Patterns of failure after use of (18)F-FDG PET/CT in integration of extended-field chemo-IMRT and 3D-brachytherapy plannings for advanced cervical cancers with extensive lymph node metastases

Abstract

Background: The study is to evaluate the patterns of failure, toxicities and long-term outcomes of aggressive treatment using (18)F-FDG PET/CT-guided chemoradiation plannings for advanced cervical cancer with extensive nodal extent that has been regarded as a systemic disease.

Methods: We retrospectively reviewed 72 consecutive patients with (18)F-FDG PET/CT-detected widespread pelvic, para-aortic and/or supraclavicular lymph nodes treated with curative-intent PET-guided cisplatin-based extended-field dose-escalating intensity-modulated radiotherapy (IMRT) and adaptive high-dose-rate intracavitary 3D-brachytherapy between 2002 and 2010. The failure sites were specifically localized by comparing recurrences on fusion of post-therapy recurrent (18)F-FDG PET/CT scans to the initial PET-guided radiation plannings for IMRT and brachytherapy.

Results: The median follow-up time for the 72 patients was 66 months (range, 3-142 months). The 5-year disease-free survival rate calculated by the Kaplan-Meier method for the patients with extensive N1 disease with the uppermost PET-positive pelvic-only nodes (26 patients), and the patients with M1 disease with the uppermost PET-positive para-aortic (31 patients) or supraclavicular (15 patients) nodes was 78.5 %, and 41.8-50 %, respectively (N1 vs. M1, p = 0.0465). Eight (11.1 %), 18 (25.0 %), and 3 (4.2 %) of the patients developed in-field recurrence, out-of-field and/or distant metastasis, and combined failure, respectively. The 6 (8.3 %) local failures around the uterine cervix were all at the junction between IMRT and brachytherapy in the parametrium. The rate of late grade 3/4 bladder and bowel toxicities was 4.2 and 9.7 %, respectively. When compared to conventional pelvic chemoradiation/2D-brachytherapy during 1990-2001, the adoption of (18)F-FDG PET-guided extended-field dose-escalating chemoradiation plannings in IMRT and 3D-brachytherapy after 2002 appeared to provide higher disease-free and overall survival rates with acceptable toxicities in advanced cervical cancer patients.

Conclusions: For AJCC stage M1 cervical cancer with supraclavicular lymph node metastases, curability can be achieved in the era of PET and chemo-IMRT. However, the main pattern of failure is still out-of-field and/or distant metastasis. In addition to improving systemic treatment, how to optimize and integrate the junctional doses between IMRT and 3D-brachytherapy in PET-guided plannings to further decrease local recurrence warrants investigation.

Fig. 1

The effects of employing integrated ¹⁸F-FDG PET/CT staging, modern multi-modalities of radiotherapy (3D-RT, IMRT, IGRT, and 3D-brachytherapy) and concurrent chemotherapy for treatment of advanced cervical cancer with extensive nodal disease but no visceral metastasis at diagnosis. Kaplan-Meier disease-free survival estimates for the 72 patients with extensive PET-positive lymph nodes grouped by their highest level of lymph node involvement after curative-intent treatment. LAP, lymphadenopathy; SC, supraclavicular

Fig. 2

Patterns of failure after ¹⁸F-FDG PET-guided RT planning. Pre-treatment combined RT planning scans of 3D-RT, IMRT and 3D-brachytherapy are fused to post-treatment recurrent ¹⁸F-FDG PET/CT scans to map the recurrent tumors in the initial RT treatment fields and dose distribution. The doses of external beam radiation and brachytherapy are transformed to EQD2 (equivalent dose to a 2-Gy fraction) for combination. a Out-of field recurrence and distant metastasis. RT dose distribution is demonstrated by colors. The lung metastasis confirmed by pathology is indicated by a white arrow. Note that the post-RT in-field structures show lower metabolic activity as compared to those in the pre-RT scan. (b) In-field recurrence. Note that the FDG-avid recurrent cervical tumor (white arrow) confirmed by pathology is located at the junctional zone of IMRT (EQD2 60 Gy) and brachytherapy (EQD2 85 Gy) in the parametrium

Fig. 3

Improved survival of cervical cancer with time in the era of ¹⁸F-FDG PET/CT and chemo-IMRT/IGRT/3D-brachytherapy: a 20-year analysis including consecutive 564 patients during 1990–2010 in one institution. a The overall survival rates for cervical cancer patients (FIGO IA2-IVA, and IVB without visceral metastasis) diagnosed at our institution from 1990 to 2010 are calculated by the Kaplan-Meier method and stratified by treatment year. (b) Comparison of the distribution of treatment modalities in each corresponding International Federation of Gynecology and Obstetrics (FIGO) stage, 1990–2001 vs. 2002–2010. RT, radiotherapy; CT, chemotherapy. (c) Kaplan-Meier survival estimates for patients with curative treatment are stratified by International Federation of Gynecology and Obstetrics (FIGO) stage and treatment year. (d) Kaplan-Meier survival estimates for advanced cervical cancer patients treated with definitive concurrent chemoradiation (CCRT) stratified by treatment year (conventional pelvic CCRT plus 2D brachytherapy in 1990–2001 vs. ¹⁸F-FDG PET-guided extended-field dose-escalating chemo-IMRT-brachytherapy in 2002–2010)