Skin Toxicity in Early Breast Cancer Patients Treated with Field-In-Field Breast Intensity-Modulated Radiotherapy versus Helical Inverse Breast Intensity-Modulated Radiotherapy: Results of a Phase III Randomised Controlled Trial.

AIMS: Skin toxicity is a common adverse effect of breast radiotherapy. We investigated whether inverse-planned intensity-modulated radiotherapy (IMRT) would reduce the incidence of skin toxicity compared with forward field-in-field breast IMRT (FiF-IMRT) in early stage breast cancer. MATERIALS AND METHODS: This phase III randomised controlled trial compared whole-breast irradiation with either FiF-IMRT or helical tomotherapy IMRT (HT-IMRT), with skin toxicity as the primary end point. Patients received 50 Gy in 25 fractions and were assessed to compare skin toxicity between treatment arms. RESULTS: In total, 177 patients were available for assessment and the median follow-up was 73.1 months. Inverse IMRT achieved more homogeneous coverage than FiF-IMRT; erythema and moist desquamation were higher with FiF-IMRT compared with HT-IMRT (61% versus 34%; P < 0.001; 33% versus 11%; P < 0.001, respectively). Multivariate analysis showed large breast volume, FiF-IMRT and chemotherapy were independent factors associated with worse acute toxicity. There was no difference between treatment arms in the incidence of late toxicities. The 5-year recurrence-free survival was 96.3% for both FiF-IMRT and HT-IMRT and the 5-year overall survival was 96.3% for FiF-IMRT and 97.4% for HT-IMRT. CONCLUSIONS: Our study showed significant reduction in acute skin toxicity using HT-IMRT compared with FiF-IMRT, without significant reduction in late skin toxicities. On the basis of these findings, inverse-planned IMRT could be used in routine practice for whole-breast irradiation with careful plan optimisation to achieve the required dose constraints for organs at risk.

Acute toxicity of hypofractionated intensity-modulated radiotherapy for prostate cancer.

BACKGROUND: Dose-escalated hypofractionated radiotherapy (hfrt) using intensity-modulated radiotherapy (imrt), with inclusion of the pelvic lymph nodes (plns), plus androgen suppression therapy (ast) in high-risk prostate cancer patients should improve patient outcomes, but acute toxicity could limit its feasibility. METHODS: Our single-centre phase ii prospective study enrolled 40 high-risk prostate cancer patients. All patients received hfrt using imrt with daily mega-voltage computed tomography imaging guidance, with 95% of planning target volumes (ptv68 and ptv50) receiving 68 Gy and 50 Gy (respectively) in 25 daily fractions. The boost volume was targeted to the involved plns and the prostate (minus the urethra plus 3 mm and minus 3 mm from adjacent rectal wall) and totalled up to 75 Gy in 25 fractions. Acute toxicity scores were recorded weekly during and 3 months after radiotherapy (rt) administration. RESULTS: For the 37 patients who completed rt and the 3-month follow-up, median age was 65.5 years (range: 50-76 years). Disease was organ-confined (T1c-T2c) in 23 patients (62.1%), and node-positive in 5 patients (13.5%). All patients received long-term ast. Maximum acute genitourinary (gu) and gastrointestinal (gi) toxicity peaked at grade 2 in 6 of 36 evaluated patients (16.6%) and in 4 of 31 evaluated patients (12.9%) respectively. Diarrhea and urinary frequency were the chief complaints. Dose-volume parameters demonstrated no correlation with toxicity. The ptv treatment objectives were met in 36 of the 37 patients. CONCLUSIONS: This hfrt dose-escalation trial in high-risk prostate cancer has demonstrated the feasibility of administering 75 Gy in 25 fractions with minimal acute gi and gu toxicities. Further follow-up will report late toxicities and outcomes.

Recommendations for the referral of patients for proton-beam therapy, an Alberta Health Services report: a model for Canada?

BACKGROUND: Compared with photon therapy, proton-beam therapy (pbt) offers compelling advantages in physical dose distribution. Worldwide, gantry-based proton facilities are increasing in number, but no such facilities exist in Canada. To access pbt, Canadian patients must travel abroad for treatment at high cost. In the face of limited access, this report seeks to provide recommendations for the selection of patients most likely to benefit from pbt and suggests an out-of-country referral process. METHODS: The medline, embase, PubMed, and Cochrane databases were systematically searched for studies published between January 1990 and May 2014 that evaluated clinical outcomes after pbt. A draft report developed through a review of evidence was externally reviewed and then approved by the Alberta Health Services Cancer Care Proton Therapy Guidelines steering committee. RESULTS: Proton therapy is often used to treat tumours close to radiosensitive tissues and to treat children at risk of developing significant late effects of radiation therapy (rt). In uncontrolled and retrospective studies, local control rates with pbt appear similar to, or in some cases higher than, photon rt. Randomized trials comparing equivalent doses of pbt and photon rt are not available. SUMMARY: Referral for pbt is recommended for patients who are being treated with curative intent and with an expectation for long-term survival, and who are able and willing to travel abroad to a proton facility. Commonly accepted indications for referral include chordoma and chondrosarcoma, intraocular melanoma, and solid tumours in children and adolescents who have the greatest risk for long-term sequelae. Current data do not provide sufficient evidence to recommend routine referral of patients with most head-and-neck, breast, lung, gastrointestinal tract, and pelvic cancers, including prostate cancer. It is recommended that all referrals be considered by a multidisciplinary team to select appropriate cases.

Analysis of intraprostatic therapeutic effects in prostate cancer patients using [(11)C]-choline pet/ct after external-beam radiation therapy.

PURPOSE: The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [(11)C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur. METHODS: The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [(11)C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt. RESULTS: Analysis of [(11)C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt. CONCLUSIONS: Our study demonstrated that intraprostatic [(11)C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [(11)C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [(11)C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [(11)C]-choline pet changes as a possible, but currently unproven, biomarker of response.

Quality-of-life outcomes in high-risk prostate cancer patients treated with helical tomotherapy in a hypofractionated radiation schedule with long-term androgen suppression.

PURPOSE: We examined the impact of hypofractionated radiation therapy and androgen suppression therapy (AST) on quality of life (QOL) in high-risk prostate cancer patients. METHODS: Between March 2005 and March 2007, 60 patients with high-risk prostate cancer were enrolled in a prospective phase ii study. All patients received 68 Gy (2.72 Gy per fraction) to the prostate gland and 45 Gy (1.8 Gy per fraction) to the pelvic lymph nodes in 25 fractions over 5 weeks. Of the 60 patients, 58 received ast. The University of California-Los Angeles Prostate Cancer Index questionnaire was used to prospectively measure QOL at baseline (month 0) and at 1, 6, 12, 18, 24, 30, and 36 months after radiation treatment. The generalized estimating equation approach was used to compare the QOL scores at 1, 6, 12, 18, 24, 30, and 36 months with those at baseline. RESULTS: We observed a significant decrease in QOL items related to bowel and sexual function. Several QOL items related to bowel function were significantly adversely affected at both 1 and 6 months, with improvement toward 6 months. Although decreased QOL scores persisted beyond the 6-month mark, they began to re-approach baseline at the 18- to 24-month mark. Most sexual function items were significantly adversely affected at both 1 and 6 months, but the effects were not considered to be a problem by most patients. A complete return to baseline was not observed for either bowel or sexual function. Urinary function items remained largely unaffected, with overall urinary function being the only item adversely affected at 6 months, but not at 1 month. Urinary function returned to baseline and remained unimpaired from 18 months onwards. CONCLUSIONS: In our study population, who received hypofractionated radiation delivered using dynamic intensity-modulated radiotherapy with inclusion of the pelvic lymph nodes, and 2-3 years of ast prescription, QOL with respect to bowel and sexual function was significantly affected; QOL with respect to urinary function was largely unaffected. Our results are comparable to those in other published studies.

The Canadian Association of Radiation Oncology scope of practice guidelines for lung, liver and spine stereotactic body radiotherapy.

AIMS: The Canadian Association of Radiation Oncology-Stereotactic Body Radiotherapy (CARO-SBRT) Task Force was established in 2010. The aim was to define the scope of practice guidelines for the profession to ensure safe practice specific for the most common sites of lung, liver and spine SBRT. MATERIALS AND METHODS: A group of Canadian SBRT experts were charged by our national radiation oncology organisation (CARO) to define the basic principles and technologies for SBRT practice, to propose the minimum technological requirements for safe practice with a focus on simulation and image guidance and to outline procedural considerations for radiation oncology departments to consider when establishing an SBRT programme. RESULTS: We recognised that SBRT should be considered as a specific programme within a radiation department, and we provide a definition of SBRT according to a Canadian consensus. We outlined the basic requirements for safe simulation as they pertain to spine, lung and liver tumours, and the fundamentals of image guidance. The roles of the radiation oncologist, medical physicist and dosimetrist have been detailed such that we strongly recommend the development of SBRT-specific teams. Quality assurance is a key programmatic aspect for safe SBRT practice, and we outline the basic principles of appropriate quality assurance specific to SBRT. CONCLUSION: This CARO scope of practice guideline for SBRT is specific to liver, lung and spine tumours. The task force recommendations are designed to assist departments in establishing safe and robust SBRT programmes.

Impact of sildenafil on marital and sexual adjustment in patients and their wives after radiotherapy and short-term androgen suppression for prostate cancer: analysis of RTOG 0215.

PURPOSE: The Radiation Therapy Oncology Group (RTOG) 0215 investigated the efficacy of sildenafil in improving erectile dysfunction following radiotherapy and neoadjuvant/concurrent androgen deprivation therapy among prostate cancer patients and found a significant improvement on drug but only in 21% of study participants. This paper reports on a secondary aim to investigate the effect of sildenafil on overall sexual and marital adjustment among both patients and their wives. METHODS: RTOG 0215 was a placebo-controlled, double-blind, crossover trial of sildenafil. Participation of wives was optional. Twenty-four married heterosexual couples (33% of heterosexual couples in study) completed the Sexual Adjustment Questionnaire and Locke's Marital Adjustment Test. Treatment differences in mean change scores were evaluated by paired t-tests, and the proportion of patients achieving a clinically meaningful change was evaluated using chi-square tests. Spearman's correlation coefficients were used to determine the association of adjustment between patients and wives. RESULTS: There was no significant change in either sexual or marital adjustment for patients. For wives, there was a trend for improvement in sexual adjustment but no significant change in marital adjustment. Change in marital adjustment between patients and wives was weakly related (r(s) = 0.15, p = 0.48), and for sexual adjustment, there was a moderate, but nonsignificant relationship (r(s) = 0.40, p = 0.09). CONCLUSIONS: Larger studies are warranted to further examine possible differences in sexual experiences and treatment needs between prostate cancer patients and their wives, as well as to assess predictors of sildenafil response.

Adaptive radiotherapy using helical tomotherapy for head and neck cancer in definitive and postoperative settings: initial results.

AIMS: To assess whether routine mid-treatment replanning in head and neck squamous cell carcinoma patients results in meaningful improvements in target or normal tissue dosimetry and to assess which patients derive the greatest benefit. MATERIALS AND METHODS: Twenty patients treated with either postoperative chemoradiotherapy or definitive chemoradiotherapy with primary or nodal disease ≥3cm in size were included in this prospective pilot study. Seven patients received adjuvant chemoradiotherapy and 13 received definitive chemoradiotherapy. Patients were planned and treated on a helical tomotherapy system. All patients had a second computed tomography scan after 15 fractions and a new plan based on this was initiated from fraction 20. RESULTS: Relative volume changes between computed tomography scans were: GTV 29%; CTV60 (adjuvant patients) 4%; parotid volume 17.5%; median reduction in neck separation 6-7 mm; weight loss 3%. For the group overall and for the definitively treated patient cohort, respectively, adapted plans resulted in reductions in PTV66 D(1) (0.3Gy, P=0.01 and 0.5Gy, P=0.01); PTV54 D(1) (0.6Gy, P<0.0001 and 0.9Gy, P=0.0002); spinal cord maximum (0.5Gy, P=0.004 and 0.6Gy, P=0.04) and volume of skin receiving ≥50Gy (16 cm(2), P=0.01 and 19 cm(2), P=0.001). Definitively treated patients also had a reduction in mean parotid dose (0.6Gy, P=0.046) and volume of normal tissue receiving ≥50Gy (67 cm(3), P=0.02). Patients with nasopharyngeal carcinoma received the greatest benefits with treatment adaptation with reduction in spinal cord maximum 1.2Gy, mean parotid dose 1.2Gy and parotid V(26) 6.3%. There was no significant benefit for adjuvant patients. Other factors associated with greater benefits were greater weight loss and greater reduction in neck separation and higher T stage. CONCLUSIONS: There is minimal benefit to routine adaptive replanning in unselected patients, and no benefit in adjuvantly treated patients. Patients with nasopharyngeal carcinoma or with greater weight loss or reduction in neck separation did have clinically significant benefits. These patients should be targeted for adaptive strategies.

Hyperbaric oxygen therapy for late radiation tissue injury in gynecologic malignancies.

BACKGROUND: Late radiation tissue injury is a serious complication of radiotherapy for patients with gynecologic malignancies. Strategies for managing pain and other clinical features have limited efficacy; however, hyperbaric oxygen therapy (HBO(2)) may be an effective option for some patients. METHODS: In a systematic review of the literature, the Ovid medline, embase, Cochrane Library, National Guidelines Clearinghouse, and Canadian Medical Association Infobase databases were searched to June 2009 for clinical practice guidelines, systematic reviews, randomized controlled trials, or other relevant evidence. Studies that did not evaluate soft tissue necrosis, cystitis, proctitis, bone necrosis, and other complications were excluded. RESULTS: Two randomized trials, eleven nonrandomized studies, and five supporting documents comprise the evidence base. In addition, information on the harms and safety of treatment with HBO(2) were reported in three additional sources. There is modest direct evidence and emerging indirect evidence that the use of HBO(2) is broadly effective for late radiation tissue injury of the pelvis in women treated for gynecologic malignancies. CONCLUSIONS: Based on the evidence and expert consensus opinion, HBO(2) is likely effective for late radiation tissue injury of the pelvis, with demonstrated efficacy specifically for radiation damage to the anus and rectum;the main indication for HBO(2) therapy in gynecologic oncology is in the management of otherwise refractory chronic radiation injury;HBO(2) may provide symptomatic benefit in certain clinical settings (for example, cystitis, soft-tissue necrosis, and osteonecrosis); andHBO(2) may reduce the complications of gynecologic surgery in patients undergoing surgical removal of necrosis.

Implications of radiation dosimetry of the mandible in patients with carcinomas of the oral cavity and nasopharynx treated with intensity modulated radiation therapy.

Intensity modulated radiation therapy (IMRT) is a newer method of delivering highly conformal, salivary gland sparing radiation treatment that is finding increasing applications in head and neck malignancies. However, the radiation dose distribution to the mandible is rarely considered with IMRT, and the potential risks of osteoradionecrosis or osseointegrated implant failure are not well characterized for this modality. In a series of 10 patients with oral cavity and nasopharyngeal cancers who previously underwent IMRT, examination of the three-dimensional mandibular dose distribution was undertaken. The findings indicate a modest potential risk of osteoradionecrosis and osseointegrated implant failure in cases where IMRT optimization constraints are not specifically aimed at sparing the mandibular bone. Significantly higher mandibular doses (P < 0.04) were received in cases of oral cavity as opposed to nasopharyngeal cancers with IMRT. Efforts to optimize IMRT to further reduce doses to the mandible should be considered, and development of software tools to integrate three-dimensional dose distributions into planning of post-radiotherapy osseointegration would be beneficial.

Variation in mitochondrial function in hypoxia-sensitive and hypoxia-tolerant human glioma cells.

We have shown previously that human glioblastoma multiforme cells vary in their ability to survive under hypoxic conditions. Under oxygen limiting conditions, hypoxia-tolerant cells decrease their oxygen consumption rate whereas hypoxia-sensitive cells continue to consume oxygen at a relatively steady rate until the oxygen supply becomes exhausted. We now show that hypoxia-tolerant and hypoxia-sensitive cells exhibit distinct patterns of mitochondrial function in response to hypoxic challenge. Hypoxia-tolerant cell lines retain stable mitochondrial membrane potential and ATP concentration when incubated under oxygen limiting conditions. In addition, hypoxia-tolerant cell lines are consistently more sensitive to a wide spectrum of inhibitors of mitochondrial function than are hypoxia-sensitive cells. In contrast, the hypoxia-sensitive cells are unable to maintain stable mitochondrial membrane potential and ATP levels when incubated at reduced oxygen tension. These results demonstrate significant differences in the mitochondrial function between these two phenotypes and reinforce previous data that suggest a regulatory role for mitochondria in the development of hypoxia tolerance.

Muscle-invasive transitional cell carcinoma of the urinary bladder: a population-based study of patterns of care and prognostic factors.

PURPOSE: Population-based cancer registries can permit the study of the survivorship of all patients with a particular diagnosis regardless of patterns of referral and practice within a specific geographic distribution. The purpose of this study is to describe the patterns of care, outcome, and prognostic factors for bladder cancer in the northern region of the province of Alberta, Canada, between 1984 and 1993. METHODS AND MATERIALS: Between 1984 and 1993, 184 patients from northern Alberta were identified from the Alberta Cancer Registry as having undergone curative treatment for biopsy-proven muscle-invasive transitional cell carcinoma of the bladder. Data were obtained, by retrospective chart review, regarding the staging, pathology, treatment, and outcome of patients treated in the northern Alberta cities of Edmonton, Grande Prairie, and Red Deer, regardless of the responsible treating institution. The prognostic significance of patient-, tumor-, and treatment-related variables were tested using univariate and multivariate analysis using the Cox proportional-hazard model. RESULTS: As the primary treatment modality, 74 patients (40%) received radical radiotherapy (RT) without surgery; surgery was used alone in 81 patients (44%), and was combined with preoperative or postoperative radiotherapy in 29 patients (16%). Seventy-three (40%) patients also received concurrent, neoadjuvant, or adjuvant chemotherapy. The Kaplan-Meier estimate of median survival was 2.2 years, and the 5-year overall survival was 30%. Univariate analysis demonstrated the prognostic significance of T classification (p < 0.001), lymph node involvement (p < 0.001), complete response to RT (p = 0.001), hydronephrosis (p = 0.017), and vascular/lymphatic involvement (p = 0.035). Multivariate analysis revealed the following to have a significant association with survival: T classification (p = 0.001), lymph node involvement (p = 0.004), complete response to RT (p = 0.054), hydronephrosis (p = 0.019), and use of chemotherapy in the treatment regimen (p = 0.025). CONCLUSION: The strongest prognostic factors in this study were tumor related, and no significant differences in survival were detected between patients treated with primary surgery vs. organ-preservation approaches. A survival advantage associated with the incorporation of chemotherapy into the management schema was detected on multivariate, but not univariate, analysis. Stratification of patients based on tumor characteristics is imperative in clinical trials for invasive bladder cancer. Novel treatment approaches are required to improve survival further in patients with apparently localized disease.

Concurrent weekly carboplatin and radiotherapy for nasopharyngeal carcinoma: report of a joint phase II study.

We report a phase I/II study of weekly concurrent carboplatin and radiotherapy in patients with nasopharyngeal carcinoma (M0 stage). Of 47 patients registered, 45 completed the treatment course. Twenty-six (55%) (95% CI, 41-69%) patients experienced > or =grade 3 acute toxicity (RTOG). Five (11%) (95% CI, 2-20%) patients experienced > or =grade 3 chronic toxicity. This regimen appears to have acceptable toxicity compared to the experimental arm of Phase III Intergroup Study 0099, but progression-free and overall survival are probably inferior. At present, there is no data to suggest that carboplatin can replace cisplatin for concurrent chemoradiation for NPC.

Vascular endothelial growth factor expression is independent of hypoxia in human malignant glioma spheroids and tumours.

We recently showed that severe hypoxia was not universally present adjacent to necrosis in human glioma xenografts and spheroids established from the M059K, M006, M006X, M006XLo and M010b cell lines. Using these glioma models, we wished to test whether oxygen serves as a regulator of cellular VEGF expression in situ. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to detect vascular endothelial growth factor (VEGF) mRNA and protein expression in sections of glioma xenografts and spheroids in which hypoxic regions and regions with well-oxygenated necrosis were identified on contiguous sections by use of the hypoxia-specific marker, 3H-misonidazole. Independent validation of the presence of radiobiologically hypoxic cells in M006 xenografts was undertaken using the comet assay. Northern blotting analyses of monolayer cells demonstrated significant up-regulation of VEGF mRNA in the M006X line at oxygen concentrations of 6% and below. ISH analysis of VEGF mRNA showed unexpectedly strong staining for VEGF mRNA across the entire viable rim of M006X and M006XLo glioma spheroids. Similarly, in virtually all xenograft tumours of the M059K, M006 and M010b lines, VEGF ISH showed similar staining across all regions of healthy cells up to the border of necrosis. Only in one M006X tumour was there a suggestion of increased VEGF expression in cells adjacent to necrosis. IHC for VEGF showed good concordance with the ISH results. IHC analysis of the VEGF receptor flt-1 showed strong tumour cell staining in M006XLo glioma cells. In human glioma spheroids and xenograft tumours, regions of severe hypoxia do not correspond to areas of up-regulated VEGF expression; in fact, VEGF expression is quite uniform. Furthermore, this and our previous study demonstrate that levels of VEGF expression vary among sublines (M006, M006X and M006XLo) derived from a single human glioma specimen.

Modulation of oxygen consumption rate and vascular endothelial growth factor mRNA expression in human malignant glioma cells by hypoxia.

Cellular responses to hypoxia include modulation of respiration rate and up-regulation of genes which encode for angiogenesis factors. We tested whether human malignant glioma cells vary in their response to hypoxic stress over the range of oxygen concentrations which exist in tumours. In five cell lines tested, decreased oxygen availability resulted in decreased rates of oxygen utilization, however substantial differences in the magnitude of the response were observed. Northern blot analysis was used to study induction of vascular endothelial growth factor mRNA in response to hypoxia. In two cell lines, modest hypoxia increased vascular endothelial growth factor mRNA levels compared with those of aerobic controls. In two additional cell lines, vascular endothelial growth factor mRNA was constitutively expressed under aerobic conditions and was not further increased by hypoxia. These findings demonstrate that differences in the response to hypoxia exist among human malignant glioma cell lines and suggest that therapies designed to exploit tumour hypoxia may have varying effects in tumours with different hypoxic stress responses.

Addition of chemotherapy to radiation therapy alters failure patterns by cell type within non-small cell carcinoma of lung (NSCCL): analysis of radiation therapy oncology group (RTOG) trials.

PURPOSE: To evaluate the influence of cell type within non-small cell carcinoma of lung (NSCCL) on failure patterns when chemotherapy (CT) is combined with radiation therapy (RT). METHODS AND MATERIALS: Data from 4 RTOG studies including 1415 patients treated with RT alone, and 5 RTOG studies including 350 patients also treated with chemotherapy (RT + CT) were analyzed. Patterns of progression were evaluated for squamous cell carcinoma (SQ) (n = 946), adenocarcinoma (AD) (n = 532) and large cell carcinoma (LC) (n = 287). RESULTS: When treated with RT alone, SQ was more likely to progress at the primary site than LC (26% vs. 20%, p = 0.05). AD and LC were more likely to progress in the brain than SQ (20% and 18% vs. 11%, p = 0.0001 and 0.011, respectively). No differences were found in intrathoracic and distant metastasis by cell type. When treated with RT + CT, AD was less likely to progress at the primary than either SQ or LC (23% vs. 34% and 40%, respectively; p = 0.057 and 0.035). AD was more likely than SQ to metastasize to the brain (16% vs. 8%, p = 0.03), and other distant sites (26% vs. 14%,p = 0.019). No differences were found in intrathoracic metastasis. LC progressed at the primary site more often with RT + CT than with RT alone (40% vs. 20%, p = 0.036). Death with no clinical progression was more likely with SQ than AD or LC for RT alone and RT + CT (p < 0.01). Brain metastasis was altered little by the addition of CT, but other distant metastases were significantly decreased (p < 0.001) in all cell types by the addition of CT. CONCLUSION: CT, although effective in reducing distant metastasis in all types of NSCCL, has different effects on the primary tumor by cell type, and has no effect on brain metastasis or death with no progression. Different treatment strategies should be considered for the different cell types to advance progress with RT + CT in NSCCL.

Variable presence of hypoxia in M006 human glioma spheroids and in spheroids and xenografts of clonally derived sublines.

Recently we reported the variable presence of hypoxia adjacent to necrosis in human glioma lines grown as subcutaneous tumours in severe combined immunodeficient (SCID) mice. To assess the basis for this observation, we examined the pattern of oxygenation in M006 and M006XLo glioma spheroids. We found a wide range of binding of [3H]misonidazole to cells adjacent to the necrotic core, analogous to the patterns seen in xenografts, indicating substantial differences in the central oxygen tension of the spheroids. Clonal selection was used to isolate single cell-derived sublines of the M006XLo line. Some sublines gave spheroids that showed narrow distributions of [3H]misonidazole binding to the cells adjacent to necrosis, whereas other sublines showed a range of binding similar to that seen in spheroids of the parent line. After additional passages in monolayer culture, clonal sublines occasionally gave rise to spheroids in which the mean oxygen tension of cells adjacent to necrosis differed substantially from that of the initial spheroids. No relationship was evident between the thickness of the rim of viable cells and the presence or absence of central hypoxia, over a wide range of rim thickness. These results indicate that different oxygenation characteristics of glioma spheroids and tumour microregions are unlikely to arise from stable genetic variants coexisting in the parent line.

Failure patterns by prognostic group determined by recursive partitioning analysis (RPA) of 1547 patients on four radiation therapy oncology group (RTOG) studies in inoperable nonsmall-cell lung cancer (NSCLC).

PURPOSE: To identify groups of patients who might benefit from more aggressive systemic or local treatment, based on failure patterns when unresectable NSCLC was treated by radiation therapy (RT) alone. METHODS: From 4 RTOG trials, 1547 patients treated by RT alone were analyzed for patterns of first failure by RPA class defined by prognostic factors, including KPS, weight loss, nodal stage, pleural effusion, age and radiation therapy dose. All patients had NSCLC AJCC Stage II, IIIA, or IIIB, KPS > 50, with no previous RT or chemotherapy. Progressions in the primary (within irradiated fields), thorax (outside irradiated area, but within thorax), brain and distant metastasis other than brain were compared (2-sided) for each failure category by RPA. RESULTS: The RPA classes were 4 distinct subgroups that had significantly different median survivals of 12.6, 8.3, 6.3 and 3.3 months for Classes I, II, III and IV, respectively, (all groups, p = 0.0002). There were 583, 667, 249 and 48 patients in Classes I, II, III and IV, respectively. Primary failure was seen in 27%, 25%, 21% and 10% for Classes I, II, III, and IV, respectively (I vs. IV, p = 0.014; II vs. IV, p = 0.022). Distant metastasis, including brain metastasis, occurred at significantly higher rates among Classes I and II (58% and 54%) than in Classes III and IV (42% and 27%). A higher rate (58%) of death without an identifiable site of failure was found in Class IV than in Classes I, II and III (27%, 28% and 36%, respectively). CONCLUSIONS: The data suggest that physiologic compromise from the intrathoracic disease in Class IV patients is sufficient to cause death before specific sites of failure became evident. Clinical investigations using treatments directed at specific sites of failure could lead to improved outcome for Class I, II and, possibly, Class III patients. Inclusion of Class IV patients in clinical trials may obscure outcomes.

Anomalous patterns of nitroimidazole binding adjacent to necrosis in human glioma xenografts: possible role of decreased oxygen consumption.

In contrast to reports of extensive hypoxia in human gliomas in situ measured by pO2 histography, non-invasive methods of assessing glioma oxygenation, including nitroimidazole binding, have yielded surprisingly contradictory results. In order to investigate the relationship of necrosis, hypoxia, nitroreductase activity and cellular respiration in human gliomas, subcutaneous models using the human glioma cell lines M059K, M006 and M010b were developed in the murine SCID host. Intracranial growth of the M006 line was achieved in nude rats. The nitroreductive capacity of glioma cell lines was assessed and found to be similar to transplanted tumours previously reported in the literature. This suggests that if substantial numbers of viable hypoxic cells were present in situ in gliomas, then nitroimidazole-binding techniques should be capable of identifying them. Inter-tumour variability in the amount of necrosis was seen. M006 xenografts growing in subcutaneous and intracranial sites revealed extensive necrotic regions histologically, some of which were surrounded by cells labelled heavily for [3H]misonidazole, while other areas were lightly labelled. Similar binding patterns were seen for subcutaneous M059K tumours, while subcutaneous M010b tumours display necroses of which almost all were surrounded by heavily labelled cells. The oxygen consumption rates of tumour cell lines grown in vivo, in which venous pO2 concentrations are of the order of 2-5%, were two to sevenfold less than those of the same lines grown as monolayers in vitro under oxygen concentrations of 18%. We postulate that glioma cell lines behave as 'oxygen conformers', in that their rate of oxygen consumption appears to vary with the availability of oxygen. Together with the misonidazole-binding data, the results in this glioma tumour model are consistent with coordinate inhibition or down-regulation of respiration under moderate hypoxia.

Measurement of hypoxia in human tumours by non-invasive spect imaging of iodoazomycin arabinoside.

Tumour oxygenation status in individual patients may be assessed using the bioreduction and linkage of 2-nitroimidazole markers to viable hypoxic cells in vivo with subsequent detection by conventional nuclear medicine techniques. Iodoazomycin arabinoside (IAZA) was radiolabelled with Iodine-123 and administered i.v. to 51 patients with newly diagnosed malignancies whose tumours were subsequently imaged by planar and single-photon emission computed tomographic (SPECT) procedures. Quantitative analyses of radiotracer avidity were performed at 24 h post-injection and tumour-normal tissue ratios of greater than 1.10 were deemed positive for tumour hypoxia. By this criterion, the frequencies of hypoxia in small-cell lung cancer, squamous cell carcinomas of head and neck and malignant gliomas were 60% (9/15), 40% (6/15) and 0% (0/11) respectively. The correlation of positive IAZA scans with tumour control and survival in patients with lung cancer and head and neck tumours is currently under study. Preliminary observations in neck metastases from squamous cell carcinoma of head and neck tumours indicates decreased local control at 3 months post-treatment in tumours with IAZA avidity. This study concludes that: (1) 123I-IAZA can be administered safely and repeatedly as an outpatient routine imaging procedure in cancer patients during initial work-up and follow-up; (2) that retained drug can be detected by conventional nuclear medicine procedures in inaccessible deep-seated tumours; and (3) that this technique could prove useful for identifying those patients for whom hypoxia-directed therapy is indicated.