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H Bartelink

Publications and source records attributed to H Bartelink.

At least 55 records · Page 3Linked to original sources
PubMed1999

The influence of the boost in breast-conserving therapy on cosmetic outcome in the EORTC "boost versus no boost" trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups. European Organization for Research and Treatment of Cancer.

PURPOSE: To evaluate the influence of a radiotherapy boost on the cosmetic outcome after 3 years of follow-up in patients treated with breast-conserving therapy (BCT). METHODS AND MATERIALS: In EORTC trial 22881/10882, 5569 Stage I and II breast cancer patients were treated with tumorectomy and axillary dissection, followed by tangential irradiation of the breast to a dose of 50 Gy in 5 weeks, at 2 Gy per fraction. Patients having a microscopically complete tumor excision were randomized between no boost and a boost of 16 Gy. The cosmetic outcome was evaluated by a panel, scoring photographs of 731 patients taken soon after surgery and 3 years later, and by digitizer measurements, measuring the displacement of the nipple of 3000 patients postoperatively and of 1141 patients 3 years later. RESULTS: There was no difference in the cosmetic outcome between the two treatment arms after surgery, before the start of radiotherapy. At 3-year follow-up, both the panel evaluation and the digitizer measurements showed that the boost had a significant adverse effect on the cosmetic result. The panel evaluation at 3 years showed that 86% of patients in the no-boost group had an excellent or good global result, compared to 71% of patients in the boost group (p = 0.0001). The digitizer measurements at 3 years showed a relative breast retraction assessment (pBRA) of 7.6 pBRA in the no-boost group, compared to 8.3 pBRA in the boost group, indicating a worse cosmetic result in the boost group at follow-up (p = 0.04). CONCLUSIONS: These results showed that a boost dose of 16 Gy had a negative, but limited, impact on the cosmetic outcome after 3 years.

Adult↗
PubMed1999

Validation of the methods of cosmetic assessment after breast-conserving therapy in the EORTC "boost versus no boost" trial. EORTC Radiotherapy and Breast Cancer Cooperative Groups. European Organization for Research and Treatment of Cancer.

PURPOSE: To evaluate both qualitative and quantitative scoring methods for the cosmetic result after breast-conserving therapy (BCT), and to compare the usefulness and reliability of these methods. METHODS AND MATERIALS: In EORTC trial 22881/10882, stage I and II breast cancer patients were treated with tumorectomy and axillary dissection. A total of 5318 patients were randomized between no boost and a boost of 16 Gy following whole-breast irradiation of 50 Gy. The cosmetic result was assessed for 731 patients in two ways. A panel scored the qualitative appearance of the breast using photographs taken after surgery and 3 years later. Digitizer measurements of the displacement of the nipple were also made using these photographs in order to calculate the breast retraction assessment (BRA). The cosmetic results after 3-year follow-up were used to analyze the correlation between the panel evaluation and digitizer measurements. RESULTS: For the panel evaluation the intraobserver agreement for the global cosmetic score as measured by the simple Kappa statistic was 0.42, considered moderate agreement. The multiple Kappa statistic for interobserver agreement for the global cosmetic score was 0.28, considered fair agreement. The specific cosmetic items scored by the panel were all significantly related to the global cosmetic score; breast size and shape influenced the global score most. For the digitizer measurements, the standard deviation from the average value of 30.0 mm was 2.3 mm (7.7%) for the intraobserver variability and 2.6 mm (8.7%) for the interobserver variability. The two methods were significantly, though moderately, correlated; some items scored by the panel were only correlated to the digitizer measurements if the tumor was not located in the inferior quadrant of the breast. CONCLUSIONS: The intra- and interobserver variability of the digitizer evaluation of cosmesis was smaller than that of the panel evaluation. However, there are some treatment sequelae, such as disturbing scars and skin changes, that can not be evaluated by BRA measurements. Therefore, the methods of cosmetic evaluation used in a study must be chosen in a way that balances reliability and comprehensiveness.

Adult↗
PubMed1999

Consequences of voice impairment in daily life for patients following radiotherapy for early glottic cancer: voice quality, vocal function, and vocal performance.

PURPOSE: To assess consequences of voice impairment in daily life for patients following radiotherapy for early glottic cancer, by means of a multidimensional analysis protocol including voice quality, vocal function, and vocal performance measures. METHODS AND MATERIALS: A total of 60 men treated with radiotherapy (66 Gy/33 fractions, 60 Gy/30 fractions, 60 Gy/25 fractions) for early T1 glottic cancer and 20 matched control speakers filled in questionnaires on vocal performance. Furthermore, perceptual analyses of voice quality and stroboscopic measures of vocal function were performed. There was a longitudinal group of 10 patients from whom data were collected before, as well as 6 months and 2 years after, radiation. Furthermore, data were collected on 5 separate groups of 10 patients each: before, 6 months after, 2 years after, 3-7 years after, and 7-10 years after radiation. RESULTS: High correlations were found between self-ratings of vocal performance and several voice measures. Patients before radiotherapy experienced poor voice characteristics that improved 6 months to 10 years after treatment, and became comparable to vocal performance of control speakers in 50% of the patients. Following radiotherapy, deviant voice characteristics and consequences in daily life occurred significantly more often for patients in whom initial diagnosis consisted of stripping the vocal cord instead of biopsies and for patients who continued smoking after treatment. CONCLUSION: Voice characteristics of patients diagnosed with early glottic cancer improved after radiotherapy, and became normal in half of our patients. Stripping the vocal cord for initial diagnosis and continued smoking after treatment decreased deviant voice characteristics.

Aged↗
PubMed1999

Alkyl-lysophospholipids activate the SAPK/JNK pathway and enhance radiation-induced apoptosis.

Alkyl-lysophospholipids (ALPs) represent a new class of antitumor drugs that induce apoptotic cell death in a variety of tumor cell lines. Although their precise mechanism of action is unknown, ALPs primarily act on the cell membrane, where they inhibit signaling through the mitogen-activated protein kinase (MAPK) pathway. Because stimulation of the stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) pathway is essential for radiation-induced apoptosis in certain cell types, we tested the effect of ALPs in combination with ionizing radiation on MAPK/SAPK signaling and apoptosis induction. Here, we present data showing that three ALPs, 1-O-octadecyl-2-O-methyl-rac-glycero-3-phosphocholine, hexadecylphosphocholine, and the novel compound octadecyl-(1,1-dimethyl-piperidinio-4-yl)-phosphate (D-21266) induce time- and dose-dependent apoptosis in the human leukemia cell lines U937 and Jurkat T but not in normal vascular endothelial cells. Moreover, in combination with radiation, ALPs strongly enhance the induction of apoptosis in both leukemic cell lines. All tested ALPs not only prevented MAPK activation, but, like radiation, stimulated the SAPK/JNK cascade within minutes. A dominant-negative mutant of c-Jun inhibited radiation- and ALP-induced apoptosis, indicating a requirement for the SAPK/JNK pathway. Our data support the view that ALPs and ionizing radiation cause an enhanced apoptotic effect by modulating the balance between the mitogenic, antiapoptotic MAPK, and the apoptotic SAPK/JNK pathways. This type of modulation of specific signal transduction pathways in tumor cells may lead to the development of new therapeutic strategies.

Apoptosis↗
PubMed1999

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSE: The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy. MATERIALS AND METHODS: Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis. RESULTS: From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16). CONCLUSIONS: The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

Analysis of Variance↗
PubMed1999

Towards prediction and modulation of treatment response.

The purpose of this paper is to evaluate new predictive assays and their potential to modulate treatment response. Their impact is presented in the context of three EORTC clinical trials in head and neck, lung and breast cancer, showing an improvement in survival by accelerated fractionation, concomitant use of cisplatin and radiotherapy and adjuvant hormonal treatment, respectively. Assays have been developed to predict the response to treatment by measuring tumor characteristics, such as the growth potential by the labeling index after i.v. injection of IdUrd, the extent of radiation-induced stable and unstable chromosome aberrations and the induction of apoptosis. These assays could guide us in the adaptation of the individual radiation doses and fractionation schedules. The measurement of the effect of cisplatin on DNA has become feasible with the development of antibodies against DNA adducts. In a recently completed 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 better survival rate than patients with a low or undetectable amount of cisplatin DNA adducts. A better understanding of the signal transduction pathways involved in radiation-induced apoptosis may help to design studies aimed at modulating the apoptotic response. We and others have recently shown that alkylphospholipids, 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 signaling-based intervention study may form the basis for new therapeutic strategies. Pretreatment levels of apoptosis may be helpful in predicting treatment outcome, although the data so far show inconsistent results. The importance of evaluating other tumor-biological parameters, including cell kinetics should be stressed. Based on assays predicting reliably the response to hormonal therapy, a more appropriate choice can be made for therapeutic intervention with hormonal therapy and for selecting the appropriate adjuvant therapy in breast cancer patients. The development of a functional estrogen receptor assay (ER-FASAY), based on a yeast growth-assay, provides a way of estimating abnormal function of the receptor in tumors with a positive estrogen receptor score as measured by a classical immuno-histochemistry assay. This yeast assay can also detect different DNA mutations of the estrogen receptor existing in an individual tumor specimen.

Antineoplastic Agents↗
PubMed1999

Prognosis after treatment for loco-regional recurrence after mastectomy or breast conserving therapy in two randomised trials (EORTC 10801 and DBCG-82TM). EORTC Breast Cancer Cooperative Group and the Danish Breast Cancer Cooperative Group.

The aim of this study was to investigate and compare the prognosis after treatment for loco-regional recurrences (LR) after (modified) radical mastectomy (MRM) or breast conserving therapy (BCT), in terms of overall survival and time to subsequent LR, in patients originally treated in two European randomised trials. In EORTC trial 10801 and DBCG trial 82-TM, 1,807 patients with stage I and II breast cancer were randomised to receive MRM or BCT from 1980 to 1989. All patients with a LR in these trials were analysed for survival and time to subsequent LR after salvage treatment. Of these, 133 patients had their LR as a first event, the majority within 5 years after initial treatment. The prognostic significance for survival and time to subsequent LR after salvage treatment was analysed in uni-, and multivariate analyses for a number of original tumour- and recurrence-related variables. After salvage treatment of LR after MRM or BCT, actuarial survival curves and the actuarial locoregional control curves were similar. The 5-year survival rates were 58% and 59% and the 5-year subsequent loco-regional control rates 62% and 63%, respectively. In a multivariate analysis, pN category (P = 0.03), pT category (P = 0.01) and vascular invasion (P = 0.02) of the primary tumour were the only independent prognostic factors for survival, whereas extensive LR (P < 0.001), interval < or = 2 years (P < 0.002) and pN+ at primary treatment (P = 0.004) were significant predictive factors for time to subsequent LR. The type of original treatment (MRM or BCT) did not have any prognostic impact. It is concluded that the survival and time to subsequent LR after treatment for an early loco-regional recurrence after MRM or BCT was similar in these two European randomised trials. This suggests that both after MRM and BCT an early LR is an indicator of a biologically aggressive tumour; early loco-regional relapse carries a poor prognosis and salvage treatment only cures a limited number of patients, whether treated by MRM or BCT originally.

Adult↗
PubMed1999

Radiotherapy: the last 25 years.

Some of the major changes in radiotherapy over the last years are reviewed in this paper. Radiotherapy has played a role in the changes in oncological practice including an increase in organ-sparing treatment and achieving good local control and improving survival. About half of all breast cancer patients are now treated with breast conserving therapy. Organ preservation, usually with multimodality therapy, has also been further developed in the treatment of cancers in the head and neck, anus, bladder and soft tissue sarcomas. Developments in radiobiology have led to the development of new fractionation schedules. Hyperfractionation allows an increase in the tumour dose whilst sparing normal tissues and accelerated fractionation combats accelerated tumour proliferation during treatment. Advances in accelerator technology and computerized treatment planning have enabled the development of three-dimensional conformal radiotherapy. This gives the oportunity to spare normal tissues and escalate the dose to the tumour. Quality control and standardization of dosimetry and treatment delivery at departmental and international level has also improved treatment results.

Dose Fractionation, Radiation↗
PubMed1999

Radiation dose homogeneity in an EORTC multicenter trial on breast irradiation.

The influence of the radiation dose on local control and cosmetic outcome in breast-conserving treatment for breast cancer is investigated in EORTC trial 2288110882. In this study 50 Gy is administered to the whole breast, and the effect of an additional dose to the tumor-bearing area (boost dose) is evaluated. The purpose of this analysis is to document the dose homogeneity of the radiation dose as reported in the first 1915 treatment forms, received at the EORTC Data Center. The dose to the prescription Point (A) was within 95 and 110% of 50 Gy in all but 13 (99.3%) patients (median dose 50 Gy) and the minimum and maximum doses in the central plane of the breast were within 95% and 110% of the dose to point A in 82% of patients. The dose to the tumor excision area (point B) was within the homogeneity criteria in 97% of patients, and the boost doses were consistent with randomization in 93% of cases. These data, based on one-third of the randomized patients in trial 22881/10882, demonstrate a high level of homogeneity in radiation doses, despite a number of ambiguities in the protocol, which were efficiently clarified a few months after the beginning of the trial. This high level of consistency is a remarkable achievement given the number of centers, the number of patients, and the number of countries involved in this trial.

Adult↗
PubMed1999

Potential of radiation-induced chromosome aberrations to predict radiosensitivity in human tumour cells.

PURPOSE: To validate whether the number of aberrations could be used as a measure of the radiosensitivity of human tumour cells. If so, this would potentially provide a more rapid method than the colony assay to predict radiocurability in human tumour biopsy material. MATERIALS AND METHODS: A panel of 13 human tumour cell lines was investigated, covering a wide range of radiosensitivities. Fluorescence in situ hybridization (FISH) employing whole chromosome probes was used to detect aberrations. RESULTS: A dose-dependent increase in radiation-induced chromosome aberrations was observed in all cell lines. A good correlation (r=0.90) was found between cell survival and total chromosome aberrations in 12 of the 13 cell lines (92%), with one exception. A poorer correlation was observed between cell survival and stable- (r=0.85) and unstable-type aberrations (r=0.81). Survival-aberration correlations for individual radiation doses were worse, although statistically significant. The exceptional cell line showed significantly more aberrations for a given level of cell kill than expected based on data for the other lines. CONCLUSION: This study indicates that radiation-induced chromosome aberrations can be used as a potential predictor of intrinsic radiosensitivity for the majority of human tumours when more than one dose level is tested. This could aid the design of radiotherapy schedules for each individual patient, or in the decision of whether to use an alternative therapy.

Cell Survival↗
PubMed1999

Multidimensional assessment of voice characteristics after radiotherapy for early glottic cancer.

OBJECTIVES/HYPOTHESIS: To assess voice characteristics of patients following radiotherapy for early glottic cancer through a multidimensional analysis protocol including vocal function and voice quality measures. METHODS: Voice analyses were performed for 60 patients treated with radiotherapy (66 Gy/33 fractions, 60 Gy/30 fractions, or 60 Gy/25 fractions) for early T1 glottic cancer and 20 matched control speakers. There was a longitudinal group of 10 patients for whom data were collected before as well as 6 months and 2 years after radiation. Furthermore, data were collected for five separate groups of 10 patients each, before, 6 months after, 2 years after, 3 to 7 years after, and 7 to 10 years after radiation. Vocal function was investigated by means of videolaryngostroboscopy, phonetography, maximum phonation time, and phonation quotient measures. Voice quality was assessed by means of objective acoustical analysis and subjective perceptual ratings by trained raters. RESULTS: Voice characteristics of patients were decreased before radiotherapy, improved after treatment, and became comparable to the voice characteristics of control speakers in at least 55% of the patients. Following radiotherapy, deviant voice quality was mainly negatively affected by increased age and stripping the vocal cord for initial diagnosis. Stroboscopy revealed that next to increasing age and stripping the vocal cord, continued smoking after treatment decreased vocal function following radiotherapy. CONCLUSION: Voices of patients diagnosed with early glottic cancer improved but did not normalize fully after radiotherapy. Stripping the vocal cord for initial diagnosis and continued smoking after treatment decreased voice characteristics. A multidimensional analysis protocol including perceptual and acoustical analysis of voice quality and stroboscopic analysis of vocal function is recommended to investigate voice characteristics following treatment for early glottic cancer.

Age Factors↗
PubMed1998

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.

Aged↗
PubMed1998

The impact of treatment time and smoking on local control and complications in T1 glottic cancer.

PURPOSE: To define the optimal treatment regimen, patients with T1N0M0 glottic larynx carcinoma were treated with six different radiotherapy (RT) schedules. To assess the influence of patient characteristics, complication rates, and to evaluate the overall larynx preservation. METHODS AND MATERIALS: Out of a consecutive series of 383 patients treated for T1N0M0 glottic larynx carcinoma between 1965 and 1992, 352 evaluable patients were treated with six different "standard" fractionation schedules: 65 Gy (20 x 3.25 Gy), 62 Gy (20 x 3.1 Gy), 61.6 Gy (22 x 2.8 Gy), 60 Gy (25 x 2.4 Gy), 66 Gy (33 x 2 Gy) and 60 Gy (30 x 2 Gy). The median follow-up of all patients was 89 months. Patient factors analyzed included: age, sex, concurrent illness, smoking habits, tumor localization and extension, tumor differentiation, the effect of tumor biopsy or stripping of the vocal cord, and the presence of visible tumor at the start of radiotherapy. Treatment parameters evaluated were: year of treatment, beam energy, treatment planning, field size, fractionation schedule, fraction size, number of fractions, total dose, treatment time and treatment gap, the use of wedges, and neck diameter. RESULTS: The overall 5-year actuarial locoregional control was 89%, varying between 83 and 93% for the different schedules. Univariately, local control decreased with increasing treatment time. This could not be explained by the confounding variables sex, tumor extension, and field length (p = 0.0065). Adjusted for these variables, 5-year local control percentage decreased from 95% (SE 2%) for 22-29 days to 79% (SE 6%) for treatment time > or = 40 days. The overall complication rate (grade I-IV) at 5 years was 15.3%, and varied between the different schedules, from 7 to 17%. No relation was found between complications and treatment factors. Patients who continued smoking had a higher complication rate than those who never smoked or stopped smoking, univariately as well as adjusted for tumor extension, macroscopic tumor, and neck diameter (p = 0.0038). Twenty-eight percent (SE 6%) of the patients who continued smoking had complications at 10 years, compared to about 13% (SE 4%) of those who stopped before or after RT. No evidence was found for any other relation between complications and patient or tumor factors. Severe edema and necrosis (grade III and IV) were not observed in the 2 Gy fraction schedules. A laryngectomy was performed in 36 patients: 30 for recurrence, 3 for complications (at 40, 161, and 272 months), and 3 for a second primary. The overall larynx preservation was 90% at 10 years, and for the different schedules it was 20 x 3.25 Gy: 97%; 20 x 3.1 Gy: 96%; 22 x 2.8 Gy: 92%; 25 x 2.4 Gy: 89%; 33 x 2 Gy: 78%; and 30 x 2 Gy: 80%. CONCLUSION: Overall treatment time is the most significant factor for locoregional control of T1 glottic cancer. A schedule of 25 x 2.4 Gy appeared to be the optimal treatment schedule considering both tumor control and long term toxicity. The complication rate was increased in patients who continued smoking.

Aged↗
PubMed1998

The role of the stress-activated protein kinase (SAPK/JNK) signaling pathway in radiation-induced apoptosis.

Ionizing radiation, like a variety of other cellular stress factors, initiates apoptosis, or programmed cell death, in many cell systems. This mode of radiation-induced cell kill should be distinguished from clonogenic cell death due to unrepaired DNA damage. Ionizing radiation not only exerts its effect on the nuclear DNA, but also at the plasma membrane level where it may activate multiple signal transduction pathways. One of these pathways is the stress-activated protein kinase (SAPK) cascade which transduces death signals from the cell membrane to the nucleus. This review discusses recent evidence on the critical role of this signaling system in radiation- and stress-induced apoptosis. An improved understanding of the mechanisms involved in radiation-induced apoptosis may ultimately provide novel strategies of intervention in specific signal transduction pathways to favorably alter the therapeutic ratio in the treatment of human malignancies.

Apoptosis↗
PubMed1998

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.

Aged↗
PubMed1998

Quality of life of early-stage breast cancer patients treated with radical mastectomy or breast-conserving procedures: results of EORTC Trial 10801. The European Organization for Research and Treatment of Cancer (EORTC), Breast Cancer Co-operative Group (BCCG).

In 1980 the EORTC-BCCG initiated a multicentre randomised clinical trial comparing modified radical mastectomy (MRM) with breast-conserving therapy (BCT) in stage I and II breast cancer. The main endpoint of the trial was survival. A brief quality of life (QoL) questionnaire consisting of two multi-item scales (body image and fear of recurrence) and two single items (satisfaction with treatment and cosmetic result) was included in the trial. A cosmetic evaluation of the breast after conservative surgery was also performed. This report concentrates on the results of the QoL study and the cosmetic evaluation. Multitrait scaling analysis was employed to verify the hypothesised scale structure of the questionnaire. Treatment comparison of the QoL scores at 2 years post-treatment was performed using a stratified Wilcoxon rank sum test. Both patients' and doctors' ratings of the cosmetic result were documented on the clinical follow-up form. A multivariate analysis was performed to identify which factors influenced the cosmetic outcome. In total, 127 patients in the MRM arm and 151 in the BCT arm completed a QoL questionnaire at approximately 2 years after randomisation (months 25-36). The Cronbach's alpha coefficients were 0.79 and 0.73 for the body image and fear of recurrence scales, respectively. Significant benefit in body image and satisfaction with treatment was observed in the BCT patients. No significant difference was observed in fear of recurrence between the two groups. Ratings of cosmetic results decreased with time, in line with clinical observations of long-term side-effects of radiotherapy. Wide excision appeared to be the most important predictive factor for poor cosmetic result. In this multicentre randomised study, BCT helped to maintain the patients' body image, resulted in higher satisfaction with treatment and yielded no significant difference from MRM with respect to fear of recurrence.

Adult↗
PubMed1998

Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines.

The purpose of this study was to investigate the influence of hyperthermia on cisplatin pharmacokinetics and DNA adduct formation. The latter was investigated both in tumour cell lines in vitro and in tumour cells and buccal cells from cancer patients. The patients had advanced ovarian carcinoma and were entered into a phase I study for cytoreductive surgery followed by hyperthermia in combination with intraperitoneal cisplatin administration. The cisplatin-DNA modifications in vivo and in vitro were studied by an immunocytochemical method with the polyclonal antiserum NKI-A59. The patient samples for pharmacokinetic determinations were analysed by flameless atomic absorption spectrometry. In vitro, the combination of hyperthermia and cisplatin enhanced cell killing compared with either treatment alone, such that the cisplatin-resistant ovarian cell line A2780/DDP became almost as sensitive as the parent A2780 cell line (resistance factor reduced from 30 to 2 at the IC50). In addition, increased cisplatin-DNA adducts were observed in the resistant cell line after the combined treatment compared with cisplatin alone. A good correlation was found between nuclear staining density and surviving fraction for all groups, indicating that the DNA adducts generated are an important determinant of toxicity and that the mechanism by which hyperthermia enhances kill is by increasing adduct levels. In the patients, the ratio of drug concentration in the peritoneal perfusate compared with that in plasma was found to be approximately 15, indicating a favourable pharmacokinetic ratio. Cisplatin-DNA adduct formation in tumour cells from patients was higher than in buccal cells, reflecting this higher drug exposure, i.e. local plus systemic versus systemic only. In addition, the tumour cells but not buccal cells were exposed to hyperthermia. The higher number of tumour adducts also suggests that a favourable therapeutic ratio could be achieved. Platinum-DNA adduct formation was found to decrease with distance from the surface of the tumour nodules. However, at a distance of 3-5 mm, the nuclear staining density levels were still measurable and higher than in buccal cells. In conclusion, the combined pharmacokinetic and adduct data in patients support the advantages of the intraperitoneal route for drug administration, and the addition of heat.

Adult↗