Concomitant boost plus large-field preoperative chemoradiation in locally advanced uterine cervix carcinoma: Phase II clinical trial final results (LARA-CC-1)

Abstract

Objective

To report the Phase II study final results in terms of pathological complete response (pCR) and complications in locally advanced cervical carcinoma (LACC) patients treated with chemoradiation (CT/RT) regimen based on accelerated fractionation, nodal extended fields and adjuvant radical surgery.

Methods

The sample size was quantified according to published data which shows that CT/RT followed by radical surgery in LACC patients provides a pCR rate above 45%. The 2-stage design by Simon was used to test the null hypothesis that the true pCR would improve by above 20%. The chemoradiation regimen was considered active if > 24/43 pCRs were recorded. 40 Gy/2 Gy fraction in 4 weeks was delivered to nodal volume extending up to L3 vertebra, concurrently with chemotherapy. 45 Gy in 20 fractions with a concomitant boost strategy was delivered to the macroscopic disease only.

Results

47 patients were enrolled. Median follow-up was 26 months (3–52 months). Pathological response was assessed in 44/47 patients: 17/44 (38.6%) showed a pCR to treatment, and 9/44 cases (20.5%) showed microscopic disease. Pelvic nodal metastases were documented in 9/44 cases (20.5%). 87.5% of recurrences were extra pelvic. Five patients (11%) developed acute severe gastrointestinal toxicity. The actuarial cumulative 2-year incidence of G ≥ 2 late cutaneous, gastrointestinal, and genitourinary toxicity was 10.3%, 8.3% and 24.9%, respectively. The 3-year DFS was 77.1%, while the 3-year OS was 80.5%.

Conclusions

Our results confirm the high tolerability and efficacy of this accelerated regimen. However, based on the study design, 45 Gy as a concomitant boost CT/RT delivered by a 3D technique does not seem sufficient to increase pCR rate.

Introduction

Exclusive concomitant chemoradiotherapy (CT/RT) represents the standard treatment for locally advanced cervical cancer (LACC) patients on the basis of results from 5 randomized phase III studies that demonstrated an advantage in terms of disease-free survival (DFS) and overall survival (OS) for CT/RT compared to exclusive radiotherapy [1], [2], [3], [4], [5], [6].

In the investigational setting several authors have explored different approaches including neoadjuvant chemotherapy or CT/RT followed by radical surgery with the aim of removing potentially chemo- and radio resistant tumor remnants hence improving local control and possibly overall survival [2], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. Clinical outcome results are quite encouraging [2], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20]. Despite the potentially higher risk of side effects and impairment of patients’ quality of life (QoL) related to the use of a trimodal treatment [2], [8], [10], [13], [14], long-term evaluation of toxicity did not show an increased rate and/or severity of complications compared to exclusive CT/RT [14], [21]. Moreover, very recent data from a prospective, longitudinal study assessing QoL and emotional distress in LACC patients with preoperative CT/RT reported an improvement of global health status and anxiety scores over time compared to baseline values although it does not in itself support the use of a trimodal therapy rather than definitive CT/RT [22].

Based on the close relationship between pathological response to treatment and outcome, in the last decade our main objectives in LACC patients were to improve the rate of pathologically assessed response hence modifying the dose and fractionation of cisplatin-based chemoradiation, the treatment time duration or the irradiated volumes [17], [18], [19], [20]. To improve local control by reducing the rate of regional failures in para-aortic nodes as well as in-field recurrences [23], [24], [11], a phase I study (LARA-CC-1 study) was set up by our group to investigate a regimen based on Gross Tumor Volume (GTV) accelerated fractionation and lymph node extended (up to L3 vertebra) field irradiation followed by radical surgery [20]. Results from LARA-CC-1 study established a total dose of 45 Gy given in fractions of 2.25 Gy to macroscopic tumor and a total dose of 40 Gy given in fractions of 2 Gy to lymph node stations as the recommended doses for future studies [20].

Here, we report the final results of LARA-CC-1 Phase II trial aimed at assessing the efficacy of this regimen in terms of pathologically assessed rate of complete response to treatment.

This prospective Phase II study (Large field Radiotherapy in Advanced Cervical Carcinoma, LARA-CC-1) was approved by the Catholic University Institutional Review Board. All patients gave written informed consent agreeing to be submitted to all the procedures described and for their data to be used prospectively. The primary end point of the study was to assess pathologic response, whereas secondary end points included the evaluation of toxicity, surgical morbidity, disease-free survival (DFS) and overall survival (OS).

Patients with histological confirmed, locally advanced (International Federation of Gynaecology and Obstetrics stages IB2–IVA) cervical cancer were eligible for the study. Inclusion criteria were the following: biopsy-proven carcinoma of the cervix, no evidence of disease outside the pelvis, age < 80 years, Eastern Cooperative Oncology Group performance status ≤ 2, adequate bone-marrow function (WBC > 3000/mm³, platelets > 120,000/mm³), adequate renal function (blood urea nitrogen < 25 mg/dL, creatinine < 1.5 mg/dL), normal liver function (bilirubin < 2 mg/dL), and no prior cancer other than basal cell carcinoma. Pre-treatment work up included medical history, clinical examination, chest radiography, abdominal pelvic magnetic resonance imaging (MRI), complete blood cell count, Squamous Cervical Cancer (SCC) and Ca 125 markers, liver and renal function, cystoscopy and proctoscopy were performed if there was any clinical suspicion of invasion.

Simulation and treatment of the patient were performed in a prone position using the UDT (up-down table) device to reduce the small bowel volume in the treatment field [25]. A full bladder during simulation and irradiation was required to minimize the small bowel volume in the boost field. A Computed Tomography (CT) scan with oral contrast was used for planning. The Clinical Target Volume 2 (CTV2) included: primary tumor and positive nodes. Gross Tumor Volume or (GTV) was the upper half or the whole vagina (if clinically involved), uterus, obturatory nodes, external iliac nodes, internal iliac nodes, pre-sacral nodes (cranially to S2–S3 vertebrae), common iliac lymphatic area (pelvic level III) up to its apex and anterior L3 vertebra [26]. The Clinical Target Volume 1 (CTV1) was the GTV plus 1 cm margin. Planning target volumes (PTV2 and PTV1) were defined as the clinical target volume (CTV2 and CTV1) with 8 mm. External beam radiation was delivered on both PTVs using a 3D box technique. The dose to PTV2 was 40 Gy in 2.0 Gy per fraction, a total of 20 fractions for 4 weeks. A concomitant boost total dose of 5 Gy with accelerated fractionation at 0.25 Gy/fraction was delivered to the PTV1 concurrently with PTV2. All the patients were treated with 10–15 MV photons by using an Elekta Precise linear accelerator (Elekta Oncology Systems, Crawley, UK). Treatment was discontinued in patients with grade ≥ 3 toxicity however only resumed if grade 2 toxicity was attained.

Cisplatin (20 mg/m², 2-hour intravenous infusion for days 1–4) and 5-fluorouracil (1000 mg/m², 24-hour continuous intravenous infusion for days 1–4) were administered in the first and last weeks of radiotherapy. In case of relapse or progression, patients were considered for salvage treatment.

Four weeks after the end of concomitant CT/RT patients were evaluated for objective response based on post-treatment MRI, SCC and Ca 125 markers and clinical examination. Five to six weeks after the end of CT/RT clinical responders underwent radical hysterectomy according to Piver et al. [27] with bilateral systematic pelvic lymphadenectomy. If pelvic nodes were intraoperatively defined as positive for tumor metastasis, para-aortic lymphadenectomy up to inferior mesenteric artery was carried out. Surgical morbidity was registered and classified [28].

Toxicity assessment was performed according to the Radiation Therapy Oncology Group toxicity criteria and Chassagne grading system [29], [28]. Patients were assessed weekly for acute toxicity during treatment. Operative complications were defined as bladder, ureteral, bowel, vascular injuries, and estimated blood loss exceeding 500 mL. Early and long-term complications were defined as any adverse event occurring within or after 30 days from surgery, respectively. Complications were considered severe (grade 3) if life threatening with permanent organ damage. After surgery, patients underwent physical examination, complete blood count, and blood chemistry every 3 months for the first 2 years and every 6 months thereafter. Chest radiography and abdominal pelvic MRI were performed every 6 months for the first 3 years and yearly thereafter.

Objective tumor response was assessed according to the response evaluation criteria in solid tumors [30]. Pathologic response was defined according to the TNM classification. However, complete response (CR) included cases with absence of any residual tumor after treatment at any site level, while microscopic partial response included cases with persistence of only microscopic foci (≤ 3 mm) at any site level [31].

The sample size was calculated based on the two-stage design by Simon [32]. The design tested the null hypothesis that the true response rate for this population would improve from 45% to the clinically relevant alternative of 65%, using an α error of 0.05 and a β error of 0.2. The sample size was quantified based on previous evidence [10] which showed a rate of pathologically assessed complete response to CT/RT of ∼ 45%. Thus, the first step was planned to include 15 patients; if > 7 patients experienced pathological complete response to treatment, the study would enroll additional 28 patients up to a total number of 43 patients. The regimen would be considered active if > 24 responses were recorded. Considering a 10% drop out rate, a total number of 47 patients were planned.

Disease-free survival (DFS) was calculated from the date of surgery to the date of relapse according to the last follow-up whereas overall survival (OS) was calculated from the date of diagnosis to the date of death or the date of the last follow-up. Medians and life tables were computed using the product limit estimate by the Kaplan–Meier method [33]. Statistical analysis was carried out using SYSTAT, version 11.0 (SPSS, Chicago, IL).