Proton beam therapy and localised prostate cancer: current status and controversies.

Proton therapy is a promising, but costly, treatment for prostate cancer. Theoretical physical advantages exist; yet to date, it has been shown only to be comparably safe and effective when compared with the alternatives and not necessarily superior. If clinically meaningful benefits do exist for patients, more rigorous study will be needed to detect them and society will require this to justify the investment of time and money. New technical advances in proton beam delivery coupled with shortened overall treatment times and declining device costs have the potential to make this a more cost-effective therapy in the years ahead.

Proton therapy of prostate cancer by anterior-oblique beams: implications of setup and anatomy variations.

Proton therapy of prostate by anterior beams could offer an attractive option for treating patients with hip prosthesis and limiting the high-dose exposure to the rectum. We investigated the impact of setup and anatomy variations on the anterior-oblique (AO) proton plan dose, and strategies to manage these effects via range verification and adaptive delivery. Ten patients treated by bilateral (BL) passive-scattering proton therapy (79.2 Gy in 44 fractions) who underwent weekly verification CT scans were selected. Plans with AO beams were additionally created. To isolate the effect of daily variations, initial AO plans did not include range uncertainty margins. The use of fixed planning margins and adaptive range adjustments to manage these effects was investigated. For each case, the planned dose was recalculated on weekly CTs, and accumulated on the simulation CT using deformable registration to approximate the delivered dose. Planned and accumulated doses were compared for each scenario to quantify dose deviations induced by variations. The possibility of estimating the necessary range adjustments before each treatment was explored by simulating the procedure of a diode-based in vivo range verification technique, which would potentially be used clinically. The average planned rectum, penile bulb and femoral heads mean doses were smaller for initial AO compared to BL plans (by 8.3, 16.1 and 25.9 Gy, respectively). After considering interfractional variations in AO plans, the target coverage was substantially reduced. The maximum reduction of V 79.2/D 95/D mean/EUD for AO (without distal margins) (25.3%/10.7/1.6/4.9 Gy, respectively) was considerably larger than BL plans. The loss of coverage was mainly related to changes in water equivalent path length of the prostate after fiducial-based setup, caused by discrepancies in patient anterior surface and bony-anatomy alignment. Target coverage was recovered partially when using fixed planning margins, and fully when applying adaptive range adjustments. The accumulated organs-at-risk dose for AO beams after range adjustment demonstrated full sparing of femoral heads and superior sparing of penile bulb and rectum compared to the conventional BL cases. Our study indicates that using AO beams makes prostate treatment more susceptible to target underdose induced by interfractional variations. Adaptive range verification/adjustment may facilitate the use of anterior beam approaches, and ensure adequate target coverage in every fraction of the treatment.

Quantitative transplantation assays of spontaneous tumors of the C3H mouse as allografts in athymic NCr/Sed-nu/nu nude mice and isografts in C3Hf/Sed mice.

Three spontaneous tumors of the C3H mouse have been used in a comparison of their transplantability and radiation response (local control) in syngeneic C3Hf/Sed mice and in allogeneic athymic NCr/Sed-nu/nu nu nude mice. The tumors were: MCaIV, a moderately well-differentiated mammary carcinoma; FSaII, a poorly differentiated fibrosarcoma; and SCCVII, a moderately well differentiated squamous cell carcinoma. The tumors were studied as fourth to seventh generation transplants. Assays to determine the number of tumor cells that, on the average, transplant the tumor to half of the recipients or transplant sites (TD50) demonstrated that these 3 tumors transplanted into the s.c. tissue of the NCr/Sed-nu/nu as readily as of C3Hf/Sed mice. The TD50 for MCaIV was slightly but significantly lower in 4-week-old NCr/Sed-nu/nu mice which had received 6 Gy whole body irradiation (WBI) 24 h before transplantation, namely, 5.8 x 10(4) (95% confidence limits, 4.5-7.6) versus 7.8 x 10(4) (6.0-10.0). The 6-Gy WBI did not affect the TD50 for 8- to 10-week-old mice. Similarly, the TD50 for SCCVII was lower in 6-Gy WBI NCr/Sed-nu/nu recipients (1.5 x 10(4) versus 3.9 x 10(4)). The TD50 for FSaII was not affected by 6-Gy WBI. Further, the TD50 for FSaII following i.v. injection of tumor cells (transplant to lung) was the same for C3Hf/Sed and NCr/Sed-nu/nu mice (this obtained for normal or 6-Gy WBI-treated subjects). The radiation doses which on the average achieve control of half of the MCaIV, FSaII, and SCCVII tumors were lower, higher, and the same in NCr/Sed-nu/nu than in C3Hf/Sed mice, respectively. The radiation doses which achieve control of half of the MCaIV and SCCVII tumors were not affected by 6-Gy WBI before transplantation.

Comparative morphometric study of tumor vasculature in human squamous cell carcinomas and their xenotransplants in athymic nude mice.

When human tumor xenotransplants into nude mice are used as experimental models, it is important to know whether their microvascular anatomy is rather host or tumor specific. Therefore a morphometric comparison of the vascular network in human squamous cell carcinomas and their xenotransplants was carried out. Biopsies were taken from surgical specimens of three squamous cell carcinomas of the oral cavity. Part of the material was processed for histology and the rest was cut into 1-mm3 cubes and transplanted s.c. into the lateral thorax of athymic nude mice [NCr/Sed(nu/nu)]. The microvascular architecture of original tumors and of three first, one second, and one late generation xenografts was compared. Capillaries were identified in original human tumors by anti-factor VIII staining and in xenografts with antilaminin staining. The median distances between interphase tumor cells and blood vessels were determined and were found to be much longer in original human tumors than in xenografts, ranging from 81 microns to 99 microns and 53 microns to 65 microns, respectively. However, the characteristic qualitative histology of tumors appeared to be preserved in xenotransplants. Analysis of the topographic distribution of mitotic figures revealed that in both original tumors and xenotransplants proliferation of tumor cells was concentrated around blood vessels. Again, vascular distances in original tumors were significantly longer than in xenotransplants. In addition, xenotransplants into nude mice from a long passaged cell line from a human pharyngeal squamous cell carcinoma, FaDu, was investigated. FaDu showed a rare-fication of the capillary network with increasing tumor volume, but a constant median distance of mitotic figures from blood vessels. In conclusion, the pattern of spatial distribution of proliferating tumor cells as well as differentiation characteristics appear to be retained in xenograft tumors, but the density of the vascular system is host specific. This has to be taken into account when physiological parameters of blood supply are studied in xenotransplanted tumors.

Quantitative comparison between the transplantability of human and murine tumors into the subcutaneous tissue of NCr/Sed-nu/nu nude and severe combined immunodeficient mice.

In previous reports, nude mice have demonstrated residual immunoreactivity against xenografts. Severe combined immunodeficient (SCID) mice lack functional T- and B-cells. These animals are expected to be better hosts in which to perform preclinical studies on human tumors. The purpose of this study is to quantitate the advantage of SCID mice over nude mice in terms of transplantability of human and murine tumors and the importance of residual immunity in SCID mice. The transplantation assays are described by an assay based on the number of tumor cells required to transplant tumor into 50% of recipients (TD50). Seven human tumors of different histology and four murine tumor cell lines were used. Serial 2-10-fold dilutions of cells were injected (0.1 ml) into the flanks of normal and whole-body irradiated WBI nude and SCID mice. The results showed that in 6 of 6 human tumor cell lines studied, TD50S for SCID mice were 2.4 to 200 times lower than that of nude mice (significant in 5 cell lines). In contrast, in 2 of 3 murine tumors, TD50S in WBI SCID mice were significantly higher than that found in nude mice. When SCID and nude mice received WBI, TD50S were lower than those of nonirradiated animals in 5 of 5 xenografts (significant in 2 cell lines for nude mice and in 5 cell lines for SCID mice). We concluded that WBI SCID mice are significantly better recipients of human tumor xenografts than nude mice. There is a factor of 10-1625 gain in TD50S in favor of the WBI SCID mice when compared to nonirradiated nude mice. WBI has, however, an important effect on SCID mice which may suggest a detectable residual immunoreactivity, perhaps due to natural killer cells. These data demonstrate that WBI SCID mice are better models for human tumor transplantation that nude mice and, although WBI at 6 Gy suppressed significantly the immune system of nude mice, a certain level of immunoreactivity against xenografts is still maintained.

Quantitative comparison between the transplantability of human and murine tumors into the brain of NCr/Sed-nu/nu nude and severe combined immunodeficient mice.

We have demonstrated (A. Taghian et al., Cancer Res., 53: 5012-5017, 1993) that the take rate of human xenografts in the s.c. tissue of severe combined immunodeficient (SCID) mice is significantly higher than that of nude mice. Earlier, this laboratory reported that the transplantability of tumor xenografts was significantly higher for intracranial (i.c.) injection than for s.c. injection in nude mice. The purpose of this study is to assess: (a) the relative i.c. transplantability of human and murine tumors in comparison with s.c. tissue in SCID mice; (b) the relative i.c. transplantability in SCID mice in comparison to nude mice; and (c) the influence of whole-body irradiation on i.c. transplantability of SCID and nude mice. The assay based on the number of cells required to transplant tumors into 50% of recipients (TD50) was used to describe the transplantability assays. Five human and four murine tumor cell lines were used. Concurrent TD50 assays were performed i.c. in whole-body irradiated and nonirradiated SCID and nude mice. Serial 2-10-fold dilutions of cells were injected in a 10-microliters volume into the right parietal lobe 3 mm below the skin. The results showed that in all tumors studied the i.c. TD50S were significantly lower than the s.c. TD50S by a factor of 1.7-1580. The average enhancement ratio (s.c. TD50/i.c. TD50) in nude mice was twice that in SCID mice. No significant difference was found between the i.c. TD50S in SCID and in nude mice, contrary to the significant difference in s.c. TD50S between both strains of mice (A. Taghian et al., Cancer Res., 53: 5012-5017, 1993). Whole-body irradiation did not significantly affect the i.c. TD50 in nude mice; however, it did affect two of three xenografts in SCID mice. In conclusion, despite the significantly lower s.c. TD50S of human xenografts in SCID mice, i.c. TD50S were almost similar to those of NCr/Sed-nu/nu nude mice. This suggests the presence of different immunoreactivities between nude and SCID mice in s.c. transplantability; however, for i.c. transplantability, nude mice behaved equally as well as SCID mice. The significant enhancement ratio in SCID mice is further evidence that this strain of mice displays a residual systemic immunoreactivity, although the immunoreactivity is significantly lower than that of nude mice.

Quantitative studies on the transplantability of murine and human tumors into the brain and subcutaneous tissues of NCr/Sed nude mice.

The transplantability of experimental tumors into the brain (i.c.) and s.c. tissues of C3Hf/Sed and athymic NCr/Sed nude mice was examined using quantitative cell transplantation assays. Studies using the immune-competent C3H animals showed that brain is a more favorable site for the transplantation of syngeneic tumor than s.c. tissue and that this is true for nonimmunogenic as well as immunogenic tumors. The capacity of the brain to act as an immunological sanctuary can be overwhelmed by a strong, systemic, secondary immune response such as that evoked by the methylcholanthrene-induced sarcoma FSal. In studies performed using NCr/Sed nude mice, the allogeneic tumor MCaIV was found not to be demonstrably immunogenic. The cell dose required to transplant the tumor into 50% of recipients (TD50) could neither be increased by immunization procedures nor decreased by six Gy whole-body irradiation (WBI) prior to transplantation. Delayed-type hypersensitivity to this tumor was not expressed by nude mice after rechallenge with tumor antigen. The TD50 was again lower for i.c. than s.c. transplantation and the ratio s.c./i.c. was comparable to that found in syngeneic C3Hf/Sed hosts. Three human tumors have been similarly tested. They were: FaDu, a pharyngeal squamous carcinoma; HFSal, a fibrosarcoma; and U87, a malignant glioma. s.c. TD50 values were in all cases significantly higher than those obtained i.c. The ratios TD50 s.c./i.c. ranged from 6.4 to greater than 50 in five studies, substantially higher than those found for transplantation of murine tumors into either the syngeneic or the allogeneic recipients. Six Gy WBI reduced the s.c. TD50 for these tumors, but in each case the value remained significantly higher than that obtained i.c. 19.4 Gy WBI given in 10 equal fractions and followed by i.v. bone marrow rescue reduced further the s.c. TD50 for FaDu. NCr/Sed nude mice demonstrated cross-reacting delayed-type hypersensitivity against FaDu and HFSal. A small proportion of FaDu tumors (less than 2%) displayed a spontaneous halt in growth or even regression. When the host cell infiltrate of these tumors was analyzed, an increase was seen in the proportion of Thy 1.2 and asialo-GM1-positive cells as compared with progressively growing tumors. These data strongly suggest that a residual low level of immune reactivity exists in nude mice against xenotransplanted human tumors. This resistance to s.c. transplantation may be diminished by WBI and is less for intracerebral implantation.

Failure of 1H nuclear magnetic resonance spectroscopy of blood plasma to detect malignancy.

Water-suppressed proton nuclear magnetic resonance (NMR) of plasma was proposed as a technique for detecting malignant tumors. In that analysis, bloods drawn from cancer patients at the Beth Israel Hospital (BIH; Boston, MA), were easily distinguished from normal subjects by measuring and averaging the proton NMR methyl and methylene line widths of plasma lipoproteins. We collected blood at the Massachusetts General Hospital (MGH), including from normal controls, patients with untreated and treated malignant tumors, and patients with nontumor diseases. The plasma NMR analyses were carried out blind. The code was not broken until all patient charts and pathology records were reviewed, plasma analyses were completed, and patients had been divided into appropriate clinical groups. Analysis of these data showed no differences between the means of the study groups (false-positive and false-negative frequencies 46% and 57%, respectively). An inverse correlation of methyl/methylene line widths with age (P less than .01), and a correlation with nitrate-requiring cardiovascular disease (P less than .05) was, however, evident. This test cannot be validly used to detect malignancy.

Bladder preservation by combined modality therapy for invasive bladder cancer.

PURPOSE: To update the efficacy of a selective multimodality bladder-preserving approach by transurethral resection (TURBT), systemic chemotherapy, and radiation therapy. PATIENTS AND METHODS: From 1986 through 1993, 106 patients with muscle-invading clinical stage T2 to T4a,Nx,M0 bladder cancer were treated with induction by maximal TURBT and two cycles of chemotherapy (methotrexate, cisplatin, vinblastine [MCV]) followed by 39.6-Gy pelvic irradiation with concomitant cisplatin. Patients with a negative postinduction therapy tumor site biopsy and cytology (a T0 response, 70 patients) plus those with less than a T0 response but medically unfit for cystectomy (six patients), received consolidative chemoradiation to a total of 64.8 Gy. Surgical candidates with less than a T0 response (13 patients) and patients who could not tolerate the chemoradiation (six patients) went to immediate cystectomy. The median follow-up duration is 4.4 years. RESULTS: The 5-year actuarial overall survival and disease-specific survival rates of all patients are 52% and 60%, respectively. For clinical stage T2 patients, the actuarial overall survival rate is 63%, and for T3-4, 45%. Thirty-six patients (34%) underwent cystectomy, all with evidence of tumor activity, including 17 with an invasive recurrence. The 5-year overall survival rate with an intact functioning bladder is 43%. Among 76 patients who completed bladder-preserving therapy, the 5-year rate of freedom from an invasive bladder relapse is 79%. No patient required cystectomy for treatment-related bladder morbidity. CONCLUSION: Combined modality therapy with TURBT, chemotherapy, radiation, and selection for organ-conservation by response has a 52% overall survival rate. This result is similar to cystectomy-based studies for patients of similar age and clinical stages. The majority of the long-term survivors retain fully functional bladders.

Loss of heterozygosity at 11q23 in squamous cell carcinoma of the head and neck is associated with recurrent disease.

Loss of heterozygosity (LOH) at chromosome 11q23 has been found in a variety of epithelial human neoplasms, suggesting that this region contains a tumor suppressor gene(s) important to tumorigenesis. We investigated whether LOH at 11q23 could be detected in squamous cell carcinoma of the head and neck (SCCHN), and whether loss at this site was associated with specific clinical parameters. Fifty-six matched blood and SCCHN tumor samples taken at the time of diagnosis were evaluated for LOH at three microsatellite markers at 11q23. Multiplex PCRs with [alpha-32P]dCTP labeling of the amplified DNA strands were performed. Clinical data were obtained from medical record review. LOH at 11q23 was found in 13 of 52 (25%) evaluable tumors. There was no association between LOH at 11q23 and amplification of the CCND1 (cyclin D1) oncogene or inactivation of the p53 gene, which had been determined previously. With a mean follow-up of 24 months, an association independent of tumor size or stage was found between LOH at 11q23 and recurrent disease (P = 0.04). Among subjects who received radiotherapy (RT) as a component of their treatment, LOH at 11q23 was associated with persistent or recurrent locoregional disease (P = 0.05). LOH at 11q23 occurs in a subset of SCCHN. It is associated with a higher likelihood of recurrent disease, perhaps related to resistance to RT. The specific gene(s) and mechanism(s) responsible remain to be identified. Until then, LOH at 11q23 might become a marker identifying patients likely to do poorly with conventional therapy.

Primary radiotherapy vs conservative management for localized prostate cancer--a population-based study.

BACKGROUND: Radiotherapy is the most common curative cancer therapy used for elderly patients with localized prostate cancer. However, the effectiveness of this approach has not been established. The purpose of this study is to evaluate the long-term outcomes of primary radiotherapy compared with conservative management in order to facilitate treatment decisions. METHOD: This population-based study consisted of 57,749 patients with T1-T2 prostate cancers diagnosed during 1992-2007. We utilized an instrumental variable (IV) analytical approach with competing risk models to evaluate the outcomes of primary radiotherapy vs conservative management. The IV was comprised of combined health service areas with high- and low-use areas corresponding to the top and bottom tertile in radiotherapy usage rates. RESULTS: In patients with low-/intermediate-risk prostate cancer, 10-year prostate cancer-specific and overall survival was similar in high- and low-radiotherapy use areas (96.1 vs 95.4% and 56.6 vs 56.3%, respectively). In patients with high-risk disease, however, areas with high-radiotherapy use had a higher 10-year cancer-specific survival (90.2 vs 88.1%, difference 2.1%; 95% CI 0.3-4.0%) and 10-year overall survival (53.3 vs 50.2%, difference 3.1%; 95% CI 1.3-6.3%). Results were similar irrespective of the type of radiotherapy used. To assess the robustness of our choice of IV, we repeated the IV analytical approach using different IVs (using the median utilization rate as the cutoff) and found the results to be similar. CONCLUSIONS: Among men >65 years of age, the benefit of primary radiotherapy for localized disease is largely confined to patients with high-risk prostate cancer (Gleason scores 7-10).

Radiation therapy or prostatectomy: an old conflict revisited in the PSA era. A radiation oncologist's viewpoint.

A close examination of the outcomes for the radical treatment of prostate cancer in the prostate-specific antigen (PSA) era shows no clear advantage to radical prostatectomy over external-beam radiation. Both modalities are highly effective against small impalpable tumors of low Gleason grade and with PSA values less than 10 ng/mL. Both modalities struggle against all other stages of prostate cancer. Radiation and surgery are currently in states of rapid evolution, and the results emerging become quickly outdated. It is hoped that the newer, more aggressive approaches will help a significant number of patients, perhaps the majority, not currently being cured by radical therapy.

The life shortening effects of treatment with doxorubicin and/or local irradiation on a cohort of young C3Hf/Sed mice.

The long-term consequences of treating a cohort of C3Hf/Sed mice in early life with either local-field single dose radiation, systemic doxorubicin, or both, are reported in this study. Significant life shortening was observed in all treatment groups. Median survival times (days) from time of treatment were: control, 690; 35 Gy, 560; 70 Gy, 460; 5 mg/kg doxorubicin, 580; 10 mg/kg doxorubicin, 350; 35 Gy + 5 mg/kg doxorubicin, 510; 70 Gy + 10 mg/kg doxorubicin, 310. Mice receiving hind limb irradiation died principally from induced sarcomas in a dose dependent fashion (80% after 70 Gy and 55% after 35 Gy). Those treated with doxorubicin alone showed an increase in the actuarial incidence of spontaneous malignancies but died mainly from non-malignant causes. Histological examination did not reveal any characteristic cardiac, renal or pulmonary lesions. Doxorubicin did not increase the rate of development of radiation induced sarcomas in mice treated with combined modality.

Conservative surgery, patient selection, and chemoradiation as organ-preserving treatment for muscle-invading bladder cancer.

Multimodality organ-sparing treatment has, during the last decade, become the standard of care for many common malignancies. In appropriately selected patients with muscle-invading bladder cancer, bladder-preserving treatment combining surgical transurethral resection (TUR) with chemoradiation therapy offers a chance for long-term cure and survival equal to cystectomy, while also affording a 60% to 70% chance of maintaining a normally functioning bladder. Selection criteria helpful in determining appropriate patients for bladder preservation include such variables as small tumor size, that a visibly complete TUR is possible, the absence of hydronephrosis and that a complete response (CR) to induction chemoradiotherapy was achieved. Selecting patients based on response to induction therapy allows for prompt cystectomy if residual disease is found or for prompt consolidation chemoradiotherapy if a CR with induction therapy is achieved. Bladder-preserving treatment usually results in a normally functioning bladder without incontinence or hematuria for stage T2 and T3a patients. Stage T3b-T4 patients are locally controlled less frequently using these techniques. However, no data exist to suggest that patients with more advanced disease are in any way disadvantaged by preoperative chemoradiotherapy as an attempt at bladder conservation. Patients require close urological surveillance as do any patients with superficial bladder cancer who are being treated conservatively. As studies addressing the possibility of organ preservation continue to show positive results, more patients will become informed about and will be offered selective bladder-sparing approaches as one-treatment option.

The Patterns of Care Survey of radiation therapy in localized prostate cancer: similarities between the practice nationally and in minority-rich areas.

PURPOSE: Over the last two decades, the chance for the cure of localized prostate cancer by radiation has been improved by the widespread use of PSA for early detection and by a number of technical advances in treatment delivery. This study was designed to determine whether the stage of presentation and the quality of radiation treatment delivered are comparable between Caucasian and minority patients nationally and within minority-rich areas. METHODS AND MATERIALS: A random survey conducted for the Patterns of Care Study in Radiation Oncology of 80 facilities treating patients with radiation in the USA. Of these, 67 comprise the "National Survey" and 13 a "Minority-Rich" survey (>40% of treated patients are minorities). Nine hundred twenty-six men with localized prostate cancer were treated in 1994. Five hundred ninety-five were in the national and 331 in the minority-rich survey. The main outcome measures were the clinical features of Caucasian and minority men at presentation and technical characteristics of the treatment delivered to them. RESULTS: African-American men presented with more advanced disease (higher-presenting PSA and T-stage) than Caucasians in both the national and the minority-rich surveys. Hispanics also presented with later disease and could be grouped with African-American men rather than Caucasians. Overall the stage and PSA at presentation was earlier than seen in the previous Patterns of Care Study survey of 1989. The quality of treatment delivered has improved since 1989, with no distinction seen between those facilities sampled nationally and those within minority-rich areas. CONCLUSION: African-American and Hispanic men with prostate cancer present for therapy at a later stage than Caucasian men, but when they do, the treatment received is of comparable quality.

Multivariate determinants of radiocurability. I: Prediction of single fraction tumor control doses.

PURPOSE: The relationship between various laboratory determinants of radiocurability considered alone and in combination, and the observed 50% tumor control dose, has been examined in rodent and xenografted human tumors. METHODS AND MATERIALS: The single fraction 50% tumor control dose (TCD50) under normal and clamp hypoxic conditions, 50% tumor cell transplant dose (Td50), and in vitro estimated tumor cell radiosensitivity parameters, were determined in each of six tumor types (four isografted murine and two xenografted human tumors). Subcutaneous transplant sites and identical or similar tumor generations were used for both the Td50 and TCD50 studies. Radiosensitivity parameters were obtained using the clonogenic assay, after allowing cells to enter the active growth phase to recover from trypsin induced alterations of cell radiosensitivity. Both control and irradiated cells were multiplicity corrected. RESULTS: No single parameter (InTd50, hypoxic fraction, or intrinsic radiosensitivity) correlated with the observed tumor control doses under aerobic or hypoxic conditions. However, when considered in combination, clonogenic fraction (estimated by Td50(-1)), and intrinsic radiosensitivity, predicted the rank-order of tumor control doses with a significant degree of accuracy, and tumor hypoxia influenced the value of the control dose. All parameters were demonstrated to be significant determinants of radiocurability, with substantial tumor to tumor variation in the relative importance of each. For the six tumor types, the combined laboratory determinants predicted 50% tumor control doses which differed from the observed TCD50s by an average of approximately 9 Gy under hypoxic conditions. CONCLUSION: The results obtained demonstrate: (a) the necessity of simultaneously considering all determinants of radiocurability if the role of a single determinant is to be assessed; (b) laboratory determinants may accurately predict tumor radiocurability.

The combination of cis-platin based chemotherapy and radiation in the treatment of muscle-invading transitional cell cancer of the bladder.

Radical cystectomy is the standard of care for patients with muscle-invading transitional cell carcinoma of the bladder. More limited surgery is only useful in highly selected patients and radiation therapy alone gives overall local-control rates under 40%. Phase II studies have shown that when radiation and trans-urethral surgery are combined with cis-platin based chemotherapy local-control rates increase such that the majority of patients preserve a tumor-free functional bladder. Up to 85% of patients selected for bladder sparing therapy on the basis of their initial response to chemo-radiation may keep their bladders. This figure could increase further when other powerful prognostic factors such as the presence of hydronephrosis, the presence of carcinoma in situ, and DNA ploidy are also taken into account in initial patient selection. The activity of cisplatin combinations in metastatic disease is not in doubt with up to 50% response rates generally reported. The hope that this will translate into the eradication of micrometastatic disease (known to be present in up to 40% of patients at diagnosis) has yet to be borne out. Those randomized trials so far reported have not shown any survival advantage when combined-modality therapy is compared to radiation alone. The addition of combination chemotherapy to radiation does not increase bladder morbidity but carries a considerable systemic penalty. Thus, despite promising Phase II studies, until local control and survival benefit is proven in a randomized trial it should continue to be regarded as experimental.

The long-term effect on PSA values of incidental prostatic irradiation in patients with pelvic malignancies other than prostate cancer.

PURPOSE: To determine the effect of external beam radiation therapy on serum prostate-specific antigen (PSA) production by the benign prostate. METHODS AND MATERIALS: We studied a cohort of 24 men receiving treatment for cancer of the bladder or rectum. The radiation fields in all cases encompassed the prostate gland, and none of the patients were known to have prostate cancer. All patients had 2 or more PSA estimations obtained in the years following their radiation treatment. A second group of 46 patients who had undergone radical external beam radiation therapy for prostate cancer and who were clinically disease free 8-22 years later were also observed, with a median of 5.8 years of PSA observations. RESULTS: Only 3 of the 24 patients in the first group showed a significant rise of > 0.2 ng/ml in their serum PSA levels, with a median of 3.3 years follow-up from the first PSA test. Seven of 24 showed progressive declines, and 14 of 24 showed steady levels. The median PSA for this group was < or = 0.5 ng/ml. Only 6 of the 46 in the second group showed a PSA rise of > 0.2 ng/ml. Thirty-four had stable values, and 6 had further declines. Again, the median PSA for the entire group was < or = 0.5 ng/ml. CONCLUSION: Recovery of prostatic secretory function is an uncommon event after external beam radiation. The concern that this might significantly confound new definitions of biochemical failure after radical radiation for prostate cancer that are based on progressively rising PSA values thus appears to be unfounded.

The growth and cell kinetics of a secondary tumor after radiation or surgical treatment of the primary tumor.

Early transplants of a spontaneous mouse fibrosarcoma (FSa II) were used to investigate whether radiation or surgical treatment of a tumor in the leg altered the growth or cell kinetics of a second tumor in the axilla. The volume doubling times and in vivo Bromodeoxyuridine labeling indices of the axillary tumors were the same in the control group and in the groups which received 70 Gy to the leg tumor or normal leg. After surgical removal of the leg tumor, there was small reduction in the time to reach 1500 mm3 (4.0 vs 4.6 days) and an increase in Bromo-deoxyuridine labeling index at Day 3 (18% to 24%) in the axillary tumors. In all groups, there was a fall in labeling index with time reflecting increasing tumor size.