted of oxaliplatin (OXA) plus 5-FU and
folates. OXA was injected i. v. at 85 mg/m2 on days 1 and 15, while 5-FU
and folates were administered i.v. at a dose of 500 mg/m2 and of 10 mg/m2
on days 1,8 and 15, thus representing a complete immunotherapeutic cycle.
The cycles were repeated every 28 days, for at least 3 cycles. In
non-progressing patients, another 2 cycles were planned after the
radiological examinations, including CT scan.
The prechemotherapeutic immunotherapy consisted of IL-2 at a dose of 3
million IU twice/daily for 3 consecutive days s.c., for a total dose of 18
million IU, during the week preceding the onset of chemotherapy.
The clinical response was assessed according to WHO criteria. The clinical
characteristics of the patients are reported in Table I. The data were
statistically analyzed by the Chi-square test and the Student's t-test, as
appropriate.
Results
As shown in Table I , the
three groups of patients with normal lymphocyte count prior to chemotherapy,
or with pretreatment lymphocytopenia undergoing chemotherapy alone, or
chemotherapy after an IL-2 prechemotherapeutic immunotherapy were
well-matched and comparable for the main prognostic variables, including
sites of metastases,
location of the primary tumor, previous chemotherapies, age and performance
status (PS), as assessed by Karnofsky's score. The clinical response
observed in the two groups of patients with normal or low lymphocyte count
prior to chemotherapy is shown in Table II. A complete response (CR) was
achieved in 5/103 (5%) patients with normal lymphocyte count prior to
therapy and in only 1/41 (2%) lymphocytopenic patients. A partial response
(PR) was achieved in 59/144 patients, while the overall response rate (CR +
PR) was 65/144 (45%). The response rate (CR + PR) achieved in patients with
normal lymphocyte count prior to therapy was significantly higher than that
found in patients with pretreatment lymphocytopenia (54/103 (52%) vs. 11/41
(27%), p<0.05).
A normalization of lymphocyte number prior to therapy, with values greater
than 1500/mm3, was reached in 12/19 patients in response to the
prechemotherapeutic immunotherapy with IL-2.
On considering the influence
of IL-2 immunotherapy on the clinical response to chemotherapy, the
response rate obtained in patients with a normal lymphocyte count was
significantly higher compared to that observed in lymphocytopenic patients,
who received no immunotherapy prior to chemotherapy (54/103 vs. 3/22,
p<0.01), whereas no difference was seen in the response rate between
patients with a normal lymphocyte count prior to therapy and
lymphocytopenic patients pretreated with IL-2 (54/103 vs. 8/19).
Finally, within the group of lymphocytopenic patients pretreated with IL-2
before the onset of chemotherapy, the response rate observed in patients
who achieved a normalization of lymphocyte count in response to IL-2
injection was higher with respect to that obtained in patients whose
lymphocyte number was not normalized by IL-2 (6/12 (50% ) vs. 2/7 (29%)),
even though the difference was not statistically significant. However, the
response rate obtained in IL-2-pretreated patients, even independently of
lymphocyte normalization, was significantly higher than that found in
lymphocytopenic patients without IL-2 immunotherapy (8/19 vs. 3/22,p<0.05).
IL-2 prechemotherapeutic immunotherapy was well tolerated and did not
influence the expected toxicity of the chemotherapy.
Discussion
In accordance with previous preliminary clinical results (4), this study
confirms that pretreatment lymphocytopenia is associated with a reduced
efficacy of chemotherapy in metastatic cancer patients. This finding is not
surprising, since lymphocyte activation would contribute to the destruction
of tumor cells induced by chemotherapy, particularly of
chemotherapy-resistant cells, which are more sensitive to the cytotoxicity
exerted by activated lymphocytes (10). In the presence of lymphocytopenia,
such participation by lymphocytes would be diminished.
The results of this study demonstrated that the correction of
lymphocytopenia by the administration of the main growth factor for
lymphocytes, IL-2, may allow enhanced efficacy of the chemotherapy,
comparable to that commonly observed in patients with a normal lymphocyte
count prior to chemotherapy. Thus, a new regimen for immunochemotherapeutic
strategies, consisting of the administration of in vivo 19: 1077-1080
(2005)
antitumor cytokines, such as IL-2, before the onset of chemotherapy, should
improve the immune status of the patients.
At present, the overall chemoimmununotherapeutic regimens with IL-2 plus
chemotherapy have utilized chemotherapy to improve the efficacy of IL-2, by
enhancing the antigenicity of cancer cells as a consequence of
chemotherapy-induced damage of cell surface molecules. In contrast, this
study would suggest the possibility of using IL-2 to enhance the efficacy
of chemotherapy, by improving the immune status of cancer patients, namely
by increasing the absolute number of lymphocytes, which play a fundamental
role in mediating an effective anticancer immune reaction.
Further studies, using different doses of IL-2 and for a longer period of
injection, will be required to better define the optimal schedule to
prepare cancer patients for the successive administration of chemotherapy.
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Correspondence to: Dr Paolo Lissoni, Divisione di Radioterapia Oncologica, Ospedale San Gerardo, 20052
Monza, Milano, Italy. Fax: 039/2332284.
Key Words: Immunotherapy, interleukin-2, lymphocytopenia, oxaliplatin.
Received April 7, 2005
Accepted August 30, 2005
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