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Although neutrophil migration from the systemic circulation involves the beta2- (or CD18) integrin family, the existence of an alternative, CD18-independent route of neutrophil extravasation to tissues has been demonstrated in animal models. The molecular interactions involved in this alternative migratory route have not yet been characterized. The objective of this study was to assess the CD18-dependency of neutrophil migration across human endothelial cells from an organ known to support CD18-independent migration, the lung, with a view to establishing an in vitro model to facilitate study of CD18-independent migration. Neutrophil migration across human pulmonary artery endothelial cells (HPAECs) in response to three different chemoattractants, formylmethionyl leucylphenyl-alanine (FMLP), interleukin (IL)-8, and leukotriene (LT) B(4), was examined. Results demonstrated that a function-blocking antibody to CD18 decreased FMLP-stimulated migration by 71.7 +/- 4.4% (P < 0.001). In contrast, migration in response to LTB(4) was decreased by only 20.5 +/- 10.2% (P < 0.01), and no significant decrease was observed with migration to IL-8. Neutrophils that migrated to FMLP had 1.7-fold more surface CD11b/CD18 compared with nonmigrated neutrophils (P < 0.01), whereas this integrin complex was not significantly upregulated on neutrophils that had migrated to IL-8 or LTB(4). Further investigation of this migratory route indicated that it did not involve the beta1 integrins (CD29) or the endothelial selectins, E- or P-selectin, nor did it require the activity of either metalloproteinases or neutrophil elastase. These results indicate that neutrophil migration across HPAECs in vitro to IL-8 and LTB(4) is predominantly CD18-independent and provides a much-needed in vitro system for examination of the neutrophil-endothelial interactions involved in this alternative migratory route.

Purpose: To test the hypothesis that the expression of potentially lethal damage (PLD) is a p53-dependent process., Materials and Methods: Previously reported data on radiation sensitivity, DNA double-strand break rejoining, PLD expression and repair (PLDR) were analyzed for a group of 12 human tumor cell lines and three human diploid fibroblast cell lines. Seven of these cell lines had normal p53 gene expression while the other eight were functionally p53-deficient. None of the cell lines was sensitive to radiation-induced apoptosis., Results: Cell lines with a normal p53 expression were more sensitive to radiation, but only when sensitivity was measured in plateau-phase cultures under conditions where PLDR was minimized. Mutation or functional inactivation of p53 by HPV E6-transformation led to a more radioresistant phenotype under these conditions as well as a significant reduction in PLDR. PLDR was inversely proportional to the percentage of radiation-induced DNA double-strand breaks rejoined in 1 h in the p53 normal cell lines., Conclusions: These results suggest that the expression of PLD is primarily a p53-dependent process. In the absence of functional p53 gene expression, the effects of PLD are minimized. These observations help clarify the role of p53 in tumor response to radiation therapy because they suggest that the effects of alterations in p53 are highly dependent on the microenvironment of the tumor, i.e. whether conditions allow for PLDR.

Purpose: A prospective Phase I dose escalation study was conducted to determine the maximally-tolerated radiation dose in men treated with three-dimensional conformal radiation therapy (3D CRT) for localized prostate cancer. This is a preliminary report of toxicity encountered on the 3DOG/RTOG 9406 study., Methods and Materials: Each participating institution was required to implement data exchange with the RTOG 3D quality assurance (QA) center at Washington University in St. Louis. 3D CRT capabilities were strictly defined within the study protocol. Patients were registered according to three stratification groups: Group 1 patients had clinically organ-confined disease (T1,2) with a calculated risk of seminal vesicle invasion of < 15%. Group 2 patients had clinical T1,2 disease with risk of SV invasion > or = 15%. Group 3 (G3) patients had clinical local extension of tumor beyond the prostate capsule (T3). All patients were treated with 3D techniques with minimum doses prescribed to the planning target volume (PTV). The PTV margins were 5-10 mm around the prostate for patients in Group 1 and 5-10 mm around the prostate and SV for Group 2. After 55.8 Gy, the PTV was reduced in Group 2 patients to 5-10 mm around the prostate only. Minimum prescription dose began at 68.4 Gy (level I) and was escalated to 73.8 Gy (level II) and subsequently to 79.2 Gy (level III). This report describes the acute and late toxicity encountered in Group 1 and 2 patients treated to the first two study dose levels. Data from RTOG 7506 and 7706 allowed calculation of the expected probability of observing a > or = grade 3 late effect more than 120 days after the start of treatment. RTOG toxicity scores were used., Results: Between August 23, 1994 and July 2, 1997, 304 Group 1 and 2 cases were registered; 288 cases were analyzable for toxicity. Acute toxicity was low, with 53-54% of Group 1 patients having either no or grade 1 toxicity at dose levels I and II, respectively. Sixty-two percent of Group 2 patients had either none or grade 1 toxicity at either dose level. Few patients (0-3%) experienced a grade 3 acute bowel or bladder toxicity, and there were no grade 4 or 5 toxicities. Late toxicity was very low in all patient groups. The majority (81-85%) had either no or mild grade 1 late toxicity at dose level I and II, respectively. A single late grade 3 bladder toxicity in a Group 2 patient treated to dose level II was recorded. There were no grade 4 or 5 late effects in any patient. Compared to historical RTOG controls (studies 7506, 7706) at dose level I, no grade 3 or greater late effects were observed in Group 1 and Group 2 patients when 9.1 and 4.8 events were expected (p = 0.003 and p = 0.028), respectively. At dose level II, there were no grade 3 or greater toxicities in Group 1 patients and a single grade 3 toxicity in a Group 2 patient when 12.1 and 13.0 were expected (p = 0.0005 and p = 0.0003), respectively. Multivariate analysis demonstrated that the relative risk of developing acute bladder toxicity was 2.13 if the percentage of the bladder receiving > or = 65 Gy was more than 30% (p = 0.013) and 2.01 if patients received neoadjuvant hormonal therapy (p = 0.018). The relative risk of developing late bladder complications also increased as the percentage of the bladder receiving > or = 65 Gy increased (p = 0.026). Unexpectedly, there was a lower risk of late bladder complications as the mean dose to the bladder and prescription dose level increased. This probably reflects improvement in conformal techniques as the study matured. There was a 2.1 relative risk of developing a late bowel complication if the total rectal volume on the planning CT scan exceeded 100 cc (p = 0.019)., Conclusion: Tolerance to high-dose 3D CRT has been better than expected in this dose escalation trial for Stage T1,2 prostate cancer compared to low-dose RTOG historical experience. With strict quality assurance standards and review, 3D CRT can be safely studied in a co

Background: General practitioner (GP) referral letters for emergency medical admissions should contain enough information to ensure that patients are managed safely and effectively., Aim: Our aim was to assess the quality of referral letters for acute medical admissions., Method: GP letters from 300 consecutive acute medical admissions were prospectively assessed by the admitting doctor and then independently assessed by a senior house officer (SHO), and a senior registrar. A random sample of 25 were assessed by a general practitioner. Content and legibility were evaluated for demographic details, current history, past history, social history, drugs and allergies, in order to grade the overall quality as "excellent", "good", "adequate" or "inadequate"., Results: Two hundred and ninety one letters were received, of which 208 (71%) were from the patients' own GP practice and 83 (28%) from a co-operative or deputising service. The admitting doctor rated 38 (13%) as excellent, 108 (37%) as good, 96 (33%) as adequate and 49 (17%) as inadequate. Kappa values for overall quality between the admitting doctors and the other doctors (senior house officer, senior registrar and our general practitioner) were 0.32, 0.26 and 0.44 respectively, representing fair to moderate interobserver agreement. Co-operatives or deputising services used proformas more often than GP practices (65/83, 78% and 17/208, 8% respectively, p < 0.01). There was no significant difference in overall quality between GP practices and co-operatives or deputising services, or between letters received on headed note paper or proformas., Conclusion: Most letters are satisfactory for the individual management of acutely ill patients, but collaborative work could usefully be undertaken to address the factors which result in the production of sub-optimal referral letters.

It has long been speculated that neutrophils deploy proteases to digest subendothelial matrix as they migrate from the bloodstream. Direct evidence for the involvement of proteases in neutrophil transendothelial migration is, however, lacking. To address this issue we used transmission electron microscopy to verify the presence of continuous basal lamina beneath pulmonary endothelial cells grown on microporous filters, and then examined the effects of protease inhibitors on neutrophil migration through the endothelial cells and their associated subcellular matrix. Inhibitors of the two major matrix-degrading protease groups present in neutrophils, the matrix metalloproteinases (MMPs) and serine proteases, were assessed for their ability to modulate neutrophil transendothelial migration in response to the chemoattractant n-formylmethionyl leucylphenylalanine (FMLP). Neither the naturally occurring MMP inhibitor, tissue inhibitor of metalloproteinase-1, nor the hydroxamic acid-based inhibitors GM-6001, BB-3103, or Ro 31-9790 had any significant effect on FMLP-stimulated neutrophil migration across endothelial cells and associated basal lamina, with >/= 80% of neutrophils migrating through the system, even in the presence of inhibitors, at concentrations that totally inhibited all the gelatinase B (MMP-9) released upon stimulation with FMLP. Similarly, with serine protease inhibitors no significant inhibition of neutrophil migration was observed with a naturally occurring inhibitor, secretory leukocyte protease inhibitor, or a low molecular-weight synthetic inhibitor, Pefabloc SC. These results indicate that neither MMP nor serine protease digestion of sub-endothelial matrix is required for successful neutrophil transendothelial migration.

The influence of expression of TP53 (formerly known as p53) on the induction of chromosome aberrations by gamma rays was examined in an isogenic pair of human tumor cell lines where TP53 expression was normal or inactivated by human papillomavirus (HPV) type 16 E6 expression. Plateau-phase cultures were exposed to 0-8 Gy gamma rays and then either immediately released by subculture or held for 24 h prior to subculture and subsequent cytogenetic analysis. Aberration frequency was determined only in cells entering their first mitosis after irradiation, and cells were sampled over a 48-h period to include cells whose progression into mitosis was delayed. While aberration frequencies were similar at early harvest times, there was evidence for a subpopulation of more heavily damaged cells in the E6-transformed cells that cycled into late mitosis. Holding cells noncycling for 24 h to allow repair of potentially lethal damage eliminated this subpopulation of more heavily damaged cells. The E6-transformed cells also had higher levels of chromatid-type aberrations and sister chromatid exchanges, consistent with an additional defect in kinetics of repair of base damage that is associated with the E6 transformation. Holding cells noncycling for 24 h eliminated the elevated levels of chromatid-type aberrations and sister chromatid exchanges. These studies demonstrate that E6 transformation of human tumor cells will influence both the frequency and types of chromosome aberrations observed after radiation exposure, and that these effects are related to the expression of potentially lethal damage.

Purpose: To examine the effect of functional loss of p53 on radiation sensitivity and potentially lethal damage repair (PLDR)., Materials and Methods: Radiation sensitivity and PLDR were examined in an isogenic pair of human tumour cell lines created by HPV-E6 transformation., Results: Inactivation of p53 by E6 transformation resulted in a cell line that was more resistant to killing by radiation but showed little enhancement in survival (PLDR) when plateau-phase cells were held non-cycling after radiation exposure. Holding p53-normal cells in plateau-phase after radiation exposure not only led to enhanced survival, but also to a reduction in the proportion of cells that blocked in G1 subsequent to release., Conclusions: These results suggest that p53 expression influences that component of radiation sensitivity associated with PLDR.

The ion, energy, lipid, nitrogen and fat-soluble vitamin contents of freshly ovulated eggs and neonates of the viviparous lizard Niveoscincus metallicus were measured to quantify uptake of nutrients across the placenta. This species is particularly interesting because it has a chorio-allantoic placenta that is intermediate in complexity compared to viviparous species that have been the focus of other studies. Newly ovulated eggs have a wet mass of 79.6+/-4.6 mg and a dry mass of 41.8+/-2.8 mg, compared to the neonates that have a wet mass of 224.2+/-8.2 mg and dry mass of 37.9+/-1.2 mg. Thus, there is no significant net uptake of dry matter across the placenta. Neonates have significantly less lipid (6.2+/-0.4 mg) than eggs (12.7+/-0.5 mg), but no significant difference in nitrogen (4.1+/-0.3 mg) compared to eggs (4.5+/-0.2 mg). Energy densities reflect the protein and lipid composition and the relative dry masses of the eggs and neonates. There is significantly more energy (1029.1+/-80.0 J) in the egg than in the neonate (858.2+/-38.6 J). The increase in the ash content of the neonates (2.9+/-0.2 mg) compared to fresh eggs (2.1+/-0.3 mg) was not significant, even though there was an approximately threefold increase in the amount of sodium (0.11+/-0.01 mg in neonates, 0.34+/-0.01 mg in eggs) and potassium (0.12+/-0.017 in neonates, 0.40+/-0.01 mg in eggs) in neonates compared to eggs. There was no significant uptake of calcium and magnesium during development. The egg lipids consisted of triacylglycerol (66.7+/-2.3 %), phospholipid (18.9+/-0.7 %), cholesteryl ester (4.9+/-1.6 %) and free cholesterol (5.6+/-1.5 %). The egg phospholipid contained comparatively high proportions of arachidonic and eicosapentanoic acids but low levels of docosahexaenoic acid (DHA), whereas the phospholipid of the neonate was greatly enriched in DHA. In the egg, the predominant vitamin E was (&agr;)-tocopherol (62.6+/-3.4 mg g(-)(1)), although there was some (&ggr;)-tocotrienol (3.5+/-0.3 mg g(-)(1)), and vitamin A was present (1.5+/-0.2 mg g(-)(1)). The ratio of neonate dry mass to egg dry mass of N. metallicus (0.91) lies between that of species with type I (0.78) and type III (1.70) chorio-allantoic placentae, confirming our conclusion that the placenta of N. metallicus is functionally intermediate, as well as intermediate in complexity, between these other two types.

Purpose: To evaluate the effectiveness of neutron beam radiotherapy (NXRT) to treat recurrent prostate cancer following radical prostatectomy (RP)., Methods and Materials: Twenty-five patients who failed RP received NXRT at our institution. The pathological stages ranged from T2c-T3c, with 16 patients having either seminal vesicle involvement and/or nodal metastases. Sixteen patients also received neoadjuvant hormones. Freedom from relapse (FFR) was defined by an undetectable PSA (PSA < or =0.2). Median follow-up was 27 months, with no patients lost to follow-up., Results: Postneutron PSA became initially undetectable in 84% of patients. The actuarial FFR is 36% at 3 years. Nine patients remain NED, 12 patients have an elevated PSA only, 2 patients have clinical recurrence, and 2 patients are dead of prostate cancer. Pre-NXRT PSA levels of < or =1.0 vs. >1.0 predicted for outcome, with a FFR at 3 years of 76 vs. 14% (p = 0.003). Patients with a persistently elevated PSA following RP were not effectively salvaged by NXRT, with a 12% FFR at 3 years compared to a 62% FFR for patients whose PSA initially normalized following RP (p = 0.03). There was no difference in treatment outcomes based on fields encompassing pelvic nodes vs. fields directed to the prostatic fossa only. There were no severe (RTOG Grade 3) late complications., Conclusion: NXRT is an effective salvage treatment for carefully selected patients. This group includes patients whose PSA initially normalized following RP, and whose pre-NXRT PSA < or =1.0.

The neutrophil-dominated inflammation of the lung in cystic fibrosis (CF) has traditionally been seen as a physiological response to continuous opportunistic infection. Recent studies suggest, however, that regulation of the inflammatory response itself may be altered in CF. Neutrophil migration from the bloodstream involves alterations in surface expression of the adhesion molecules L-selectin and Mac-1 (CD11b/CD18). The aim of this study was to assess neutrophil adhesion molecule expression and responsiveness in CF. Neutrophils from chronic (n = 16) and acutely infected (n = 13) CF patients and 15 normal control subjects were directly assessed by Fluorescence-activated cell sorter (FACS) analysis for surface expression of L-selectin and CD11b before and after stimulation with interleukin 8 (IL-8) or f-Met-Leu-Phe (fMLP). Neutrophils from stable (n = 5) and acutely infected (n = 5) non-CF bronchiectasis patients were also assessed. Surface upregulation of CD11b was similar in all groups. Basal levels of L-selectin were also comparable among all groups, however, when stimulated, neutrophils from both stable and acutely infected CF patients shed significantly less L-selectin than those from control subjects (p < 0.05 and p < 0.01, respectively). This decreased responsiveness was not observed in either stable or acutely infected non-CF bronchiectasis patients. These results add to the accumulating evidence suggestive of a defective inflammatory response in CF.

Primary tumor control remains a major problem in the treatment of locally advanced prostate carcinoma. Clinical local failure rates approach 30-40% and may be significantly higher when results of prostatic biopsy or prostate-specific antigen (PSA) levels are considered. The low growth rate and cycling fraction of prostate adenocarcinoma suggest potential therapeutic advantage for the high linear energy transfer (LET) of neutrons. The Radiation Therapy Oncology Group (RTOG) performed a multi-institutional randomized trial (RTOG 77-04) comparing mixed beam (neutron plus photon) irradiation to conventional photon irradiation for the treatment of locally advanced prostate cancer. A subsequent trial by the Neutron Therapy Collaborative Working Group (NTCWG 85-23) compared pure neutron irradiation to standard photon irradiation. Both randomized trials demonstrate significant improvement in locoregional control with neutron irradiation compared to conventional photon irradiation in the treatment of locally advanced prostate carcinoma. To date, only the mixed beam trial has shown a significant survival benefit. Future analysis of the larger NTCWG trial at the 10-year point should confirm whether or not improved locoregional control translates into a survival advantage. These findings have significant implications for all local treatment strategies including dose-escalated conformal photon irradiation, prostate implantation, and neutron radiation. Given the large numbers of patients afflicted with this disease, a positive survival advantage for neutrons or mixed beam therapy would provide a strong incentive for the development of economically feasible clinical neutron facilities.

The aim of this study was to examine the hypothesis that alveolar macrophages represent a significant source of matrix-degrading proteinases in the emphysematous lung. Macrophages from bronchoalveolar lavage fluid of 10 patients with emphysema and 10 normal volunteers were maintained in vitro for 24 h and assessed semiquantitatively for mRNA transcript levels of the matrix metalloproteinases (MMPs) gelatinases A and B, macrophage metalloelastase (MME), and interstitial collagenase. Release of these MMPs into the culture medium and secretion of neutrophil elastaselike activity was also assessed. Elevated levels of mRNA transcripts for gelatinase B (p < 0.0005) and interstitial collagenase (p < 0.0005) were observed in macrophages from emphysematous patients. Increased collagenase (p < 0.01) and neutrophil elastaselike activities (p < 0.001) were also measured in conditioned medium from patient macrophages. With gelatinase B, complexed forms of the enzyme were secreted by patient but not by control macrophages. No difference in transcript levels of gelatinase A or MME was observed between patient and control samples, and neither enzyme was detected in macrophage-conditioned media from either group. These results directly demonstrate that alveolar macrophages from the emphysematous lung produce elevated quantities of matrix-degrading enzymes with both elastolytic and collagenolytic activities.

Background: Matrix degradation in emphysema has long been attributed to the action of neutrophil elastase (NE). More recently a role for other proteases, particularly the matrix metalloproteinases (MMPs), in the pathogenesis of this disease has been proposed. To date, however, the presence of MMPs in the lungs of patients with emphysema has not been demonstrated., Methods: Samples of bronchoalveolar lavage (BAL) fluid from 10 patients with emphysema and from control subjects matched for sex and current smoking status were assessed for collagenase, gelatinase, and NE activity. Pulmonary function tests and computed tomographic (CT) scans were carried out on all study subjects., Results: Collagenase activity was detected in BAL fluid samples from all emphysematous patients but in only one smoking control (p < 0.001). Gelatinase B was present in six patients and in two smoking controls (p < 0.03). The concomitant presence of gelatinase B in complex with lipocalin (NGAL) in the gelatinase positive samples suggests that the neutrophil is a significant source of the gelatinase B observed. NE was detected in six of the 10 patients with emphysema and in two smoking controls (p < 0.01), indicating that collagenase was more useful in discriminating between disease and control groups than either NE or gelatinase B. No relationship was observed between any of the enzymes measured and pulmonary function or CT density score., Conclusions: This study demonstrates, for the first time, the presence of increased levels of matrix metalloproteinases in the lungs of patients with emphysema and suggests that, in BAL fluid, collagenase activity may be a better indicator of the presence of emphysema than elastase.

Purpose: To develop a checkpoint-based strategy for preferential radiosensitization of human tumors with deficient and/or mutant p53., Methods and Materials: A549 human lung adenocarcinoma cell lines differing in their expression of the p53 tumor suppressor gene were produced by transduction with the E6 oncogene from human papilloma virus type 16. The cells expressing E6 (E6+) lack a G1 arrest in response to ionizing radiation, are deficient in p53 and p21 expression, and exhibit a fivefold greater clonogenic survival following 10 Gy radiation., Results: Postirradiation incubation with millimolar concentrations of the methylxanthine pentoxifylline (PTX) results in preferential radiosensitization of the E6+ cells compared to the LXSN+ vector transduced controls. There is a threefold sensitization of the LXSN+ cells and a 15-fold sensitization of the E6+ cells, which results in equal clonogenic survival of the two lines. Flow cytometry reveals PTX abrogation of the radiation induced G2 arrest for both cell lines. PTX also prolongs G1 transit for both cell lines. Preliminary results are presented using a novel methylxanthine, lisofylline (LSF), which has similar cell cycle effects on G1 and G2 and achieves differential radiosensitization at micromolar concentrations that are sustainable in humans., Conclusion: This checkpoint-based strategy is a promising approach for achieving preferential radiosensitization of p53- tumors relative to p53+ normal tissues.

The development of clinical neutron facilities in the 1980s, capable of delivering high energy neutrons spurred full scale phase III testing of neutron beam radiotherapy in a number of tumors including salivary gland, head and neck, prostate, and non small-cell lung cancer. The Radiation Therapy Oncology Group (RTOG) and the Medical Research Council (MRC) jointly sponsored a randomized trial for the treatment of advanced stage salivary gland tumors comparing neutron to conventional photon and/or electron radiotherapy. Although no improvement in survival was seen, the study demonstrated a striking and statistically significant difference in the local-regional control of unresectable salivary gland tumors (56 vs 17%), favoring neutron beam irradiation. Subsequent clinical trials of neutron beam irradiation were initiated by the Neutron Therapy Collaborative Working Group (NTCWG) sponsored by the National Cancer Institute (NCI). A phase III trial comparing neutron to photon radiotherapy for inoperable regional non-small cell lung cancer showed no overall improvement in survival. However, a statistically significant improvement in survival was observed in the subset of patients with squamous cell histology. The NTCWG trial comparing fast-neutron therapy versus conventional photon irradiation in the treatment of advanced squamous cell carcinomas of the head and neck showed a statistically significant improvement in initial complete response (70 vs 52%) favoring neutrons. However, subsequent failures erased any difference in ultimate local-regional control rates and survival curves were essentially the same in both arms. The randomized study of the NTCWG for locally advanced prostate cancer demonstrated a significant decrease in local-regional failure (11 vs 32%) at 5 years, favoring the neutron arm. Furthermore, biochemical measures of disease control also favored the neutron arm with prostate specific antigen (PSA) levels elevated in 17% of the neutron-treated patients compared to 45% of the photon-treated patients at 5 years. At the 5-year analysis, no significant difference in survival was observed between the two arms; however, longer follow-up is necessary to assess the ultimate impact of improved local-regional control on survival. An analysis of complications in this series revealed the importance of beam shaping and treatment planning capabilities in maintaining long-term sequelae following neutron irradiation at an acceptably low level.

We have examined the effect of abrogation of the G2 checkpoint on the radiosensitivity of G1 checkpoint-proficient and G1 checkpoint-deficient cells. A549 human lung adenocarcinoma cells were transduced with the E6 oncogene of the human papillomavirus type 16 to eliminate their radiation-induced G1 arrest. These E6+ cells exhibited a dose-dependent increase in radiation resistance compared to control A549 cells transduced with the vector alone. Treatment (96 h) with 2 mM caffeine resulted in an abrogation of the cellular G2 checkpoint in both E6+ and control cells and a differential radiosensitizing effect on the two cell lines such that the E6+ clones and the vector controls became equally radiosensitive. These data show that human tumors which are radioresistant due to the loss of the p53-mediated G1 checkpoint can be made radiosensitive by abrogation of the G2 checkpoint. The implications of these results for cancer therapy are discussed.

Purpose: There is currently substantial clinical interest in pentoxifylline as an inhibitor of radiation-related normal tissue injury. To further assess this drug's potential toxicity-sparing effects, pentoxifylline was studied in rats using a radiation-induced lung injury model., Methods and Materials: Adult male rats were exposed to either sham irradiation or a single fraction of 21 Gy delivered to the left hemithorax. Four study groups were defined: those that received neither radiation nor pentoxifylline, those that received pentoxifylline (500 mg/L in drinking water) but no irradiation, those that underwent irradiation without pentoxifylline, and those that received both pentoxifylline and radiation. Lung injury was measured by changes in relative left:right lung perfusion ratios derived from quantitative gamma camera imaging of 99mTechnetium-macroaggregated albumin uptake in the pulmonary circulation. Serial scans were done over a 40-week period following radiation. Skin toxicity was also assessed. After 40 weeks, the animals were killed, and lung tissue was assayed for angiotensin converting enzyme activity as a marker for endothelial cell damage., Results: Both groups of radiated (with or without pentoxifylline) rats showed equivalent acute sharp decreases in left:right lung perfusion ratios compared to the nonirradiated groups, reaching a mean nadir value of 0.29 at week 4. Irradiated lung perfusion in subsequent weeks in the radiation-only group showed minimal recovery, with a plateau mean ratio of 0.37 (0.36-0.39). However, there was apparent later recovery of lung perfusion in the radiation with pentoxifylline group from weeks 14 through 40, to a mean ratio of 0.47 (0.43-0.52) (p < 0.01 compared to the radiation-only group). Angiotensin converting enzyme activity correlated closely with lung perfusion data. No effect of pentoxifylline on acute or late skin toxicity was detected., Conclusions: This study suggests that pentoxifylline does not have any measurable effect on acute lung injury following hemithoracic irradiation in rats, but does result in sparing of later lung toxicity.

An overview of the University of Washington neutron radiotherapy facility is presented. The utility of the multi-leaf, programmable, variable collimator is emphasized. Due to success in the treatment of salivary gland tumors, such patients comprise an ever increasing portion of the patients being treated. A cooperative randomized clinical trial for the treatment of salivary gland tumors was undertaken comparing fast neutrons against photon/electron radiation. At ten years, there was a statistically significant improvement in local/regional control for the neutron group (56% vs 25%, p = 0.009), but there was no improvement in survival (15% vs 25%, p = n.s.). Distant metastases were the primary reason for the failure of improved local/regional control to impact survival in the neutron group. The University of Washington experience is summarized with special emphasis on the treatment of adenoid cystic carcinomas. Excellent local/regional control can be achieved with neutrons even for large tumors arising in the paranasal sinuses. We conclude that the potential morbidity of a surgical debulking procedure is not warranted in most clinical situations.

Purpose: To evaluate the effectiveness of fast neutron radiation therapy in treatment of locally advanced carcinomas of the prostate., Methods and Materials: From April 1986 to October 1990, 178 patients were entered on a prospective, multi-institutional randomized study of the NCI-sponsored Neutron Therapy Collaborative Working Group. This trial compared external beam photon irradiation (7000-7020 cGy) with external beam neutron irradiation (2040 ncGy) for patients with high-grade T2 or T3-4, N0-1, M0 adenocarcinomas of the prostate. Eighty-nine patients were randomized to each treatment. Six patients were subsequently judged to be ineligible, leaving 85 photon and 87 neutron randomized patients eligible for analysis., Results: With a follow-up time ranging from 40 to 86 months (68 months median follow-up) the 5-year actuarial clinical local-regional failure rate for patients treated with neutrons was 11%, vs. 32% for photons (p < 0.01). Incorporating the results of routine posttreatment prostate biopsies, the resulting "histological" local-regional tumor failure rates were 13% for neutrons vs. 32% for photons (p = 0.01). To date, actuarial survival and cause-specific survival rates are statistically indistinguishable for the two patient cohorts, with 32% of the neutron-treated patient deaths and 41% of the photon-treated patient deaths caused by prostate cancer (p = n.s.). Prostate specific antigen (PSA) values were elevated in 17% of neutron-treated patients and 45% of photon-treated patients at 5 years (p < 0.001). Severe late complications of treatment were higher for the neutron-treated patients (11% vs. 3%), and were inversely correlated with the degree of neutron beam shaping available at the participating institutions. Neutron treatment delivery utilizing a fully rotational gantry and multileaf collimator did not result in an increase in severe late effects when compared to photon treatment., Conclusion: High energy fast neutron radiotherapy is safe and effective when adequate beam delivery systems and collimation are available, and it is significantly superior to external beam photon radiotherapy in the local-regional treatment of large prostate tumors.

The results of phase III trials comparing neutrons to photons for head and neck squamous cell cancers, non-small cell lung cancers, and prostate adenocarcinomas are reviewed, with emphasis given to the most recent U.S. National Cancer Institute sponsored randomized clinical studies in which fast neutrons were delivered using modern, hospital-based, high-energy, isocentric-capable cyclotrons. In locally advanced squamous cell head and neck cancers, neutrons showed no convincing advantage over photons. Fast neutron radiotherapy may have provided a therapeutic benefit in selected patients with inoperable non-small cell lung cancers. For locally advanced prostate adenocarcinomas, neutron therapy resulted in significantly superior clinical and histological loco-regional tumor control, which may translate to improved survival with additional follow-up. In general, severe late complications were more frequent with neutrons, especially in patients treated on older physics laboratory-based equipment. Even with modern state-of-the-art neutron generators, careful beam collimation and treatment planning are required to minimize side effects.

Purpose: To quantify, based on pretreatment computer tomographic measurements, potential groin node depths, which will aid in optimal treatment planning for patients requiring groin node radiation., Methods and Materials: The pretreatment computer tomographic scans of 50 gynecologic cancer patients were reviewed to determine the distance of each femoral vessel beneath the overlying skin surface, as an indicator of potential groin node depth. Correlative data regarding height and weight were obtained from patient medical records, and were used to calculate the Quetelet index, defined as (weight in kg)/(height in m)2. Treatment parameters of 5 patients who failed prophylactic groin radiation in a recently published study were assessed to determine if underdosage represented a possible cause of failure., Results: Individual femoral vessel depths ranged from 2.0 to 18.5 cm. When the depths of all four femoral vessels were averaged in each patient, the mean "4-vessel average" depth for this patient population was 6.1 cm. The median Quetelet index for the group was 25.6, and there was a strong correlation between femoral vessel depth and patient Quetelet index. Recalculation of doses provided to the 5 patients failing prophylactic groin radiation in the Gynecologic Oncology Group study showed that all had received potential tumor doses < 4700 cGy, with 3 patients being underdosed by > 30%., Conclusion: While surgery is often indicated in the management of patients with potential groin node metastases, the role of prophylactic groin radiation should not be rejected. Data from this study may aid in the optimal design and implementation of groin node radiotherapy.

Purpose: To determine, in a retrospective single institutional study, the role of concurrent radiotherapy and chemotherapy in the treatment of local-regionally advanced vulvar cancer., Methods and Materials: From 1984 to 1991, 20 patients with locally extensive primary or recurrent carcinoma of the vulva were treated with initial combined radiotherapy and chemotherapy. Seven patients had Federation Internationale de Gynecologie et d'Obstretrique Stage III disease, 10 had Stage IV disease, and three were treated for recurrent disease. None of these patients were considered candidates for primary radical vulvectomy and groin node dissection. Median radiation doses to regions of microscopic disease and gross tumor were 40 Gy (range 30-54 Gy) and 54 Gy (34-70.4 Gy), respectively. All patients received 2 or 3 cycles of 5-Fluorouracil concurrently with radiotherapy. In addition, five patients received Cis-platinum, and one Mitomycin-C. Median at-risk follow-up interval was 37 months., Results: Ten patients had complete resolution of tumor to initial chemoradiotherapy, and eight of these have remained free of tumor relapse. Eight other patients had partial responses, with tumor bulk reduced by > 50%, while the remaining two patients had local-regionally progressive disease. Six of the patients with partial responses had residual tumor successfully resected, although four subsequently recurred. For the entire group of 20 patients, the actuarial 3- and 5-year local control rates were 48% each, and the corresponding disease-specific survival rates were 59% and 49%. There was a suggestion that better local control was obtained in patients who received gross tumor radiation doses > or = 50 Gy. Skin reaction was the major acute toxicity and responded well to conservative management. Long-term sequalae were limited to skin and subcutaneous atrophy., Conclusion: These results indicate that initial combined radiotherapy and chemotherapy is effective in the management of advanced vulvar cancer.

The current data involving the use of prostate-specific antigen (PSA) in the radiotherapeutic management of localized prostatic cancer is reviewed. Controversies and ongoing debate notwithstanding, a number of general conclusions have been made. (1) PSA as a screening test has increased prostate cancer detection rates and is recommended as part of routine screening to supplement digital rectal examination. (2) Preradiotherapy PSA levels are correlated with tumor stage but also provide prognostic information that is independent of tumor stage and histological grade. (3) Following the completion of radiotherapy, PSA levels must decline to normal values to assure a successful treatment outcome. Disagreement persists as to what constitutes a normal PSA value after radiotherapy, and in what time frame after treatments such a level must be achieved. (4) Different proposed models of PSA decline after radiotherapy are discussed, but it remains premature to assess their relative success as predictors of subsequent clinical events. (5) Postradiotherapy prostate biopsy results (negative versus positive) correlate reasonably well with post-treatment PSA status (normal versus elevated). (6) The management of patients with a rising PSA following radiotherapy must be individualized, with early hormonal intervention being an attractive, although unproven, therapeutic option for selected patients. (7) PSA data confirm the value of adjuvant radiotherapy for positive surgical margins and strengthens the indications for its use. (8) Preliminary data regarding PSA levels following transperineal interstitial brachytherapy implantation of the prostate appear favorable.

Between June 1977 and April 1983 the Radiation Therapy Oncology Group (RTOG) sponsored a Phase III randomized trial investigating the use of fast neutron radiotherapy for patients with locally advanced (Stages C and D1) adenocarcinoma of the prostate gland. Patients were randomized to receive either conventional photon radiation or fast neutron radiation used in a mixed-beam (neutron/photon) treatment schedule. A total of 91 analyzable patients were entered into the study, and the two patient groups were balanced with respect to the major prognostic variables. Actuarial curves are presented for local/regional control and "overall" survival. Ten-year results for clinically assessed local control are 70% for the mixed-beam group versus 58% for the photon group (p = 0.03) and for survival are 46% for the mixed-beam group versus 29% for the photon group (p = 0.04). This study suggests that a regional method of treatment can influence both local tumor control and survival in patients with locally advanced adenocarcinoma of the prostate gland.

The records of 143 patients treated at 5 institutions with external beam megavoltage irradiation for localized prostatic cancer were reviewed to evaluate post-treatment changes in prostate specific antigen (PSA) in the context of subsequent events. Complete responders were defined as patients clinically well with normal PSA, clinical failures were patients with documented local tumor recurrence or distant metastases and chemical failures were patients clinically well but with a PSA level above the upper limits of normal. Correlations with pre-treatment PSA values were also made for the 50 of 143 patients for whom pre-treatment PSA data were available. Median patient followup was 27 months (range 18 to 91 months). The data were analyzed with parametric and nonparametric univariate and multivariate statistical procedures. Pre-treatment PSA levels increased with increasing tumor stage (p = 0.004) but not with increasing summed Gleason pattern scores (p = 0.15). The probability of remaining a complete responder decreased with increasing stage (p = 0.008) but not with increasing Gleason score (p = 0.14). Increasing pre-treatment PSA correlated with clinical failure (p = 0.01) and chemical failure (p = 0.006). Of the patients with a pre-treatment PSA level of less than 4 times the upper limits of normal 83% remained as complete responders compared to 30% of those with a higher pre-treatment PSA (p = 0.0002). The return of PSA levels to the normal range within 6 months after treatment was strongly correlated with a favorable outcome when analyzed by multivariate logistic regression. The status at last followup of patients who had a normal PSA level at 6 months versus those with an elevated PSA level 6 months after treatment is 94% versus 8% for complete responders (p = 0.0001), 0% versus 60% for clinical failures (p = 0.002) and 6% versus 32% for chemical failures (p = 0.14). Similar results occurred when analyzing outcomes in relationship to PSA normalization within 12 months after treatment (p = 0.001 for clinical failures, p = 0.02 for chemical failures and p = 0.001 for complete responders). We conclude that the pre-treatment level of PSA is an independent prognostic factor for prostate cancer patients treated with primary radiation therapy, and that the failure of PSA to return to the normal range within 1 year after completion of treatment identifies a group of patients at high risk for tumor recurrence.

Thirty-four patients have completed treatment on a bladder-preservation protocol using primary irradiation combined with infusion 5-fluorouracil (5-FU). 4,000 cGy pelvic irradiation was delivered in 5 weeks, with 1,000 mg/m2/day of 5-FU administered as a 96 hr infusion on days 1-4 of week 1 and 4. After a 3-week rest period, patients eligible for cystectomy underwent cystoscopy and biopsy. Those with residual tumor underwent cystectomy, and those without tumor received an additional cycle of chemotherapy and irradiation. Patients ineligible for cystectomy for reasons medical, surgical, or refusal received a third cycle without the 4-week delay or re-evaluation. With a median follow-up of 18 months (range 2-45 months), and with 25/34 patients having T3 (16) or T4 (9) tumors, 17 patients are NED, 4 have died of intercurrent deaths, 7 have died with bladder cancer, and 6 are alive with tumor (2 confined to the bladder). The actuarial cancer-specific survival for the entire group of patients is 64% (+/- 12%) at 45 months, with a freedom from relapse of invasive cancer of 54% (+/- 10%). Twenty-four of the 34 patients retained intact bladders, with 20/24 reporting entirely normal voiding. Of 18 potential surgical candidates, 13/16 (81%) who underwent pathologic re-staging after 2 cycles of chemoradiotherapy had no histologic evidence of residual cancer. Of these 13 patients, 8 remain NED and 2/13 have locally recurrent non-invasive tumors only. Treatment was well-tolerated, with 28/34 patients having received 100% of the planned 5-FU and 34/34 having received greater than 80%. This regimen appears more successful than radiotherapy alone in achieving complete tumor responses, and is an attractive alternative for patients who are unable to receive more aggressive chemotherapy/radiation combinations.

The records of 132 patients participating in clinical trials using fast neutron (n = 94), mixed neutron and photon (n = 16), or conventional photon (n = 22) irradiation for primary management of prostatic cancer were retrospectively reviewed to assess treatment-related neurological complications. With a median follow-up of 14 months (range 1 to 101 months), 31/132 patients (26 neutron, 3 mixed beam, 2 photon) have experienced either sciatica beginning during or shortly after treatment, or diminished bladder or bowel continence that developed at a median time of 6.5 months following treatment. Sciatica responded to oral steroids and was usually self-limited, whereas sphincter dysfunction appears to be permanent. Pre-treatment risk factors for complications included a history of hypertension, diabetes, cigarette smoking or peripheral vascular disease, with 81% of affected patients having one or more risk factors compared with 55% of unaffected patients (p = 0.01). Seven patients have moderate (5) or severe (2) residual problems, all in the cohorts receiving neutrons (6/7) or mixed beam therapy (1/7).

The palliation of hepatic metastases represents a major therapeutic problem in oncology. The generally unfavorable prognosis of patients with liver metastasis may complicate the evaluation of the efficacy and toxicity of various therapeutic modalities. The Radiation Therapy Oncology Group (RTOG) is evaluating new accelerated fractionation schemes for hepatic irradiation. In designing this study it became necessary to identify a favorable subpopulation of patients with an expected median survival of 6 months in whom the late effects of treatment could be evaluated. Data from two RTOG liver metastases studies (7605 and 8003) were analyzed using multi-variate techniques. Cases with a serum bilirubin level of greater than 1.5 mg%, performance score of less than 50, and gastric or pancreatic primary carcinomas were initially excluded because of the adverse influence of these factors on survival. One hundred and ninety cases met the criteria for inclusion in this analysis. A loglinear model was used to identify the patient characteristics associated with a favorable prognosis for survival. These included a performance score of 80-100, colorectal carcinoma primary, and no extrahepatic metastases. A logistic regression equation was derived and confirmed that the probability of surviving at least 6 months depended on the effects of performance score, primary site and the presence or absence of extra-hepatic metastases. Patients with all three favorable factors constituted 30% of the evaluable study population and had a predicted survival of 50% at 6 months. A patient population with these characteristics will be used to study the late effects of accelerated fractionated radiation therapy on the liver.

Seventy-three patients with biopsy-proven limited non-small cell lung cancer (NSCLC) were entered on a combined modality study at the University of Washington. Seventy-five percent (55 of 73) of the patients had a histologic diagnosis of adenocarcinoma or large cell carcinoma, whereas 25% (18 of 73) had squamous cell carcinoma. After two cycles of chemotherapy, patients without evidence of progressive disease received prophylactic cranial irradiation (PCI) and chest radiotherapy, followed by two additional cycles of chemotherapy. Brain computed tomography (CT) scans were performed at 3-month intervals after completion of therapy in all patients, and were additionally performed whenever signs or symptoms developed suggesting neurologic dysfunction or recurrent brain disease. Sixty-five patients were treated with PCI. No clinical or CT evidence of recurrence in the brain has developed in patients who completed PCI. PCI appears to be effective in greatly reducing the incidence of brain relapse in patients with limited NSCLC.

The records of 59 patients with lymphocyte predominant Hodgkin's disease (LPHD) evaluated and treated at Stanford University Medical Center between 1963 and 1983 were reviewed. Of these 59 patients, 92% are alive at 10 years following treatment, 78% are relapse-free, and none have died of Hodgkin's disease. Compared with the other histologic subtypes of Hodgkin's disease, LPHD presents more frequently as stage I or II disease (78% vs. 55%) and less frequently with constitutional symptoms (7% vs. 32%). Despite these factors, there is no statistically significant difference in either survival or freedom-from-relapse (FFR) between the histologic subtypes when comparisons are made on a stage-for-stage basis. Analysis of sites of presentation and relapse reveals that LPHD rarely involves intrathoracic structures. Patients with C.S. I disease presenting in inguinofemoral or high cervical lymph nodes do not require staging laparotomy as none of these patients were upstaged by surgery. Patients with stage I disease involving high cervical lymph nodes may be treated with limited field irradiation employing fields no more extensive than a mantle and Waldeyer's ring field, as no relapses have been seen in such patients treated in this fashion. Although limited field irradiation was used successfully for LPHD presenting in other localized sites, inadequate patient numbers preclude assessment of this treatment for those clinical presentations.

At the present time, standard therapy for invasive bladder cancer includes radical cystectomy and urinary diversion. Clearly, there is a population of patients who can be rendered tumor free by combinations of irradiation and chemotherapy, or irradiation and surgery. These patients may not require total cystectomy to be cured. Only time and experience will tell which treatment regimens can provide both cure and preservation of the urinary bladder.

One hundred seventy-nine consecutive children with Hodgkin's disease seen at Stanford University Medical Center between the years 1961-1980 have been analyzed for survival and freedom-from-relapse as a function of clinical versus laparotomy staging as well as primary treatment modalities. Of laparotomy-staged patients, 86% are alive at 10 years after primary radiation with chemotherapy reserved for relapse, as compared with 90% managed by planned combined modality therapy (p = 0.62). Patients who were clinically staged and managed with primary radiation have only a 69% survival (p = 0.05). A favorable subgroup of patients with lymphocyte-predominant Hodgkin's disease experienced a low relapse rate regardless of primary treatment modality. Patterns of relapse in clinically staged patients reflect understaging, with most relapses in distant, nonirradiated sites, whereas the less frequent relapses in laparotomy-staged patients usually reflect regional recurrence. It is concluded that laparotomy staging is highly desirable to allow greatest flexibility in optimizing individual therapy. Routine combined modality treatment for all patients would overtreat certain favorable subgroups, who can be managed more conservatively as long as the information derived from surgical staging is available. For young children, in whom bone growth issues are paramount, combined modality treatment using low-dose radiation is recommended. For older children and adolescents, where concerns over chemotherapy-related leukemogenesis and infertility are more important than height considerations, radiation alone may be used for stages I-IIIA with equal overall success.

The records of 91 patients enrolled between June 1977 and April 1983 in the Radiation Therapy Oncology Group (RTOG) randomized study investigating fast neutron radiation therapy in the treatment of locally advanced prostate cancer were reviewed. Patients with stages C and D1 adenocarcinoma were randomized to receive either combined fast neutron and photon irradiation (mixed-beam) or conventional photon irradiation alone. Survival (actuarial) at eight years for the mixed-beam cohort was 63% vs 13% for the patients receiving photons alone (P = .01). Corresponding "determinental" survival rates, adjusted by exclusion of intercurrent deaths, were 82% and 54%, respectively (P = .02). Freedom from locally recurrent prostate cancer was 77% for mixed-beam patients and 31% for patients receiving photons alone (P less than .01). Analyses of outcomes accounting for all major prognostic determinants confirm the greater efficacy of mixed beam treatment with P less than .05 for survival, determinental survival, and local control.

Fourteen patients with transitional cell carcinoma of the urinary bladder were treated with 4,000 cGy of pelvic irradiation concurrent with two 96-hour infusions of 5-fluorouracil (5-FU). Three weeks after completion of this regimen, patients underwent repeat cystoscopy and deep-muscle biopsy at the site of their original neoplasms. Eight of 14 (57%) had no tumor left in the biopsy specimen, and they received an additional course of chemotherapy and radiation therapy to a total dose of 4,400 cGy to the pelvis and 6,000 cGy to the bladder. Five of the 14 had residual tumor in the biopsy specimen (one did not undergo biopsy) and went on to planned cystectomy. Two of the five had no tumor in the cystectomy specimen. Overall, ten of the 14 patients (71%) have been downstaged to a condition of P0 (no tumor) following 4,000 cGy and two courses of 5-FU. Of eight patients with retained bladders, seven remain well at a median follow-up of 7 months. At a range of follow-up of 3-21 months and a median of 7 months, 13 of 14 patients remain tumor-free. This regimen results in a greater percentage of downstaging than conventional irradiation alone, and may allow bladder preservation for those with radiation therapy- and chemotherapy-responsive tumors.

A total of 17 patients with superficial transitional cell carcinoma of the bladder underwent treatment with pelvic external beam irradiation followed by an intracavitary 137cesium implant via a triple lumen Foley catheter. Of these patients 11 had recurrent and multifocal superficial cancer, with 8 having relapse after prior intravesical chemotherapy. External beam doses of 3,600 to 5,066 cGy. were followed by implant doses delivering 2,000 to 3,200 cGy. to the bladder mucosa, with the sum of external and intracavitary doses totaling 6,500 to 7,500 cGy. Of 15 patients evaluable with a median followup of 48 months, and including 13 followed for more than 2 years, 11 (73 per cent) remain free of disease, 3 (20 per cent) have recurrence in the bladder but have retained the bladder and only 1 has required cystectomy. All 4 failures occurred in the subgroup of 8 patients who had received prior intravesical chemotherapy. This bladder-sparing approach is well tolerated, is an alternative to cystectomy in patients with recurrent superficial transitional cell carcinoma of the bladder and in our series has salvaged 50 per cent (4 of 8) of the patients even after failure of intravesical chemotherapy.

The major clinical investigation employing fast neutrons in the treatment of invasive bladder cancer are reviewed. Although data suggest that preoperative radiation schedules employing neutrons may result in a greater degree of pathologic downstaging than conventional precystectomy photon regimens, this has not led to an improved survival rate for neutron-treated patients over photon-treated patients. Randomized clinical trials comparing primary neutron irradiation and primary photon irradiation do not disclose an advantage for neutrons over photons as measured by survival rate or freedom from local tumor recurrence. The late complications in normal pelvic tissues following neutron irradiation with low-energy beams exceed those experienced after photon irradiation and have led to an unexpectedly high rate of treatment-related morbidity and mortality. A partial explanation for the toxicity may be attributed to the use of neutron beams with poor depth dose characteristics for the treatment of what is a deep-seated malignancy. An additional explanation is the documented lack of a differential in radioresponsiveness to neutrons between the bladder primary tumor and adjacent normal pelvic tissues.

Over 200 patients have been entered in five studies investigating the use of fast neutron radiation therapy in the treatment of non-small-cell carcinomas of the lung since 1983. The results of these studies have been inconsistent. Most studies did not show survival rates or local control advantages over standard photon radiation therapy. Side effects from studies employing mixed photon-neutron treatment plans or clinically oriented, high-energy cyclotrons were seen to be comparable to those of standard courses of radiation therapy, representing a considerable improvement over those studies utilizing low-energy cyclotrons for a full course of radiation therapy, which resulted in unacceptably high complication rates. A new phase III study utilizing high-energy isocentric neutron beams has been designed and implemented, and over 100 patients have been entered to date. The current status of fast neutron radiation therapy in the treatment of non-small-cell lung cancer is reviewed.

A technique for high dose (5600-6100 cGy) extended field irradiation to the para-aortic lymph nodes is described. Fourteen patients have been treated with this technique, of whom 10 have had histologic confirmation of para-aortic node metastases. With follow-up ranging from 11 to 78 months, 7 of 14 patients are alive and clinically cancer-free. Acute effects of extended field treatment on patient weight and circulating blood counts are analyzed, and late treatment morbidity assessed. The findings suggest that such treatment, executed with modern equipment and appropriate technique, is not significantly more hazardous than pelvic irradiation, and can result in a substantial probability of disease-free survival.

5-Chloro-2'-deoxycytidine (Cld/Cyd) is hypothesized to have preferential incorporation into tumor DNA on the basis of elevated deoxycytidine-5'-phosphate deaminase and deoxycytidine kinase levels in tumors. Radiosensitization by Cld/Cyd was evaluated in exponentially growing Chinese hamster ovary cells by determining the ratio of radiation doses in control and treated cells to produce the same degree of cell killing (sensitizer enhancement ratio). Sensitizer enhancement ratios of 1.2-1.8 are seen at Cld/Cyd concentrations of 3-100 microM, 64 h incubation, and 200-600 cGy irradiation. Coincubation with tetrahydrouridine (H4Urd), a proposed inhibitor of Cld/Cyd catabolism by plasma cytidine deaminase resulted in no enhanced drug or radiation cytotoxicity. C3H mice given implants of RIF-1 tumors received 72-h continuous i.p. infusions of Cld/Cyd with or without H4Urd, or 5-bromo-2'-deoxyuridine (BrdUrd). Excised tumors were irradiated as single cell suspensions in vitro. Infusions of equimolar (0.4 mmol/kg/day) Cld/Cyd or BrdUrd resulted in greater radiosensitization by BrdUrd with no potentiation of Cld/Cyd by coinfusion with 0.8 mmol/kg/day H4Urd. Infusions with equitoxic doses of Cld/Cyd (0.8 mmol/kg/day) or BrdUrd (0.4 mmol/kg/day) yielded equal BrdUrd and Cld/Cyd sensitizer enhancement ratios of 1.6, without H4Urd potentiation of Cld/Cyd. Fluorescence-activated cell sorter analysis of tumor cell suspensions using a monoclonal antibody reactive with BrdUrd and Cld/Cyd disclosed a population of noncycling cells in tumors treated with Cld/Cyd/H4Urd that is not seen in tumors exposed to either BrdUrd or Cld/Cyd alone.

Twenty-five women have been treated with a second course of irradiation for recurrent cancer or a second primary carcinoma arising within a previously irradiated pelvic volume. Fourteen patients have been rendered cancer-free (56%) with follow-up ranging from 10 to 61 months. Three of these patients have died of intercurrent disease. Seven of these patients have experienced major complications (50%), necessitating surgical intervention in three cases. The rationale for reirradiation and techniques of retreatment are discussed. Prognostic factors are analyzed and criteria for patient selection are identified.

Twenty-five patients underwent adjunctive extrafascial hysterectomy 14-60 days following completion of external and intracavitary irradiation for bulky carcinoma of the uterine cervix. Review of the operative histopathology and correlation with subsequent patient outcomes suggests that morphologically persistent cancer is prognostically ominous and that cancer near the surgical margin is viable in the majority of instances.

Primary intramedullary spinal cord tumors are frequently difficult to localize for radiation treatment planning. Conventional imaging techniques, including unenhanced magnetic resonance (MR) scans, cannot clearly distinguish residual tumor from surrounding normal spinal cord. Recently, contrast agents have been developed for MR that have considerable promise for improving tumor volume definition. This report describes the impact of contrast-enhanced MR on the treatment planning process for four patients with primary spinal cord tumors and discusses the significance of this technique for patients with these neoplasms.

Between June, 1977, and April, 1983, the Radiation Therapy Oncology Group (RTOG) sponsored a phase III study comparing fast neutron radiotherapy as part of a mixed beam (neutron/photon) regimen with conventional photon (x-ray) radiotherapy for patients with locally advanced (Stages C and D1) adenocarcinoma of the prostate. A total of 91 analyzable patients were entered into the study with the two treatment groups balanced in regard to all major prognostic variables. The current analysis is for a median follow-up of 6.7 years (range 3.4-9.0 yrs.). The results are statistically significant in favor of the mixed-beam group of all parameters mentioned. At five years the freedom from local/regional relapse rate is 81 percent on the mixed-beam arm compared with 60 percent on the photon arm. The actuarial overall survival rate at five years is 70 percent on the mixed beam compared with 56 percent on the conventional photon arm. The determinantal survival at five years (which excluded death due to intercurrent disease in patients clinically free of cancer) was 82 percent on the mixed-beam arm compared with 61 percent on the photon arm. The type of therapy appeared to be the most important predictor of both local tumor control and patient survival in a step-wise Cox analysis. There was no difference in the treatment-related morbidity for the two patient groups. Mixed-beam therapy may be superior to standard photon radiotherapy for treatment of locally advanced prostate cancer.

Thirty-two patients with inoperable, recurrent, or gross residual malignant salivary gland tumors received fast neutron radiotherapy at the University of Washington. Eleven patients were treated with low energy neutrons alone, four received a combined photon-low energy neutron treatment regimen ("mixed beam"), and 17 were treated with high energy neutrons alone. Patients treated for microscopic residual tumor after a surgical resection were excluded from this study. With a minimum follow-up period of one year, (maximum 12 years), the overall locoregional tumor control rate for the entire series was 81%. The 5-year locoregional tumor control rate was 69%. The overall 5-year survival rate was 33% (50% for T3 tumors and 0% for T4 tumors). Compared to results obtained with conventional photon and/or electron treatment for advanced salivary gland tumors, fast neutron radiotherapy appears to offer a significant advantage.

The basic radiobiological rationale for the use of fast neutron radiotherapy in the treatment of classically radioresistant tumors such as soft tissue sarcomas, osteogenic sarcomas, and chondrosarcomas is reviewed. There are no definitive randomized studies comparing high and low linear energy transfer radiotherapy for these tumor systems, but a review of published series is highly suggestive of a therapeutic advantage for fast neutrons. For soft tissue sarcomas, the local control rate is 53% (158 of 297) with fast neutrons, compared with 38% (49 of 128) with photons/electrons; for osteogenic sarcomas, the local control rate is 55% (40 of 73) with fast neutrons, compared with 21% (15 of 73) with photons/electrons; and for chondrosarcomas, the local control rate is 49% (25 of 51) with fast neutrons, compared with 33% (10 of 30) with photons/electrons. An ongoing clinical trial for these tumors is also described.

The record of 18 patients with Stage II Hodgkin's disease and large mediastinal masses, who received radiation therapy as sole treatment for their disease, were reviewed. The ratio of each patient's maximum tumor diameter to his maximum transthoracic diameter was measured from radiographs taken prior to treatment, and at two intervals approximating 1/3 and 2/3 the total radiation dose. The slopes of the resulting graphed data points were correlated with patient outcomes. No correlation could be drawn between prompt or slow tumor regression and freedom from tumor recurrence. It is concluded that the rate of tumor mass regression in Hodgkin's disease is not predictive of the ultimate success or failure of radiation therapy, and should not be used as a criterion by which to judge the need for additional systemic chemotherapy.

The major clinical experiences using fast neutrons for the treatment of locally advanced prostatic carcinomas are reviewed. In all trials to date, there is evidence that treatment regimens employing a component of fast neutrons achieve results that equal or surpass those obtainable with conventional megavoltage external beam irradiation for comparable groups of patients. Late complications of neutron treatment have not exceeded the complication rate expected by photon irradiation. The structure of the current Radiation Therapy Oncology Group phase III randomized trial comparing neutron and photon treatment of patients with stages B2, C, and D1 disease is discussed.