FIELD OF THE INVENTION
The present invention relates to the use of nemorubicin
for the treatment of liver cancer. In particular, it refers to a treatment schedule
of nemorubicin administered via the intrahepatic artery every 6 weeks to patients
with liver cancer.
BACKGROUND OF THE INVENTION
The present invention relates to the use of nemorubicin
for the treatment of a liver cancer; in particular, it refers to the intrahepatic
administration of nemorubicin for use in the liver tumor theraphy according to a
particular treatment schedule.
Nemorubicin hydrochloride, namely 3'desamino-3'[2(S)methoxy-4-morpholinyl]doxorubicin-hydrochloride
(below referred to as nemorubicin only) of formula
is a doxorubicin derivative obtained with the substitution of the -NH2
at position 3' in the sugar moiety with a methoxymorpholino group. The compound
was synthesized in the course of a research program aimed at identifying new anthracyclines
with at least partially novel modes of action, and possessing broad spectrum of
activity, including activity on multidrug resistant (mdr) tumors.
Robert J. et al., Cancer Surveys, Vol. 13, 1993, pages 219-252
, describe the metabolic pathway of known anthracyclines such as doxorubicin,
epirubicin and idarubicin and the rationale for intra-arterial administration of
said anthracyclines.
Kirk S. et al., Surgery, Vol. 109, No. 6, 1991, pages 694-697
, describe the investigation and treatment of 14 patients with primary
hepatocellular carcinoma with infusion of iodized oil and doxorubicin hydrochloride.
Vasey et al., Cancer Research, Vol. 55, No. 10, 1995, pages 2090-2096
, describe phase I clinical and pharmacokinetic studies with nemorubicin
administered by i.v. bolus injection in patients with refractory solid tumors including
patients with liver metastases from colorectal cancer.
Nemorubicin is active in vitro and in vivo
on tumor cells resistant to anthracyclines and presenting the mdr phenotype, this
last mechanism being recognized to occur also in man.
No cross-resistance was observed on tumor cells resistant
to L-PAM or cDDP, or on cells resistant to Topoisomerase II inhibitors (at-mdr).
Nemorubicin is active after i.p., i.v. or oral administration,
with good antitumor activity on murine leukemias, and on solid murine and human
tumor models.
The compound differs from most anthracyclines in being
highly potent when administered in vivo, the optimal i.v. dose being at least
80 fold less than that of doxorubicin. This result, and the observation that the
cytotoxic activity of nemorubicin is increased in vitro in the presence of
mouse, rat and human liver microsomes, suggests that nemorubicin may be transformed
into highly cytotoxic metabolite(s).
A well-known pathway of the metabolic transformation of
the antitumor anthracyclines in mammals is the side-chain carbonyl group reduction,
giving the corresponding 13-dihydro derivative. The reduced derivative of nemorubicin
maintains activity in vitro and in vivo against doxorubicin-resistant
models, at doses however 10 fold higher as compared to the parent drug.
The high lipophilicity of the molecule, which confers to
the compound the ability to reach high intracellular concentrations and is most
likely one of the reasons of its efficacy on resistant models, makes it effective
also after oral administration. The oral antitumor efficacy of nemorubicin has been
examined in a panel of different tumor types with various schedules of administration.
The results demonstrate that the oral treatment with nemorubicin is associated,
in all the animal models examined, with an antitumor activity comparable to that
observed after intravenous (i.v.) administration. In these models, the effective
oral doses of nemorubicin are 1.3-2 fold higher than the effective i.v. doses. In
particular, in liver metastases from M5076 murine fibrosarcoma, the best result
(doubling of survival time) was achieved with the oral formulation, administered
daily for 5 days; the injectable formulation was less effective. This might be a
reflection of a different behavior of the drug, due to first pass effect to the
liver.
In addition, the liver is a common site of metastasis in
many human cancers.
Primary Liver Cancer
Tumors of the liver are among the most common malignancies
in the world. The annual international incidence of the disease is approximately
1 million cases, with a male to female ratio of approximately 4:1. There is a huge
geographic variation incidence corresponding to 2/100,000 in North America to 30/100,000
in South East Asia, although these numbers refer often to "total liver cancer",
without a differentiation between primary and secondary.
The highest incidence of liver cancer is seen in the Far
East and is associated with high endemic hepatitis B carrier rates, contamination
of foodstuffs, stored grains, drinking water and soil. Advances in the management
of these malignancies will likely depend on immunization strategies for hepatitis
B and C and on developing a means of decreasing cirrhosis of any origin. Cirrhosis
is frequently associated with HCC, especially in Europe and USA. Systemic chemotherapy
is generally disappointing, with response rate averaging less than 20%.
A wide variety of both surgical and nonsurgical therapies
have become available for HCC. Surgical resection and orthotopic transplantation
are the only curative options, but it is estimated that less than 10% of patients
are suitable for this approach and long-term results are poor. The low resectability
and the high recurrent rate (40% in five years after surgery), together with the
fact that HCC tends to be fatal because of local hepatic progression rather than
widespread metastasis, stimulated the development of several locoregional therapeutic
approaches, including intra-arterial chemotherapy. Higher response rates appear
to be reported for intra hepatic artery (IHA) chemotherapy administered along with
embolizing agents, such as LIPIODOL® gel foam and degradable starch
microspheres. This approach is increasingly used in the Far East. Anthracyclines
(doxorubicin and epirubicin) are widely used in this setting. However, no substantial
improvement in survival is obtained with current chemotherapeutic attempts. The
need for new effective treatments remains high.
Secondary Liver Cancer
Liver is a common site of metastasis in many human cancers
and hepatic involvement is often the major cause of morbidity and mortality in disseminated
malignancy. In particular, the liver, by virtue of the portal venous drainage system,
is usually the first - and may be the only - site of metastases in many patients
with primary colorectal cancer. Gastric and pancreatic cancers - but also melanoma,
lung and breast cancers - may also frequently metastasize to the liver. Metastatic
liver tumors are often the first evidence of the progression of a patient's cancer,
and particularly in colorectal cancer are the only tumors detected. Colorectal carcinoma
is a disease of industrialized nations. It is estimated that in USA over 160,000
new cases were diagnosed yearly and that 75,000 deaths occurred as a result of the
advanced disease. Epidemiological studies show that the incidence of colorectal
carcinoma is increasing. Involvement of the liver is found in 40-70% of patients
with progressive disease and liver is the sole site of initial tumor recurrence
in up to 30% of patients with metastatic disease. Left untreated, metastatic lesions
to the liver from colorectal cancers are associated with survival of 3 to 24 months.
For patients with isolated liver metastases, surgical resection
is the best treatment option, with 20-30% 5-year survival rate. Surgery is only
possible in about 10% of cases and it is estimated that up to 25% of patients undergoing
surgical resection will recur with metastatic liver cancer.
Palliation with systemic chemotherapy is currently offered
to most patients with extensive or multiple liver metastases. To date, systemic
5-fluoruracil (5-FU) plus folinic acid is considered the optimum treatment for metastatic
colorectal cancer, yielding response rates of only 20% and overall survival of around
12 months. Irinotecan hydrochloride trihydrate is the standard treatment after failure
of 5-FU leucovorin, with a response rate of 15% and median survival time of approximately
9 months.
In case the disease is confined to the liver and it is
inoperable, regional intraarterial chemotherapy may be indicated. With the hepatic
arterial infusion of 5-FU or of its analogue, 5-fluorodeoxyuridine (FUDR), attempts
have been made to maximise the clinical outcome (response rate in up to 50% of cases)
but with no substantial effect on survival.
Nemorubicin represents a therapeutic option in the treatment
of a liver cancer.
The expectation that nemorubicin is effective in liver
neoplasms comes from the findings of phase I and phase IB studies conducted by intravenous
route (i.v.), on a total of 197 patients in Europe and United States. During this
evaluation, regressions of liver metastases were repeatedly observed in colorectal
and renal cancer patients. Tumor shrinkage occurred at doses of 1250 and 1500 mcg/m2.
The principle toxicities were nausea and vomiting (requiring intravenous antiemetic
treatment), myelosuppression and transient elevations in transaminases.
In addition, in a phase II study evaluating i.v. therapy
in breast cancer patients with liver metastases previously untreated for the advanced
disease, 1 complete response (CR), 3 partial responses (PRs)(2 confirmed and 1 unconfirmed)
were observed in liver lesions of 4 out of 6 patients treated at 1500 mcg/m2
i.v..
These findings suggest a potential activity of nemorubicin
on liver lesions, even in tumor types resistant to conventional chemotherapy such
as colorectal cancer and renal cancer.
Strong evidence of antitumor efficacy in liver is also
supported by preclinical data. Activity of nemorubicin against liver metastases
from M5076 murine reticulosarcoma is higher after oral administration as compared
to the i.v. route, suggesting that a first pass effect may favor the efficacy of
the compound in liver. In addition, nemorubicin administered orally is more effective
on the liver metastases than on the solid primary in the same animal model.
This specific effect on liver metastases might be due to
metabolite(s) produced by liver enzymes. This hypothesis is reinforced by several
results showing nemorubicin being activated in vitro by liver microsomes to a highly
cytotoxic product. This metabolic conversion is believed to occur also in humans.
The hints of activity observed in the current clinical
experience, coupled with the activity of nemorubicin in mdr models and in liver
metastasis models, raise the expectation of an improved clinical outcome for patients
with hepatic neoplastic lesions.
International patent application WO 00/15203
discloses a method for achieving high nemorubicin concentration at the
hepatic tumor site, by providing a method for administration of nemorubicin to a
patient suffering from a liver tumor, which reduces the nemorubicin amount without
decreasing the nemorubicin's antitumor activity at the hepatic tumor site by directly
injecting nemorubicin into the hepatic artery.
According to
WO 00/15203
, nemorubicin is to be administered via the hepatic artery, for example,
as an infusion of from about 15 minutes to about 30 minutes every 4 weeks or preferably,
as a 5-10 minute bolus every 8 weeks, to adult patients with either a hepatic metastatic
cancer, for example, patients with colorectal cancer who have progressed after receiving
intravenous chemotheraphy or intrahepatic 5-fluorouracil or 5-fluorodeoxyuridine
(FUDR) chemotheraphy, or patients with previously untreated primary liver carcinoma
such as, for example, hepatocellular carcinoma or cholangiocarcinoma involving the
liver. According to
WO 00/15203
, nemorubicin is to be administered to a patient in a dosage ranging from,
e.g., about 100 mcg/m2 to about 1000 mcg/m2, preferably from
about 100 mcg/m2 to about 800 mcg/m2, for example, in a dosage
of about 200 mcg/m2.
It has now been found, and this form the subject of the
present invention, that nemorubicin presents a better safety profile and allows
the increase of dose intensity over the previous preferred every 8 weeks regimen,
when the time interval between treatments is shorten from every 8 weeks to every
6 weeks regimen.
DESCRIPTION OF THE INVENTION
It is therefore a first object of the present invention
the use of nemorubicin for the preparation of a medicament for the treatment of
a human liver tumor, which comprises intrahepatic administration of nemorubicin
via the hepatic artery in a dosage ranging from 100 mcg/m2 to 800 mcg/m2,
preferably from 200 mcg/m2
to 600 mcg/m2, for example in a dosage of 200, 400 or 600 mcg/m2
every 6 weeks, characterised in that the appropriate dose of nemorubicin, is mixed
with a suitable amount of iodized oil, which remains selectively in a liver tumor
after its injection through the hepatic artery
Nemorubicin may be administered via the hepatic artery,
for example, as a 5-10 minutes infusion every 6 weeks, to adult patients with a
liver cancer.
In a still more particular embodiment of the present invention,
the appropriate dose of nemorubicin is preferably previously dissolved in saline
solution. Preferably, the amount of iodized oil (LIPIODOL®), may
vary from 5 ml to 30 ml, depending on the tumor size.
LIPIODOL® is a lipid lymphographic agent,
which has been found to remain selectively in liver tumor after its injection through
the hepatic artery so it is particularly useful as a carrier of anticancer agents.
The following table illustrates the suitable LIPIODOL®
volumes referred to tumor size.
Table
Tumor size (cm)
LIPIODOL® volume (ml)
2-6
5-10
>6-10
>10-15
>10
>15-30
Tumor size= sum of the longest dimensions of all tumors
For example, for intrahepatic therapy, freeze-dried vials
containing 500 mcg of nemorubicin diluted with 1 ml of sterile saline for injection
to obtain a nemorubicin concentration of 500 mcg/ml. The appropriate dose of nemorubicin
to be given to the patient is optionally mixed with a suitable amount of LIPIODOL®.
The active drug can be administered directly into the lateral
entry of an i.v. line inserted into the bung of an intrahepatic potacath lying beneath
the upper anterior abdominal wall. The drug can administered, for example, over
5-10 minutes infusion in a suitable volume of normal saline, optionally with LIPIODOL®.
Flushing of the device with 10-20 ml of saline can be done after drug infusion to
assure that all the drug is given.
Patients who do not have a portacath have a catheter inserted
into the hepatic artery by a femoral Seldinger approach and the drug can be infused,
for example, over 30 minutes infusion in a volume of 100 ml of normal saline. The
catheter is inserted under local anesthesia and can then be removed from the groin,
a pressure bandage applied and nursing observations continued overnight in hospital.
According to the present invention, a liver tumor can be
a tumor primarily confined to the liver such as, e.g. a hepatocellular carcinoma
or a cholangiocarcinoma, or a liver metastasis.
The following Experimental Protocol illustrates the present
invention.
EXPERIMENTAL PROTOCOL
The objective of the study was to shorten the time interval
between treatment administrations from every 8 weeks (q8wk) of the protocol as reported
in
WO 00/15203
to every 6 weeks (q6wk). This was done in the attempt of improving the
therapeutic potential of nemorubicin treatment through an increase of the dose intensity
of the therapy, simultaneously safeguarding patient safety.
The available results are as follows:
- Overall, 13 patients were treated with the q8wk schedule (total 25 cycles administered;
doses ranged from 200 to 800 mcg/m2), and 11 patients were treated with
the q6wk schedule (total 32 cycles administered; doses were 200 and 600 mcg/m2).
- The NCI-Common Toxicity Criteria grading system (CTC Grade), Version 2.0, was
used to report toxicities.
-
Hematological toxicity: in both schedules Grade 1-2 thrombocytopenia was
observed in most cases, reaching maximum severity Grade 3 in only one patient treated
at 600 mcg/m2 q8wk after repeated cycles (Table 1). A slight cumulative
effect (i.e., increase in frequency but not in severity) was observed after repeated
cycles for leucopenia and neutropenia (Tables 2 and 3), mainly with the q8wk schedule.
Table 1 - Hematological Toxicity - Platelets
Platelets
Worst CTC Grade by cycle
Schedule
Eval. cycles*
Grade 1-2 (%)
Grade 3 (%)
All Grades (%)
200
Cycle 1
3
3 (100%)
-
3 (100%)
mcg/m2
Cycles > 1
2
2 (100%)
-
2 (100%)
q8wk
All cycles
5
5 (100%)
-
5 (100%)
400
Cycle 1
3
1 (33%)
-
1 (33%)
mcg/m2
Cycles > 1
1
-
-
-
q8wk
All cycles
4
1 (25%)
-
1 (25%)
600
Cycle 1
4
4 (100%)
-
4 (100%)
mcg/m2
Cycles > 1
4
3 (75%)
1 (25%)
4 (100%)
q8wk
All cycles
8
7 (87%)
1 (12%)
8 (100%)
800
Cycle 1
3
2 (67%)
-
2 (67%)
mcg/m2
Cycles > 1
-
-
-
-
q8wk
All cycles
3
2 (67%)
-
2 (67%)
200
Cycle 1
5
4 (80%)
-
4 (80%)
mcg/m2
Cycles > 1
6
6 (100%)
-
6 (100%)
q6wk
All cycles
11
10 (91%)
-
10 (91%)
600
Cycle 1
6
6 (100%)
-
6 (100%)
mcg/m2
Cycles > 1
12
11 (92%)
-
11 (92%)
q6wk
All cycles
18
17 (94%)
-
17 (94%)
* Evaluable cycle: a cycle is
evaluable if at least 2 assessments exist between days 15-28 (inclusive), or if
a Grade 3 or 4 is observed.
Table 2 - Hematological Toxicity - Leucocytes
Leucocytes
Worst CTC Grade by cycle
Schedule
Evaluable Cycles°
Grade 1-2 (%)
Grade 3 (%)
All Grades (%)
200 mcg/m2
Cycle 1
3
2 (67%)
-
2 (67%)
q8wk
Cycles > 1
2
2 (100%)
-
2 (100%)
All cycles
5
4 (80%)
-
4 (80%)
400 mcg/m2
Cycle 1
3
1 (33%)
-
1 (33%)
q8wk
Cycles > 1
1
-
-
-
All cycles
4
1 (25%)
-
1 (25%)
600 mcg/m2
Cycle 1
4
3 (75%)
-
3 (75%)
q8wk
Cycles > 1
4
4 (100%)
-
4 (100%)
All cycles
8
7 (87%)
-
7 (87%)
800 mcg/m2
Cycle 1
3
2 (67%)
-
2 (67%)
q8wk
Cycles > 1
1
1 (100%)
-
1 (100%)
All cycles
4
3 (75%)
-
3 (75%)
200 mcg/m2
Cycle 1
5
-
1 * (20%)
1 (20%)
q6wk
Cycles > 1
6
3 (50%)
-
3 (50%)
All cycles
11
3 (27%)
1* (9%)
4 (36%)
600 mcg/m2
Cycle 1
6
2 (33%)
-
2 (33%)
q6wk
Cycles > 1
12
6 (50%)
-
6 (50%)
All cycles
18
8 (44%)
-
8 (44%)
* Grade 3 in one patient due
to hypersplenism syndrome
° Evaluable cycle: a cycle is evaluable if at least 2 assessments exist between
days 15-28 (inclusive), or if a Grade 3 or 4 is observed
Table 3 - Hematological Toxicity - Neutrophils
Neutrophils
Worst CTC Grade by cycle
Schedule
Evaluable cycles*
Grade 1-2 (%)
Grade 3-4 (%)
All Grades (%)
200 mcg/m2 q8wk
Cycle 1
3
1 (33%)
-
1 (33%)
Cycles > 1
2
2 (100%)
-
2 (100%)
All cycles
5
3 (60%)
-
3 (60%)
400 mcg/m2 q8wk
Cycle 1
3
1 (33%)
-
1 (33%)
Cycles > 1
1
-
-
-
All cycles
4
1 (25%)
-
1 (25%)
600 mcg/m2 q8wk
Cycle 1
4
-
-
-
Cycles > 1
4
2 (50%)
-
2 (50%)
All cycles
8
2 (25%)
-
2 (25%)
800 mcg/m2 q8wk
Cycle 1
3
1 (33%)
-
1 (33%)
Cycles > 1
1
-
-
-
All cycles
4
1 (25%)
-
1 (25%)
200 mcg/m2 q6wk
Cycle 1
5
2 (40%)
-
2 (40%)
Cycles > 1
6
2 (33%)
-
2 (33%)
All cycles
11
4 (36%)
-
4 (36%)
600 mcg/m2 q6wk
Cycle 1
6
1 (17%)
-
1 (17%)
Cycles > 1
12
2 (17%)
-
2 (17%)
All cycles
18
3 (17%)
-
3 (17%)
* Evaluable cycle: a cycle is
evaluable if at least 2 assessments exist between days 15-28 (inclusive), or if
a Grade 3 or 4 is observed
Liver toxicity (Table 4): although Grade 1-2 transaminases elevation (due
to all causes, including tumor-related events) seemed to increase in frequency in
the q6wk schedule, when considering the most clinically relevant events (i.e., grade
3-4 events), frequency of transaminitis was lower in the q6wk than in the q8wk schedule,
allowing administration of repeated cycles.
Table 4 - Liver Toxicity
Schedule
Evaluable cycles°
Worst CTC Grade by cycle (increased of at least one Grade versus baseline Grade)
Grade 1-2 (%)
Grade 3-4 (%)
All Grades (%)
SGOT
200 mcg/m2 q8wk
5
3 (60%)
-
3 (60%)
400 mcg/m2 q8wk
4
1 (25%)
3 (75%)
4 (100%)
600 mcg/m2 q8wk
7
2 (28%)
2* (28%)
4 (57%)
800 mcg/m2 q8wk
5
1 (20%)
3 (60%)
4 (80%)
200 mcg/m2 q6wk
12
8 (67%)
1 (8%)
9 (75%)
600 mcg/m2 q6wk
17
14 (82%)
2 (12%)
16 (94%)
SGPT
200 mcg/m2 q8wk
5
4 (80%)
-
4 (80%)
400 mcg/m2 q8wk
4
2 (50%)
1 (25%)
3 (75%)
600 mcg/m2 q8wk
7
1 (14%)
3* (43%)
4 (57%)
800 mcg/m2 q8wk
6
-
5 (83%)
5 (83%)
200 mcg/m2 q6wk
12
7 (58%)
-
7 (58%)
600mcg/m2q6wk
18
14 (78%)
2 (11%)
16 (89%)
Total Bilirubin
200 mcg/m2 q8wk
5
5 (100%)
-
5 (100%)
400 mcg/m2 q8wk
4
2 (50%)
-
2 (50%)
600 mcg/m2 q8wk
7
7 (100%)
-
7 (100%)
800 mcg/m2 q8wk
5
3 (60%)
1 (20%)
4 (80%)
200 mcg/m2 q6wk
12
10 (83%)
-
10 (83%)
600 mcg/m2 q6wk
18
13 (72%)
1 (5%)
14 (77%)
* Excluding one case of grade
4 SGOT/SGPT attributed to iodinated oil overdose
° Evaluable cycle: a cycle is evaluable if at least 2 assessments exist between
days 2-16 (inclusive), or if Grade 3 or 4 is observed.
Efficacy: Overall, partial tumor responses (PRs) were observed
in 6/24 treated patients (25%). The tumor response was confirmed at least 4 weeks
apart in 3 cases (at 200 mcg/m2 q8wk and at 200 and 600 mcg/m2
q6wk; one case each) and was unconfirmed in the other 3 cases (at 200, 600 and 800
mcg/m2 q8wk; one case each). The six responses are commented here below.
SCHEDULE q8wk
(number of treated patients =13)
200 mcg/m2 dose level
Unconfirmed PR was observed in one patient (American Joint Committee on Cancer,
AJCC, stage II), who had one measurable lesion in the right liver lobe at study
entry. After 2 cycles PR was achieved (85.9% decrease in tumor area versus baseline);
the response was not subsequently confirmed due to the appearance of a lesion in
the non-perfused left lobe, although it was confirmed in the perfused right lobe.
Based on this, the patient was withdrawn from therapy. At the last follow-up (more
than 11 months later), the lesion in the right lobe was still in PR and the lesion
appeared in the left lobe had not increased in size. Overall, the PR in the original
lesion (right lobe) lasted, overall, 12+ months.
Confirmed PR was reported in one patient (AJCC stage III), who presented
at study entry 2 lesions in the right liver lobe (one measurable and one evaluable).
During the treatment period, only the measurable lesion was monitored, showing a
shrinkage of 78.45% versus baseline after 1 cycle. In the second cycle, the lesion
area further decreased (assessment performed 26 days after the assessment of cycle
1; 95.3% reduction versus baseline) and the tumor response was regarded as downstaging,
i.e. the tumor was made resectable. However, the patient refused surgery and went
off study. At the last contact, 8 months later, the patient was alive, no other
antitumor therapy had been started and no additional tumor assessment had been performed.
600 mcg/m2 dose level
One patient (AJCC stage III), enrolled in the study with
one measurable lesion in the right liver lobe, was judged to be in PR after one
cycle (54.3% decrease of lesion area versus baseline). The tumor response was
unconfirmed in cycle 2 due to the appearance of a small lesion in the left
non perfused lobe, although it was confirmed in the perfused right lobe (68.2% decrease
in tumor area versus baseline). Based on this, the treating physician judged appropriate
to administer an additional cycle (cycle 3), at the end of which disease progression
was observed in both lesions; the patient was withdrawn from the study and started
another antitumor therapy. The PR in the original lesion (right lobe) lasted, overall,
about 3 months.
800 mcg/m2 dose level
Unconfirmed PR was observed in one patient (AJCC stage III), who had one
measurable lesion in the right liver lobe at study entry. PR was achieved after
3 cycles, with a 52% decrease of the tumor area versus baseline. At the end of the
same cycle the patient was taken off study and started a conventional intrahepatic
artery therapy.
SCHEDULE q6wk
(number of treated patients =11)
200 mcg/m2 dose level
Confirmed PR was reported in one patient (AJCC stage II), who presented at
study entry one measurable lesion in the right liver lobe. PR was achieved after
2 cycles, with 64% tumor shrinkage versus baseline; at that time the patient withdrawn
his consent and went off study. However, he agreed to go back to the hospital after
5 weeks for a CT scan assessment, based on which the PR was confirmed (70% lesion
area reduction versus baseline). At the last contact, 2 months later, the patient
was alive and had not started any other antitumor therapy.
600 mcg/m2 dose level
Confirmed and long-lasting PR was observed in one patient (AJCC stage III),
who had 3 lesions in the right liver lobe (two small evaluable lesions and one measurable
lesion) at study entry. The overall tumor response was PR since the first treatment
cycle, with a 48.4% reduction of the measurable lesion area and disappearance of
the two small lesions. The tumor shrinkage was confirmed in the subsequent 2 cycles
(78.2% reduction of measurable lesion area in cycle 3 versus baseline), at the end
of which the treating physician planned to take the patient off study and proceed
with alcohol perfusion. MRI performed in the third cycle showed that the original
tumor was still supported by a small vessel, then justifying two additional nemorubicin
administrations. After a total of 5 cycles, the patient was withdrawn from the trial
still in PR, further confirmed 2 months later at the last follow up visit. Overall,
the PR lasted 8+ months.
Conclusion: In the q6wk schedule efficacy is very well maintained, with two
confirmed PR out of 11 treated patients, versus one confirmed PR out of 13 treated
patients in the q8wk schedule.
As for safety, the most relevant effect of the compound
is the induction of mild-moderate thrombocytopenia and leucopenia. The available
data indicate that the q6wk schedule does not increase the frequency of thrombocytopenia
and leucopenia after repeated cycles with respect to the q8wk schedule and can be
therefore considered safely administrable. This is particularly relevant due to
the fact that, in patients with hepatocellular carcinoma, platelets and white blood
cells count decrease as a consequence of disease-associated portal hypertension
and hypersplenism.
Regarding the effect on liver transaminases, the q6wk schedule
is definitely not worse than the q8wk schedule in producing severe transaminitis.
Therefore, the q6wk schedule represents and advantage over
the q8wk since ensures good tolerability and allows the increase of dose intensity,
being potentially more beneficial for the patients, as suggested by the two confirmed
partial remissions (lasting up 8 months in one case).