Adjuvant chemotherapy following chemoradiotherapy as primary treatment for locally advanced cervical cancer versus chemoradiotherapy alone (OUTBACK): an international, open-label, randomised, phase 3 trial.

BACKGROUND: Standard treatment for locally advanced cervical cancer is chemoradiotherapy, but many patients relapse and die of metastatic disease. We aimed to determine the effects on survival of adjuvant chemotherapy after chemoradiotherapy. METHODS: The OUTBACK trial was a multicentre, open-label, randomised, phase 3 trial done in 157 hospitals in Australia, China, Canada, New Zealand, Saudi Arabia, Singapore, and the USA. Eligible participants were aged 18 year or older with histologically confirmed squamous cell carcinoma, adenosquamous cell carcinoma, or adenocarcinoma of the cervix (FIGO 2008 stage IB1 disease with nodal involvement, or stage IB2, II, IIIB, or IVA disease), Eastern Cooperative Oncology Group performance status 0-2, and adequate bone marrow and organ function. Participants were randomly assigned centrally (1:1) using a minimisation approach and stratified by pelvic or common iliac nodal involvement, requirement for extended-field radiotherapy, FIGO 2008 stage, age, and site to receive standard cisplatin-based chemoradiotherapy (40 mg/m2 cisplatin intravenously once-a-week for 5 weeks, during radiotherapy with 45·0-50·4 Gy external beam radiotherapy delivered in fractions of 1·8 Gy to the whole pelvis plus brachytherapy; chemoradiotherapy only group) or standard cisplatin-based chemoradiotherapy followed by adjuvant chemotherapy with four cycles of carboplatin (area under the receiver operator curve 5) and paclitaxel (155 mg/m2) given intravenously on day 1 of a 21 day cycle (adjuvant chemotherapy group). The primary endpoint was overall survival at 5 years, analysed in the intention-to-treat population (ie, all eligible patients who were randomly assigned). Safety was assessed in all patients in the chemoradiotherapy only group who started chemoradiotherapy and all patients in the adjuvant chemotherapy group who received at least one dose of adjuvant chemotherapy. The OUTBACK trial is registered with ClinicalTrials.gov, NCT01414608, and the Australia New Zealand Clinical Trial Registry, ACTRN12610000732088. FINDINGS: Between April 15, 2011, and June 26, 2017, 926 patients were enrolled and randomly assigned to the chemoradiotherapy only group (n=461) or the adjuvant chemotherapy group (n=465), of whom 919 were eligible (456 in the chemoradiotherapy only group and 463 in the adjuvant chemotherapy group; median age 46 years [IQR 37 to 55]; 663 [72%] were White, 121 [13%] were Black or African American, 53 [6%] were Asian, 24 [3%] were Aboriginal or Pacific islander, and 57 [6%] were other races) and included in the analysis. As of data cutoff (April 12, 2021), median follow-up was 60 months (IQR 45 to 65). 5-year overall survival was 72% (95% CI 67 to 76) in the adjuvant chemotherapy group (105 deaths) and 71% (66 to 75) in the chemoradiotherapy only group (116 deaths; difference 1% [95% CI -6 to 7]; hazard ratio 0·90 [95% CI 0·70 to 1·17]; p=0·81). In the safety population, the most common clinically significant grade 3-4 adverse events were decreased neutrophils (71 [20%] in the adjuvant chemotherapy group vs 34 [8%] in the chemoradiotherapy only group), and anaemia (66 [18%] vs 34 [8%]). Serious adverse events occurred in 107 (30%) in the adjuvant chemotherapy group versus 98 (22%) in the chemoradiotherapy only group, most commonly due to infectious complications. There were no treatment-related deaths. INTERPRETATION: Adjuvant carboplatin and paclitaxel chemotherapy given after standard cisplatin-based chemoradiotherapy for unselected locally advanced cervical cancer increased short-term toxicity and did not improve overall survival; therefore, it should not be given in this setting. FUNDING: National Health and Medical Research Council and National Cancer Institute.

Prognostic significance of FIGO 2018 staging of loco-regionally advanced cervical cancer (LRACC) with the use of MRI and PET and implications for treatment selection.

INTRODUCTION: The FIGO 2018 staging of cervix cancer recognizes a total of 11 categories of loco-regionally advanced cervix cancer (LRACC). Whilst incorporating imaging is an improvement over clinical staging (FIGO 2009), this had led to more categories of disease which are not prognostically discrete groups. We aimed to analyze survival according to 2018 FIGO stages of cervix cancer and identify isoprognostic groups of patients based on primary tumor volume and nodal status. METHODS: Patients referred for radiotherapy with curative intent between 1996 and 2014 were eligible. Baseline clinico-pathological and follow up information was retrieved from an ethics-approved institutional prospective database. Patients were classified according to FIGO 2018 staging based on histo-pathology, MRI (tumor volume and local compartmental spread assessment) and PET results (nodal spread). Kaplan-Meier method was used to estimate survival at five years. Following survival analysis using recognized prognostic factors, isoprognostic categories were identified and merged to form 5 isoprognostic groups. RESULTS: Seven hundred and forty-four LRACC patients were included. The median (IQR) follow-up was 5.1 (2.6-8.4) yrs. Stage migration occurred in most patients, showing heterogeneous 5 years survival according to 2018 FIGO stages. In contrast progressively worsening prognosis could be demonstrated in the 5 observed isoprognostic clusters (p < 0.002). CONCLUSION/IMPLICATIONS: Prognosis in LRACC depends on the interplay between primary tumor characteristics, type of local spread and nodal disease. A prospective study of survival and patterns of failure according to isoprognostic clusters would be useful to determine the most appropriate treatment modality and estimate survival as well as better patient selection for clinical trials.

The role of positron emission tomography in the selection of patients for salvage hysterectomy following chemoradiotherapy for locally advanced cervical cancer.

BACKGROUND: Patients selection for salvage hysterectomy following chemoradiotherapy of cervical cancer is vital to avoid significant morbidity. The purpose of this study was to describe the role of post-treatment F18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scanning (FDG-PET/CT) in patient selection for salvage hysterectomy. METHODS: This was a retrospective analysis of 49 patients with cervical cancer treated between January 1996 and December 2012 who were candidates for salvage hysterectomy. RESULTS: Three groups were defined based on institutional treatment guidelines, as experience in using post-treatment FDG-PET/CT to guide management evolved. Group 1 consisted of 15 patients who underwent planned hysterectomy based on clinical, cytological, or histological suspicion. Of these, only three (20%) patients had residual disease on histology. Group 2 consisted of 13 patients who had post-treatment FDG-PET/CT 3-6 months after the completion of chemoradiotherapy due either to suspicion of recurrence on examination or patients thought to be at high risk of recurrence at the primary site. Of these, eight patients had hysterectomy and four patients showed positive histology for residual tumor. Group 3 had 21 patients who showed isolated FDG uptake at the primary site on first FDG-PET/CT scanning at 6 months. A subsequent FDG-PET/CT scan after 3 months showed disease progression in seven and complete metabolic response in 14, and surgery was avoided in all patients. CONCLUSION: FDG-PET/CT scanning at 6 months after radiotherapy is a good tool for assessing treatment response in patients with cervical cancer. In patients with persistent uptake on 6 months post-treatment FDG-PET/CT, repeat imaging at a 3-month interval helps in selecting patients for salvage hysterectomy.

Surgical treatment of "intermediate risk" lymph node negative cervical cancer patients without adjuvant radiotherapy-A retrospective cohort study and review of the literature.

OBJECTIVES: The role of adjuvant radiotherapy for lymph node-negative stage IB patients with tumor-related negative prognostic factors is not uniformly accepted. It is advocated based on the GOG 92 trial, which was initiated in 1989. The aim of the current study is to report the oncological outcome of "intermediate risk" patients treated by tailored surgery without adjuvant radiotherapy. Data from two institutions that refer these patients for adjuvant radiotherapy served as a control group. METHODS: Included were patients with stage IB cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy, who had negative pelvic lymph nodes but a combination of negative prognostic factors adopted from the GOG 92 trial. Data were obtained from prospectively collected databases of three institutions. Radical surgery was a single-treatment modality in one of them and in the remaining two institutes it was followed by adjuvant chemoradiation. RESULTS: In 127 patients who received only radical surgery, with a median follow-up of 6.1 years, the local recurrence rate was 1.6% (2 cases), and total recurrence was 6.3% (8 cases). Disease-specific survival at 5 years was 95.7% (91.9%; 99.4%) and 91% (83.7%; 98.3%) at 10 years. The only significant factor for disease-specific survival was tumor size ≥4 cm (P = 0.032). The recurrence rate, local control or overall survival did not differ from the control group. Adjuvant radiotherapy was not a significant prognostic factor within the whole cohort. CONCLUSIONS: An excellent oncological outcome, especially local control, can be achieved by both radical surgery or combined treatment in stage IB lymph node-negative cervical cancer patients with negative prognostic factors. The substantially better outcome than in the GOG 92 trial can be attributed to more accurate pre-operative and pathological staging and an improvement in surgical techniques.

Advances and Concepts in Cervical Cancer Trials: A Road Map for the Future.

OBJECTIVE: Cervical cancer is responsible for more than a quarter of a million deaths globally each year, mostly in developing countries, making therapeutic advances in all health care settings a top priority. The Gynecologic Cancer InterGroup (GCIG) is a worldwide collaboration of leading national research groups that develops and promotes multinational trials in gynecologic cancer. In recognition of the pressing need for action, the GCIG convened an international meeting with expert representation from the GCIG groups and selected large sites in low- and middle-income countries. METHODS: The focus was to develop a consensus on several concepts for future clinical trials, which would be developed and promoted by the GCIG and launched with major international participation. The first half of the meeting was devoted to a resume of the current state of the knowledge and identifying the gaps in need of new evidence, validating control arms for present and future clinical trials and identifying national and international barriers for studies of cervix cancers. The second half of the meeting was concerned with achieving consensus on a path forward. RESULTS AND CONCLUSIONS: There were 5 principal outcomes as follows: first, a proposal to expand fertility-preserving options with neoadjuvant chemotherapy; second, validation of the assessment of sentinel lymph nodes using minimally invasive surgery with an emphasis on identification and management of low-volume metastasis, such as isolated tumor cells and micrometastasis; third, evaluation of hypofractionation for palliative and curative radiation under the umbrella of the GCIG Cervix Cancer Research Network; fourth, adding to the advances in antiangiogenesis therapy in the setting of metastatic disease; and fifth, developing a maintenance study among women at high risk of relapse. The latter 2 systemic interventions could study PI3K (phosphatidylinositol-3-kinase) inhibitors, immunotherapy, anti-human papillomavirus approaches, or novel antiangiogenic agents/combinations.

Neuraxial Anesthesia Reduces Lymphatic Flow: Proof-of-Concept in First In-Human Study.

Dilation of lymphatic vessels may contribute to iatrogenic dissemination of cancer cells during surgery. We sought to determine whether neuraxial anesthesia reduces regional lymphatic flow. Using nuclear lymphoscintigraphy, 5 participants receiving spinal anesthesia for brachytherapy had lower extremity lymph flow at rest compared with flow under conditions of spinal anesthesia. Six limbs were analyzed. Four limbs were excluded because of failure to demonstrate lymph flow (1 patient, 2 limbs), colloid injection error (1 limb), and undiagnosed deep vein thrombosis (1 limb). All analyzed limbs showed reduced lymph flow washout from the pedal injection site (range 62%-100%) due to neuraxial anesthesia. Lymph flow was abolished in 3 limbs. We report proof-of-concept that neuraxial anesthesia reduces lymphatic flow through a likely mechanism of sympathectomy.

¹8F-FDG PET/CT following chemoradiation of uterine cervix cancer provides powerful prognostic stratification independent of HPV status: a prospective cohort of 105 women with mature survival data.

PURPOSE: To report 5-year outcomes of a prospective registry study investigating posttherapy FDG PET/CT in women with locally advanced cervical cancer. A secondary analysis assessing the prognostic significance of HPV infection was performed. METHODS: Patients underwent definitive chemoradiation followed by a single FDG PET/CT scan for response assessment. A complete metabolic response (CMR) was defined as no evidence of FDG-avid disease. Patients were dichotomized according to HPV infection status into a 'higher-risk' group and a 'lower-risk' group, with the higher-risk group comprising those with alpha-7 strain HPV (subtypes 18, 39 and 45) and those who were HPV-negative and the lower-risk group comprising those with alpha-9 strain HPV (subtypes 16, 31, 33, 52 and 58) and those with mixed strains. Survival outcomes, patterns of failure and salvage therapy outcomes were investigated for their association with metabolic response and HPV status. RESULTS: In 105 patients the median prospective follow-up was 5.2 years. The 5-year cancer-specific, overall and progression-free survival rates in patients with a CMR were 97 %, 93 % and 86 %, respectively. In patients without a CMR, the corresponding 5-year survival rates were 36 %, 22 % and 0 % respectively (p < 0.01). PET response was associated with patterns of failure (p < 0.01), with the 5-year freedom from local, nodal and distant failure in patients with a CMR being 94 %, 90 % and 94 %, respectively. Of 16 patients who underwent salvage therapy, 12 had disease detected on the surveillance PET scan, and 8 achieved a post-salvage CMR of whom all were alive at a median of 4.9 years. DNA adequate for HPV analysis was extracted in 68 patients. The likelihood of a PET metabolic response was not influenced by HPV infection status, with 71 % and 75 % of higher-risk and lower-risk patients, respectively, achieving CMR (p = 0.83). Higher-risk patients had a poorer OS (HR 2.6, range 1.0 - 6.6, p = 0.05) in univariable analysis but not multivariable analysis (p = 0.11). CONCLUSION: At 5 years CMR remains a powerful factor predicting survival after initial and salvage therapy. Metabolic response was not associated with HPV infection risk. Further studies are required to establish the association with HPV infection risk and survival after chemoradiation.

The role of positron emission tomography/computed tomography in planning radiotherapy in endometrial cancer.

OBJECTIVE: The optimal method of assessing disease distribution in endometrial cancer is widely debated. Knowledge of disease distribution assists in planning adjuvant radiotherapy; in this study we used positron emission tomography/computed tomography (PET/CT) to assess disease distribution before radiotherapy. METHODS: Seventy-three consecutive patients referred to the Peter MacCallum Cancer Centre for adjuvant radiotherapy for endometrial cancer, with either high-risk disease after a hysterectomy or recurrent disease, had a PET/CT before treatment. The findings on PET/CT and clinical course were recorded. RESULTS: PET/CT found additional disease in 35% of postoperative patients, changing planned treatment in 31%. In the group with known recurrence, additional disease was found in 72%, changing management in 36%. CONCLUSIONS: PET/CT is a valuable tool for planning radiotherapy in endometrial cancer.

Smokers with cervix cancer have more uterine corpus invasive disease and an increased risk of recurrence after treatment with chemoradiation.

BACKGROUND: Smoking is a risk factor for cervix cancer and causes hypoxemia, which promotes tumor infiltration and potentially impacts on treatment outcome. We performed a retrospective study to determine if smokers had an increased risk of uterine corpus infiltration, which is associated with more advanced disease and/or treatment failure after primary chemoradiation. METHODS: Results from a prospective database of patients treated with primary chemoradiation for locally advanced cervix cancer with a pretreatment MRI were analyzed. Smoking status was assessed by self-report at presentation. RESULTS: Smoking status was recorded for 346 of the 362 patients with 98 current smokers (28%), 56 ex-smokers (16%), and 192 nonsmokers (55%). Median age was 58 years with ever-smokers having a younger age at diagnosis than nonsmokers. Histologic type, International Federation of Gynecology and Obstetrics stage, tumor volume, and nodal involvement were similar across groups, as were toxicities of treatment. Ever-smokers were more likely to have corpus uterine invasion than nonsmokers. Ever-smokers had more recurrences than nonsmokers, with nonsmokers having a longer median overall survival (50.1 vs 38.7 months, P = 0.004) and relapse-free survival (46.8 vs 28.5 months, P = 0.003). In multifactor analysis, ever-smoking status was a significant predictor of developing corpus invasive disease and of inferior relapse-free and overall survival after treatment. CONCLUSIONS: Smokers have a greater risk for developing corpus invasive cervix cancer. Although nonsmokers have an older age at diagnosis, they live longer and have fewer recurrences after a diagnosis of locally advanced carcinoma of the cervix.

Hemoglobin level in cervical cancer: a surrogate for an infiltrative phenotype.

OBJECTIVE: Hemoglobin (Hb) is a prognostic factor in cervical cancer, but the underlying mechanisms remain unknown. In this study, we hypothesized that low Hb level, either before or during radiotherapy (RT), is a surrogate for a more infiltrative and therefore aggressive disease, with uterine corpus invasion and nodal metastases. METHODS AND MATERIALS: Prospectively collected data of patients with locally advanced cervical cancer treated with curative intent using chemoradiation at a tertiary academic center was reviewed. All eligible patients had a positron emission tomographic scan and pelvic magnetic resonance imaging. Hemoglobin levels before RT and Hb nadir during RT were collected from the medical record. RESULTS: The median follow-up for 263 eligible patients was 38.7 months. Ninety-six patients (36.5%) had both uterine corpus invasion and positron emission tomography-positive nodal disease (C+N+). Patients with pretreatment Hb level of less than 120 g/L were more likely to have C+N+ disease (47%) compared with patients with a high pretreatment Hb level (32%; P = 0.034). The 3-year disease-free survival and overall survival (OS) were significantly lower in the C+N+ group compared with the remaining patients (40.1% vs 76.1%, P < 0.001, and 59.7% vs 83.1%, P < 0.001, respectively). Patients with low Hb nadir were more likely to have a C+N+ disease (P < 0.001), and low Hb nadir during RT was significantly an indicator of a higher recurrence rate (P = 0.002) and lower OS (P < 0.001). In multifactor analysis, statistically significant prognostic factors for OS included histology, high-echelon nodal involvement, tumor volume on magnetic resonance imaging, C+N+ status, and Hb nadir during treatment. Pretreatment Hb level was not an independent prognostic factor. CONCLUSIONS: The combination of corpus invasion and nodal metastases is associated with lower Hb level and inferior prognosis. Because C+N+ state is related to tumor growth from early invasion to the time of presentation, it is unlikely that the correction of Hb level during treatment will have a major impact on outcome.

Prognostic significance of lymphovascular space invasion and nodal involvement in intermediate- and high-risk endometrial cancer patients treated with curative intent using surgery and adjuvant radiotherapy.

OBJECTIVE: The aim of this study was to assess whether lymphovascular space invasion (LVSI) and nodal status provide adequate prognostic information in comparison with the entire set of traditional prognostic factors in intermediate- and high-risk endometrial cancer patients treated and staged with primary surgery and adjuvant radiotherapy. METHODS: Three hundred twenty-four previously untreated high-intermediate- and high-risk endometrial cancer patients with FIGO (International Federation of Gynecology and Obstetrics) stage I to IIIC; endometrioid, serous, or clear cell histology; diagnosed between November 1995 and December 2006; who presented to Peter MacCallum Cancer Centre for adjuvant radiotherapy were included in these analyses. All traditionally recognized prognostic factors and newly created 4 pairs of combination of LVSI and nodal status were studied with respect to survival and patterns of failure. RESULTS: The median follow-up time was 4.8 years. Five-year failure-free survival for all patients according to FIGO stage I, II, and III were 87.4%, 89.0%, and 62.4 %, respectively. In multivariable analysis for relapse, positive LVSI had a hazard ratio of 4.9 (P = 0.000), which increased to 8.8 (P = 0.004) in the presence of positive nodes. For overall survival, only LVSI was significant, with a hazard ratio of 3.02 (P = 0.003). In particular, in the presence of LVSI and nodes, histological type, grade, and myometrial invasion were not significant prognosticators for relapse or overall survival. CONCLUSIONS: This model enables the separation of good prognosis patients even among poorly differentiated endometrioid, serous, and clear cell carcinoma patients and can be used in simplifying the staging of endometrial cancer and for selecting patients for high-risk endometrial cancer studies.

Reviewing the role of parametrial boost in patients with cervical cancer with clinically involved parametria and staged with positron emission tomography.

OBJECTIVE: Primary objective was to validate the practice of not treating clinically involved parametria by parametrial boost. Secondary objective was to validate the adequacy of nodal boost in node-positive patients regardless of parametrial status. MATERIAL AND METHODS: A retrospective analysis of 193 patients with locoregionally advanced cervical cancer treated with curative intent using external beam radiotherapy and brachytherapy. All patients were staged clinically (International Federation of Gynecology and Obstetrics) and radiologically using magnetic resonance imaging and positron emission tomography. The positron emission tomography positive nodes were boosted to an additional dose of 6 to 10 Gy after 40 Gy to the whole pelvis. Parametrial boost was not used. Patients with stages IB to IIa and stages IIB to IIIB disease were allocated to groups A and B, respectively. RESULTS: The pelvic failure (P = 0.430) and extrapelvic failure (P = 0.437) did not differ significantly between groups A and B. In multifactor analysis, tumor volume was significantly associated with pelvic failure (P = 0.009) and node positivity was significantly associated with extrapelvic failure (P = 0.002). Clinical parametrial involvement in the absence of parametrial boost was not related to either pelvic or extrapelvic failure. None of the node-positive patients had isolated pelvic nodal failure. CONCLUSION: Cervical cancer with clinically involved parametria can be adequately treated without parametrial boost. A dose of 46 to 50 Gy was adequate to avoid isolated pelvic nodal failure.

Tumor control after palliative hypofractionated, "Quad-shot," external beam radiotherapy followed by brachytherapy: An effective approach in medically compromised and/or elderly patients with cervix cancer.

Context: Cervix cancer is still a leading cause of death in developing countries. Concurrent chemoradiation (CCRT) over 5 weeks followed by brachytherapy is standard of care in locoregionally advanced cervix cancer. Such prolonged treatment may not be tolerated in medically compromised patients. High-dose interrupted hypofractionated Quad-Shot (QS) radiotherapy with brachytherapy treatment was well tolerated. Aims: This study aims to assess the locoregional tumor control in cervix cancer patients who were treated with QS regimen. Settings and Design: Retrospective. Subjects and Methods: Newly diagnosed histologically confirmed cervix cancer patients who were unfit for conventional CCRT and who were treated with QS protocol between 1999 and 2016 were analyzed. Tumor stage, treatment, and follow-up details were retrieved from an ethics-approved prospective departmental database. Statistical Analysis Used: Descriptive statistics and Kaplan-Meier method were used for estimating survival. Results: Thirty-six patients were available for analysis. The median age was 70.5 (32-92) years. Twenty-two of 36 (61.1%) patients had nodal disease while 33% of all patients had distant metastasis. Of 27 patients who died during follow-up, the local and pelvic control was 75% and 60%, respectively. The median overall survival and progression-free survival were 18.6 months. Grade 3-4 toxicity was observed (16%) in the bowel only. Conclusions: Hypofractionated QS radiotherapy with brachytherapy resulted in an overall 82.1% at least stable disease at the primary site. This treatment regimen was well tolerated and may be considered appropriate for patients who may not be suitable for conventional fully fractionated CCRT.

Impact of post-therapy positron emission tomography on prognostic stratification and surveillance after chemoradiotherapy for cervical cancer.

BACKGROUND: A study was undertaken to investigate the detection of relapse and survival outcomes in patients with cervical cancer treated with curative intent chemoradiotherapy, and evaluated with a post-therapy (18) F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan. METHODS: Between January 2002 and June 2007, 105 consecutive patients were prospectively enrolled into a registry study designed to assess outcomes of chemoradiotherapy. A FDG-PET scan was performed between 3 and 12 months (median, 4.9 months) post-treatment at clinician discretion. Tumor response was graded as complete metabolic response, partial metabolic response, or progressive metabolic disease. RESULTS: Median follow-up was 36 months. At post-therapy FDG-PET, 73 (70%) patients had complete metabolic response, 10 (9%) had partial metabolic response, and 22 (21%) had progressive metabolic disease. Overall survival at 3 years was 77% in all patients, and 95% for those with complete metabolic response. On multivariate analysis, complete metabolic response (P < .0001) and pretreatment tumor volume (P = .041) were strong predictors for overall survival. The number of involved lymph nodes (P < .005) and International Federation of Gynecology and Obstetrics stage (P = .04) were predictive of relapse-free survival. In total, 18 patients relapsed at a single site, and 13 underwent salvage, with a 3-year survival of 67%. Patients with complete metabolic response had a distant failure rate 36-fold less than those with partial metabolic response (P < .0001). After complete metabolic response, only 1 patient (1.6%) relapsed without symptoms and was detected through physical examination. CONCLUSIONS: The presence of a complete metabolic response at post-therapy FDG-PET is a powerful predictor for survival after chemoradiation. The very low rate of recurrence in patients with a complete metabolic response justifies a conservative follow-up approach for these patients, because relapse is usually symptomatic and not detected by routine clinical review.

Phase 1 study of tirapazamine in combination with radiation and weekly cisplatin in patients with locally advanced cervical cancer.

INTRODUCTION: Hypoxia is an adverse prognostic factor in locoregionally advanced cervical cancer treated with radiation. The aim of this phase I study was to develop a well-tolerated regimen that added tirapazamine to the standard regimen of radiation and weekly low-dose cisplatin. METHODS: Eligible patients had previously untreated carcinoma of the cervix, stages IB2 to IVA. The starting schedule was radiotherapy (45-50.4 Gy external beam radiation followed by brachytherapy), with concomitant weekly intravenous cisplatin, 40 mg/m on weeks 1 to 6 and weekly intravenous tirapazamine, 290 mg/m in weeks 1 to 5. RESULTS: Eleven patients were enrolled. The median age was 52 years (range, 31-65 years). Ten patients had squamous cell carcinoma and 1 patient had adenocarcinoma; 5 patients had stage 1B2 disease, 1 had stage IIA, 3 had stage IIB-3, 1 had stage IIIB, and 1 had stage IVA. The first 2 patients on dose level 1 experienced a dose-limiting toxicity (DLT): 1 experienced grade 3 alanine amino transferase elevation and grade 4 pulmonary embolism, and 1 experienced grade 3 ototoxicity. Doses were decreased to dose level -1 with a 30-mg/m dose of cisplatin and a 260-mg/m dose of tirapazamine. Three patients were treated without any DLTs. Six patients were then treated on dose level -1a: a 35-mg/m dose of cisplatin and a 260-mg/m doses of tirapazamine with 2 DLTs--grade 3 neutropenia with dose omission and grade 4 pulmonary embolism with major hemodynamic compromise. Three of 10 evaluable patients have experienced locoregional failure. CONCLUSIONS: The combination of weekly tirapazamine and cisplatin with radiation for locally advanced cervical cancer was associated with more toxicity than anticipated with the recommended dose level being tirapazamine 260 mg/m and cisplatin 30 mg/m. Further study of this weekly schedule is not warranted.

Patterns of failure and prognostic factor analyses in locally advanced cervical cancer patients staged by positron emission tomography and treated with curative intent.

PURPOSE: The aim of this retrospective analysis was to assess whether parameters derived from magnetic resonance imaging (MRI) and positron emission tomography (PET) provide incremental prognostic value compared with International Federation of Gynecology and Obstetrics (FIGO) stage in cervix cancer patients treated with curative intent using concurrent chemoradiotherapy. MATERIALS AND METHODS: This was a retrospective study of patients with locoregionally advanced cervical cancer staged by examination under anesthesia and pretreatment MRI and PET. Potential prognostic factors examined were derived from either clinical evaluation (age, FIGO stage, clinical diameter, histology), MRI (corpus invasion, tumor volume), or PET (lymph node metastasis). Outcome measures examined were overall survival, relapse-free survival, time to failure, local failure, nodal failure, and distant failure. RESULTS: There were 206 eligible patients. The mean potential follow-up was 4.4 years. At 5 years, for all patients, overall survival rate was 59%. For all outcome measures apart from local failure, for which adenocarcinoma histology was the most powerful adverse prognostic factor (HR, 4.29; P < 0.0001), lymph node status on PET was the dominant unifactor and multifactor prognostic factor. Corpus involvement on MRI was significantly associated with nodal involvement on PET but of MRI-derived parameters only tumor volume has prognostic value, limited to time to failure and nodal failure. CONCLUSIONS: Nodal status on PET was the major predictor of outcome in locally advanced cervix cancer treated with chemoradiation and was superior to FIGO staging. Tumor volume measured from MRI appears to be an important predictor of loco-regional relapse.

Patterns of care for radiotherapy in vulvar cancer: a Gynecologic Cancer Intergroup study.

BACKGROUND: This study aimed to describe radiotherapeutic practice in the treatment of vulvar cancer in member study groups of the Gynecologic Cancer Intergroup (GCIG). METHODS: A survey was developed and distributed to representatives of the member study groups of the GCIG, targeting the use of radiotherapy (RT) in vulvar cancer. RESULTS: Thirty-two surveys were returned from 12 different cooperative groups. The most common indications for neoadjuvant RT include unresectable disease or International Federation of Gynecology and Obstetrics stage >/=III. For the neoadjuvant treatment of vulvar cancer, pelvic doses were 48.2 +/- 5.0 Gy (mean +/- SD). The upper border of the pelvic field was L4/5 in 4, L5/S1 in 12, and not specified in 4. Of 21 groups that perform neoadjuvant RT, 17 use concomitant chemotherapy and 4 individualize treatment. Weekly cisplatin was the most commonly used chemotherapy. For the neoadjuvant RT treatment of the inguinal region, doses were 49.9 +/- 5.5 Gy (mean +/- SD). Sixteen of 18 groups used computed tomographic simulation for planning. After initial surgery, the most common indications for RT included positive lymph nodes or positive margins. Chemotherapy was not routinely used after surgery. CONCLUSIONS: Doses of RT among GCIG members are similar; however, the indications for treatment, treatment fields, and use of chemotherapy differ somewhat between groups. This is likely due to the rarity of the disease. The lack of randomized trials may contribute to the absence of a broadly accepted standard. This underscores the importance of international cooperation as in GCIG to gather more reliable data for uncommon tumors in gynecologic oncology.

Incidence of intraoperative hypotension in acute traumatic spinal cord injury and associated factors.

OBJECTIVE: The importance of maintaining mean arterial pressure (MAP) > 85 mm Hg for patients with acute spinal cord injury (SCI) is well documented, because systemic hypotension greatly increases the risk of secondary SCI. Current literature focuses on the ICU setting; however, there is a paucity of data describing the changes in MAP in the operating room (OR). In the present study, the authors investigated the incidence of intraoperative hypotension for patients with acute traumatic SCI as well as any associated factors that may have impacted these findings. METHODS: This retrospective study was performed at a level 1 trauma center from 2015 to 2016. All patients with American Spinal Injury Association (ASIA) score A-D acute traumatic SCIs from C1 to L1 were identified. Those included underwent spinal instrumentation and/or laminectomy decompression. Associated factors investigated include the following: age, body mass index, trauma mechanism of injury, Injury Severity Score, level of SCI, ASIA score, hospital day of surgery, total OR time, need for laminectomy decompression, use of spinal fixation, surgical positioning, blood loss, use of blood products, length of hospital stay, length of ICU stay, and discharge disposition. Intraoperative minute-by-minute MAP recordings were used to determine time spent in various MAP ranges. RESULTS: Thirty-two patients underwent a total of 33 operations. Relative to the total OR time, patients spent an average of 51.9% of their cumulative time with an MAP < 85 mm Hg. Furthermore, 100% of the study population recorded at least one MAP measurement < 85 mm Hg. These hypotensive episodes lasted a mean of 103 cumulative minutes per operative case. Analysis of associated factors demonstrated that fall mechanisms of injury led to a statistically significant increase in intraoperative hypotension compared to motor vehicle collisions/motorcycle collisions (p = 0.033). There were no significant differences in MAP recordings when analyzed according to all other associated factors studied. CONCLUSIONS: This is the first study reporting the incidence of intraoperative hypotension for patients with acute traumatic SCIs, and the results demonstrated higher proportions of relative hypotension than previously reported in the ICU setting. Furthermore, the authors identified that every patient experienced at least one MAP below the target value, which was much greater than the initial hypothesis of 50%. Given the findings of this study, adherence to the MAP protocol intraoperatively needs to be improved to minimize the risk of secondary SCI and associated deleterious neurological outcomes.

Lateral position and utility of navigation for posterior fixation of unstable cervical fracture with ankylosing spondylitis.

BACKGROUND: Ankylosing spondylitis (AS) is a seronegative spondyloarthropathy within the spectrum of rheumatologic diseases. The systemic inflammation that characterizes AS leads to bone resorption and reformation. Pathologic remodeling may include kyphosis, osteoporosis, and multi-segment auto-fusion. Cervical fractures account for 53-78% of spinal trauma seen with AS. Surgical planning is often challenging owing to spinal deformity, medical comorbidities, the cervicothoracic foci of injury, and gross instability of these fracture. CASE DESCRIPTION: A 55-year-old male with AS was presented with a three-column injury at the C6 level. The C6 vertebra was fractured, minimally displaced, and there was a focal kyphotic deformity. Attempted posterior fixation 2 days after presentation was aborted; the patient could not tolerate prone positioning, and there were further technical limitations to a posterior approach. Cervicothoracic fixation from C2 to T2 was then performed using the right lateral decubitus position employing the Mayfield head holder, a beanbag, and spinal neuronavigation. CONCLUSION: In this study, we presented a unique approach to posterior fixation of an unstable cervicothoracic fracture in a patient with AS utilizing the lateral position and neural navigation under intraoperative physiological monitoring.