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.

Inclusion Criteria:

- Patients must have IB2 and IIA tumors greater than 4 cm in diameter, IIB, IIIB without
hydronephrosis or non-functioning kidney, and IVA without invasion to the bladder or
rectum, primary, previously untreated, and histologically confirmed invasive squamous
cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix.

- Negative, non-suspicious para-aortic nodes determined by CT lymphangiogram, MRI or
lymphadenectomy.

- Adequate bone marrow function: ANC greater ≥ 1,500/mm3, platelets ≥ 100,000/mm3.

- Adequate renal function: serum creatinine ≤ 1.5 mg/100 mL.

- Adequate hepatic function: bilirubin less than or equal to 1.5 x upper limit of normal
(ULN) and SGOT and alkaline phosphatase less than or equal to 3 x ULN.

- Zubrod Performance Status of 0 or 1

- Patients of childbearing potential must have a negative serum pregnancy test within14
days of enrolling in this study and use an effective form of contraception during the
study period.

- Patients who are medically suitable for treatment with radical intent using concurrent
chemotherapy and pelvic radiation.

Exclusion Criteria:

- Patients with Stage IA, IB1, IB2 and IIa tumors less than 4 cm in diameter, IIIA or
IVB disease.

- Patients who have known metastases to para-aortic or scalene nodes or metastases to
other organs outside the radiation field at the time of the original clinical and
surgical staging.

- Extensive tumor preventing intracavitary irradiation.

- Distal vaginal involvement or any disease such that an interstitial implant might be
necessary

- Previous pelvic or abdominal radiation, cytotoxic chemotherapy, or previous therapy of
any kind for this malignancy.

- Patients who might require an emergency surgical procedure to relieve hydronephrosis,
or who are at risk of perforating the bladder and might require surgery.

- Patients with renal abnormalities, such as pelvic kidney, horseshoe kidney, or renal
transplantation, that would require modification of radiation fields

- Life expectancy of less than 12 weeks

- Current, recent (within 4 weeks of the first infusion of this study), or planned
participation in an experimental drug study other than a Genentech-sponsored
bevacizumab cancer study.

- Septicemia or severe infection

- Patients who have circumstances that will not permit completion of this study or the
required follow-up.

- Patients who are pregnant at the time of diagnosis and do not wish pregnancy
termination prior to initiation of treatment.

- Other concomitant malignancies, with the exception of nonmelanoma skin cancer, who had
(or have) any evidence of other cancer present within the last 5 years.

- Bevacizumab-Specific Exclusions

- Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or
diastolic blood pressure > 100 mmHg on antihypertensive medications)

- Any prior history of hypertensive crisis or hypertensive encephalopathy

- New York Heart Association (NYHA) Grade II or greater congestive heart failure

- Known CNS disease

- Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

- Symptomatic peripheral vascular disease

- Evidence of bleeding diathesis or coagulopathy

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to study enrollment or anticipation of need for major surgical procedure during
the course of the study

- Core biopsy or other minor surgical procedure, excluding placement of a vascular
access device, within 7 days prior to study enrollment

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
within 6 months prior to study enrollment

- Serious, non-healing wound, ulcer, or bone fracture

- Proteinuria at screening as demonstrated by either

- Urine protein:creatinine (UPC) ratio ≥1.0 at screening OR

- Urine dipstick for proteinuria ≥ 2+ (patients discovered to have ≥ 2+ proteinuria on
dipstick urinalysis at baseline should undergo a 24 hour urine collection and must
demonstrate ≤ 1g of protein in 24 hours to be eligible).

- Known hypersensitivity to any component of bevacizumab

- Pregnant (positive pregnancy test) or lactating. Use of effective means of
contraception (men and women) in subjects of child-bearing potential

- Any history of stroke or transient ischemic attack at any time

- History of myocardial infarction or unstable angina within 6 months of study
enrollment

- Carboplatin-Specific Exclusions

- History of severe allergic reactions to cisplatin or other platinum-containing
compounds.

- Patients with severe bone marrow depression or significant bleeding.