Long-term results of PET-guided radiation in patients with advanced-stage diffuse large B-cell lymphoma treated with R-CHOP.

Consolidative radiation therapy (RT) for advanced-stage diffuse large B-cell lymphoma (DLBCL) remains controversial, with routine practice continuing to include RT in patients with initial bulky disease or residual masses. Positron emission tomography (PET)-computed tomography is a sensitive modality for detecting the presence of residual disease at the end of treatment (EOT). A PET-guided approach to selectively administering RT has been the policy in British Columbia since 2005. Patients with advanced-stage DLBCL diagnosed from 1 January 2005 to 1 March 2017 and treated with at least 6 cycles of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone plus rituximab), who underwent EOT PET, were included in this analysis. Those with complete metabolic response (PET-negative [PET-NEG]) were observed; those with PET-positive (PET-POS) scans were offered consolidative RT, when feasible. Of the patient records reviewed, 723 were identified, with median follow-up of 4.3 years: 517 (72%) were PET-NEG; 206 (28%) were PET-POS. Time to progression (TTP) and overall survival (OS) at 3 years were 83% vs 56% and 87% vs 64%, in patients with PET-NEG and PET-POS scans, respectively. PET-POS patients with nonprogressing disease treated with consolidative RT (109 and 206; 53%) had outcomes approaching those of PET-NEG patients, with 3-year estimates of 76% and 80% for TTP and OS. PET-NEG patients who had bulky disease (≥10 cm) at diagnosis had outcomes indistinguishable from those without bulk, despite the omission of RT. These data suggest that patients with advanced-stage DLBCL who are PET-NEG at EOT and receive no RT have excellent outcomes. 18F-fluorodeoxyglucose-PET can reliably guide selective administration of consolidative RT, even in patients with initially bulky disease.

Incidence of ano-genital and head and neck malignancies in women with a previous diagnosis of cervical intraepithelial neoplasia.

OBJECTIVE: The objective of this study was to determine if women with a history of Cervical Intraepithelial Neoplasia grades 2 and 3 (CIN2 and CIN3) are at increased long-term risk for developing non-cervix HPV-related malignancies. MATERIAL AND METHODS: Women diagnosed with CIN2 or CIN3 between 1980 and 2005 were identified from the British Columbia (BC) Cancer Agency Cervical Cancer Screening Program's database. These patients' records were then cross-referenced with the BC Cancer Registry for diagnosis of vulvar, vaginal, anal or head and neck (HN) cancers during the period subsequent to their diagnosis of CIN. Standardized incidence ratios (SIR) were generated according to expected rates of each cancer. RESULTS: 54,320 women with a diagnosis of CIN2 or CIN3 were identified between 1985 and 2005. The crude incidence rate for non-cervix HPV-related cancers was 35.4 per 100,000 person-years (8.6 for vagina, 17.6 for vulva, 3.7 for anal canal and 5.5 for HN). The SIR was 1.9 (95% CI 1.3-2.7) for all non-cervix cancers, 6.7 (95% CI: 3.0-12.8) for vagina, 2.9 (95% CI: 1.7-4.6) for vulva, 1.8 (95% CI: 0.4-4.7) for anal canal, and 0.6 (95% CI: 0.2-1.4) for HN. There were statistically significant increases in anal cancers for years 5-9 and in HN cancers for years 0.5-5. CONCLUSION: BC women with a history of CIN2 or CIN3 are at relatively high risk of developing non-cervical HPV-related malignancies. The findings of this study suggest that interventions such as vaccination against high-risk HPV or long-term screening for these other cancers should be evaluated.

Population-based treatment and outcomes of Stage I uterine serous carcinoma.

OBJECTIVE: Uterine serous carcinoma (USC) is a rare type of endometrial cancer that often recurs in patients with Stage I disease. Our objective was to evaluate treatment and outcomes in Stage I USC in the context of a population-based study. METHODS: This was a population-based retrospective cohort study of all patients with Stage I USC in British Columbia, Canada from 2004 to 2012. The British Columbia Cancer Agency (BCCA) recommends three cycles of paclitaxel and carboplatin chemotherapy followed by pelvic radiotherapy for all women with Stage I USC and any myometrial invasion (Stage IA MI-). If no myometrial invasion (Stage IA MI-), no postoperative treatment is given. Patient and disease characteristics, surgery, adjuvant therapy, recurrence rates and sites, and 5-year disease-free survival rates were evaluated. RESULTS: Of the 127 patients with Stage I USC, 41 were Stage IA MI-, 56 Stage IA MI+, and 30 Stage IB. Median follow-up was 25 months (2-98 months). Five year disease-free survival rates were 80.7%, 74.4%, and 48.5% for Stages IA MI-, IA MI+, and IB, respectively, and recurrence rates according to BCCA guidelines were 10%, 2.9% and 30%, respectively. Of the 18 with recurrences, 13 had a distant component (72.2%). There were no pelvic recurrences among those receiving adjuvant radiotherapy. CONCLUSION: Our current protocol of observation alone postoperatively for Stage IA MI- and chemoradiotherapy for Stage IA MI+ is associated with a low recurrence rate. In contrast, those with Stage IB USC have a higher recurrence rate despite chemoradiotherapy, and likely require alternate treatment strategies.

The importance of adjuvant chemotherapy and pelvic radiotherapy in high-risk early stage endometrial carcinoma.

OBJECTIVE: To determine the impact of a policy change in which women with high-risk early stage endometrioid endometrial cancer (EEC) received adjuvant chemoradiotherapy. METHODS: This is a population-based retrospective cohort study of British Columbia Cancer Registry patients diagnosed from 2008 to 2012 with high-risk early stage EEC, who received adjuvant chemoradiotherapy after primary surgery. High-risk early stage was defined as the presence of two or more high-risk uterine factors: grade 3 tumor, more than 50% myometrial invasion, and/or cervical stromal involvement. Adjuvant therapy consisted of 3 or 4 cycles of carboplatin and paclitaxel chemotherapy, followed by pelvic radiotherapy. Sites and rate of recurrence were compared to a historical cohort diagnosed from 2005 to 2008 in which none of the patients received adjuvant chemoradiotherapy. Five-year progression-free and overall survival rates were calculated. RESULTS: The study includes 55 patients. All patients except for 2 received at least 3 cycles of chemotherapy. All patients received pelvic radiotherapy except for 2 who received brachytherapy only. Median follow-up was 27 months (7-56 months). Four patients (7.3%) recurred, including three with distant recurrence only and one with both a pelvic and paraaortic nodal recurrence. The historical cohort had a 29.4% recurrence rate, and therefore the hazard ratio for recurrence was 0.27 (95% CI 0.02-4.11). Five-year progression-free and overall survival rates were 88.6% and 97.3%, respectively. CONCLUSION: Patients with high-risk early stage endometrial carcinoma treated with adjuvant chemoradiotherapy have a low rate of recurrence compared to those not receiving such therapy.

Preoperative radiotherapy for inoperable stage II endometrial cancer: insights into improving treatment and outcomes.

OBJECTIVE: To review recurrence patterns and survival outcomes of women receiving preoperative radiotherapy for clinical stage II endometrial cancer in British Columbia. METHODS: We performed a retrospective population-based cohort study of all patients with clinical stage II endometrial cancer who were referred to the British Columbia Cancer Agency from 2000 to 2008, deemed ineligible for primary surgery, and therefore offered preoperative radiotherapy followed by surgery. Patient demographics, uterine risk factors, timing and details of treatments, and timing and sites of recurrence were obtained from patient records. Primary outcome measures were the sites and rates of recurrence and recurrence-free survival. RESULTS: We identified 29 patients with a mean age of 61 years (range 41 to 83) and median follow-up of 3.1 years (range 0.3 to 5.3). Three-year overall survival was 79%, and median recurrence-free survival was 2.5 years. Eight patients had recurrence of disease (27.6%), with a median time to recurrence of 1.3 years, (range 0.4 to 2.7). Six of these eight women had two or more high-risk uterine factors (deep myometrial invasion, grade 3 tumour), ovarian involvement, or adverse histological type (carcinosarcoma), compared with only one of 21 patients without recurrence. Seven of eight women had recurrence outside the radiated volume of tissue. Median survival after recurrence was 1.0 years (range 0.4 to 2.2). CONCLUSIONS: Women with clinical stage II endometrial cancer had a significant risk of recurrence when treated with preoperative radiotherapy followed by surgery. They were more likely to have distant recurrences, implying the need for an alternate treatment paradigm.

Objectif : Passer en revue les profils de récurrence et les issues en matière de survie, en ce qui concerne les femmes qui reçoivent une radiothérapie préopératoire en raison de la présence d'un cancer de l'endomètre de stade clinique II en Colombie-Britannique. Méthodes : Nous avons mené une étude de cohorte rétrospective en population générale qui portait sur toutes les patientes présentant un cancer de l'endomètre de stade clinique II qui ont été orientées vers la British Columbia Cancer Agency entre 2000 et 2008, qui étaient estimées comme étant inadmissibles à la chirurgie primaire et qui, donc, se sont vu offrir une radiothérapie préopératoire suivie d'une chirurgie. Les caractéristiques démographiques des patientes, les facteurs de risque utérins, la chronologie et les détails des traitements, et la chronologie et les sites des récurrences ont été tirés des dossiers des patientes. La survie sans récurrence et les sites et les taux de récurrence constituaient les critères d'évaluation primaires. Résultats : Nous avons identifié 29 patientes dont l'âge moyen était de 61 ans (plage de 41 à 83) et dont le suivi médian était de 3,1 ans (plage de 0,3 à 5,3). Le taux global de survie à trois ans était de 79 % et la survie médiane sans récurrence était de 2,5 ans. Huit patientes ont connu une récurrence de la maladie (27,6 %), le délai médian avant l'apparition de la récurrence étant de 1,3 an (plage de 0,4 à 2,7). Six de ces huit femmes présentaient deux facteurs de risque utérins élevés ou plus (envahissement myométrial profond, tumeur de grade 3), un envahissement ovarien ou un type histologique indésirable (carcinosarcome), par comparaison avec seulement une des 21 patientes n'ayant pas connu de récurrence. Sept des huit femmes ont connu une récurrence au-delà du volume de tissu irradié. La survie médiane à la suite de la récurrence était de 1,0 an (plage de 0,4 à 2,2). Conclusions : Les femmes présentant un cancer de l'endomètre de stade clinique II étaient exposées à un risque significatif de récurrence lorsqu'elles ont été traitées au moyen d'une radiothérapie préopératoire suivie d'une chirurgie. Elles étaient plus susceptibles de présenter des récurrences distantes, ce qui sous-entend la nécessité de formuler un autre paradigme de traitement.

Efficacy of Palliative Radiation Therapy (RT) for Chemotherapy Relapsed or Refractory Diffuse Large B-Cell Lymphoma: A Population-Based Retrospective Review.

PURPOSE: The study objective was to investigate the effectiveness of palliative radiation therapy (RT) for patients with diffuse large B-cell lymphoma (DLBCL) and to identify factors, such as chemotherapy relapsed/refractory (R/R) disease, that may influence RT outcomes. METHODS AND MATERIALS: Patients with DLBCL who received palliative RT from 2001 to 2015 in British Columbia were reviewed for patient characteristics, treatment details, and outcomes. Univariable and multivariable analyses for response and local progression were performed. RESULTS: Three-hundred and seventy courses of palliative RT in 217 patients were identified. Median equivalent dose in 2 Gy fractions was 19 Gy (range, 2-42 Gy). Clinical and/or radiologic response occurred in 230 (83%) of the 276 courses with response data available. Local control following palliative RT at 6 months was 66.7%. On univariable analysis, R/R disease was not associated with lower clinical response rates but had higher risk of progression (hazard ratio [HR], 0.5; P = .040). On multivariable analyses, patients with R/R disease who did not require concurrent steroids had greater response compared with those who received upfront palliative RT (odds ratio, 3.5; P = .011). Response to first-line chemotherapy and smaller lesion size were associated with improved local progression rates (HR, 0.2; P < .001 and HR, 0.5; P = .020, respectively). RT dose fractionation factors were not significant on any analyses. CONCLUSIONS: Palliative RT for DLBCL is effective for symptom improvement, including in the chemotherapy R/R setting. Not requiring concurrent steroids, response to first-line chemotherapy, and smaller lesion size predicted better RT outcomes. There was no association between dose fractionation and response rates or local control to suggest that higher RT doses are more effective for palliation.

Reduction in Doses to Organs at Risk and Normal Tissue During Breast Radiation Therapy With a Carbon-Fiber Adjustable Reusable Accessory.

PURPOSE: This pilot study (ClinicalTrials.gov NCT04543851) investigates a novel breast positioning device using a low density, high tensile carbon-fiber cradle to support the breast, remove the inframammary fold, and reduce dose to organs at risk for whole breast radiation therapy in the supine position. METHODS AND MATERIALS: Thirty patients with inframammary folds ≥1 cm or lateral ptosis in supine treatment position were planned with standard positioning and with a carbon-fiber Adjustable Reusable Accessory (CARA) breast support. Twenty patients received whole breast with or without regional nodal irradiation with 42.5 Gy in 16 fractions or 50 Gy in 25 fractions using CARA. Median body mass index was 32 in this study. RESULTS: CARA removed all inframammary folds and reduced V20Gyipsilateral lung, V105%breast, and V50% body, without compromising target coverage. Median (range) V20Gyipsilateral lung for whole breast radiation therapy was 12.3% (1.4%-28.7%) with standard of care versus 10.9% (1.2%-17.3%) with CARA (Wilcoxon P = .005). Median V105% breast was 8.0% (0.0%-29%) with standard of care versus 4.0% (0.0%-23%) with CARA (P = .006) and median V50% body was 3056 mL (1476-5285 mL) versus 2780 mL (1415-5123 mL) with CARA (P = .001). CARA was compatible with deep inspiration breath hold and achieved median V25Gyheart = 0.1% (range 0%-1.9%) for all patients with left breast cancer. Skin reactions with CARA were consistent with historical data and daily variation in treatment setup was consistent with standard supine positioning. CONCLUSIONS: CARA can reduce V105%breast, lung and normal tissue dose, and remove the inframammary fold for breast patients with large or pendulous breasts and high body mass index treated in the supine position, without compromising target coverage. CARA will undergo further study in a randomized controlled trial.

gammaH2AX expression in tumors exposed to cisplatin and fractionated irradiation.

PURPOSE: Is retention of gammaH2AX foci useful as a biomarker for predicting the response of xenograft tumors to cisplatin with X-ray? Is a similar approach feasible using biopsies from patients with cervical cancer? EXPERIMENTAL DESIGN: Mice bearing SiHa, WiDr, or HCT116 xenograft tumors were exposed to cisplatin and/or three daily doses of 2 Gy. Tumors were excised 24 h after treatment and single cells were analyzed for clonogenic fraction and retention of gammaH2AX foci. Tumor biopsies were examined using 47 paraffin-embedded sections from untreated tumors and 24 sections from 8 patients undergoing radiochemotherapy for advanced cancer of the cervix. RESULTS: Residual gammaH2AX measured 24 h after cisplatin injection accurately predicted surviving fraction in SiHa and WiDr xenografts. When a clinically equivalent protocol using cisplatin and fractionated irradiation was employed, the fraction of xenograft cells lacking gammaH2AX ranked survival accurately but underestimated tumor cell kill. Residual gammaH2AX foci were detected in clinical samples; on average, only 25% of tumor nuclei exhibited one or more gammaH2AX foci before treatment and 74% after the start of treatment. CONCLUSION: gammaH2AX can provide useful information on the response of human tumors to the combination of cisplatin and radiation, but prediction becomes less accurate as more time elapses between treatment and tumor biopsy. Use of residual gammaH2AX as a biomarker for response is feasible when cell survival exceeds approximately 20%, but heterogeneity in endogenous and treatment-induced gammaH2AX must be considered.

Metastatic Gallbladder Adenocarcinoma to the Endometrium: A Case Report and Review of Literature.

Gallbladder carcinoma (GBC) metastasis to the uterine cervix is very rare, accounting for less than 10 reported cases. GBC is an uncommon neoplasm with a poor prognosis. Many patients remain asymptomatic until it reaches an advanced stage or discovered incidentally. Most metastatic diseases occur in the lung, liver, and bones. We report a case of a patient treated for GBC with a good clinical response, who presented with metastasis in the uterine cervix. Uterine cervix metastasis from any extragenital primary is rare and poses a radiologic, pathologic, and clinical diagnostic challenge. Here, we review and discuss the published literature on uterine cervix metastasis from extragenital sources. Gynecologic clinicians should be wary of these rare presentations of metastatic disease, as the diagnosis can alter the management.

Is mastectomy superior to breast-conserving treatment for young women?

PURPOSE: To examine whether modified radical mastectomy (MRM) improves outcomes compared with breast-conserving treatment (BCT) in young women. METHODS AND MATERIALS: Women aged 20-49 years, diagnosed with early breast cancer between 1989 and 1998, were identified. Management with BCT or MRM was compared for local (L), locoregional (LR), and distant relapse-free survival (DRFS) and breast cancer-specific survival (BCSS) by age group (20-39 years, 40-49 years). The analysis was repeated for patients considered "ideal" candidates for BCT: tumor size < or =2 cm, pathologically negative axillary nodes, negative margins, and no reported ductal carcinoma in situ. RESULTS: A total of 1,597 women received BCT, and 801 had MRM. After a median follow-up of 9.0 years, the outcomes (L, LR, BCSS) were worse for the younger age group; however, the outcomes were not statistically different by type of local treatment. For women aged 20-39 years considered "ideal" for BCT, those treated with BCT had slightly lower LRFS compared with those treated with MRM (p = 0.3), but DRFS and BCSS were similar. CONCLUSIONS: A difference in LRFS at 10 years potentially favored MRM among women aged 20-39 years considered "ideal" BCT candidates but was not statistically significant and did not translate into a noticeable difference in DRFS or BCSS. Our data suggest that young age alone is not a contraindication to BCT.

Reduced expression of hypoxia-inducible factor-1alpha in perinecrotic regions of solid tumors.

Hypoxia that develops in solid tumors stabilizes the hypoxia-inducible factor-1alpha (HIF-1alpha) subunit of the HIF-1 transcription factor, leading to up-regulation of dozens of hypoxia-regulated genes that increase glycolysis and oxygen delivery. HIF-1alpha and its downstream target gene CA9 have both been used as surrogate hypoxia markers, and, in general, high expression predicts for a poor response to treatment. Combinations of hypoxia markers offer the opportunity to measure changes in tumor oxygenation that may be relevant to tumor response to treatment. We compared the degree of colocalization of two endogenous markers for hypoxia, HIF-1alpha and carbonic anhydrase IX (CAIX), with a chemical marker for hypoxia, pimonidazole. Unexpectedly, expression of HIF-1alpha was reduced in the most hypoxic regions that border necrosis in xenograft tumors composed of SiHa cervical carcinoma, WiDr colon carcinoma, or M006 astrocytoma cells. Similar results were obtained for samples from three cervical cancer biopsies. However, CAIX was present in these perinecrotic cells that were also capable of metabolizing and binding a chemical marker for hypoxia, pimonidazole. In vitro experiments using tumor cells and tumor cubes incubated under anoxic conditions indicated that nutrient deprivation seems to be largely responsible for the lack of HIF-1alpha expression in perinecrotic regions. The half-life of CAIX was sufficiently long that, once formed, it remained for days in the absence of continued HIF-1alpha expression. These results have implications for the use of HIF-1alpha as an indicator of tumor hypoxia and aggressiveness as well as development of hypoxia-directed antitumor therapies based on the expression of HIF-1alpha.

Association of bladder dose with late urinary side effects in cervical cancer high-dose-rate brachytherapy.

PURPOSE: The purpose of this work was to study the association between specific urinary sequelae and locally accumulated dose to the bladder wall and bladder neck in the treatment of cervical cancer with multifraction high-dose-rate (HDR) brachytherapy. METHODS AND MATERIALS: A cohort of 60 cervical cancer patients, treated with both external beam and five HDR brachytherapy insertions between 2008 and 2014 at the BC Cancer Agency, was identified. The accumulated dose received over five brachytherapy sessions was evaluated for the bladder wall and bladder neck of each patient using dosimetric parameters calculated from deformably registered image data sets. These parameters were examined as potential predictors of urinary sequelae including hematuria, frequency, urgency, incontinence, stream, nocturia, and dysuria. Two different dichotomization schemes were evaluated for grouping patients into Case and Control groups. The two-sample Student's t test was used for normally distributed samples and the Mann-Whitney nonparametric U test for non-normal distributions. RESULTS: A strong association between dose to the bladder neck and incontinence was found (p = 0.001). A statistically significant association (p < 0.05) was also observed between urgency and certain bladder-wall parameters. CONCLUSIONS: Localized dose to the bladder neck is a potential predictor of urinary incontinence, whereas weaker associations were observed between urgency and some bladder-wall parameters.

Stage IIIC Endometrial Cancer: Relapse and Survival Outcomes in Women Treated With Pelvic or Extended Field Para-Aortic Nodal Radiation Therapy.

PURPOSE: The optimal radiation (RT) volume for node-positive endometrial cancer is controversial. This study evaluates clinical outcomes in patients with stage IIIC, N1 endometrial cancer who received RT to the pelvis (PV RT) or pelvis plus para-aortic nodes (PV-PAN RT). METHODS: Overall, there were 89 women with stage IIIC endometrial cancer. Of these, 57 women had N1-only disease, forming the study cohort. Clinicopathologic characteristics, recurrence rates, endometrial cancer-specific survival (ECSS), and overall survival (OS) were examined among patients treated with pelvic RT (n=23) compared with pelvic plus para-aortic RT (n=34). Multivariable analysis of ECSS and OS was performed using Cox regression modeling. RESULTS: Median follow-up was 5.1 years. Adjuvant chemotherapy was used in 51/57 (89%) of N1 cases. Women with N1 disease who received PV-PAN RT compared with PV RT experienced lower recurrence (26% vs. 52%, P=0.06) and higher survival rates (5 y ECSS 81.5% vs. 47.0%, P=0.04 and OS 79.1% vs. 47.0%, P=0.01). On multivariable analysis, RT volume was not significantly associated with OS, whereas chemotherapy was associated with improved ECSS and OS. CONCLUSIONS: RT conferred excellent local control, whereas chemotherapy was associated with improved survival in women with N1 endometrial cancer. Distant relapse remains the most common site of recurrence despite chemotherapy.

A Patient-centered Approach to Evaluate the Information Needs of Women With Ductal Carcinoma In Situ.

OBJECTIVE: To evaluate the information needs of ductal carcinoma in situ (DCIS) patients. METHODS: Four focus groups involving 24 previously treated DCIS patients were conducted to develop a comprehensive list of questions they felt were important to have answered at the time of diagnosis. Using a survey, a separate group of patients treated for DCIS then rated the importance of having each of these questions addressed before treatment decision making. Response options were "essential," "desired," "not important," "no opinion," and "avoid." For each essential/desired question, respondents specified how addressing it would help them: "understand," "decide," "plan," "not sure," or "other." RESULTS: Focus group participants generated 117 questions used in the survey. Fifty-seven patients completed the survey (55% response rate). Respondents rated a median of 66 questions as essential. The most commonly cited reason for rating a question essential was to "understand," followed by to "decide." The top questions women deemed essential to help them understand were disease specific, whereas the top questions deemed essential to help women decide were predominantly treatment specific, pertaining to available options, recurrence and survival outcomes, and timelines to decide and start treatment. CONCLUSIONS: DCIS patients want a large number of questions answered, mostly for understanding, and also for deciding and planning. A core set of questions that most patients consider essential for decision making has been formulated and may be used in the clinical setting and in research to develop educational resources and decision-making tools specific to DCIS.

The fate of hypoxic (pimonidazole-labelled) cells in human cervix tumours undergoing chemo-radiotherapy.

BACKGROUND AND PURPOSE: A subset of patients in a clinical study where sequential biopsies were to be obtained during multifraction radiotherapy received pimonidazole prior to initiating treatment, allowing a unique opportunity of following hypoxic cells in situ during therapy. MATERIAL AND METHODS: After institutional ethics review and with informed consent, women expecting to undergo radical treatment for cancer of the cervix received pimonidazole hydrochloride, with a biopsy approximately 24h later. Therapy was then started, and weekly biopsies were obtained. In the laboratory, the biopsies were reduced to single cell suspensions for flow cytometry analysis of DNA content, pimonidazole, and proliferation markers. RESULTS: Pre-treatment pimonidazole-positive cells were largely in G(0)/G(1). Pimonidazole-labelled cells, though expected to be radioresistant, were markedly decreased even early into treatment, and continued to disappear with a half-time of about 3 days. Concurrently, the cell cycle distribution of the previously hypoxic cells changed from predominantly quiescent to mostly proliferating. CONCLUSIONS: While a part of the rapid apparent loss of hypoxic cells was certainly due to loss of pimonidazole adducts through repair and dilution by cell division, the speed with which this occurred suggests that many labelled cells could rapidly re-enter the proliferative pool, a result consistent with many of those pimonidazole-labelled human cervix tumour cells being cyclically, rather than continuously, hypoxic.

The prognostic value of pimonidazole and tumour pO2 in human cervix carcinomas after radiation therapy: a prospective international multi-center study.

BACKGROUND AND PURPOSE: Hypoxia adversely affects treatment outcome in human uterine cervical cancer. Here, we present the results of a prospective international multi-centre study evaluating the prognostic value of pre-treatment tumour oxygen partial pressure (pO(2)) and the hypoxia marker pimonidazole (pimo). MATERIALS AND METHODS: One hundred and twenty-seven patients with primary cervix cancer were entered. Pre-treatment tumour pO(2) measurements were obtained, and reported by the median tumour pO(2), the fraction of pO(2) values

Bladder accumulated dose in image-guided high-dose-rate brachytherapy for locally advanced cervical cancer and its relation to urinary toxicity.

The purpose of this study was to estimate locally accumulated dose to the bladder in multi-fraction high-dose-date (HDR) image-guided intracavitary brachytherapy (IG-ICBT) for cervical cancer, and study the locally-accumulated dose parameters as predictors of late urinary toxicity. A retrospective study of 60 cervical cancer patients who received five HDR IG-ICBT sessions was performed. The bladder outer and inner surfaces were segmented for all sessions and a bladder-wall contour point-set was created in MATLAB. The bladder-wall point-sets for each patient were registered using a deformable point-set registration toolbox called coherent point drift (CPD), and the fraction doses were accumulated. Various dosimetric and volumetric parameters were calculated using the registered doses, including [Formula: see text] (minimum dose to the most exposed n-cm3 volume of bladder wall), r V n Gy (wall volume receiving at least m Gy), and [Formula: see text] (minimum equivalent biologically weighted dose to the most exposed n-cm3 of bladder wall), where n = 1/2/5/10 and m = 3/5/10. Minimum dose to contiguous 1 and 2 cm3 hot-spot volumes was also calculated. The unregistered dose volume histogram (DVH)-summed equivalent of [Formula: see text] and [Formula: see text] parameters (i.e. [Formula: see text] and [Formula: see text]) were determined for comparison. Late urinary toxicity was assessed using the LENT-SOMA scale, with toxicity Grade 0-1 categorized as Controls and Grade 2-4 as Cases. A two-sample t-test was used to identify the differences between the means of Control and Case groups for all parameters. A binomial logistic regression was also performed between the registered dose parameters and toxicity grouping. Seventeen patients were in the Case and 43 patients in the Control group. Contiguous values were on average 16 and 18% smaller than parameters for 1 and 2 cm3 volumes, respectively. Contiguous values were on average 26 and 27% smaller than parameters. The only statistically significant finding for Case versus Control based on both methods of analysis was observed for r V3 Gy (p = 0.01). DVH-summed parameters based on unregistered structure volumes overestimated the bladder dose in our patients, particularly when contiguous high dose volumes were considered. The bladder-wall volume receiving at least 3 Gy of accumulated dose may be a parameter of interest in further investigations of Grade 2+ urinary toxicity.

Measurement of tumor hypoxia using single-cell methods.

A growing appreciation for the importance of hypoxia in tumor progression and response to treatment has driven efforts to develop methods that could be used routinely in the clinic to identify tumors containing hypoxic cells. The ideal method would be noninvasive and could be used both before treatment to determine the presence of hypoxia and during therapy to assess tumor reoxygenation. Although this goal is being approached, there are still questions about how best to measure tumor oxygenation and whether noninvasive imaging methods can provide the necessary sensitivity. Analysis of hypoxia at the level of the individual cell can provide the following information that cannot be obtained in other ways: the degree of hypoxia, the lifetime of hypoxic cells, and the dynamic nature of hypoxia. This review will describe methods that have been used to detect hypoxia in individual cells, the relation between these measurements and patient response to treatment, and indicate where these methods can provide important additional insights into the consequences of tumor hypoxia.