Author:
Howard Hansen
Date: 27
February 2008
Introduction
Gemcitabine (Gemzar) belongs to the family
of drugs called antimetabolites. Antimetabolites are very similar to
normal substances within the cell - in this case they interfere with DNA
and ribonucleic acid (RNA) growth. When the cells incorporate these
substances into the cellular metabolism, they are unable to divide. Antimetabolites are cell-cycle specific. They attack cells at
a very
specific phase in the cycle, i.e., the "S" phase which is the DNA synthesis
phase.
Antimetabolites are classified according
to the substances with which they interfere:
Folic acid antagonist: Methotrexate;
Pyrimidine antagonist:
5-Fluorouracil, Foxuridine, Cytarabine, Capecitabine, and Gemcitabine;
Purine antagonist: 6-Mercaptopurine and 6-Thioguanine Adenosine
deaminase inhibitor: Cladribine, Fludarabine and Pentostatin.
While currently not approved for
HRPC disease, there are several studies that have been done that
indicate sufficient efficacy for HRPC disease that gemcitabine should be
on the list of possible 2nd line chemotherapies. In some cases,
gemcitabine would be used as a 3rd or 4th or even 5th line chemotherapy.
Clinical Trials Using
Gemcitabine (Gemzar)
Selected studies involving
gemcitabine in HRPC patients are summarized in table 1 below. The
1st study listed by Di Lorenzo et al (1) might suggest the best choice
for a 2nd line chemotherapy.
|
Table 1. Gemcitabine
Clinical Trials for HRPC disease |
| Study |
Gemcitabine Dose & Schedule |
Other Drug(s) |
PSA RR (≥ 50% decrease in PSA) |
Measurable Disease RR |
Progression Free Survival |
Overall Survival |
| Di Lorenzo et al, (1), Phase
II, Urology 2007. 22 patients previously treated with taxotere-based
regimens. (a,b) |
1000 mg/m2, days 1 and 14
every 28 days. |
Prednisone 10 mg orally on
days 1 to 7 and 14 to 21.
Zoledronic acid 4mg every 4 weeks. |
23% (5 of 22 patients).
9% (2 patients) had < 50% PSA drop. |
14% (1 of 7 patients) had a partial
response.
43% (3 of 7) had stable disease.
|
- |
Median 32 weeks (range 14-48 wks). |
|
Cricca A, et al (2); Phase II
Anticancer Res. 2006. Chemo naive
(e) |
gemcitabine 800 mg/m2 on days
1 and 8, recycled every 21 days. |
Mitoxantrone 8 mg/m2 day 1. Prednisone 10mg/day. |
RR: 15 patients (38%) plus
stable disease (SD) in 16 patients (41%). |
10 (63%) had stable disease. |
- |
median overall survival was 15
months (range, 1-41). |
|
Morant R, et al (3),
Phase II; Ann Oncol 2000.
43 Patients.
(c) |
1200 mg/m2 for 2 hrs, later decreased to 1000mg/m2 on days
1, 8, 15 of 28 day cycle, 30 min. |
None |
7% (3 of 43 patients). 16% (7 patients) had stable disease. |
1 patient had a partial response of lymph node metastases (1
of 16 patients.) |
Stable disease had a median duration of 7.1 months (6.1-11.7
mos) |
- |
|
Qin ZK, et al (4); [in Chinese], Ai Zheng. 2004. 15
patients.
(d)
|
1000 mg/m2, days 1 and 8 of a 28 day cycle. |
Cisplatin: 100mg/m2 day 1 or 30mg/m2 days 1 to 5 within each
28 day cycle. |
14 of 15 patients. In one patient there was no change in
PSA. |
3 of 3 had a partial response. |
PSA Stable period was 12.3 months. |
Median of 14.7 months. |
|
Hoshi S, et al (5); ASCO 2006 Prostate Cancer Sympos.
Abstract #363. |
2nd line chemo:
3 patients who failed "CUDD"
rec'd 700 mg/m2, day 1, 8, 15,
every 4 weeks.
|
1st line chemo:
Low-dose cisplatin, UFT, DES, Dexamethasone
(CUDD), 40 patients. |
3 of 3? Abstracts says "all 3 responded" |
- |
- |
- |
|
A. Reissigl et al (6); phase
II, European Society for Medical Oncology (ESMO), abstract
no. 304, 1998.
16 patients. |
1200 mg/m2, days 1, 8, 15 of a 28 da cycle (30 min
infusion.) |
None. |
None. 2 patients had decreases
≥ but they did not last long enough to meet the response
criteria. |
No complete or partial responses. 10 patients
(62.5%) had stable disease. |
Median time to progression was 4.1 months. |
|
(a) Patients had failed taxotere 75mg/m2 every 3
weeks. Eleven had 2nd line chemotherapies - mitoxantrone (9)
and vinorelbine (2).
(b) Of the 22 men, 23% had pain
improvement. The most important hematologic toxicity was neutropenia
(grade 3 in 18%).
(c) There was a beneficial impact on pain in spite
of limited PSA response. Patient-related pain and the use of analgesics
as a combined endpoint provided palliation for 14 patients for at least
8 weeks (32%). 9 of the 14 had at least stable disease and 5
indicated a benefit in spite of progressive disease.
(d) Patients had multiple bone metastatses; One
patient had a hepatic metastasis, 1 had an adrenal metastasis, and 1 had
an intracranial metastasis. At study entry, 12 patients had bone pain (4
grade 1, 5 grade 2, 3 grade 3). After chemotherapy, 9 patients had no
pain, 2 had grade 1 and 1 had grade 2 pain. Mean time of pain remission was
13.6 months. Toxicities included nausea/vomiting, leukopenia, decreased
hemoglobin, and thrombocytopenia.
(e) Pain remission was recorded in 15/41 patients
(36%). Hematological toxicity was mild: Grade 3-4 neutropenia was
observed in five (12%) patients.
Studies of HRPC Cell Lines to Gemzar treatment
Including Possible Synergism
There are at least two cell level studies that have
been done (both in vitro and in vivo) that indicate some possible future
clinical trials exploring synergism for more effective treatments with
gemcitabine.
M. Kanzaki et al (7) combined low concentrations of
the histone deacetylase inhibitor FK228 (depsipeptide) as a
pre-treatment to sensitize the HRPC cells to either gemcitabine or
docetaxel. They used HRPC DU145 cells and D145 xenografts.
They found that the cytotoxicity of both gemcitabine and docetaxel were
enhanced but gemcitabine was enhanced the most.
M. Sun et al (8) studied the combination of paclitaxel (Taxol) and
gemcitabine Gemzar) for synergism using the PC-3 cell line. Their
conclusion was that "gemcitabine can enhance paclitaxel-induced tumor
cell growth suppression and apoptosis in a synergistic manner both in
vitro and in vivo, suggesting their great potential in clinical
treatment of androgen-independent prostate cancer."
Anecdotal Reports
Anecdotal reports are not meant to provide proof that something will be
effective in any particular person. They do, however, indicate
that at least some patient has had some success.
a.
My husband had an excellent response to gemcitabine after carbo/VP-16
failure. I'm not qualified to suggest that Gemzar (gemcitabine) would do
the same for you or even be useful, but it is a consideration.
b. A friend's husband, was also on Gemzar a few years before
my husband was.
He had no noticable side effects
from Gemzar. Eventually his psa began rising again. I don't have my log
close at hand so I can't check but I have a good memory for his overall
complications during the chemo treatments.
References
1. Di Lorenzo G, Autorino R, Giuliano
M, Morelli E, Giordano A, Napodano G, Russo A, Benincasa G, D'Armiento
M, Altieri V, De Placido S., Phase II trial of gemcitabine, prednisone,
and zoledronic acid in pretreated patients with hormone refractory
prostate cancer, Urology 2007 Feb;69(2):347-351.
2.
Cricca A, Marino A, Valenti D, Melotti B, Amaducci E, Guardigli C, Lenzi
M, Martorana G, Buli P, Martoni AA,
Gemcitabine plus mitoxantrone and prednisone in the palliative treatment
of hormone-resistant prostate cancer (HRPC): A phase II study (GOAM
01.01 study),
Anticancer Res. 2006 May-Jun;26(3B):2301-2306.
PMID: 16821606
3.
Morant R, Bernhard J, Maibach R, Borner M, Fey MF, Thurlimann B, Jacky
E, Trinkler F, Bauer J, Zulian G, Hanselmann S, Hurny C, Hering F,
Response and palliation in a phase II trial of gemcitabine in
hormone-refractory metastatic prostatic carcinoma. Swiss Group for
Clinical Cancer Research (SAKK),
Ann Oncol. 2000 Feb;11(2):183-188. PMID: 10761753
4. Qin ZK, Yang GW, Zhou FJ, Han H, Liu ZW, Zhou NN, Wu ZG,
[Short-term efficacy of combined chemotherapy of
gemcitabine and cisplatin on advanced hormone refractory prostate
cancer.][Article in Chinese], Ai Zheng. 2004 Dec;23(12):1700-3.
PMID: 15601564
5.
S. Hoshi, K. Ono, K. Suzuki, T. Kobayashi, T. Kobayashi, O.
Sugano,
Metronomic low-dose cisplatin, UFT, diethylstilbestrol, and
dexamethasone (CUDD) for hormone refractory prostate cancer (HRPC).
Meeting: 2006 Prostate Cancer Symposium,
Abstract No: 363.
6. A. Reissigl et al, Gemcitabine in
hormone-refractory prostate cancer: A phase II study, European Society
for Medical Oncology (ESMO), abstract no. 304, 1998.
