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.
This trial is designed to study the safety and efficacy of the combination of carboplatin, bevacizumab, and pelvic radiation therapy.~Rationale for substituting cisplatin with carboplatin:~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 Gynecologic Oncology Group protocols for cervical cancer have used cisplatin and radiation therapy as in two of the five landmark trials. However, the benefit in survival given by cisplatin has not been without toxicity. In summary, in the trial by Keys 35% of patients receiving cisplatin and radiotherapy experienced moderate or severe toxicities. In the one by Rose, only 49 % completed the intended 6 cycles of chemotherapy.~Based on the toxicity profile of cisplatin, Higgins performed a phase II study of concurrent carboplatin with pelvic radiation therapy in the primary treatment of cervix cancer. He demonstrated the ability to administer carboplatin with concurrent radiation therapy with significantly less toxicity and with 94 % of the planned treatments delivered.~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. 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.~Rationale for bevacizumab:~Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that binds to and inhibits the biologic activity of vascular endothelial growth factor (VEGF) which stimulates tumor and tumor blood vessel growth. Targeting VEGF with bevacizumab could potentially be of benefit in cervical cancer patients by starving the tumor's blood supply and potentially enhancing the effect of radiotherapy and carboplatin chemotherapy.