Trial Information

Para-Aortic Lymph Nodal Staging and Evaluation of Treatment Outcome by 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in Advanced Cancer Cervix

BACKGROUND AND RATIONALE:

Carcinoma Cervix is the commonest malignancy and a leading cause of cancer mortality seen in
Indian women. At Tata Memorial Hospital, Carcinoma Cervix constitutes approximately 10% of
all cancers (1). Nearly 85% of the patients present with advanced stages (FIGO Stage
II/III). The main stay of treatment has traditionally been radical radiation therapy with
80-90% of patients requiring radiation in their lifetime and over decades the survival rates
have achieved a plateau of 30 - 55% at 5 years. In patients with advanced stages (stages IIB
to IVA), 15 - 38% have para-aortic lymph nodal metastases (2). Identification of para-aortic
nodal status allows modification of radiation therapy fields to include this nodal disease,
which, because of intestinal morbidity, is not routinely included in the treatment field by
most of the Radiation Oncologists. Extended field radiation therapy that includes the
para-aortic nodes is associated with a 31% to 50% 5 year-survival, depending on the location
and extent of para-aortic nodal metastasis and the likelihood of controlling the pelvic
disease (3-5) Therefore, in advanced cervical cancer, it has been reported that
progression-free survival is significantly related to para-aortic lymph node metastasis
(6-8). In a collective series of Gynecologic Oncology Group protocols, Para aortic nodal
status was the most significant indication of recurrence (6).

A number of noninvasive modalities have been used to evaluate the status of para-aortic
nodal metastasis. The introduction of Computed Tomographic (CT) Scanning in the mid-1970s
provided a method of para-aortic nodal disease evaluation (9). CT Scanning has been widely
used for clinical staging, but its sensitivity for nodal metastasis is only 44% (10). In
contrast to CT, which primarily relies on the morphologic criteria, FDG-PET can
non-invasively assess metabolic activity in cancers and metastatic lesions. The
differentiation capability for malignant lesions of FDG-PET is not compromised by using
morphologic size criteria. Even malignant lesions less than 1 cm in diameter that manifest
high FDG uptake can be differentiated from nonmalignant tissue by using PET. Therefore,
FDG-PET can detect metastatic para-aortic lymph nodes in patients with advanced cervical
cancer whose lymph nodes have not been abnormally enlarged.

Many published data have previously reported the clinical value of 18F FDG PET for imaging
the primary tumor, staging the nodal and visceral involvement, and also detecting a
recurrent disease (11-19). Rose et al. (11) used FDG-PET for evaluating nodal metastasis in
locally advanced cervical cancer before surgical staging, with a sensitivity of 75% and a
specificity of 92% to detect the metastases of para-aortic lymph nodes. They found that the
accuracy of FDG-PET was greater than that of CT in detecting the para-aortic lymph nodal
metastasis. In a similar series, Wu et al. have reported a sensitivity of 85.7%, a
specificity of 94.4%, and an accuracy of 92% with FDG PET to detect para-aortic lymph nodal
metastasis in patients with advanced cervical cancer and negative abdominal CT findings.
Grigsby et al. (12) demonstrated that FDG-PET detects more abnormal lymph node regions than
does CT, and that FDG-PET findings are a better predictor of survival than those of CT in
patients with cervical cancer.

Magnetic Resonance Imaging (MRI) has also been reviewed in evaluating both the primary
disease at cervix and also para-aortic nodal staging. MRI has been recognized as an
important imaging modality for the management of cervical cancer because of its multiplanar
capability, distinct tissue contrast characteristics using various pulse sequences, and
excellent tissue contrast, particularly between tumor and surrounding normal tissues.
However, PET findings were most often compared to CT results, while MRI is nowadays
considered as the modality of choice for staging the primary tumor (20,21). Only one study
by Narayan et al. has compared the respective value of MRI and PET for staging
loco-regionally advanced cervical cancer (22). Their study found that the primary tumor was
similarly detected by the two imaging techniques with a sensitivity of 100%. On the other
hand, except for small-volume metastases, PET had a sufficiently high positive predictive
value (91%) in the pelvis and para-aortic region, to obviate lymph node sampling. More
recent studies have shown that the 3D quantitative imaging-based method of tumor size
assessment using MRI is highly accurate in determining actual tumor size and extent (23-27)
and may be superior to clinical palpation in predicting local tumor control (23,25,28)
Conversely, MRI accuracy was insufficient for nodal management. If MRI remains the modality
of choice for evaluating the loco-regional status of the primary tumor, metabolic imaging
i.e FDG PET seems particularly useful for staging, in one session, extra pelvic nodal
metastases. Thus, PET may have a significant impact on treatment decision-making.

Identification of para-aortic nodal status allows modification of radiation therapy fields
to include this nodal disease. Stehman et al. previously demonstrated the prognostic
importance of para-aortic nodal status in locally advanced cervical carcinoma (6). In
advanced cervical cancer, it has been reported that progression-free survival is
significantly related to para-aortic lymph node metastasis (6-8). Recent studies have shown
a survival benefit in patients with positive para-aortic nodes treated by extended-field
irradiation and concurrent radio-sensitizing chemotherapy (29-31).

PET is also of great value for optimally confirming a complete remission and detecting a
recurrence non-invasively in post-treatment follow-up. More recently, positron emission
tomography (PET) with the glucose analogue, 18 F-fluorodeoxyglucose (FDG) has demonstrated
promising results in evaluating tumor response and predicting survival after primary
treatment with radiation therapy or chemotherapy for several tumor types, including
head-and-neck cancer, breast cancer, seminoma, colorectal cancer, lymphoma, and lung cancer
(33-40). Recently, Grigsby et al have reported the role of FDG PET in posttherapy
surveillance monitoring in a series of 75 patients with cervical cancer. They have concluded
that FDG-PET is a valuable tool to evaluate the response of both at primary and its lymph
node disease after radiation therapy and chemotherapy and for the Post-Rx surveillance of
patients to detect asymptomatic recurrence (41).