Assessment of the current and emerging criteria for the histopathological classification of lung neuroendocrine tumours in the lungNENomics project.

BACKGROUND: Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers. PATIENTS AND METHODS: Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm2. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value. RESULTS: The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value. CONCLUSIONS: This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.

Pulmonary neuroendocrine neoplasms with well differentiated morphology and high proliferative activity: illustrated by a case series and review of the literature.

OBJECTIVES: Pulmonary neuroendocrine neoplasms (NENs) are subdivided in carcinoids and neuroendocrine carcinomas (small cell lung carcinoma and large cell neuroendocrine carcinoma (LCNEC)), based on the presence of necrosis and mitotic index (MI). However, it is unclear if tumors with well differentiated morphology but high proliferation rate should be regarded as LCNEC or as high grade carcinoids. In previous case series, a longer overall survival then expected in LCNEC has been suggested. We describe 7 of those cases analyzed for pRb expression and overall survival. MATERIAL AND METHODS: Cases with well differentiated morphology, but MI > 10/2mm2 and/or Ki-67 proliferation index >20% were selected based on pathology reports of consecutive NENs in our university medical center (Maastricht UMC+, 2007-2018) and confirmed by pathological review. Immunohistochemistry was performed to assess pRb expression. RESULTS: Seven stage IV cases were included in this study. Median overall survival was 8 months (95% confidence interval 5-11 months). Cases with well differentiated morphology and preserved pRb expression (4/7) had a median overall survival of 45 months. CONCLUSION: A subgroup of pulmonary NENs with well differentiated morphology but high proliferation rate likely exists. pRb staining might be helpful to predict prognosis, but clinical relevance remains to be studied.

Integrative and comparative genomic analyses identify clinically relevant pulmonary carcinoid groups and unveil the supra-carcinoids.

The worldwide incidence of pulmonary carcinoids is increasing, but little is known about their molecular characteristics. Through machine learning and multi-omics factor analysis, we compare and contrast the genomic profiles of 116 pulmonary carcinoids (including 35 atypical), 75 large-cell neuroendocrine carcinomas (LCNEC), and 66 small-cell lung cancers. Here we report that the integrative analyses on 257 lung neuroendocrine neoplasms stratify atypical carcinoids into two prognostic groups with a 10-year overall survival of 88% and 27%, respectively. We identify therapeutically relevant molecular groups of pulmonary carcinoids, suggesting DLL3 and the immune system as candidate therapeutic targets; we confirm the value of OTP expression levels for the prognosis and diagnosis of these diseases, and we unveil the group of supra-carcinoids. This group comprises samples with carcinoid-like morphology yet the molecular and clinical features of the deadly LCNEC, further supporting the previously proposed molecular link between the low- and high-grade lung neuroendocrine neoplasms.

Procedural and long-term outcome of primary percutaneous coronary intervention in octogenarians.

Background/objectives. To investigate the procedural and long-term outcome of primary percutaneous coronary intervention (PCI) in octogenarians with an acute myocardial infarction.Methods. We performed a retrospective analysis of all consecutive octogenarian patients (n=98) with an acute myocardial infarction treated with primary PCI in the Catharina Hospital in the year 2006. We compared procedural results and outcome with a matched control group composed of non-octogenarians undergoing primary PCI. Follow-up period was one year.Results. The initial success rate of PCI was similar in the two groups but short-term mortality was higher among the elderly patients: 30-day mortality 26.3 vs. 9.6%. Age-adjusted mortality between 30 days and one year was comparable in the two groups and similar to natural survival in the Netherlands. Octogenarians were less likely to have a normal left ventricular function during follow-up (48.3 vs. 66.7%). New York Heart Association (NYHA) class and recurrence rate of myocardial infarction was higher among octogenarians.Conclusion. Technical success rate during primary PCI was as good for octogenarians as in younger patients, but 30-day mortality, though acceptable, was higher among the elderly. After 30 days, age-adjusted mortality was comparable in both groups. (Neth Heart J 2010;18:129-34.).

Sequential treatment for recurrent localized prostate cancer.

To compare toxicity and efficacy of both salvage prostatectomy and salvage radiotherapy for prostate cancer a retrospective analysis was conducted. Thirty-two and 41 patients were treated with external beam radiotherapy or prostatectomy for cT1c-T2 prostate cancer later requiring salvage surgery or radiotherapy. Salvage surgery was performed when a local recurrence was biopsy confirmed and life-expectancy was more than 10 years. Salvage external beam radiotherapy was performed when PSA rose over 0.1 ng/ml in the absence of systemic disease. Ten-year PSA-recurrence free survival after primary treatment in the salvage surgery group and salvage radiotherapy groups was 55% and 44% (P > 0.05) respectively whereas prostate cancer specific survival was 93% and 89%, respectively (P > 0.05). Both, biopsy Gleason score prior to primary treatment and PSADT prior to salvage treatment were predictive of PSA-recurrence free survival. Patients after salvage radiotherapy (13%) were less likely to wear pads for urinary incontinence compared to patients after salvage surgery (56%). Erectile dysfunction was more frequent after salvage surgery (81%) compared to salvage radiotherapy (61%). Salvage surgery and salvage prostatectomy after primary cT1-2 prostate cancer provide comparable PSA-recurrence free survival after primary treatment. Genitourinary functions were better preserved in the salvage radiotherapy group compared to the salvage prostatectomy group.

Survival after bladder-preservation with brachytherapy versus radical cystectomy; a single institution experience.

OBJECTIVE: To evaluate the long-term survival following brachytherapy and following cystectomy of patients with invasive bladder cancer treated in our institution. PATIENTS AND METHODS: Between 1988 and 2000 108 patients with solitary, organ confined T1-T2 invasive bladder cancer of < or = 5 cm were treated with a transurethral resection, and a course of external beam radiotherapy (30 Gy) followed by 40 Gy brachytherapy. The overall and disease specific survival rates of these patients are compared with those of 77 patients with T1-T2 invasive bladder cancer treated with cystectomy between 1988-2003. RESULTS: The 5/10 year overall survival rates were 62%/50% after brachytherapy and 67%/58% after cystectomy (p = 0.67). The 5/10 year disease specific survival rates were 73%/67% after brachytherapy and 72%/72% after cystectomy (p = 0.28). When adjusted for age, multiplicity, T-stage, N-stage and grade, the 5/10 year overall survival rates were 65%/53% after brachytherapy and 62%/51% after cystectomy, respectively. The adjusted disease specific survival rates were 75%/70% after brachytherapy and 66%/66% after cystectomy. CONCLUSIONS: This study does not provide evidence regarding survival against the use of bladder preservation with brachytherapy for patients with solitary, T1-T2 invasive bladder cancer of < or = 5 cm diameter, seeking bladder-sparing alternatives to radical cystectomy.

Implementation of anticoagulation guidelines in general practice: a practice report.

There is evidence that patients with atrial fibrillation (AF) are not being anticoagulated according to the published guidelines. Difficulty in identifying such patients may partly explain this. In this study, we examined the yield of different methods for detecting people with AF in a single general practice: hospital discharge letters, referrals to cardiology, staff recall of cases, records of relevant prescriptions from the local pharmacist and similar records from the GMS Payments Board. A review of all files of patients over 45 was undertaken as the definitive method of case identification. Recommended anticoagulation guidelines were applied using structured patient interviews. The practice population was 5,473. Sixty-eight patients with AF were identified giving a practice prevalence of 1.2%. The GMS Payment Board records for the prescribing of all specified medications was the most sensitive method (58.8%) with a positive predictive value of 21.6%. Of nine patients without cognitive impairment at consultation, four (44.4%) opted to change to the recommended treatment. Reluctance of patients to adopt current treatment guidelines points to the need for further work in this area.

Prognostic factors in transitional cell cancer of the bladder: an emerging role for Bcl-2 and p53.

BACKGROUND AND PURPOSE: In a recent study on patients with transitional cell cancer of the bladder treated with curative radiotherapy following TUR-T, we demonstrated that a low apoptotic index and p53 positivity were associated with poor local control. The purpose of this study was to assess the prognostic significance of additional markers implicated in regulation of cell cycle and apoptosis. PATIENTS AND METHODS: Bcl-2, Bax and p21 positivity were detected immunohistochemically on paraffin-embedded pre-treatment biopsies from 83 patients with invasive transitional cell cancer (TCC) of the bladder, treated with radiotherapy. In addition, markers determined in an earlier analysis, i.e.: p53, apoptotic index, cyclin D1, retinoblastoma protein and Ki-67 were included in the multivariate analysis. A stepwise proportional hazard analysis was performed, adjusting for classic prognostic factors (T-stage, grade, multifocality and macroscopic completeness of the TUR). Positivity was defined as >10% of tumor cells staining positive for Bcl-2, Bax and p21, and >20% for p53. RESULTS: Bcl-2 positivity was found in 63%, Bax was positive in 52% and p21 in 55% of cases. In the PH analysis Bcl-2 positivity was found to be related to poor local control (36 vs. 72% at 3 years; P=0.003), as well as to shorter disease-specific survival (74 vs. 94% at 3 years; P=0.017). Evidence for an adverse effect of p53 positivity was also found (local control: 32 vs. 69% at 3 years;P=0.037, disease-specific survival: 76 vs. 92% at 3 years; P=0.043). In an additional PH analysis, we found poor local control rates for bladder cancers with combined Bcl-2 and p53 positivity (17 vs. 65% at 3 years; P=0.0017), and lower disease specific survival (60 vs. 92%; P=0.0024), disease-free survival (7 vs.35%, P=0.0023) and overall survival (39 vs. 80%; P=0.0018). CONCLUSION: This study provides evidence for a poor outcome in patients treated with radiotherapy for TCC of the bladder expressing both Bcl-2 and p53. This relationship was found for local control and disease-free, disease-specific and overall survival.

Sexuality preserving cystectomy and neobladder: initial results.

PURPOSE: Standard cystectomy for bladder cancer in males and females includes removal of organs that are vital to normal sexual function. We report the initial results of modified cystectomy in males and females meant to preserve all sexual function, called sexuality preserving cystectomy and neobladder. MATERIALS AND METHODS: Sexuality preserving cystectomy and neobladder consists of pelvic lymph node dissection followed by cystectomy alone with preservation of the vasa deferentia, prostate and seminal vesicles in males, and all internal genitalia in females. An ileal neobladder is anastomosed to the margins of the prostate in males and urethra in females. Indications for this type of surgery are bladder cancer stages T1-T3 with absent tumor growth in the bladder neck in males and females, absent tumor in the prostatic urethra in males and absent invasive tumor in the trigone in females. Further requirements are patient motivation for the preservation of sexual function, no prostate cancer and no cervical/uterine abnormalities. Preoperative evaluation in males involves prostate specific antigen measurement and transrectal ultrasound with sextant prostate biopsies, while females undergo gynecological examination with a cervical smear and transvaginal ultrasound. Voiding and sexual function are assessed by a structured interview with preoperative urodynamics. Erectile function is evaluated by RigiScan (UroHealth Systems, Inc., Laguna Niguel, California) nocturnal penile erection measurement. A short course of 20 Gy. external radiation therapy to the bladder is given shortly before surgery. No patient has been lost to followup, which involves repeat RigiScan examination and regular endoscopy. All patients were entered in a prospective clinical trial approved by the medical ethics committee. RESULTS: From 1995 to 1998, 10 males and 3 females 38 to 71 years old (mean age 55) were enrolled in this protocol. Bladder cancer was stage T carcinoma in situ N0M0 in 1 case, Ta multiple grade 3 N0M0 in 1, T1 multiple grade 3 N0M0 in 4, T2 grade 3 N0M0 in 5, T2 grade 3 N1M0 in 1 and T3 grade 3 N1M0 in 1. Mean followup was 3.5 years (range 3 to 6). Two patients died of widespread metastasis without local recurrence. In 1 case prostate cancer developed 5 years after sexuality preserving cystectomy and neobladder, which was treated with external radiation therapy. Erection was normal in 7 men with antegrade ejaculation in 5 and vaginal lubrication was reported to be normal in all women. Daytime continence was achieved in 9 of the 10 males and 2 of the 3 females, while nighttime continence was achieved in 7 and 2, respectively. One woman and 3 men perform intermittent catheterization because of post-void residual urine after voiding. Postoperatively a vaginal fistula and ureteral stenosis developed in 1 case each. CONCLUSIONS: Sexuality preserving cystectomy and neobladder achieves maximal tissue conservation, resulting in preserved normal sexual function and satisfactory urinary tract reconstruction. Using strict criteria oncological results have not been jeopardized to date.

Apoptosis, proliferation and p53, cyclin D1, and retinoblastoma gene expression in relation to radiation response in transitional cell carcinoma of the bladder.

PURPOSE: To determine whether the apoptotic index, the Ki67 index, and the expression of the p53, cyclin D1, and retinoblastoma genes correlate with local control, overall survival, and time to distant metastases in invasive bladder cancer treated with external beam radiation. METHODS AND MATERIALS: Paraffin-embedded pretreatment biopsies from 83 patients with invasive transitional cell carcinoma of the bladder were scored morphologically for apoptosis and immunohistochemically for Ki67, p53, cyclin D1, and retinoblastoma gene expression. Survival analysis methods were used to assess overall survival, local control, and freedom from distant metastases. A multiple proportional hazard (PH) regression analysis was performed to study the prognostic value of the abovementioned biologic parameters (all divided into two categories, except Ki67) in addition to classical prognostic factors such as T stage, histologic grade, multifocality of the tumor, and completeness of transurethral resection. All patients were treated with external beam radiation as sole treatment. Median follow-up for the 19 patients still living was 7.5 years. RESULTS: Apoptotic index varied from 0% to 3.4% with a mean of 0.8% and a median of 0.6%. Ki67 index varied from 0% to 60% with a mean of 14% and a median of 12%. P53 protein was detectable in 61% of the tumors. Overexpression of cyclin D1 was observed in 39% of the tumors and loss of retinoblastoma protein in 23% of the tumors. High Ki67 index was found to be significantly associated with p53 expression (p = 0.04) and cyclin D1 overexpression (p = 0.023). Cyclin D1 overexpression was found more often in Rb-positive tumors than in Rb-negative tumors (p = 0.006). Other associations between the markers are less clear. Biologic markers were not correlated with T stage or grade. In the PH analysis local control was found to be significantly better for tumors with wild-type p53 (p = 0.028). Also, tumors with an apoptotic index above the median value (0.6%) had a significantly better local control rate (p = 0.035). Ki67 index (p = 0.35), retinoblastoma gene expression (p = 0.30) and cyclin D1 overexpression (p = 0.61) were not found to have an additional predictive value regarding local tumor control. None of the tested biologic parameters were found to be associated with overall survival. Time to distant metastases was significantly shorter for tumors with high Ki67 index (p = 0.01) and tumors with an apoptotic index less than median (p = 0.009). CONCLUSIONS: The results of our study provide evidence for a prognostic value of p53 expression and apoptotic index with respect to the radiation response in bladder cancer in addition to more conventional prognosticators. The value of these parameters as a predictive assay for radiation response warrants confirmation in larger and prospective studies.

Translational research offers individually tailored treatments for cancer patients.

The measurement of the effect of cisplatin on DNA has become feasible with the development of antibodies against DNA adducts. In a phase II dose escalation trial with concomitant radiotherapy and daily cisplatin in lung cancer, we found that patients with high DNA adduct levels measured in the buccal mucosa had a much higher survival rate than patients with a low or undetectable amount of cisplatin-DNA adducts. The use of this assay may therefore allow the selection of individual patients for concomitant treatment with cisplatin and radiotherapy, as has been shown to be effective in randomized trials in patients with lung, head and neck, and cervix malignancies. To predict the response to radiation treatment, assays have been developed for tumor growth potential by measuring the labeling index after intravenous injection of IdUrd or by estimating cyclin D1 expression. Intrinsic radiation sensitivity of human tumors can be estimated by conventional techniques, which are probably too slow or cumbersome for routine use, or with more rapid assays, such as those for chromosome damage with fluorescent probes. These assays should be able to guide us in the adaptation of the individual radiation doses that should be applied and to select patients for an accelerated or hyperfractionated regimen. Pretreatment levels of apoptosis may also be helpful in predicting treatment outcome, although the data so far show inconsistent results. A better understanding of the signal transduction pathways involved in radiation-induced apoptosis may help in the design of studies aimed at modulating the apoptotic response, thereby increasing cell kill. We have recently shown that alkyllysophospholipids, which inhibit mitogenic signaling, induce apoptosis in a variety of tumor cell lines. In combination with ionizing radiation, these compounds cause an enhancement of apoptotic cell kill. This type of a signaling-based intervention could form the basis for new therapeutic strategies. The role of hormonal therapy in breast cancer patients, both in an adjuvant setting and for the treatment of disseminated disease, is becoming increasingly important. The development of a functional assay for the estrogen receptor (ER-FASAY), based on a yeast growth assay, provides a better way than the classical immunohistochemistry assay of estimating abnormal function of the receptor in tumors. These assays are simply examples, illustrating how clinicians could improve the therapeutic outcome for their patients by implementing knowledge obtained in the laboratory in clinical decision making. With further optimization of these assays, this holds the promise for the future that the treatment for each patient can be tailored rationally to the biology of the individual.

[Total prostatectomy--a good option for residual prostate carcinoma after I-125 implantation of external radiotherapy]. / Totale prostatectomie goede mogelijkheid bij residueel prostaatcarcinoom na jodium-125-behandeling of uitwendige radiotherapie.

OBJECTIVE: To evaluate the results of salvage prostatectomy after previous radiation therapy for locally confined prostate cancer. DESIGN: Retrospective. METHOD: Data were collected from the records of all patients with prostate cancer who underwent salvage prostatectomy after I-125 implantation or external radiation therapy in the Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands, 1991-1997. Indications for surgery were: locally confined histologically proven residual cancer, good life expectancy, fit for surgery. Standard preoperative workup was done together with a tumour marker measurement, transrectal ultrasound with biopsy of the prostate and a bonescan. Per- an postoperative complications, pathology result and postoperative PSA were assessed. Progression free survival, overall survival and cancer specific survival were calculated according to the Kaplan-Meier method. RESULTS: 10 patients with a mean age of 67.2 years (range: 57-79) and a median follow up of 78 months (range: 0-89) underwent a total prostatectomy after I-125 implantation (7 patients) or external radiation therapy (3 patients). One patient died after the operation from acute tubular necrosis. One patient developed an internal hernia, requiring surgery. Four patients needed pads during the daytime for stress incontinence for urine. The 5-year progression free survival was 72% (95% confidence interval (95% CI): 44-100), the overall survival was 90% (95% CI: 73-100) and the cancer specific survival was 90% (95% CI: 73-100). No local recurrences were detected. CONCLUSION: The local control and the 5-year survival were good in this selected patient group.

Muscle-invasive bladder cancer treated with external beam radiation: influence of total dose, overall treatment time, and treatment interruption on local control.

PURPOSE: To evaluate and eventually quantify a possible influence of tumor proliferation during the external radiation course on local control in muscle invasive bladder cancer. METHODS AND MATERIALS: The influence of total dose, overall treatment time, and treatment interruption has retrospectively been analyzed in a series of 379 patients with nonmetastasized, muscle-invasive transitional cell carcinoma of the urinary bladder. All patients received external beam radiotherapy at the Netherlands Cancer Institute between 1977 and 1990. Total dose varied between 50 and 75 Gy with a mean of 60.5 Gy and a median of 60.4 Gy. Overall treatment time varied between 20 and 270 days with a mean of 49 days and a median of 41 days. Number of fractions varied between 17 and 36 with a mean of 27 and a median of 26. Two hundred and fourty-four patients had a continuous radiation course, whereas 135 had an intended split course or an unintended treatment interruption. Median follow-up was 22 months for all patients and 82 months for the 30 patients still alive at last follow-up. A stepwise procedure using proportional hazard regression has been used to identify prognostic treatment factors with respect to local recurrence as sole first recurrence. RESULTS: One hundred and thirty-six patients experienced a local recurrence and 120 of these occurred before regional or distant metastases. The actuarial local control rate was 40.3% at 5 years and 32.3% at 10 years. In a multivariate analysis total dose showed a significant association with local control (p = 0.0039), however in a markedly nonlinear way. In fact only those patients treated with a dose below 57.5 Gy had a significant higher bladder relapse rate, whereas no difference in relapse rate was found among patients treated with doses above 57.5 Gy. This remained the case even after adjustment for overall treatment time and all significant tumor and patient characteristics. The Normalized Tumor Dose (NTD) (alpha/beta = 10) and NTD (alpha/beta = 15) were not significantly related to local control (p = 0.96 and p = 0.053, respectively). Only weak evidence was found for an association between local control and overall treatment time (p = 0.067). No difference in bladder relapse rate was found among patients treated with a continuous course and patients who had treatment interruptions (p = 0.099). Neither the length of the interruption, nor the actual number of treatment days has a significant influence on local control (p = 0.04 and p = 0.09, respectively). CONCLUSION: In contrast to two earlier, but smaller reports, in this study no significant effect of treatment prolongation on outcome after radiotherapy could be demonstrated and thus no support was found for an important role for tumor proliferation as the cause of treatment failure in muscle-invasive bladder cancer. Results of large-sized phase III trials will have to be awaited to show any benefit from reduction of the overall treatment time and to quantify the potential effect of tumor proliferation.

[Iodine-125 implantation in localized cancer of the prostate; too early for rejoicing]. / Jodium-125-implantatie bij gelokaliseerd prostaatcarcinoom: niet te vroeg juichen.

The role of I-125 implantation in treatment with curative intent of carcinoma of the prostate is not yet perfectly clear. No long-term results in large groups of patients have so far been published. An inherent restriction of the technique is that it is difficult to attain a high dose of radiation in the periphery of the prostate. Consequently, the technique appears to be less or not appropriate for peripherally located tumours or tumours with extracapsular spread. Implantation of I-125 should for the moment be regarded as an experimental therapy. Its application should be limited to strictly selected patients and should be carried out as a part of trials.

The use of a transverse CT image for the estimation of the dose given to the rectum in intracavitary brachytherapy for carcinoma of the cervix.

BACKGROUND AND PURPOSE: The three-dimensional (3D) dose distribution in combination with 3D anatomy of 13 patients treated for cervical carcinoma with intracavitary brachytherapy was analyzed. The aim of this study was to determine the correlation between a dose value obtained from the integral dose volume histogram (DVH) of the rectum and (a) the Nederlands Kanker Instituut (NKI) point of reference for the rectum dose (R) and (b) the highest dose to the frontal rectum wall in the transverse CT slice near the top of the vagina through point R. RESULTS: The correlation between the DVH rectum dose value for 2 cm3 in the highest dose region and the rectum dose at point R was poor (regression coefficient 0.50). On the contrary, however, the correlation between the DVH rectum dose value for 2 cm3 in the highest dose region and the maximum rectum dose value in a transverse CT slice through point R was good (regression coefficient 0.90). CONCLUSIONS: The maximal rectum dose value obtained from a transverse CT slice near the top of the vagina through point R was found to be a more representative point for the rectal dose burden and might therefore show a good correlation with complications. The point of reference for the rectal dose (R) was found not to be a reliable estimation of the maximal dose in the rectum.

Muscle-invasive bladder cancer treated with external beam radiotherapy: pretreatment prognostic factors and the predictive value of cystoscopic re-evaluation during treatment.

PURPOSE: To determine the relationship between tumour and patient characteristics and local control and survival for patients with T2 and T3 bladder cancer treated with radical external beam radiotherapy and to evaluate the predictive value of cystoscopic response evaluation during radiation on final outcome. MATERIALS AND METHODS: Records from 379 patients with non-metastasized T2 or T3 transitional cell carcinoma of the bladder were reviewed. All patient received external beam radiotherapy at The Netherlands Cancer Institute during the period from 1977 to 1990. The total dose varied from 50 to 75 Gy with a mean of 60.5 Gy and a median of 60.4 Gy. The median follow-up was 22 months for all patients and 82 months for the 30 patients still alive at last follow-up. A stepwise procedure using proportional hazard regression was used to identify prognostic factors with respect to local recurrence and survival. RESULTS: One hundred thirty-six patients experienced a local recurrence and 120 of these occurred before regional or distance metastases. The actuarial results at 5 years were 40.3% local control (SE 4.0%), 24.9% disease-free rate (SE 3.0%) and 22.2% overall survival (SE 2.2%). In the univariate analysis age, performance status, result of intravenous pyelography (IVP) and T-stage were found to be related to overall survival and multifocality was related to local control. Multivariate analysis revealed that only age and T-stage were related to survival and only multifocality was related to local control. In patients with solitary tumours who were identified as having the most favourable outcome. local control was 50% at 5 years. Local control in 89 patients who had a cystoscopic evaluation during treatment was identical regardless of whether a complete, partial or no response was observed. Furthermore, local control was identical in patients selected on the basis of a favourable response and in unselected patients. CONCLUSIONS: Although we identified some significant prognostic factors, their predictive value is not strong enough to allow accurate estimation of treatment effect and disease outcome. Cystoscopic response evaluation during treatment was found not to provide reliable information to direct further treatment. Prospective studies to identify ways to select patients for bladder conservation using definitive radiotherapy are urgently needed.

An analysis of the effect of ovoid shields in a selectron-LDR cervical applicator on dose distributions in rectum and bladder.

PURPOSE: A disadvantage of ovoid shields in a Fletcher-type applicator is that these shields cause artifacts on postimplant CT images. CT images, however, make it possible to calculate the dose distribution in the rectum and the bladder. To be able to estimate the possible advantage of having CT information over the use of ovoid shields without having CT information, we investigated the influence of shielding segments in a Fletcher-type Selectron-LDR applicator on the dose distribution in rectum and bladder. METHODS AND MATERIALS: Contours of rectum and bladder were delineated on transaxial CT slices of 15 unshielded applications. Of the volumes contained within these structures dose-volume histograms (DVHs) were calculated. In a similar way, DVHs of simulated shielded applications were calculated. The reduction, due to shielding, of the dose to the 2 cm3 (D2) and 5 cm3 (D5) volume of the cumulative DVHs of rectum and bladder, were determined. An isodose pattern in the sagittal plane through the center of each applicator was plotted to compare the location of the shielded area with the location of maximum dose in rectum and bladder in the unshielded situation. In two cases local dose reductions to the rectal wall were determined by calculating the dose in points at 10-mm intervals on the rectal contours. RESULTS: For the rectum, the reduction of D2 ranged from 0 to 11.1%, with an average of 5.0%; the reduction of D5 ranged from 2.3 to 12.1%, with an average of 6.4%. The reduction of D2 and D5 for the bladder ranged from 0 to 11.9% and from 0 to 11.6%, with average values of 2.2 and 2.6%, respectively. In 8 out of 15 cases the rectal maximum dose was located inferior to the shielded area. In all cases except one the bladder maximum dose was located superior to the shielded area. Local dose reductions on the rectal wall can be as high as 30% or more in an optimally shielded area. CONCLUSIONS: Reductions of D2 and D5 to rectum and bladder due to shielding are rather small, because the shielded area does usually not coincide with the high dose region and even if it does, the shielded area is too small to result in large reductions of these values. Because local dose reductions vary largely, one should proceed with caution when calculating the dose in just one rectal or bladder reference point. Because large overall dose reductions cannot be achieved with shielding, it is safe to use an unshielded applicator when post implant CT images are used to realize optimized dose distributions.

A feasibility study of accelerated fractionation in radiotherapy of carcinoma of the urinary bladder.

PURPOSE: To establish the shortest possible overall treatment time, with respect to acute and late toxicity, in which a radiation dose of 66 Gy in 2 Gy/fraction can be administered to the urinary bladder. METHODS AND MATERIALS: In a stepwise fashion the overall treatment time of our routinely used conventional treatment schedule (66 Gy in 2 Gy/fraction in 6.5 weeks) was reduced to 5 weeks (Step 1) and then 4 weeks (Step 2). Shortening of the overall treatment time was obtained by giving two daily fractions during the last part of the treatment. The interfraction interval was a minimum of 6 h. Toxicity was scored according to a modified scheme of the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer. Fifteen patients received the 5-week schedule and 25 patients received the 4-week schedule. RESULTS: Note that feasibility was very good for the 5-week schedule. No Grade > or = 3 acute bowel or bladder toxicity was seen in these patients. Severe late complications did not occur. In the 4-week schedule, acute bladder toxicity was unaffected but acute bowel toxicity was considerably increased. Of the 25 patients, 16 suffered from Grade 3 toxicity, 3 from Grade 4, and 1 from Grade 5 toxicity. Actuarial analysis at 3 years showed a 31% incidence of Grade 4 late bladder complications. CONCLUSION: It is concluded that the 5-week schedule is well tolerated. In contrast, the 4-week schedule shows unacceptable acute bowel toxicity and an increased incidence of late bladder complications (p = 0.043).