Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer.

Background: In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (two cycles of cisplatin 50 mg/m2 in weeks 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required before patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation. Patients and methods: A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n = 395) and the UK (n = 900), and for 1226/1295 (95%) matching review and original reports were available. In total, 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the UK, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ). Results: In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70). Conclusion: Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved. This study is registered with ISRCTN (ISRCTN14387080, www.controlled-trials.com) and with ClinicalTrials.gov (NCT00411138).

Follow-up for cervical cancer: a Program in Evidence-Based Care systematic review and clinical practice guideline update.

BACKGROUND: In 2009, the Program in Evidence-based Care (pebc) of Cancer Care Ontario published a guideline on the follow-up of cervical cancer. In 2014, the pebc undertook an update of the systematic review and clinical practice guideline for women in this target population. METHODS: The literature from 2007 to August 2014 was searched using medline and embase [extended to 2000 for studies of human papillomavirus (hpv) dna testing]. Outcomes of interest were measures of survival, diagnostic accuracy, and quality of life. A working group evaluated the need for changes to the earlier guidelines and incorporated comments and feedback from internal and external reviewers. RESULTS: One systematic review and six individual studies were included. The working group concluded that the new evidence did not warrant changes to the 2009 recommendations, although hpv dna testing was added as a potentially more sensitive method of detecting recurrence in patients treated with radiotherapy. Comments from internal and external reviewers were incorporated. RECOMMENDATIONS SUMMARY: Follow-up care after primary treatment should be conducted and coordinated by a physician experienced in the surveillance of cancer patients. A reasonable follow-up strategy involves visits every 3-4 months within the first 2 years, and every 6-12 months during years 3-5. Visits should include a patient history and complete physical examination, with elicitation of relevant symptoms. Vaginal vault cytology examination should not be performed more frequently than annually. Combined positron-emission tomography and computed tomography, other imaging, and biomarker evaluation are not advocated; hpv dna testing could be useful as a method of detection of recurrence after radiotherapy. General recommendations for follow-up after 5 years are also provided.

Tumor factors predictive of response to hypofractionated radiotherapy in a randomized trial following breast conserving therapy.

PURPOSE: To determine whether tumor grade, molecular subtype and hypoxia predict response to hypofractionated versus standard radiotherapy (RT) following breast-conserving surgery (BCS) for node-negative breast cancer in a randomized controlled trial (RCT). PATIENTS AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor blocks were available on 989 of 1234 patients enrolled in the Hypofractionation Whole Breast Irradiation (HWBI) Trial. A central pathology review and assessment of tumor grade using the Nottingham grading system was carried out. Tumors were classified by molecular subtype as luminal A, luminal B, HER2 enriched, basal-like or unclassified using a six-biomarker panel; ER, PR, HER-2, Ki67, CK5/6 and EGFR. Tumors were also classified as hypoxic based on the expression of HIF1α, CAIX or GLUT-1. The primary end point was local recurrence (LR). RESULTS: Median follow-up was 12 years. In the multivariable Cox model, molecular subtype was the only factor predictive of LR, the 10-year cumulative incidence was 4.5% for luminal A and basal-like, 7.9% for luminal B and 16.9% for HER-2 enriched tumors (P < 0.01). Tumor grade, molecular subtype or hypoxia did not predict response to hypofractionation. CONCLUSIONS: In women enrolled in the HWBI trial following BCS tumor molecular subtype predicted LR. However tumor grade, molecular subtype and hypoxia did not predict response to hypofractionation suggesting that patients with node-negative breast tumors of all grades and molecular subtypes may be safely treated with hypofractionated RT regimens.

Radiotherapy Quality Assurance in the PORTEC-3 (TROG 08.04) Trial.

AIMS: Quality assurance in radiotherapy (QART) is essential to ensure the scientific integrity of a clinical trial. This paper reports the findings of the retrospective QART assessment for all centres that participated in PORTEC-3; a randomised controlled trial that compared pelvic radiotherapy with concurrent chemoradiotherapy to the pelvis followed by adjuvant chemotherapy. The trial showed an overall survival benefit for the addition of the chemotherapy in the management of women with high-risk endometrial cancer. MATERIALS AND METHODS: Clinicians were invited to upload a randomly selected case/s treated at each of the participating sites. Panel reviewers analysed the contours to certify that the target volumes and organ at risk structures were contoured according to guidelines. The results were categorised into acceptable, minor variation, major variation or unevaluable. The radiotherapy plans were dosimetrically evaluated using the well-established Trans-Tasman Radiation Oncology Group (TROG) protocol. RESULTS: Between August 2010 and January 2018, data from 146 patients of 686 consecutively treated patients were retrospectively reviewed. All 16 Australia and New Zealand and 71 of 77 international centres uploaded data for evaluation. In total, 3514 dosimetric and contour variables were reviewed. Of these, 3136 variables were deemed acceptable (89.2%), with 335 minor (9.6%) and 43 major variations (1.2%). Major contour variations included the clinical target volume vaginal vault, clinical target volume parametria and differential planning target volume vault expansion. CONCLUSION: The results of the QART assessment confirmed high uniformity and low rates of both minor and major deviations in contouring and dosimetry in all sites. This supports the safe introduction of the PORTEC-3 treatment protocol into routine clinical practice.

Personalizing post-treatment cancer care: a cross-sectional survey of the needs and preferences of well survivors of breast cancer.

Background: Improved treatments resulting in a rising number of survivors of breast cancer (bca) calls for optimization of current specialist-based follow-up care. In the present study, we evaluated well survivors of bca with respect to their supportive care needs and attitudes toward follow-up with various care providers, in varying settings, or mediated by technology (for example, videoconference or e-mail). Methods: A cross-sectional paper survey of well survivors of early-stage pT1-2N0 bca undergoing posttreatment follow-up was completed. Descriptive and univariable logistic regression analyses were performed to examine associations between survivor characteristics, supportive care needs, and perceived satisfaction with follow-up options. Qualitative responses were analyzed using conventional content analysis. Results: The 190 well survivors of bca who participated (79% response rate) had an average age of 63 ± 10 years. Median time since first follow-up was 21 months. Most had high perceived satisfaction with in-person specialist care (96%, 177 of 185). The second most accepted model was shared care involving specialist and primary care provider follow-up (54%, 102 of 190). Other models received less than 50% perceived satisfaction. Factors associated with higher perceived satisfaction with non-specialist care or virtual follow-up by a specialist included less formal education (p < 0.01) and more met supportive care needs (p < 0.05). Concerns with virtual follow-up included the perceived impersonal nature of virtual care, potential for inadequate care, and confidentiality. Conclusions: Well survivors of bca want specialists involved in their follow-up care. Compared with virtual follow-up, in-person follow-up is perceived as more reassuring. Certain survivor characteristics (for example, met supportive care needs) might signal survivor readiness for virtual or non-specialist follow-up. Future work should examine multi-stakeholder perspectives about barriers to and facilitators of shared multimodal follow-up care.

Outcomes in Patients Treated with Post-mastectomy Chest Wall Radiotherapy without the Routine Use of Bolus.

AIMS: The use of bolus in post-mastectomy radiotherapy (PMRT) varies significantly between institutions. We report on chest wall recurrence and acute toxicity rates for PMRT patients treated with selective use of bolus. MATERIALS AND METHODS: We analysed PMRT patients who received adjuvant chest wall radiotherapy for invasive breast cancer between 2004 and 2009. Patient, tumour and cancer outcomes were collected from a prospective database, with additional radiotherapy and acute toxicity details supplemented retrospectively. Chest wall bolus was reserved for patients considered at high risk of local recurrence. RESULTS: There were 314 patients suitable for analysis: 52 received bolus, 262 did not. The mean age was 53.2 years. The median follow-up was 4.2 years. The most common T stage was T2 (37%), followed by T3/T4 (33%). There were 229 patients (73%) who had N+ disease; 213 (68%) patients had grade 3 cancer. Oestrogen receptor was positive in 176 (56%) cases, progesterone receptor was positive in 134 (43%) and HER2 receptor was positive in 24 (8%). Lymphovascular space invasion was present in 146 patients (46%), dermal invasion in 30 patients (10%) and positive margin in 14 patients (4%). The 4 year chest wall recurrence rate was 14% (95% confidence interval 5.4-26.8%) in the bolus group and only 3.5% (95% confidence interval 1.6-6.4%) in the non-bolus group. On univariate analysis, use of bolus was associated with a significant difference in chest wall recurrence (hazard ratio 3.09; 1.15-8.33; P = 0.025). However, when taking into account margin status, this significance was lost (hazard ratio = 2.45; 95% confidence interval 0.80-7.50, P = 0.12). There was a higher rate of acute grade 2 skin toxicity in patients receiving bolus compared with those without, 40% versus 21% (P = 0.01). CONCLUSIONS: The selective use of bolus resulted in a small risk of chest wall recurrence rates for low-risk patients. This suggests that the routine use of bolus in PMRT patients may be unnecessary.

Prognostic Significance of Human Papilloma Virus and p16 Expression in Patients with Vulvar Squamous Cell Carcinoma who Received Radiotherapy.

AIMS: Human papilloma virus (HPV) has been identified as an aetiological agent in a subset of patients with vulvar squamous cell carcinoma (VSCC). The prognostic role of HPV status in VSCC patients treated with radiotherapy has not yet been determined. We investigated the associations between HPV, p16 and clinical outcome in these women. MATERIALS AND METHODS: Patients undergoing potentially curative radiation treatment for VSCC at a single institution from 2000 to 2009 were retrospectively identified. Those who received definitive or peri-operative radiotherapy as part of treatment, and who had available pathological specimens, were included for analysis. HPV infection was detected using Roche Linear array hybridisation and p16 by immunohistochemistry. The locoregional relapse (LRR) rate was estimated using a cumulative incidence function to account for competing risks. Disease-free survival (DFS) and overall survival were analysed using the Kaplan-Meier method. The median follow-up was 4.9 years. RESULTS: Forty patients were suitable for analysis, with a median age of 69.5 years. HPV was detected in 14/40 (35%) patients, HPV16 being the most common serotype (79%). Patients with HPV-positive tumours had lower 5 year LRR compared with those with HPV-negative tumours (14.3% versus 79.3%, Gray test P = 0.003). Tumour p16 positivity was also associated with lower 5 year LRR (15.4% versus 81.2%, Gray test P = 0.002). Patients with p16-positive tumours had higher 5 year DFS compared with those with p16-negative tumours (62% versus 7%, Log-rank test P = 0.02). CONCLUSIONS: We have identified a favourable prognostic group in VSCC, with p16-positive patients showing improved outcomes. p16 has the potential to be a predictive marker allowing the identification of women more likely to have a favourable response to radiotherapy.

A multi-institutional analysis of intraoperative radiotherapy for early breast cancer: Does age matter?

BACKGROUND: Single-session intraoperative radiation therapy (IORT) minimizes treatment demands associated with traditional whole breast radiation therapy (WBRT) but outcomes on local disease control and morbidity among the elderly is limited. METHODS: A multi-institutional retrospective registry was established from 19 centers utilizing IORT from 2007 to 2013. Patient, tumor, and treatment variables were analyzed for ages <70 and ≥70. RESULTS: We evaluated 686 patients (<70 = 424; ≥70 = 262) who were margin and lymph node negative. Patients <70 were more likely to have longer operative time, oncoplastic closure, higher rates of IORT used as planned boost, and receive chemotherapy and post-operative WBRT. Wound complication rates were low and not significantly different between age groups. Median follow-up was 1.06 (range 0.51-1.9) years for < 70 and 1.01 (range 0.5-1.68) years for ≥ 70. There were 5 (0.73%) breast recurrences (4 in <70 and 1 ≥ 70, p = 0.65) and no axillary recurrences during follow-up. CONCLUSIONS: IORT was associated with a low rate of wound complication and local recurrence on short-term follow-up in this cohort.

Interstitial fluid pressure predicts survival in patients with cervix cancer independent of clinical prognostic factors and tumor oxygen measurements.

The purpose of this study was to determine the independent prognostic significanceof interstitial fluid pressure (IFP) measurements in cervix cancer. A total of 102 patients with newly diagnosed cervix cancer were accrued to this prospective study. There were 31 International Federation of Gynecology and Obstetrics stage IB or IIA tumors, 40 IIB tumors, and 31 IIIB tumors. The median size was 5 cm (range, 2-10 cm). Pelvic lymphadenopathy was identified radiographically in 20 patients. IFP was measured at examination under anesthesia using a wick-in-needle technique. Multiple measurements were made in each tumor. The mean IFP in individual tumors ranged from -3 to 48 mm Hg, and the median for the entire cohort was 19 mm Hg. Treatment consisted of external beam and intracavitary radiation without chemotherapy. Median follow-up was 2.5 years. The 3-year disease-free survival of all of the patients was 53%. Disease-free survival was 34% in patients with IFP >19 mm Hg, and 68% in those with lower IFP (P = 0.002). To evaluate rigorously the independent prognostic significance of IFP measurements relative to established clinical factors, a multivariate model was first developed using stepwise selection of clinical covariates. Tumor size (P = 0.0003) and pelvic lymph node status (P = 0.0016) comprised the clinical model. IFP, when added to this model, provided additional independent prognostic information (P = 0.0013). IFP was also significant (P = 0.0027) when the clinical factors and hypoxic proportion as determined with the Eppendorf electrode were analyzed together. Patients with high IFP were more likely to recur both locally and at distant sites. This study is the first to document a strong, independent prognostic importance of pretreatment IFP measurements in cervix cancer. Patients with high IFP are significantly more likely than those with low IFP to recur after radiotherapy and die of progressive disease, independent of clinical prognostic factors and the results of tumor oxygen measurements.

Building a New Model of Care for Rapid Breast Radiotherapy Treatment Planning: Evaluation of the Advanced Practice Radiation Therapist in Cavity Delineation.

AIMS: Breast radiotherapy treatment is commonly managed by a multidisciplinary team to ensure optimal delivery of care. We sought a new model of care whereby a clinical specialist radiation therapist (CSRT) delineates the cavity target for whole breast radiotherapy treatment planning and the radiation oncologist validates the contour during final plan review. This study evaluated the radiation oncologist's acceptance of these contours and identified characteristics of cavities suitable for CSRT-directed contouring. MATERIALS AND METHODS: Following specialised breast oncology education and training by the radiation oncologist, the CSRT prospectively delineated cavities in 30 tangential breast radiotherapy cases and consulted the radiation oncologist in 'complex' cases but directed 'non-complex' cases for treatment planning. Changes to CSRT contours were evaluated using the conformity index. Breast density, time since surgery and cavity location, size and visualisation score [CVS: range 1 (no visible cavity) to 5 (homogenous cavity)] were captured. RESULTS: Of the 30 CSRT delineated cavities contours, the CSRT directed 20 (66.7%) cases for planning without radiation oncology review; 19 were accepted (without changes) by the radiation oncologist upon final plan review and one was changed by the radiation oncologist (conformity index = 0.93) for boost treatment and did not affect the tangential treatment plan. Ten (33.3%) cases, all CVS ≤ 3, were reviewed with the radiation oncologist before planning (conformity index = 0.88 ± 0.12). CVS was inversely correlated with breast density and cavity size (P < 0.01). CONCLUSIONS: The CSRT delineated cavities appropriate for clinical radiotherapy treatment planning in women with well-visualised cavities, whereas 'complex' cases with dense breast parenchyma, CVS ≤ 3, and/or cases needing boost radiotherapy treatment required review with the radiation oncologist before planning.

Omission of Breast Radiotherapy in Low-risk Luminal A Breast Cancer: Impact on Health Care Costs.

AIMS: The economic burden of cancer care is substantial, including steep increases in costs for breast cancer management. There is mounting evidence that women age ≥ 60 years with grade I/II T1N0 luminal A (ER/PR+, HER2- and Ki67 ≤ 13%) breast cancer have such low local recurrence rates that adjuvant breast radiotherapy might offer limited value. We aimed to determine the total savings to a publicly funded health care system should omission of radiotherapy become standard of care for these patients. MATERIALS AND METHODS: The number of women aged ≥ 60 years who received adjuvant radiotherapy for T1N0 ER+ HER2- breast cancer in Ontario was obtained from the provincial cancer agency. The cost of adjuvant breast radiotherapy was estimated through activity-based costing from a public payer perspective. The total saving was calculated by multiplying the estimated number of luminal A cases that received radiotherapy by the cost of radiotherapy minus Ki-67 testing. RESULTS: In 2010, 748 women age ≥ 60 years underwent surgery for pT1N0 ER+ HER2- breast cancer; 539 (72%) underwent adjuvant radiotherapy, of whom 329 were estimated to be grade I/II luminal A subtype. The cost of adjuvant breast radiotherapy per case was estimated at $6135.85; the cost of Ki-67 at $114.71. This translated into an annual saving of about $2.0million if radiotherapy was omitted for all low-risk luminal A breast cancer patients in Ontario and $5.1million across Canada. CONCLUSION: There will be significant savings to the health care system should omission of radiotherapy become standard practice for women with low-risk luminal A breast cancer.

Tumor hypoxia has independent predictor impact only in patients with node-negative cervix cancer.

PURPOSE: This prospective clinical study was begun in 1994 to validate the independent prognostic impact of tumor hypoxia in patients with cervix cancer treated with definitive radiation therapy. PATIENTS AND METHODS: Between May 1994 and January 1999, 106 eligible patients with epithelial cervix cancer had tumor oxygen pressure (PO(2)) measured using the Eppendorf probe. Oxygenation data are presented as the hypoxic proportion, defined as the percentage of PO(2) readings less than 5 mm/Hg (abbreviated as HP(5)) and the median PO(2). RESULTS: The median HP(5) in individual patients was 48%, and the median PO(2) was HP(5). Progression-free survival (PFS) for patients with hypoxic tumors (HP(5) > 50%) was 37% at 3 years versus 67% in those patients with better oxygenated tumors (P =.004). In multivariate analysis, only tumor size (risk ratio [RR], 1.33; P =.0003) and evidence of pelvic nodal metastases on imaging studies (RR, 2.52; P =.0065) were predictive of PFS. However, an interaction between nodal status and oxygenation was observed (P =.006), and further analysis indicated that HP(5) was an independent predictor of outcome in patients with negative nodes on imaging (P =.007). There was a significant increase in the 3-year cumulative incidence of distant metastases in the hypoxic group (41% v 15% in those with HP(5) < 50%; P =.0023), but not in pelvic relapse (37% v 27%; P =.12). CONCLUSION: Tumor hypoxia is an independent predictor of poor PFS only in patients with node-negative cervix cancer, in addition to tumor size. Its impact appears to be related to an increased risk of distant metastases rather than to an effect on pelvic control.

Role of mitomycin C in the development of late bowel toxicity following chemoradiation for locally advanced carcinoma of the cervix.

PURPOSE: To determine if the inclusion of mitomycin C (MMC) in chemoradiation protocols for locally advanced cervical cancer (LACC) significantly enhances the development of serious (Grade 3) late bowel toxicity (SLBT). METHODS AND MATERIALS: The incidence of SLBT in 154 patients with LACC entered in six consecutive chemoradiotherapy protocols between February 1982 and June 1987 was determined. Fifty-four patients who were treated with MMC, 5-fluorouracil (5-FU), and radiation were compared to 100 patients who received similar treatment without MMC. Univariate and multivariate analyses assessed the effect of the following parameters on the development of SLBT: (a) external beam dose, (b) rectal and rectosigmoid dose, (c) paraaortic radiation, (d) intracavitary dose and dose rate, (e) volume of tissue irradiated to a total dose of 60 Gy, (f) International Federation of Gynecology and Obstetrics stage, (g) age, (h) number of courses of 5-FU, (i) previous abdominopelvic surgery, (j) split versus continuous radiation, and (k) administration of MMC. RESULTS: The overall incidence of SLBT was 15.6%: 14 of 54 (26%) versus 10 of 100 (10%) for patients who did or did not receive MMC, respectively (p = 0.009). Multivariate analysis revealed the administration of MMC as the only factor predictive for the development of SLBT (p = 0.012, odds ratio = 3.15; 95% confidence interval 1.3-7.7). A significant reduction in SLBT was observed with the elimination of MMC from the chemoradiation protocols despite dose escalation of both radiation and 5-FU. No increase in overall survival was observed in patients receiving MMC, 5-FU, and radiation compared with 5-FU and radiation alone. CONCLUSION: The inclusion of MMC in these chemoradiation protocols for LACC is associated with significant enhancement in serious late bowel toxicity.

The relationship between elevated interstitial fluid pressure and blood flow in tumors: a bioengineering analysis.

PURPOSE: To examine the hypothesis that elevated interstitial fluid pressure (IFP) is a cause of reduced blood flow in tumors. MATERIALS AND METHODS: A physiologic model of tumor blood flow was developed based on a semipermeable, compliant capillary in the center of a spherical tumor. The model incorporates the interaction between the tumor vasculature and the interstitium, as mediated by IFP. It also incorporates the dynamic behavior of the capillary wall in response to changes in transmural pressure, and the effect of viscosity on blood flow. RESULTS: The model predicted elevated tumor IFP in the range of 0 to 56 mmHg. The capillary diameter in the setting of elevated IFP was greatest at the arterial end, and constricted to between 3.2 and 4.4 microm at the venous end. This corresponded to a 2.4- to 3.5-fold reduction in diameter along the length of the capillary. The IFP exceeded the intravascular pressure distally in the capillary, but vascular collapse did not occur. Capillary diameter constriction resulted in a 2.3- to 9.1-fold steady-state reduction in tumor blood flow relative to a state of near-zero IFP. CONCLUSION: The results suggest that steady-state vascular constriction occurs in the setting of elevated IFP, and leads to reduced tumor blood flow. This may in turn contribute to the development of hypoxia, which is an important cause of radiation treatment failure in many tumors.

Cervix cancer oxygenation measured following external radiation therapy.

PURPOSE: Tumor hypoxia may be an important factor predicting relapse following radiation therapy. This study was designed to determine the relationship between the oxygenation parameters measured using a polarographic oxygen electrode, prior to and during treatment in patients with cervix cancer, and to assess these results with regard to patient survival. MATERIALS AND METHODS: Forty-three patients had pretreatment oxygen assays performed and measurements repeated following external beam radiation to a median dose of 50 Gy (range 26-52 Gy). Stage distribution showed 15 patients in Stage IB, 17 in Stage II, and 11 in Stage III. The median tumor size was 5 cm (range 3-10 cm). RESULTS: The median proportion of pO2 values <5 mm Hg (the HP5) was 41% following radiation, and the median pO2 was 12 mm Hg. These results were not significantly different from the pretreatment HP5 or pO2 of 37% and 12 mm Hg, respectively. Disease-free survival at 2 years was 50% in patients with posttreatment HP5 < or =50%, compared to 60% when posttreatment HP5 was >50% (p = 0.35). CONCLUSIONS: Unlike pretreatment results, tumour oxygenation measured following external radiation does not appear to be a useful predictive assay in patients with cervical cancer.

Heterogeneity of polarographic oxygen tension measurements in cervix cancer: an evaluation of within and between tumor variability, probe position, and track depth.

PURPOSE: To evaluate the heterogeneity of cervix cancer oxygenation as measured using the Eppendorf polarographic electrode and define the optimal number of measurements required to adequately sample a cervix cancer. METHODS AND MATERIALS: Two to 6 tracks with 20-30 measurements per track were obtained in each of the 44 patients evaluated. One hundred sixty-eight tracks and 4719 measurements formed the basis of this analysis. Median pO2 and hypoxic proportion (HP5), defined as the percentage of pO2 values <5 mmHg, were calculated for each track and for each tumor. Within-tumor (W) and between-tumor (B) variability in oxygenation was evaluated using a variance component analysis. The standard error of the measured HP5 with each additional track in each patient was analysed as a function of the total number of tracks. RESULTS: The ratio W/W + B was 0.67 and 0.76 for median pO2 and HP5, respectively, indicating that multiple measurements are needed to adequately sample a tumor. The median value of the standard error of the HP5 decreased from 7.0 to 4.0% from the first to the fifth track, respectively. It was estimated that adding the sixth track would only result in a small change (<0.3%) in the standard error. There was no significant difference in oxygen tension measurements as a function of the location of the measurements around the circumference of the cervix or the depth along the measurement tracks. CONCLUSIONS: There is significant within tumor variability in oxygen tension in cervix cancer. Five tracks with 20-30 measurements per track is optimal to sample the oxygenation status of a cervix cancer. The present data does not suggest that there is a significant difference related to the position in the tumor at which the pO2 measurements were taken.

Tumor size and oxygenation are independent predictors of nodal diseases in patients with cervix cancer.

PURPOSE: To determine the relationships between tumor oxygenation and nodal stage in a prospective study of patients with cervix cancer, controlling for other prognostic factors. METHODS AND MATERIALS: Between 1994 and 1999, 128 eligible patients with cervix cancer were entered into a prospective study of tumor oxygenation assessed by Eppendorf oxygen electrode before primary radiation therapy. Oxygenation was evaluated using the proportion of pO(2) values < 5 mmHg (HP(5)), and tumors were classified as hypoxic if the HP(5) was > 50%. Patients were assigned to one of three groups: those with no imaging evidence of nodal (pelvic or para-aortic) or distant metastatic disease (N group; n = 67), those with equivocal findings (E group; n = 28), and those with nodal or distant metastatic disease (P group; n = 33). RESULTS: The proportion of hypoxic tumors in the P, E, and N groups were 67%, 50%, and 40%, respectively (p = 0.014), with median HP(5) values of 63%, 48%, and 36%, respectively (p = 0.0024). In a multivariate analysis including tumor size, stage, HP(5), and hemoglobin, it was found that tumor size and HP(5) were the only independently significant variables for the finding of metastatic disease (p = 0.009 and 0.017, respectively). CONCLUSION: In this patient population, there was a significantly increased risk of nodal or distant metastases in patients with hypoxic tumors, and this finding was independent of tumor size. These results are consistent with the hypothesis that tumor hypoxia is an adverse prognostic factor associated with selection for a metastatic phenotype.

Effect of filgrastim (G-CSF) during chemotherapy and abdomino-pelvic radiation therapy in patients with ovarian carcinoma.

PURPOSE: To evaluate the safety and effectiveness of filgrastim (granulocyte colony-stimulating factor, G-CSF) in reducing neutropenia and treatment interruptions during whole abdominal radiotherapy for ovarian cancer. METHODS AND MATERIALS: Sixteen patients with ovarian cancer treated with 2 to 6 courses of cisplatin-containing chemotherapy and abdomino-pelvic radiation therapy received filgrastim for neutrophil counts <2 x 10(9)/L. Endpoints for analysis included the ability to maintain the neutrophil count in the target range, number of treatment interruptions due to neutropenia, and toxicity attributed to filgrastim. RESULTS: Fourteen patients received a mean of 2.9 courses of filgrastim (each with a mean duration of 4.1 days), with no treatment interruptions due to neutropenia. The majority of neutrophil counts were maintained above the target range of 2 x 10(9)/L during treatment. Thrombocytopenia requiring treatment interruption was seen in six patients and necessitated platelet transfusions in one. Thrombocytopenia occurred at a mean abdominal radiation dose of 2207 cGy and in all but one patient was preceded by one or more episodes of neutropenia. In comparison with a control group of 31 patients treated without filgrastim there was no reduction in treatment interruptions. Four patients did not complete treatment because of persistent thrombocytopenia yet received a mean of 94% of the planned abdominal radiation dose and 69% of the planned pelvic dose. Filgrastim toxicity was limited to mild skeletal pains in six patients and a Grade 1 skin rash in two patients. CONCLUSIONS: Filgrastim is safe and effective in preventing neutropenia and reducing neutropenic treatment interruptions during abdominal radiotherapy in patients with ovarian cancer. However, there was no clear benefit to the use of filgrastim as thrombocytopenia became the dose-limiting toxicity resulting in a risk of treatment interruptions and early termination of radiotherapy.

A randomized study of two doses of abdominopelvic radiation therapy for patients with optimally debulked Stage I, II, and III ovarian cancer.

PURPOSE: To determine whether an increased dose of abdominal radiation therapy results in improved disease control and survival in patients with early ovarian cancer. METHODS AND PATIENTS: Between 1981 and 1990, 125 patients with optimally debulked Stage I, II, and III ovarian cancer were entered into a prospective randomized clinical trial of abdominopelvic radiation therapy. Patients were stratified and randomized to either the control arm, treated with an abdominal dose of 22.5 Gy in 22 fractions, or the experimental arm of 27.5 Gy in 27 fractions. A pelvic boost dose of 22.5 Gy was used in both arms. There were 43 patients with Stage I tumors, 71 Stage II tumors, and 11 Stage III tumors. Nineteen patients had grade 1 histology, 77 grade 2, and 29 grade 3. Three patients had small-volume residual disease (<2 cm) in the pelvis alone and the remainder had no gross tumor following surgery. Median follow-up was 6.6 years (range 1.4-9.9). RESULTS: Overall survival (OS) at 5 years was 83% in the low-dose arm and 72% in the high-dose arm (p = 0.3). Disease-free survival (DFS) at 5 years was 74% and 67% in the low-dose and high-dose arms, respectively (p = 0.5). The difference in OS between the two arms was -11%, with 95% confidence intervals of -26% (favoring low-dose treatment) to 4% (in favor of high dose). The difference in DFS was -7% (95% confidence interval, -23 to 9%). Failure in the pelvis alone predominated (n = 15); six patients had abdominal and pelvic failure and seven patients failed in the abdomen alone. There were no differences in patterns of relapse, hematologic toxicity, or late complications between the two arms. Serious bowel toxicity was seen in three patients: two in the low-dose and one in the high-dose arm. A Cox proportional hazards model was used to assess the effect of treatment when adjusting for other prognostic variables. Ascites (p = 0.03, relative risk 2.05) was the only significant covariate in predicting disease-free survival, but was not prognostic for overall survival. CONCLUSIONS: There was no difference in survival, tumor control, or toxicity between high-dose and low-dose abdominopelvic radiation therapy. High-dose abdominopelvic radiation therapy is unlikely to be associated with an increase in OS of more than 4% or DFS of more than 9%.

Borderline epithelial ovarian tumors: a review of 81 cases with an assessment of the impact of treatment.

Optimal management of borderline epithelial ovarian tumors remains controversial because of the lack of clear, universally accepted pathologic criteria for diagnosis, the lack of complete understanding of the significance of intraperitoneal implants, and the desire to employ more limited surgery in young women. We reviewed the experience with borderline epithelial ovarian tumors at Princess Margaret Hospital in order to assess the natural history of the disease, to determine prognostic factors that would aid in management decisions, and to determine if adjuvant therapy influenced outcome. Eighty-one patients were analyzed. The mean age was 48 years. Seventy-two percent of tumors were of the serous histologic sub-type and 28% were mucinous. Seventy-eight percent were Stage I, 11% Stage II, and 11% Stage III. Peritoneal washings contained malignant cells in 14 of 32 patients (not recorded or obtained in 49), cyst rupture occurred in 25%, surface excrescences in 40%, and adhesions in 46%. None of these factors had a significant effect on recurrence rate or survival. Eleven patients received adjuvant radiation therapy (10 abdomino-pelvic and 1 pelvic alone), four adjuvant chemotherapy, and one both radiation therapy and chemotherapy. The rest (65) received no adjuvant therapy. Due to the small numbers and infrequent events, it was not possible to analyze and thus draw valid conclusions regarding the effect of adjuvant therapy on survival or recurrence. The overall survival (OS) and cause specific survival (CSS) were 85% and 96% at 10 years, respectively. No Stage I patient died of tumor. OS for Stage I patients was 90% at 10 years, the majority of whom (61 of 63) received no adjuvant therapy, and is thus unnecessary in Stage I disease. The adequacy of unilateral oophorectomy or ovarian cystectomy could not be confirmed because of small numbers. The 10 year OS and disease-free survival in Stage II and III were 75% and 50%, respectively, despite the use of adjuvant radiation therapy, chemotherapy, or both. It is necessary to create a multi-center tumor registry in order to acquire a prospective data base from which to develop sound therapeutic decisions.