AVF3963s Neoadjuvant Bevacizumab and Carboplatin Followed by Concurrent Bevacizumab, Carboplatin and Radiotherapy in the Primary Treatment of Cervix Cancer
Five landmark trials in cervical cancer prompted the National Cancer Institute in February
of 1999 to issue a clinical announcement stating that "strong consideration should be given
to adding concurrent chemotherapy in the treatment of invasive cervical cancer". The
chemotherapeutic agent which was a common denominator to all 5 trials was cisplatin, and
ever since it has become part of the standard of care for the treatment of stage IIB, III,
and IVA cervical cancers. In addition, chemoradiotherapy with cisplatin is also considered
one of the standard treatment options for IB2 and IIA tumors greater than 4 cm in diameter.
The most recent GOG protocols for cervical cancer have used cisplatin 40 mg/m2 on days 1, 8,
15, 22, 29 of radiation therapy and once during parametrial brachytherapy boost for a total
of 6 cycles. This cisplatin schedule was used in 2 of the 5 landmark trials by Rose [3] and
Keys [4], respectively. However, the benefit in survival given by cisplatin, has not been
without toxicity. Note that in the trial reported by Rose there was no radiotherapy alone
arm for comparison. In summary, in the trial by Keys 35% of patients experienced grade 3
(moderate) or grade 4 (severe) toxicities, compared with 13 % in the radiotherapy alone arm.
Specifically, 21 % experienced grade 3 or 4 leukopenia. Similarly, in the one by Rose, 23 %
experienced grade 3 or 4 leukopenia, and only 49.4 % completed the intended 6 cycles of
chemotherapy.
Based on the toxicity profile of cisplatin, Higgins et al. [5] performed a phase II study of
concurrent carboplatin with pelvic radiation therapy in the primary treatment of cervix
cancer. They demonstrated the ability to administer carboplatin dose based on an AUC of 2.0
on schedule with concurrent radiation therapy in the treatment of cervix cancer. Grade 3
leukopenia was observed in only 10 % of the patients, and no grade 4 leukopenia was
observed. This is approximately half the incidence of leukopenia seen with cisplatin. More
importantly, carboplatin was administered with an AUC of 2 in 175 out of 186 (94%) planned
treatments. Treatment with carboplatin in this study had a similar excellent response rate,
but with reduced hematologic side effects. A comprehensive analysis of the literature from
1998 which compared the efficacy of carboplatin versus cisplatin in solid tumors concluded
that for ovarian cancer and lung cancer the effectiveness of carboplatin was comparable to
cisplatin, while for germ cell tumors, bladder cancer, and head and neck cancer cisplatin
appeared superior [6]. There was no mention of cervical cancer in this review, since at
present there is no phase III trial comparing carboplatin versus cisplatin in cervix cancer.
Targeted therapies
Angiogenesis has been described in the majority of the cancer types affecting the female
genital tract [7-14]. Multiple growth factors and cytokines are involved in the angiogenic
process that accompanies cervical carcinogenesis. VEGF has a predominant role acting as an
endothelial cell specific mitogen [15-17], and stimulates cell proliferation and increases
vascular permeability. Various cancer types including breast, endometrial, ovarian, bladder,
and lung cancer exhibit elevated VEGF expression at advanced stages [18-25], and has also
been associated with high-grade intraepithelial lesions and cervical cancer [26-32]. VEGF
protein levels have been shown to correlate with local tumor progression, metastasis and
poor prognosis in the uterine cervix, based on immunohistochemical or enzyme immunoassay
studies [26-31]. In patients undergoing primary radiotherapy for cervical cancer, serum VEGF
influenced the progression free survival [33]. However, other reports have suggested that
VEGF does not have a prognostic value [32]. In addition, Soufla et al. found a highly
significant increase of VEGF mRNA expression upon cervical neoplastic transformation, and
that high-grade squamous intraepithelial lesions exhibited higher VEGF mRNA levels than
low-grade lesions [34].
Treatment of endothelial cells with carboplatin significantly increases the expression of
VEGF [35]. Neutralization of secreted VEGF with specific polyclonal anti-VEGF antibodies
sensitizes endothelial cells to carboplatin treatment and increases apoptosis several-fold
[35]. Treatment with polyclonal anti-VEGF antibodies and carboplatin has been shown in vivo
models to significantly enhance solid tumor growth inhibition over individual monotherapies
[35]. Therefore, targeting VEGF could potentially be of benefit in cervical cancer patients.
Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits
the biologic activity of VEGF. Since bevacizumab may cause proteinuria and hypertension,
carboplatin, which has less potential for renal toxicity than cisplatin, seems a better
choice for combining with bevacizumab. The combination of radiotherapy, carboplatin, and
bevacizumab could result in better results with decreased toxicity.
Interventional
Allocation: Non-Randomized, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
To determine the safety of the proposed treatment in this patient population.
5 years
Yes
Gloria Frelix, MD
Principal Investigator
East Carolina University School of Medicine
United States: Food and Drug Administration
AVF3963s
NCT00600210
January 2008
April 2011
Name | Location |
---|---|
East Carolina University School of Medicine | Greenville, North Carolina 27858-4354 |