Predictive factors for persistent and late radiation complications in breast cancer survivors.

PURPOSE: With improved diagnostic techniques and treatments of breast cancer, overall survival times are longer, giving more opportunity for normal tissue complications of treatment to manifest. Radiation late effects (RLEs) could have profound long-term impacts on the quality of life of the survivors. The aim of this study was to identify predictive factors influencing timing and types of complications in patients referred to the Adult Radiation Late Effects Clinic (ARLEC). METHODS: In a period of 16 years, 296 breast cancer patients were referred to the ARLEC. The clinical records were retrospectively studied to collect epidemiologic, medical and treatment data. Associations were sought between candidate predictive factors and time to the first complication after radiation treatment (RT) completion (primary outcome), and pain or swelling (secondary outcomes) using univariable and multivariable linear and logistic regression analyses. All analyses were performed in SAS, version 9.4. RESULTS: All patients were female with a mean age of 56.3 years. The first treatment-related complication occurred after a median of 3 months. Patients were followed at ARLEC for a median of 18 months. Older age and delay from surgery to RT (S-RT delay) were associated with earlier onset of complications (both p < 0.001). The most common complications were breast pain (62.1%) and swelling (45.9%). Histology and RT boost were associated with pain (p = 0.035 and 0.013). RT boost and S-RT delay on the other hand were associated with swelling (p = 0.013 and 0.005). CONCLUSIONS: Clinical factors identified could help recognize the patients at high risk for developing RLEs and alert physicians to initiate earlier diagnostic and therapeutic measures.

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.

Impact of body mass index on short-term and long-term survival in prevalent hemodialysis patients.

INTRODUCTION: Numerous studies showed that higher body mass index (BMI) is associated with better survival in hemodialysis (HD) patients. Most of them evaluated short-term mortality. It has been suggested that presence of inflammation may be a key modifier of relationship between BMI and mortality in incident HD patients. We examined whether presence of inflammation modifies the association between BMI and mortality in both short-term and long-term follow-up in a large group of prevalent HD patients. METHODS: A total of 3.252 HD patients from 41 HD centers were enrolled; the patients were divided into quartiles based on time-averaged BMI (Q1 < 21.5, Q2 21.5 to <24.3, Q3 24.3 to <27.4, Q4 ≥ 27.4 kg/m2 ). Inflammation status was defined as present (inflamed) (C-reactive protein (CRP) ≥1.0 mg/dL and/or serum albumin ≤3.5 g/dL) or absent (noninflamed). FINDINGS: During 7 years of follow-up 1386 patients (42.6%) died. Compared to noninflamed patients, inflamed patients in the lowest BMI quartile showed 5-fold increased risk for mortality in the short-term (95% confidence interval [CI] 2.82-9.22, P < 0.001) and 3-fold in the long-term (95%CI 2.42-4.27, P < 0.001) compared to the highest BMI quartile. Whereas, inflamed patients in the highest BMI quartile experienced 2-fold increased risk in short-term (95%CI 1.17-3.74, P = 0.01) and 1.68-fold increased risk in long-term (95%CI 1.30-2.18, P < 0.001) than in noninflamed patients. The protective effect of BMI for overall mortality was present in all age groups, in both genders, in patient with and without diabetes. BMI was not a mortality predictor in patients with HD duration more than 76 months at baseline. The protective effect of BMI was observed in all albumin tertiles. In patients in the lowest CRP tertile, BMI was not associated with mortality. DISCUSSION: Higher BMI is associated with lower short-term and long-term mortality risk, especially in patients with inflammation in a prevalent HD population.

Preoperative radiotherapy in the management of retroperitoneal liposarcoma.

BACKGROUND: Histological subtype influences both prognosis and patterns of treatment failure in retroperitoneal sarcoma. Previous studies on the efficacy of neoadjuvant radiotherapy (NRT) have incorporated multiple histological types with heterogeneous tumour biology. The survival impact of NRT specifically for patients with retroperitoneal liposarcoma is poorly defined. METHODS: Patients who underwent resection with curative intent for retroperitoneal liposarcoma and who received NRT or surgery alone were identified in the US National Cancer Data Base (2004-2013). Cox regression was used to identify co-variables associated with overall survival. NRT and surgery-alone cohorts were matched 1 : 1 by propensity scores based on the survival hazard on Cox modelling. Overall survival was compared by Kaplan-Meier estimates. RESULTS: A total of 2082 patients with retroperitoneal liposarcoma were identified; 1908 underwent surgery alone and 174 received NRT before surgical resection. Median tumour size was 22·0 cm and 34·9 per cent of tumours were high grade. In the unmatched cohort, NRT was not associated with improved overall survival (χ2 = 3·49, P = 0·062). In the propensity score-matched cohort, NRT was associated with an improvement in survival (median overall survival 129·2 versus 84·3 months; P = 0·046; hazard ratio (HR) 1·54, 95 per cent c.i. 1·01 to 2·36). This effect appeared most pronounced for tumours with adjacent organ invasion (median overall survival not reached versus 63·8 months; P = 0·044; HR 1·79, 1·01 to 3·19). CONCLUSION: NRT improved survival in patients undergoing surgery for retroperitoneal liposarcoma, particularly those with high-risk pathological features.

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.

The Brain Metastases Symptom Checklist as a novel tool for symptom measurement in patients with brain metastases undergoing whole-brain radiotherapy.

PURPOSE: We evaluated the feasibility, reliability, and validity of the Brain Metastases Symptom Checklist (bmsc), a novel self-report measure of common symptoms experienced by patients with brain metastases. METHODS: Patients with first-presentation symptomatic brain metastases (n = 137) referred for whole-brain radiotherapy (wbrt) completed the bmsc at time points before and after treatment. Their caregivers (n = 48) provided proxy ratings twice on the day of consultation to assess reliability, and at week 4 after wbrt to assess responsiveness to change. Correlations with 4 other validated assessment tools were evaluated. RESULTS: The symptoms reported on the bmsc were largely mild to moderate, with tiredness (71%) and difficulties with balance (61%) reported most commonly at baseline. Test-retest reliability for individual symptoms had a median intraclass correlation of 0.59 (range: 0.23-0.85). Caregiver proxy and patient responses had a median intraclass correlation of 0.52. Correlation of absolute scores on the bmsc and other symptom assessment tools was low, but consistency in the direction of symptom change was observed. At week 4, change in symptoms was variable, with improvements in weight gain and sleep of 42% and 41% respectively, and worsening of tiredness and drowsiness of 62% and 59% respectively. CONCLUSIONS: The bmsc captures a wide range of symptoms experienced by patients with brain metastases, and it is sensitive to change. It demonstrated adequate test-retest reliability and face validity in terms of its responsiveness to change. Future research is needed to determine whether modifications to the bmsc itself or correlation with more symptom-specific measures will enhance validity.

The role of elective para-aortic lymph node irradiation in patients with locally advanced cervical cancer.

AIMS: Pelvic lymph node positivity in cervical cancer is known to be an adverse prognostic factor and is associated with an elevated risk of clinically occult para-aortic lymph node metastases. The purpose of this study was to examine the benefit of elective para-aortic lymph node radiotherapy (PART) in patients with no clinical or radiographic evidence of para-aortic lymph node metastases receiving concurrent cisplatin chemotherapy. MATERIALS AND METHODS: Patients treated with radiotherapy and concurrent cisplatin for cervical cancer from 1999 to 2009 were identified in two prospective databases. All patients received external beam pelvic radiotherapy (PRT) to a median dose of 50 Gy concurrently with weekly cisplatin 40 mg/m(2). This was followed by pulse dose rate intracavitary brachytherapy to a median dose of 40 Gy. Patients at high risk of occult para-aortic metastases also received PART to a median dose of 40 Gy. RESULTS: There were 228 patients suitable for analysis; the median follow-up was 4.6 years. The addition of PART to PRT was not associated with a significant difference in disease-free survival (hazard ratio 1.1, confidence interval 0.7-1.8, P = 0.75) or overall survival (hazard ratio 1.6, confidence interval 0.9-2.7, P = 0.11) on multivariate analysis. There was no significant difference in the rate of para-aortic relapse with PART versus PRT (hazard ratio 2.01, confidence interval 0.79-5.12, P = 0.14). The 3 year grade 3-4 late toxicities were 11% for the PART group versus 8% for PRT (hazard ratio 1.39, confidence interval 0.58-3.37, P = 0.47). CONCLUSIONS: These results suggest that cervical cancer patients treated with radiotherapy and concurrent cisplatin do not benefit from elective PART.

Assessment of HER2 gene amplification in adenocarcinomas of the stomach or gastroesophageal junction in the INT-0116/SWOG9008 clinical trial.

BACKGROUND: Trastuzumab has been approved for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic gastric carcinoma; however, relatively little is known about the role of HER2 in the natural history of this disease. PATIENTS AND METHODS: Patients enrolled in the INT-0116/SWOG9008 phase III gastric cancer clinical trial with available tissue specimens were retrospectively evaluated for HER2 gene amplification by FISH and overexpression by immunohistochemistry (IHC). The original trial was designed to evaluate the benefit of postoperative chemoradiation compared with surgery alone. RESULTS: HER2 gene amplification rate by FISH was 10.9% among 258 patients evaluated. HER2 overexpression rate by IHC was 12.2% among 148 patients evaluated, with 90% agreement between FISH and IHC. There was a significant interaction between HER2 amplification and treatment with respect to both disease-free survival (DFS) (P = 0.020) and overall survival (OS) (P = 0.034). Among patients with HER2-non-amplified cancers, treated patients had a median OS of 44 months compared with 24 months in the surgery-only arm (P = 0.003). Among patients with HER2-amplified cancers, there was no significant difference in survival based on treatment arm. HER2 status was not a prognostic marker among patients who received no postoperative chemoradiation. CONCLUSION: Patients lacking HER2 amplification benefited from treatment as indicated by both DFS and OS. CLINICAL TRIAL: INT-0116/SWOG9008 phase III.

A hypofractionated radiotherapy regimen (0-7-21) for advanced gynaecological cancer patients.

AIMS: To evaluate the efficacy of a palliative three fraction radiation regimen delivered on days 0, 7 and 21 (0-7-21 regimen) for advanced stage gynaecological cancer patients. MATERIALS AND METHODS: Fifty-one patients with advanced gynaecological cancer who were treated with the 0-7-21 regimen between 1998 and 2008 were identified. The median follow-up period was 1.4 months (range 0.2-33.4). Treatment completion data, symptomatic response, toxicity and survival were retrospectively analysed. RESULTS: Forty-eight patients received at least two of the three planned fractions. Complete and partial responses of vaginal bleeding were seen in 92% of 26 evaluable patients. Complete and partial responses of pain were seen in 76% of 25 evaluable patients. Eighteen of the 33 evaluable patients experienced grade 1/2 acute toxicity. No patients experienced grade 3/4 toxicity. Grade 1/2 and grade 3 late toxicity occurred in four and one of 12 evaluable patients, respectively. Grade 5 toxicity was assigned in two patients. It was uncertain whether these deaths were radiation related or due to tumour progression. Eleven patients survived longer than 12 months. CONCLUSIONS: The 0-7-21 regimen provided effective and rapid symptomatic relief with acceptable toxicity, and offered the advantage of convenience for most patients. It offers an alternate treatment option for carefully selected patients with incurable gynaecological malignancies.

A computer-assisted depression intervention in primary care.

BACKGROUND: The clinical benefit for depression of an interactive computer-assisted cognitive-behavioral program on CD-ROM, the Wellness Workshop (WW), was evaluated in a randomized controlled trial. METHOD: A total of 191 individuals referred by primary-care physicians were randomly assigned to a control group, where physician-directed treatment as usual (TAU) was provided, or to a treatment group, where TAU was supplemented with the WW CD-ROM, delivered by mail (WW+TAU). Data were collected at baseline, at 6 weeks' post-intervention, and at a 6-month follow-up assessment. Participants were given a strong incentive by a reimbursement of $75 for completion of each assessment. Measures included symptom ratings obtained via structured clinical diagnostic interviews, as well as a battery of self-report questionnaires on symptoms specifically targeted by the intervention. RESULTS: Analysis of results demonstrated evidence for skill acquisition for improving dysfunctional thinking and reducing anxiety. Among those who met diagnostic criteria for depression, WW+TAU participants were three times more likely to remit at 6 weeks' post-test than TAU participants. CONCLUSIONS: The evidence supports the conclusion that the WW intervention added benefit to traditional care for depression. No placebo comparison group was included and the WW+TAU participants received slightly more attention (a supportive telephone contact, ≤ 5 min from a psychologist 2 weeks after receiving the program). Overall, the findings add support to the accumulating evidence for the potential clinical benefit of computer-assisted behavioral health interventions.

Workshop report: A practical approach and general principles of re-irradiation for in-field cancer recurrence.

In-field cancer recurrence after previous adjuvant or radical radiotherapy presents particularly challenging clinical issues to the oncologists. A Canadian pattern of practice survey showed a wide range of approaches in treatment intent, planning and dose fractionation. A workshop on re-irradiation was conducted at the 2009 Canadian Association of Radiation Oncology annual scientific meeting, under the guidance of the Symptom Control Committee, in an effort to promote a uniform approach among radiation oncologists in their approach to re-irradiation. The workshop has made various recommendations in an effort to bring consistency among radiation oncologists across Canada to their approach towards re-irradiation.

Factors influencing the use of single vs multiple fractions of palliative radiotherapy for bone metastases: a 5-year review.

AIMS: Evidence from a number of randomised trials and meta-analyses supports the use of single-fraction radiotherapy for the palliation of painful bone metastases. This study explores patient and treatment factors that influence the choice of single compared with multiple-fraction radiotherapy for the treatment of bone metastases in clinical practice. MATERIALS AND METHODS: The Princess Margaret Hospital Palliative Radiation Oncology Program Database served as the basis for our report. All courses of treatment delivered for bone metastases were extracted. Courses were classified into single or multiple fractions. Clinical characteristics were compared between the two groups. RESULTS: Between 1998 and 2002, 882 courses of radiotherapy were delivered for the treatment of bone metastases, of which 283 (32%) were a single fraction. The proportion of single-fraction treatments was 37% in 1998, 30% in 1999 and 43% in 2000, but dropped to 26% and 28% in 2001 and 2002, respectively (P = 0.02). Patients treated with single fractions were significantly older (68 +/- 12 years vs 64 +/- 12 years), and had more weight loss and poor performance status. Single fractions included 20% of treatments in palliative irradiation of the spine, 36% in the pelvis and long bones, and 59% in the chest wall (P < 0.001). There was no significant difference in patients' gender, primary cancers, number of metastatic sites, treating physicians, enrollment in a clinical trial and general radiotherapy waiting time in our department. Multivariate analysis indicated age (P = 0.001), performance status (P < 0.001), anatomical site (P < 0.001) and year of radiotherapy (P = 0.006) as significant. CONCLUSION: One-third of palliative radiotherapy courses for bone metastases in our programme were given as single fractions. Performance status, age and anatomical site were significant factors affecting single compared with multiple fractionation. The variation in the use of single fractions over time may reflect the dynamic process of interpretation and application of evidence from clinical trials to practice.

Proton beam therapy.

Conventional radiation therapy directs photons (X-rays) and electrons at tumours with the intent of eradicating the neoplastic tissue while preserving adjacent normal tissue. Radiation-induced damage to healthy tissue and second malignancies are always a concern, however, when administering radiation. Proton beam radiotherapy, one form of charged particle therapy, allows for excellent dose distributions, with the added benefit of no exit dose. These characteristics make this form of radiotherapy an excellent choice for the treatment of tumours located next to critical structures such as the spinal cord, eyes, and brain, as well as for paediatric malignancies.

Computed tomographic simulation in palliative radiotherapy: the Princess Margaret Hospital experience.

AIM: To examine the pattern of palliative radiation planning and the use of computed tomographic simulation (CTSIM) for this purpose. MATERIALS AND METHODS: We reviewed our department's external radiotherapy database for all courses of treatment with a palliative intent during the period of April to June 2002. Patient characteristics and treatment details were compared based on whether CTSIM had been used or not. RESULTS: During the above period, 593 courses of external radiation treatment were delivered with palliative intent in our department. Of these, 100 treatments (17%) were planned with the help of CTSIM. The mean age of patients with CTSIM (62.9 years) was not significantly different with the patients planned without CTSIM (63.6 years). CTSIM use varied by treatment location, being highest in mediastinum/oesophagus (48%) and pancreas/stomach (47%) treatments, and lowest in spine (6%), lung (3%) and long bones (4%) (P < 0.01). Only 3% of palliative treatments without CTSIM were prescribed using multiple/complex fields (all field arrangements more complex than a single field or two opposed parallel fields). Although significantly higher (P < 0.001), this proportion was also only 24% in the cases planned with CTSIM. Only 12% of treatments without CTSIM were prescribed with more than 5 fractions, whereas 32% of CT-simulated treatments included more than 5 fractions (P < 0.001). CONCLUSION: CTSIM was used much less frequently in our department's palliative radiotherapy compared with its use in radical treatments. The relatively low rate of multiple/complex fields planned in CT-simulated cases suggested that CTSIM was mostly used to improve tumour localisation. The optimal role of CTSIM in palliative radiotherapy will most probably evolve, based on an enhanced understanding of the implications from improved localisation and optimal planning techniques on clinical outcomes, patient convenience and resource accessibility.

Symptom response after palliative radiotherapy for patients with brain metastases.

Whole brain radiotherapy (RT) is frequently used to palliate symptoms in patients with brain metastases, but the palliative benefit to patients has not been well documented. We conducted a longitudinal observational prospective study of patients receiving standard RT (20 Gray (Gy)/5 fractions) for symptomatic brain metastases. End-points were observer rating of neurological symptoms, patient-rated symptoms, performance status, neurological functional status, cognitive function and quality of life (QOL). Median survival for the 75 patients was 86 days (95% confidence interval (CI): 65-101 days). At 1 month, 19% of patients showed an improvement or resolution of presenting symptoms, 23% were stable and 55% had progressed or died. Patient-rated symptoms were increased at 1 month in comparison to baseline data. Only 4 patients had an improved performance status and 22 were stable. Many patients with brain metastases have a short life expectancy and may not benefit from even short duration radiation schedules. Further effort is needed to optimise patient selection and tailor treatment appropriately.

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.

Comparative treatment planning between proton and X-ray therapy in pancreatic cancer.

With the utilization of new biologic agents and experimental chemotherapy in the treatment of pancreatic cancer, the issue of local-regional control will become increasingly important. This study was undertaken to determine the feasibility of dose escalation using proton therapy, as compared to conventional 3-dimensional conformal radiation, by minimizing the dose to normal tissues. The photon treatment plans of 4 patients with unresectable pancreatic cancer treated on a biologic therapy trial were utilized. Each patient was treated using a 3- or 4-field photon plan with 45 Gy to the clinical target volume (CTV), followed by a boost of 14.4 Gy to the gross target volume (GTV). Using a Helax treatment planning system, proton plans were generated to encompass the same CTV and GTV to the same prescribed dose. Dose-volume histograms (DVHs) were generated for the GTV, CTV, spinal cord, liver, and right and left kidneys. Each DVH was compared between the photon and proton plans. Proton plans utilized either a 2- or 3-field technique. Available energies included 130 or 180 MeV. Range modulators and bolus were used as needed to conform to the target volume. With the CTV and GTV receiving the same dose from the proton and photon plans, all individual proton plans were superior to the photon plans in reduction of normal tissue dose. For the 4 patients, the average dose reduction to 50% of the organ at risk was 78% to spinal cord (p = 0.003), 73% to left kidney (p = 0.025), 43% to right kidney (p = 0.059), and 55% to liver (p = 0.061). These comparative treatment plans show proton therapy results in significant reductions of dose to normal tissue compared to conventional photons while treating the same target volumes. This allows for the design of dose-escalation protocols using protons in combination with new biologic therapies and chemotherapy.

Radiotherapy for brain metastases: defining palliative response.

BACKGROUND AND PURPOSE: Most patients with brain metastases are treated with palliative whole brain radiotherapy (WBRT). There is no established definition of palliative response. The aim of this study was to develop and test clinically useful criteria for response following palliative WBRT. MATERIALS AND METHODS: A prospective study was conducted of patients with symptomatic brain metastases treated with WBRT (20 Gy/5 fractions) and standardised steroid tapering. Assessments included observer rating of neurological symptoms, patient-completed symptom checklist and performance status (PS). Response criteria were operationally defined based on a combination of neurological symptoms, PS and steroid dose. RESULTS: Seventy-five patients were accrued. At 1 month, presenting neurological symptoms were improved in 14 patients, stable in 17, and worse in 21; 23 patients were not assessed, mainly due to death or frailty. Using response criteria defined a priori, 15% (95% CI 7-23%) of patients were classified as having a response to RT, 25% no response, and 29% progression; 27% were deceased at or soon after 1 month. A revised set of criteria was tested, with less emphasis on complete tapering of steroids: they increased the proportion of patients responding to 39% (95% CI 27-50%) but didn't change the large proportion who did not benefit (44%). CONCLUSIONS: Clinical response to RT of patients with brain metastases is multifactorial, comprising symptoms, PS and other factors. Assessment of degree of palliation depend on the exact definition used. More research is needed in this important area, to help validate criteria for assessing palliation after WBRT.

Intratumoral sickling in a patient with cervix cancer and sickle trait: effect on blood flow and oxygenation.

BACKGROUND: Sickle trait affects approximately 8% of the black population in the United States and up to 40% of individuals in some parts of tropical Africa, but rarely causes clinically significant illness. This report provides the first conclusive evidence that erythrocytes in patients with sickle trait may sickle in the microvasculature of solid tumors, leading to impaired perfusion and hypoxia. CASE: A black woman who was sickle trait positive presented with stage IIIB squamous cell carcinoma of the cervix. A biopsy showed extensive intravascular sickling of erythrocytes. An aspirate of blood obtained directly from the tumor also showed numerous sickled cells. A peripheral blood smear was normal. Direct measurement of oxygen tension using the Eppendorf electrode revealed the tumor to be markedly hypoxic, with 93% of a total of 142 individual oxygen reading <5 mm Hg. CONCLUSIONS: Erythrocytes in patients with sickle trait may sickle in the microvasculature of solid tumors and contribute to reduced blood flow and the development of hypoxia. Hypoxia is a strong independent prognostic factor in patients with cervix cancer, and further study is needed to evaluate the impact of intratumoral sickling on long-term outcome.

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.