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Abstract: Objective: To determine the optimal recommended program for the follow-up of patients who are disease free after completed primary therapy for cervical cancer. Methods: Systematic search of MEDLINE, EMBASE and the Cochrane Library databases (1980–November 2007). Results: Seventeen retrospective trials were identified. Most studies reported similar intervals for follow-up and ranged from a low of 9 visits to a high of 28 visits over 5 years. Follow-up visits typically occurred once every 3–4 months for the first 2 years, every 6 months for the next 3 years and then annually until year 10. All 17 trials reported that a physical exam was performed at each visit. Vaginal vault cytology was analyzed in 13 trials. Other routine surveillance tests included chest x-ray, ultrasound, CT scans, MRI, intravenous pyelography and tumour markers. Median time to recurrence ranged from 7–36 months after primary treatment. Rates of recurrence ranged from 8–26% with 14–57% of patients recurring in the pelvis, and 15–61% of patients recurring at distant or multiple sites. Of the 8–26% of patients who experienced disease recurrence, the vast majority, 89–99%, had recurred by year 5. Upon recurrence, median survival was 7–17 months. Asymptomatic recurrent disease was detected using physical exam in 29–71%, chest x-ray in 20–47%, CT in 0–34% and vaginal vault cytology in 0–17% of patients, respectively. Conclusion: There is modest low quality evidence to inform the most appropriate follow-up strategy for patients with cervical cancer who are clinically disease free after receiving primary treatment. Follow-up visits should include a complete physical examination whereas, frequent vaginal vault cytology does not add significantly to the detection of early disease recurrence. Patients should return to annual population-based screening after 5 years of recurrence-free follow-up. [Copyright &y& Elsevier]

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. 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. 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. 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. National Health and Medical Research Council and National Cancer Institute. [ABSTRACT FROM AUTHOR]

Background: We determined the effect of breast irradiation plus tamoxifen on disease-free survival and local relapse in women 50 years of age or older who had T1 or T2 node-negative breast cancer. Methods: Between December 1992 and June 2000, 769 women with early breast cancer (tumor diameter, 5 cm or less) were randomly assigned to receive breast irradiation plus tamoxifen (386 women) or tamoxifen alone (383 women). The median follow-up was 5.6 years. Results: The rate of local relapse at five years was 7.7 percent in the tamoxifen group and 0.6 percent in the group given tamoxifen plus irradiation (hazard ratio, 8.3; 95 percent confidence interval, 3.3 to 21.2; P<0.001), with corresponding five-year disease-free survival rates of 84 percent and 91 percent (P=0.004). A planned subgroup analysis of 611 women with T1, receptor-positive tumors indicated a benefit from radiotherapy (five-year rates of local relapse, 0.4 percent with tamoxifen plus radiotherapy and 5.9 percent with tamoxifen alone; P<0.001). Overall, there was a significant difference in the rate of axillary relapse at five years (2.5 percent in the tamoxifen group and 0.5 percent in the group given tamoxifen plus irradiation, P=0.049), but no significant difference in the rates of distant relapse or overall survival. Conclusions: As compared with tamoxifen alone, radiotherapy plus tamoxifen significantly reduces the risk of breast and axillary recurrence after lumpectomy in women with small, node-negative, hormone-receptor–positive breast cancers. N Engl J Med 2004;351:963-70. [ABSTRACT FROM AUTHOR]

Purpose: Accurate target definition is critical for the appropriate application of radiation therapy. In 2008, the Radiation Therapy Oncology Group (RTOG) published an international collaborative atlas to define the clinical target volume (CTV) for intensity modulated pelvic radiation therapy in the postoperative treatment of endometrial and cervical cancer. The current project is an updated consensus of CTV definitions, with removal of all references to bony landmarks and inclusion of the para-aortic and inferior obturator nodal regions.Methods and Materials: An international consensus guideline working group discussed modifications of the current atlas and areas of controversy. A document was prepared to assist in contouring definitions. A sample case abdominopelvic computed tomographic image was made available, on which experts contoured targets. Targets were analyzed for consistency of delineation using an expectation-maximization algorithm for simultaneous truth and performance level estimation with kappa statistics as a measure of agreement between observers.Results: Sixteen participants provided 13 sets of contours. Participants were asked to provide separate contours of the following areas: vaginal cuff, obturator, internal iliac, external iliac, presacral, common iliac, and para-aortic regions. There was substantial agreement for the common iliac region (sensitivity 0.71, specificity 0.981, kappa 0.64), moderate agreement in the external iliac, para-aortic, internal iliac and vaginal cuff regions (sensitivity 0.66, 0.74, 0.62, 0.59; specificity 0.989, 0.966, 0.986, 0.976; kappa 0.60, 0.58, 0.52, 0.47, respectively), and fair agreement in the presacral and obturator regions (sensitivity 0.55, 0.35; specificity 0.986, 0.988; kappa 0.36, 0.21, respectively). A 95% agreement contour was smoothed and a final contour atlas was produced according to consensus.Conclusions: Agreement among the participants was most consistent in the common iliac region and least in the presacral and obturator nodal regions. The consensus volumes formed the basis of the updated NRG/RTOG Oncology postoperative atlas. Continued patterns of recurrence research are encouraged to refine these volumes. [ABSTRACT FROM AUTHOR]

Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates.Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively.Results: Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results.Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient. [ABSTRACT FROM AUTHOR]

Background: Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses on effects of radiotherapy predated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis used GEP information with pooled individual-level data to evaluate the impact of omitting radiotherapy on recurrence and mortality.Methods: We considered trials that evaluated or administered radiotherapy after lumpectomy in women with low-risk breast cancer. Women included had undergone lumpectomy and were treated with hormonal therapy for stage I, ER+ and/or PR+, HER2- breast cancer with Oncotype scores no greater than 18. Recurrence-free interval (RFI), type of RFI (locoregional or distant), and breast cancer-specific and overall survival were compared between no radiotherapy and radiotherapy using adjusted Cox models. All statistical tests were two-sided.Results: The final sample included 1778 women from seven trials. Omission of radiotherapy was associated with an overall adjusted hazard ratio of 2.59 (95% confidence interval [CI] = 1.38 to 4.89, P = .003) for RFI. There was a statistically significant increase in any first locoregional recurrence (P = .001), but not distant recurrence events (P = .90), or breast cancer-specific (P = .85) or overall survival (P = .61). Five-year RFI rate was high (93.5% for no radiotherapy vs 97.9% for radiotherapy; absolute reduction = 4.4%, 95% CI = 0.7% to 8.1%, P = .03). The effects of radiotherapy varied across subgroups, with lower RFI rates for those with Oncotype scores of less than 11 (vs 11-18), older (vs younger), and ER+/PR+ status (vs other).Conclusions: Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest increase in locoregional recurrence event rates, but does not appear to increase the rate of distant recurrence or death. [ABSTRACT FROM AUTHOR]

Background Our aim was to assess the effect of adjuvant radiotherapy on recurrence and survival for elderly women (≥70) with early-stage hormone receptor-positive breast cancer treated with breast conserving surgery (BCS) and Tamoxifen. Materials and methods MEDLINE, EMBASE, and Evidence-Based Medicine Reviews were systematically searched through August 12, 2016 for randomized controlled trials (RCTs) comparing radiotherapy to no radiotherapy and presenting outcomes for women ≥70 years. Two investigators screened citations, abstracted results, and appraised studies using Cochrane Risk of Bias tool. Pooled risk ratios (RR) for breast, axillary, and distant recurrence, and overall survival were determined using weights from fixed-effects models. Results Four RCTs with low risk of bias were identified (2387 elderly women). Tamoxifen plus radiotherapy reduced breast recurrence compared to Tamoxifen alone from 60 to 10 (95% CI 6–20) per 1000 patients at 5 years (RR 0.18, 95% CI 0.10–0.34; 4 trials, 2387 patients). This effect was maintained at 10 years (RR 0.27, 95% CI 0.13–0.54; 2 trials, 891 patients). Radiotherapy minimally reduced axillary recurrence from 12 to 3 (95% CI 1–10) per 1000 at 5 years (RR 0.28, 95% CI 0.10–0.81; 3 trials, 2287 patients). Radiotherapy did not affect distant recurrence (RR 1.49, 95% CI 0.87–2.54; 3 trials, 2287 patients) or overall survival (RR 0.98, 95% CI 0.79–1.22; 3 trials, 2287 patients). Conclusion For elderly women (≥70), radiotherapy reduces the risk of breast and axillary recurrence, but does not impact distant recurrence or overall survival in early-stage breast cancer treated with BCS and Tamoxifen. The value of this risk reduction must be weighed by women and their physicians when considering the omission of adjuvant radiotherapy. [ABSTRACT FROM AUTHOR]

Purpose: ERCC1 (excision repair cross-complementation group 1) expression has been shown to be a molecular marker of cisplatin resistance in many tumor sites, but has not been well studied in cervical cancer patients. The purpose of this study was to measure tumoral ERCC1 in patients with locally advanced cervical cancer treated with chemoradiation therapy (CRT) in a large multicenter cohort, and to correlate expression with clinical outcome parameters. Methods and Materials: A total of 264 patients with locally advanced cervical cancer, treated with curative-intent radical CRT from 3 major Canadian cancer centers were evaluated. Pretreatment formalin-fixed, paraffin-embedded tumor specimens were retrieved, and tissue microarrays were constructed. Tumoral ERCC1 (FL297 antibody) was measured using AQUA (R) technology. Statistical analysis was performed to determine the significance of clinical factors and ERCC1 status with progression-free survival (PFS) and overall survival (OS) at 5 years. Results: The majority of patients had International Federation of Gynecology and Obstetrics (FIGO) stage II disease (n=119, 45%); median tumor size was 5 cm. OS was associated with tumor size (HR 1.16, P=.018), pretreatment hemoglobin status (HR 2.33, P=.00027), and FIGO stage. In addition, tumoral ERCC1 status (nuclear to cytoplasmic ratio) was associated with PFS (HR 2.33 [1.05-5.18], P=.038) and OS (HR 3.13 [1.27-7.71], P=.013). ERCC1 status was not significant on multivariate analysis when the model was adjusted for the clinical factors: for PFS (HR 1.49 [0.61-3.6], P=.38); for OS (HR 2.42 [0.94-6.24] P=.067). Conclusions: In this large multicenter cohort of locally advanced cervical cancer patients treated with radical CRT, stage, tumor size, and pretreatment hemoglobin status were significantly associated with PFS and OS. ERCC1 status appears to have prognostic impact on univariate analysis in these patients, but was not independently associated with outcome on multivariate analysis. [Copyright &y& Elsevier]

BACKGROUND: Hedgehog (Hh) signaling was assessed in patients with primary cervical carcinoma who were receiving chemoradiation. Because the up-regulation of Hh has been reported in response to hypoxia, the authors examined associations between Hh gene expression and measurements of HP5 (the percentage of oxygen pressure readings in each tumor <5 mm Hg) and interstitial fluid pressure (IFP). METHODS: Sonic hedgehog (SHH), Indian hedgehog (IHH), patched 1 and 2 (PTCH1 and PTCH2), smoothened (SMO), and glioma-associated oncogene family zinc finger 1 (Gli1) expression levels were determined using quantitative reverse transcriptase-polymerase chain reaction analysis on 85 frozen samples of primary cervical carcinoma and on 16 normal cervical samples. Clinicopathologic data were collected prospectively. Possible correlations between Hh expression and tumor hypoxia (HP5 and IFP) measured at the time of biopsy, the time to local recurrence, and disease-free survival (DFS) were examined. RESULTS: At least 1 member of the Hh pathway was elevated in all but 1 tumor compared with normal tissue ( P < .0001). Hh gene expression was heterogeneous with SHH, IHH, and GLI exhibiting bimodal distribution. Elevation of SHH expression ( P = .04) and low SMO expression ( P = .0007) were associated with HP5. The risk of local recurrence was associated with the up-regulation of SMO (hazard ratio [HR], 2.41; 95% confidence interval [CI], 1.00-5.82; P = .044), the up-regulation of >3 Hh genes (HR, 2.56; 95% CI, 1.09-6.00; P = .026), tumor size (HR, 1.41; 95% CI, 1.14-1.74; P = .0015), and lymph node-positive disease (HR, 2.82; 95% CI, 1.16-6.86; P = .022). CONCLUSIONS: The proportion of tumors that expressed Hh genes in cervical cancer was very high. The current data support a role for the Hh pathway in repopulation after chemoradiation and suggest that SMO may be a valid therapeutic target. The authors concluded that further investigation into this pathway after radiation and Hh inhibition are warranted. Cancer 2012;118: 3105-15. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: Adjuvant whole breast radiotherapy (WBRT) for ductal carcinoma in situ (DCIS) improves local control, however an optimal dose fractionation remains undefined. WBRT following breast-conserving surgery for invasive breast cancer demonstrates equivalent efficacy and morbidity for conventional and hypofractionated treatment. Our group policy allowed for the use of both schedules, therefore we compared local control in women with DCIS following breast-conserving surgery. Patients and methods: Two hundred and sixty-six patients treated between January 1999 and December 2004 with conventional (50Gy in 25 fractions) or hypofractionated (42.4Gy in 16 fractions or 40Gy/16+12.5Gy boost) WBRT after breast-conserving surgery for DCIS were retrospectively reviewed. Median follow-up was 3.76years (range 0.1–8.9years). Results: One hundred and four patients (39%) were treated with conventional and 162 (61%) with hypofractionated WBRT. The median age was 56.7years (range 32.2–83.8years), and prognostic features were well matched in both groups, apart from a small increase in tumour size in the conventional arm (1.75 vs. 2.12cm, p =0.05). Actuarial risk of recurrence at 4years was 7% with hypofractionated WBRT and 6% with the conventional schedule (p =0.9). Univariate analysis showed an increased risk of recurrence with high nuclear grade tumours (11% at 4years for grade 3 vs. 4% for grade 1/2, p =0.029). Conclusions: Hypofractionated adjuvant WBRT following breast-conserving surgery for DCIS has comparable local control to a conventional radiation schedule. Hypofractionated WBRT is more convenient for patients, has equivalent morbidity and should be considered in this patient group. [Copyright &y& Elsevier]

: PurposeTo define the minimal number of pO2 measurements, with 90% sensitivity and 90% specificity, needed to categorize cervical tumors as either hypoxic or oxic.: Methods and materialsUsing Eppendorf oxygen probe data from our ongoing prospective trial, we simulated the measurement of tumor oxygenation with a smaller number of data points in 135 patients with cervical cancer. The hypoxic proportion, defined as the percentage of pO2 values <5 mm Hg (HP5), was calculated for each tumor. Hypoxic tumors were defined as those with a median HP5 >50%, and tumors with normal oxygen levels as those with a median HP5 ≤50%. A small number of pO2 measurements were randomly selected from the Eppendorf measurements in each tumor, or per Eppendorf track, and used to define the tumor as hypoxic or oxic. The sensitivity and specificity were calculated, considering the classification as given by the complete set of Eppendorf measurements as the reference standard.: ResultsThe probability of falsely classifying the tumor decreased as the selected number of pO2 measurements per tumor increased, and at 16 measurements was approximately 10%. Adding additional measurements per tumor beyond 24 improved the ability to classify the tumor accurately only slightly. The probability of falsely classifying the tumor decreased as the pO2 measurements per track increased. At five measurements per track, the probability of falsely classifying the tumor was approximately 9%.: ConclusionApproximately 20 measurements per tumor, or five measurements per track, using the Eppendorf pO2 histograph, are sufficient to categorize cervical tumors as hypoxic or oxic. The results of this study will serve as a guide for research clinicians in the use of this and other systems in the assessment of tumor oxygenation in humans. [Copyright &y& Elsevier]

Purpose: To determine whether breast pain affects quality of life (QOL) after breast-conserving surgery and tamoxifen (TAM) with or without adjuvant breast radiotherapy (RT).Methods and Materials: A randomized clinical trial was carried out at the Princess Margaret Hospital between 1992 and 2000 to evaluate the need for breast RT in addition to TAM in women ≥50 years treated with breast-conserving surgery for T1-T2N0 breast cancer. A companion study to assess breast pain was carried out during the last 2 years of the randomized clinical trial. The short-form McGill Pain Questionnaire (SF-MPQ), the European Organization for Research and Treatment of Cancer (EORTC) QOL (QLQ-C30) and EORTC breast cancer module (QLQ-BR23) questionnaires were completed by patients within 1 week of randomization in the randomized clinical trial (baseline) and at 3, 6, and 12 months.Results: Eighty-six patients participated in the breast pain study; 41 received RT plus TAM and 45 received TAM alone. The median age was 70 years (range 51–80). The baseline pain and QOL scores were similar for the two groups. No significant difference was found between the two groups for each scale of the QLQ-C30 and QLQ-BR23 questionnaires at 3, 6, or 12 months (p >0.100), except that at 12 months, the score for role function (QLQ-C30) was higher in the RT plus TAM group than in the RT-only group (p = 0.02). At 3 months, the difference between the mean scores for the SF-MPQ was 0.553 (p = 0.47). At 12 months, the pain scores had decreased in both groups; the difference was 0.199 (p = 0.71). The number of breast operations or surgical complications did not correlate with breast pain in either group. Acute RT toxicity scores did not correlate with breast pain or QOL scores at 12 months.Conclusion: These results suggest that breast RT does not significantly contribute to breast pain or adversely impact the QOL up to 12 months after treatment in postmenopausal patients with node-negative breast cancer who take TAM. [Copyright &y& Elsevier]

Purpose: To investigate the relations between hypoxia-inducible factor-1 (HIF-1), tumor oxygenation, and clinical correlates in patients with locally advanced carcinoma of the uterine cervix.Methods and Materials: Biopsies from 42 patients with invasive cervical carcinoma and previous polarographic O2 measurements were assessed for the expression of HIF-1α using digitized microscopic imaging and analysis.Results: The HIF-1α expression levels ranged from <0.1% to 10.7% of the total tumor area; the positive staining was localized exclusively to the nuclei. Three distinct arrangement patterns of HIF-1α-positive cells in relation to blood vessels were identified using spatial image mapping: (1) most HIF-1α-positive cells were located within the typical oxygen diffusion distance in tissue (≤150 μm to the nearest blood vessel); (2) most HIF-1α-positive cells were located in the vicinity (≤60 μm) of the blood vessels; and (3) no apparent spatial relationship was found between HIF-1α-positive cells and blood vessels. A statistically significant association was found between HIF-1α expression and tumor oxygenation (Spearman correlation coefficient = 0.4, p <0.01), as determined with the Eppendorf pO2 histograph. No correlation was found between the level of HIF-1α expression and patient outcome, using disease-free survival as the end point.Conclusion: Our results suggest that HIF-1α expression may represent a useful biologic marker for hypoxia in uterine cervical cancer. [Copyright &y& Elsevier]