Impact of 3D image-based PDR brachytherapy on outcome of patients treated for cervix carcinoma in France: results of the French STIC prospective study.

Purpose To assess the physics contributions and clinical outcome with three-dimensional magnetic resonance imaging-guided pulsed-dose-rate (PDR) intracavitary brachytherapy in cervical cancer patients. Methods and Materials The data from 45 patients with primary locally advanced cervical carcinoma were analyzed. The median tumor cervical volume was 64.0 cm 3 (range, 3–178). Of the 45 patients, 24 (53%) had histologic and/or radiologic pelvic involvement. After pelvic with or without para-aortic concomitant chemoradiotherapy, a PDR brachytherapy boost was delivered to a three-dimensional magnetic resonance imaging-based clinical target volume, taking into account the dose–volume constraints for critical organs and optimization of the target volume coverage. Results At a median follow-up of 26 months (range, 9–47), the 2-year overall survival and disease-free survival rate was 78% and 73%, respectively. At the last follow-up visit, the disease of all patients remained locally controlled. Adding external beam radiotherapy and PDR using the equivalent dose in 2-Gy fractions model, the median dose received by 100% and 90% of the target was 54.4 Gy α/β10 and 63.5 Gy α/β10 for the intermediate-risk clinical target volume and 61.6 Gy α/β10 and 74.9 Gy α/β10 for the high-risk clinical target volume, respectively. Of the 45 patients, 23 and 2 developed acute Grade 1-2 and Grade 3 complications, respectively; 21 patients presented with delayed Grade 1-2 complications. One other patient presented with Grade 3 vesicovaginal fistula. No Grade 4 or greater complications, whether acute or delayed, were observed. Conclusion Magnetic resonance imaging-guided PDR brachytherapy with optimization integrating the limits of tolerance to critical organs allows for excellent local control rates. Moreover, the present results have confirmed that the ability to optimize dwell times can contribute to an improvement in local control rates with a low level of late side effects.

Physics Contributions and Clinical Outcome With 3D-MRI–Based Pulsed-Dose-Rate Intracavitary Brachytherapy in Cervical Cancer Patients

In locally advanced cervical cancer, 18F-fluorodeoxyglucose (FDG) PET/CT has become important in the initial evaluation of disease extent. It is superior to other imaging modalities for lymph node status and distant metastasis. PET-defined cervical tumour volume predicts progression-free and overall survival. Higher FDG uptake in both primary and regional lymph nodes is strongly predictive of worse outcome. FDG PET is useful for assessing treatment response three months after completing concurrent chemo-radiotherapy (CRT) and predicting long-term survival, and in suspected disease recurrence. In the era of image-guided adaptive radiotherapy, accurately defining disease areas is critical to avoid irradiating normal tissue. Based on additional information provided by FDG PET, radiation treatment volumes can be modified and higher doses to FDG-positive lymph nodes safely delivered. FDG PET/CT has been used for image-guided brachytherapy of FDG-avid tumour volume, while respecting low doses to bladder and rectum. Despite survival improvements due to CRT in cervical cancer, disease recurrences continue to be a major problem. Biological rationale exists for combining novel non-cytotoxic agents with CRT, and drugs targeting specific molecular pathways are under clinical development. The integration of these targeted therapies in clinical trials, and the need for accurate predictors of radio-curability is essential. New molecular imaging tracers may help identifying more aggressive tumours. 64Cu-labeled dyacetyl-di(N(4)-methylthiosemicarbazone) (64Cu-ATSM) is taken up by hypoxic tissues, which may be valuable for prognostication and radiation treatment planning. PET/CT imaging with novel radiopharmaceuticals could further impact cervical cancer treatment as surrogate markers of drug activity at the tumour microenvironment level. The present article reviews the current and emerging role of PET/CT in the management of cervical cancer.

/pdf/the-role-of-pet-ct-in-cervical-cancer-8fnbxvliov.pdf

The role of PET/CT in cervical cancer

Purpose: To evaluate the toxicity and effectiveness of celecoxib in combination with definitive chemoradiotherapy (CRT) in women with locally advanced cervical cancer. Methods and Materials: Thirty-one patients were accrued to a phase I–II trial of celecoxib 400 mg by mouth twice per day for 2 weeks before and during CRT. Tumor oxygenation (HP 5 ) and interstitial fluid pressure (IFP) were measured before and 2 weeks after celecoxib administration alone. The median follow-up time was 2.7 years (range, 1.1–4.4 years). Results: The most common acute G3/4 toxicities were hematologic (4/31, 12.9%) and gastrointestinal (5/31, 16.1%) largely attributed to chemotherapy. Late G3/4 toxicity was seen in 4 of 31 patients (13.7% actuarial risk at 2 yr), including fistulas in 3 patients (9.7%). Within the first year of follow-up, 25 of 31 patients (81%) achieved complete response (CR), of whom 20 remained in CR at last follow-up. After 2 weeks of celecoxib administration before CRT, the median IFP decreased slightly (median absolute, –4.6 mm Hg; p = 0.09; relative, –21%; p = 0.07), whereas HP 5 did not change significantly (absolute increase, 3.6%; p = 0.51; median relative increase, 11%; p = 0.27). No significant associations were seen between changes in HP 5 or IFP and response to treatment ( p = 0.2, relative HP 5 change and p = 0.14, relative IFP change). Conclusions: Celecoxib in combination with definitive CRT is associated with acceptable acute toxicity, but higher than expected late complications. Celecoxib is associated with a modest reduction in the angiogenic biomarker IFP, but this does not correspond with tumor response.

A prospective phase I-II trial of the cyclooxygenase-2 inhibitor celecoxib in patients with carcinoma of the cervix with biomarker assessment of the tumor microenvironment.

To evaluate intensity-modulated radiation therapy (IMRT) as an alternative to conformal radiotherapy (CRT) or 4-field box boost (4FB) in women with gynecologic malignancies who are unsuitable for brachytherapy for technical or medical reasons. Dosimetric and toxicity information was analyzed for 12 patients with cervical (8), endometrial (2) or vaginal (2) cancer previously treated with external beam pelvic radiotherapy and a CRT boost. Optimized IMRT boost treatment plans were then developed for each of the 12 patients and compared to CRT and 4FB plans. The plans were compared in terms of dose conformality and critical normal tissue avoidance. The median planning target volume (PTV) was 151 cm3 (range 58–512 cm3). The median overlap of the contoured rectum with the PTV was 15 (1–56) %, and 11 (4–35) % for the bladder. Two of the 12 patients, both with large PTVs and large overlap of the contoured rectum and PTV, developed grade 3 rectal bleeding. The dose conformity was significantly improved with IMRT over CRT and 4FB (p ≤ 0.001 for both). IMRT also yielded an overall improvement in the rectal and bladder dose-volume distributions relative to CRT and 4FB. The volume of rectum that received the highest doses (>66% of the prescription) was reduced by 22% (p < 0.001) with IMRT relative to 4FB, and the bladder volume was reduced by 19% (p < 0.001). This was at the expense of an increase in the volume of these organs receiving doses in the lowest range (<33%). These results indicate that IMRT can improve target coverage and reduce dose to critical structures in gynecologic patients receiving an external beam radiotherapy boost. This dosimetric advantage will be integrated with other patient and treatment-specific factors, particularly internal tumor movement during fractionated radiotherapy, in the context of a future image-guided radiation therapy study.

/pdf/dosimetric-comparison-of-intensity-modulated-conformal-and-2fdo284adg.pdf

Dosimetric comparison of intensity-modulated, conformal, and four-field pelvic radiotherapy boost plans for gynecologic cancer: a retrospective planning study

Purpose: To compare survival and severe late radiation toxicity between patients who received continuous low-dose-rate (LDR) brachytherapy (BT) and pulsed-dose-rate (PDR) BT for cervical cancer. Methods and Materials: A retrospective review of cervical cancer patients who underwent primary radiotherapy with or without concurrent cisplatin was performed. Late Grade 3 or worse toxicities were assessed using the National Cancer Institute Common Toxicity Criteria. The study endpoints were overall and disease-free survival and the probability of severe late toxicity. Results: A total of 109 patients (65.7%) received LDR BT and 57 (34.3%) received PDR BT. Seventy patients received concurrent chemotherapy with cisplatin. The 3-year overall survival and disease-free survival rate was 70% and 57% for the LDR group and 82% and 70% for the PDR group, respectively ( p = 0.25 and p = 0.19). The 3-year probability rate for late Grade 3 or worse toxicity was 7.4% for LDR BT patients and 7.6% for PDR BT patients, respectively ( p = 0.69) and 6.9% and 7.6%, respectively, for concurrent chemotherapy vs. none ( p = 0.69). Conclusion: No difference was found in severe late toxicity, overall survival, or disease-free survival between the LDR and PDR groups.

Comparison of late toxicity between continuous low-dose-rate and pulsed-dose-rate brachytherapy in cervical cancer patients

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Comparison of late toxicity between continuous low-dose-rate and pulsed-dose-rate brachytherapy in cervical cancer patients