An Immune Gene Expression Risk Score for Distant Metastases after Radiotherapy for Cervical Cancer.

PURPOSE: To develop an immune-based gene expression risk score to identify patients with cervical cancer at increased risk of distant metastases (DM). EXPERIMENTAL DESIGN: Tumor biopsies were obtained from 81 patients prior to chemoradiotherapy. Whole-transcriptome RNA sequencing was performed (Illumina NextSeq500). Beginning with 4,723 immune-related genes, a 55-gene risk score for DM was derived using Cox modeling and principal component analysis. It was validated in independent cohorts of 274 patients treated at the Norwegian Radium Hospital (NRH) and 206 patients from The Cancer Genome Atlas (TCGA). RESULTS: The risk score was predictive of DM (HR, 2.7; P < 0.0001) and lower cause-specific survival (CSS) by univariate analysis (HR, 2.0; P = 0.0003) and multivariate analysis adjusted for clinical factors (DM HR, 3.0; P < 0.0001; CSS HR, 2.2; P = 0.0004). The risk score predicted DM (HR, 1.4; P = 0.05) and CSS (HR, 1.48; P = 0.013) in the NRH cohort and CSS (HR, 1.4; P = 0.03) in TCGA cohort. Higher risk scores were associated with lower CIBERSORT estimates of tumor-infiltrating immune cells, including CD8 T cells and M1 and M2 macrophages (all P < 0.001). Higher risk scores were associated with lower expression (all P < 0.001) of important chemokines (CXCL12, CXCR4), IFN-regulated genes (IRF1, STAT1, IDO1), and immune checkpoint regulators (PD-1, PD-L1, CTLA-4). CONCLUSIONS: The immune metastatic risk score addresses important challenges in the treatment of cervical cancer-identifying patients at high risk of DM after radiotherapy. The findings of this study indicate that high tumor mutational burden and a "cold," immune-excluded tumor microenvironment influence distant metastatic recurrence. Further validation of the risk score is needed.

Omitting Radiotherapy after Breast-Conserving Surgery in Luminal A Breast Cancer.

BACKGROUND: Adjuvant radiotherapy is prescribed after breast-conserving surgery to reduce the risk of local recurrence. However, radiotherapy is inconvenient, costly, and associated with both short-term and long-term side effects. Clinicopathologic factors alone are of limited use in the identification of women at low risk for local recurrence in whom radiotherapy can be omitted. Molecularly defined intrinsic subtypes of breast cancer can provide additional prognostic information. METHODS: We performed a prospective cohort study involving women who were at least 55 years of age, had undergone breast-conserving surgery for T1N0 (tumor size <2 cm and node negative), grade 1 or 2, luminal A-subtype breast cancer (defined as estrogen receptor positivity of ≥1%, progesterone receptor positivity of >20%, negative human epidermal growth factor receptor 2, and Ki67 index of ≤13.25%), and had received adjuvant endocrine therapy. Patients who met the clinical eligibility criteria were registered, and Ki67 immunohistochemical analysis was performed centrally. Patients with a Ki67 index of 13.25% or less were enrolled and did not receive radiotherapy. The primary outcome was local recurrence in the ipsilateral breast. In consultation with radiation oncologists and patients with breast cancer, we determined that if the upper boundary of the two-sided 90% confidence interval for the cumulative incidence at 5 years was less than 5%, this would represent an acceptable risk of local recurrence at 5 years. RESULTS: Of 740 registered patients, 500 eligible patients were enrolled. At 5 years after enrollment, recurrence was reported in 2.3% of the patients (90% confidence interval [CI], 1.3 to 3.8; 95% CI, 1.2 to 4.1), a result that met the prespecified boundary. Breast cancer occurred in the contralateral breast in 1.9% of the patients (90% CI, 1.1 to 3.2), and recurrence of any type was observed in 2.7% (90% CI, 1.6 to 4.1). CONCLUSIONS: Among women who were at least 55 years of age and had T1N0, grade 1 or 2, luminal A breast cancer that were treated with breast-conserving surgery and endocrine therapy alone, the incidence of local recurrence at 5 years was low with the omission of radiotherapy. (Funded by the Canadian Cancer Society and the Canadian Breast Cancer Foundation; LUMINA ClinicalTrials.gov number, NCT01791829.).

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.

NRG Oncology/RTOG Consensus Guidelines for Delineation of Clinical Target Volume for Intensity Modulated Pelvic Radiation Therapy in Postoperative Treatment of Endometrial and Cervical Cancer: An Update.

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.

Effects of Radiotherapy in Early-Stage, Low-Recurrence Risk, Hormone-Sensitive Breast Cancer.

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.

Simulation Modeling of Cancer Clinical Trials: Application to Omitting Radiotherapy in Low-risk Breast Cancer.

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.

Effect of Positron Emission Tomography Imaging in Women With Locally Advanced Cervical Cancer: A Randomized Clinical Trial.

Importance: In women with locally advanced cancer of the cervix (LACC), staging defines disease extent and guides therapy. Currently, undetected disease outside the radiation field can result in undertreatment or, if disease is disseminated, overtreatment. Objective: To determine whether adding fludeoxyglucose F 18 positron emission tomography-computed tomography (PET-CT) to conventional staging with CT of the abdomen and pelvis affects therapy received in women with LACC. Design, Setting, and Participants: A randomized clinical trial was conducted. Women with newly diagnosed histologically confirmed International Federation of Gynecology and Obstetrics stage IB to IVA carcinoma of the cervix who were candidates for chemotherapy and radiation therapy (CRT) were allocated 2:1 to PET-CT plus CT of the abdomen and pelvis or CT alone. Enrollment occurred between April 2010 and June 2014 at 6 regional cancer centers in Ontario, Canada. The PET-CT scanners were at 6 associated academic institutions. The median follow-up at the time of the analysis was 3 years. The analysis was conducted on March 30, 2017. Interventions: Patients received either PET-CT plus CT of the abdomen and pelvis or CT of the abdomen and pelvis. Main Outcomes and Measures: Treatment delivered, defined as standard pelvic CRT vs more extensive CRT, ie, extended field radiotherapy or therapy with palliative intent. Results: One hundred seventy-one patients were allocated to PET-CT (n = 113) or CT (n = 58). The trial stopped early before the planned target of 288 was reached because of low recruitment. Mean (SD) age was 48.1 (11.2) years in the PET-CT group vs 48.9 (12.7) years in the CT group. In the 112 patients who received PET-CT, 68 (60.7%) received standard pelvic CRT, 38 (33.9%) more extensive CRT, and 6 (5.4%) palliative treatment. The corresponding data for the 56 patients who received CT alone were 42 (75.0%), 11 (19.6%), and 3 (5.4%). Overall, 44 patients (39.3%) in the PET-CT group received more extensive CRT or palliative treatment compared with 14 patients (25.0%) in the CT group (odds ratio, 2.05; 95% CI, 0.96-4.37; P = .06). Twenty-four patients in the PET-CT group (21.4%) received extended field radiotherapy to para-aortic nodes and 14 (12.5%) to common iliac nodes compared with 8 (14.3%) and 3 (5.4%), respectively, in the CT group (odds ratio, 1.64; 95% CI, 0.68-3.92; P = .27). Conclusions and Relevance: There was a trend for more extensive CRT with PET-CT, but the difference was not significant because the trial was underpowered. This trial provides information on the utility of PET-CT for staging in LACC. Trial Registration: ClinicalTrials.gov Identifier: NCT00895349.

Tamoxifen with radiotherapy compared with Tamoxifen alone in elderly women with early-stage breast cancer treated with breast conserving surgery: A systematic review and meta-analysis.

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 ≥70years. 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 5years (RR 0.18, 95% CI 0.10-0.34; 4 trials, 2387 patients). This effect was maintained at 10years (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 5years (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.

TARGIT-R (Retrospective): North American Experience with Intraoperative Radiation Using Low-Kilovoltage X-Rays for Breast Cancer.

BACKGROUND: Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America. METHODS: A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed. RESULTS: From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p < 0.001). The median patient age was 66.8 years. Most patients had disease that was <2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated. CONCLUSIONS: IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.

Association between Metformin Use and Mortality after Cervical Cancer in Older Women with Diabetes.

BACKGROUND: To examine the association between metformin use and mortality in patients with diabetes and cervical cancer. METHODS: Using Ontario health databases, a retrospective, population-based cohort study was conducted in women with diabetes ≥ age 66 years diagnosed with cervical cancer between 1997 and 2010. The association between metformin exposure and cervical cancer-specific mortality was examined using Fine-Gray regression models, with noncancer death as a competing risk and cumulative metformin use as a time-varying exposure. The association with overall mortality was examined using Cox regression models. RESULTS: Among the 181 women with diabetes and cervical cancer, there were 129 deaths, including 61 cervical cancer-specific deaths. The median follow-up was 5.8 years (interquartile range 4.2-9.6 years) for surviving patients. Cumulative dose of metformin after cervical cancer diagnosis was independently associated with a decreased risk of cervical cancer-specific mortality and overall mortality in a dose-dependent fashion [HR 0.79; 95% confidence interval (CI), 0.63-0.98; and HR 0.95; 95% CI, 0.90-0.996 per each additional 365 g of metformin use, respectively]. There was no significant association between cumulative use of other antidiabetic drugs and cervical cancer-specific mortality. CONCLUSION: This study suggests an association between cumulative metformin use after cervical cancer diagnosis and lower cervical cancer-specific and overall mortality among older women with diabetes. IMPACT: Cumulative dose of metformin use after cervical cancer diagnosis among older women with diabetes may be associated with a significant decrease in mortality. This finding has important implications if validated prospectively, as metformin is inexpensive and can be easily combined with standard treatment for cervical cancer.

Identification of a Low-Risk Luminal A Breast Cancer Cohort That May Not Benefit From Breast Radiotherapy.

PURPOSE: To determine the prognostic and predictive value of intrinsic subtyping by using immunohistochemical (IHC) biomarkers for ipsilateral breast relapse (IBR) in participants in an early breast cancer randomized trial of tamoxifen with or without breast radiotherapy (RT). PATIENTS AND METHODS: IHC analysis of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6, epidermal growth factor receptor, and Ki-67 was conducted on 501 of 769 available blocks. Patients were classified as luminal A (n = 265), luminal B (n = 165), or high-risk subtype (luminal HER2, n = 22; HER2 enriched, n = 13; basal like, n = 30; or triple-negative nonbasal, n = 6). Median follow-up was 10 years. RESULTS: Classification by subtype was prognostic for IBR (10-year estimates: luminal A, 5.2%; luminal B, 10.5%; high-risk subtypes, 21.3%; P < .001). Luminal subtypes seemed to derive less benefit from RT (luminal A hazard ratio [HR], 0.40; luminal B HR, 0.51) than high-risk subtypes (HR, 0.13); however, the overall subtype-treatment interaction term was not significant (P = .26). In an exploratory analysis of women with clinical low-risk (age older than 60 years, T1, grade 1 or 2) luminal A tumors (n = 151), 10-year IBR was 3.1% versus 11.8% for the high-risk cohort (n = 341; P = .0063). Clinical low-risk luminal A patients had a 10-year IBR of 1.3% with tamoxifen versus 5.0% with tamoxifen plus RT (P = .42). Multivariable analysis showed that RT (HR, 0.31; P < .001), clinical risk group (HR, 2.2; P = .025), and luminal A subtype (HR, 0.25; P < .001) were significantly associated with IBR. CONCLUSION: IHC subtyping was prognostic for IBR but was not predictive of benefit from RT. Further studies may validate the exploratory finding of a low-risk luminal A group who may be spared breast RT.

High tumor interstitial fluid pressure identifies cervical cancer patients with improved survival from radiotherapy plus cisplatin versus radiotherapy alone.

Radiotherapy (RT) with concurrent cisplatin (CRT) is standard treatment for locally advanced cervical cancer. However, not all patients benefit from the addition of cisplatin to RT alone. This study explored the value of pretreatment tumor interstitial fluid pressure (IFP) and hypoxia measurements as predictors of cisplatin response in 291 patients who were treated with RT (1994-1998) or RT plus concurrent cisplatin (1999-2009). Clinical characteristics were similar between the two groups, apart from a greater proportion of patients with pelvic lymph node metastases and hypoxic tumors in the CRT cohort. Patients were followed for a median duration of 5.6 years. Information about recurrence and survival was recorded prospectively. The addition of cisplatin to RT improved survival compared to treatment with RT alone (HR 0.61, p = 0.0097). This improvement was confined to patients with high-IFP tumors at diagnosis (HR 0.40, p = 0.00091). There was no benefit of adding cisplatin in those with low-IFP tumors (HR 1.05, p = 0.87). There was no difference in the effectiveness of cisplatin in patients with more or less hypoxic tumors. In conclusion, patients with locally advanced cervical cancer and high tumor IFP at diagnosis have greater benefit from the addition of cisplatin to RT than those with low IFP. This may reflect high tumor cell proliferation, which is known to influence IFP, local tumor control and patient survival.

The significance of tumoral ERCC1 status in patients with locally advanced cervical cancer treated with chemoradiation therapy: a multicenter clinicopathologic analysis.

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.

Hedgehog pathway signaling in cervical carcinoma and outcome after chemoradiation.

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.

Local control with conventional and hypofractionated adjuvant radiotherapy after breast-conserving surgery for ductal carcinoma in-situ.

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 0.1-8.9 years). RESULTS: One hundred and four patients (39%) were treated with conventional and 162 (61%) with hypofractionated WBRT. The median age was 56.7 years (range 32.2-83.8 years), and prognostic features were well matched in both groups, apart from a small increase in tumour size in the conventional arm (1.75 vs. 2.12 cm, p=0.05). Actuarial risk of recurrence at 4 years 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 4 years 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.

Follow-up for women after treatment for cervical cancer: a systematic review.

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.

Effect of distributional heterogeneity on the analysis of tumor hypoxia based on carbonic anhydrase IX.

Immunohistochemistry (IHC) is used extensively to assess markers for prognosis and sensitivity to novel anticancer agents, as well as in the routine clinical assessment of cancers. Yet, although it is well known that tumors are highly heterogeneous, the resulting sampling error in the measurement of histological markers is often ignored, particularly in basic scientific studies. In this paper, we tested the hypothesis that the optimization of tissue sampling to compensate for heterogeneity improves the correlation between histological measurements of the intrinsic hypoxia marker carbonic anhydrase IX (CAIX) and global tumor oxygenation status. The study was based on a group of 24 patients with invasive cervical carcinoma from whom multiple biopsies were obtained at the time of direct pO2 assessment within the tumor, done as part of a research study. Measurements were made by image analysis of multiple deep sections cut through these biopsies, labeled for CAIX using both immunofluorescence and immunohistochemical techniques, and included tissue microarray (TMA) simulations. Variance and correlation analysis showed that the size of the tissue sample (biopsy or TMA core) was the major factor affecting accuracy of measurement in the sample. Sampling of multiple biopsies/cores also improved the global tumor assessment, provided that these were sufficiently separated in space. Optimization of sampling resulted in an improved correlation of CAIX staining with tumor pO2 measurements, consistent with the hypothesis. However, CAIX was inferior to pO2 measurements as a tool for patient stratification. Improved analytical methods to account for intratumoral heterogeneity are needed to provide reliable measurements of molecular markers.

Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy.

PURPOSE: The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biology of hypoxia as it relates to cancer and cancer therapy, and to define clinical scenarios in which in vivo hypoxia imaging could prove valuable. RESULTS: Hypoxia, or low oxygenation, has emerged as an important factor in tumor biology and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiology and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold standard for measuring hypoxia; Eppendorf measurement of pO(2) has been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques. CONCLUSIONS: This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biology.

Tamoxifen with or without breast irradiation in women 50 years of age or older with early breast cancer.

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.

Estimating hypoxic status in human tumors: a simulation using Eppendorf oxygen probe data in cervical cancer patients.

PURPOSE: To define the minimal number of pO(2) measurements, with 90% sensitivity and 90% specificity, needed to categorize cervical tumors as either hypoxic or oxic. METHODS AND MATERIALS: Using 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 pO(2) 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 < or =50%. A small number of pO(2) 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. RESULTS: The probability of falsely classifying the tumor decreased as the selected number of pO(2) 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 pO(2) measurements per track increased. At five measurements per track, the probability of falsely classifying the tumor was approximately 9%. CONCLUSION: Approximately 20 measurements per tumor, or five measurements per track, using the Eppendorf pO(2) 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.