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Item does not contain fulltext Importance: Prognostic factors of ipsilateral breast tumor recurrence (IBTR) may change over time following breast-conserving therapy. Objective: The EORTC "boost no boost" trial showed that young age and high-grade invasive carcinoma were the most important risk factors for IBTR. This study reanalyses pathological prognostic factors related to IBTR using long-term follow-up. Design, Setting, and Participants: Participants included 5569 early-stage breast cancer patients, treated with breast-conserving surgery (BCS) and whole-breast irradiation (WBI), who were randomized between no boost and a 16-Gy boost in the EORTC phase III "boost no boost" trial (1989-1996). A total of 1616 patients with a microscopically complete resection (according to local pathologists), included in the central pathology review, have been analyzed in this study. Median follow-up was 18.2 years. Interventions: No further treatment or 16-Gy boost, after BCS and 50-Gy WBI. Main Outcomes and Measures: Time to ipsilateral breast tumor recurrence (IBTR) as first event. Results: The 20-year cumulative incidence of IBTR in 1616 patients (160 events observed) was 15% (95% CI, 12%-17%). Young age (P < .001) and presence of ductal carcinoma in situ (DCIS) (HR, 2.15; 95% CI, 1.36-3.38; P = .001) were associated with an increased risk of IBTR in multivariable analysis. The cumulative incidence of IBTR at 20 years was 34% (95% CI, 25%-41%), 14% (95% CI, 10%-18%), and 11% (95% CI, 8%-15%), in patients 40 years or younger, 41 to 50 years and 50 years or older, respectively (P < .001). This incidence was 18% (95% CI, 14%-22%) and 9% (95% CI, 6%-12%) for tumors with and without DCIS (P < .001). High-grade tumors relapsed more frequently early during follow-up but the relative effect of age and presence of DCIS seemed stable over time. The boost reduced the 20-year IBTR incidence from 31% (95% CI, 22%-39%) to 15% (95% CI, 8%-21%) (HR, 0.37; 95% CI, 0.22-0.62; P < .001) in high-risk patients (

Item does not contain fulltext BACKGROUND: Carotid artery vasculopathy is a potential long-term complication after radiotherapy (RT) of the neck, resulting in cerebrovascular events. The underlying pathophysiology is not well understood and early markers are lacking. We aimed to study whether RT of the neck is associated with increase in carotid intima-media thickness (IMT) and stroke in the first 2 years after RT in patients with head and neck cancer (HNC). METHODS: In this prospective cohort study patients treated with RT of the neck were assessed for measurement of IMT before and 2 years after RT. Endpoints were changed in IMT and incidence of first-ever stroke. RESULTS: Between 2003 and 2008 we included 69 patients (median age, 57 years [25%-75% quartile, 51-64 years], median dose of RT 66 Gy [interquartile range, 60-70]) with baseline and follow-up measurement of IMT. Median IMT at baseline and follow-up was .60 and .62 mm (ratio of geometric means 1.01; 95% confidence interval, .96-1.08; P = .63). Four of 69 patients suffered from a stroke. Mean interval from RT to stroke was 6.8 months. CONCLUSIONS: Our study showed no increase of carotid IMT in the first 2 years after RT of the neck in patients treated for HNC. This indicates that the IMT is not a reliable early marker for postirradiation vasculopathy. However, a high rate of strokes was observed. A longer follow-up period is needed to find the starting point of RT-induced vascular changes.

The EORTC 22881-10882 trial showed that for patients treated with breast conserving therapy (BCT), a 16Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. A model to estimate the risk of ipsilateral breast relapse (IBR) already exists, but now a model has been developed which takes boost treatment into account and is based on centrally reviewed pathology.A Cox model was developed based on central pathology review data and clinical data of 1603 patients from the EORTC 22881-10882 trial with a median follow-up of 11.5years. From a predefined set of variables, predictors with a maximal effect on 10-year IBR rate4% were retained in the model. Bootstrap re-sampling was used to assess model calibration and discrimination. The results are presented in the form of a nomogram.Apart from young age and no boost, presence of DCIS adjacent to the invasive tumor was associated with increased risk of IBR (HR 1.96, p=0.001). Patients with high grade invasive tumors were younger than patients with low/intermediate grade (p0.0001). The nomogram includes histologic grade, DCIS, tumor diameter, age, tamoxifen, chemotherapy, and boost with a concordance probability estimate of 0.68.The nomogram for predicting IBR 10years after BCT includes seven factors, with young age, presence of DCIS and boost treatment as the most dominant factors. The nomogram estimates IBR and confirms the importance of a boost dose. Combined with a model to predict fibrosis published previously, the nomogram presented here may assist in decision making for individual patients.

Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene. We have studied genes encoding important breast cancer-related proteins using a model for survival-type data that is based on natural splines and the Cox proportional hazard model, thereby removing the linearity assumption. Expression data of 16 genes were studied in relation to metastasis-free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute. The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors. There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for ESR1, ERBB4, VEGF, CCNE2, EZH2, and UPA; for ERBB2, ERBB3, CCND1, CCNE1, EED, CXCR4, CCR7, SDF1, and PAI1 there is no clear increase or decrease; and for EGFR there seems to be a non-linear relation. Multivariable analysis showed that the 70-gene prognosis profile outperforms all the other variables in the model (hazard-rate 5.4, 95% CI 2.5-11.7; P = 0.000018). EGFR-expression seems to have a non-linear relation with disease outcome, indicating that lower but also higher expression of EGFR are associated with worse outcome compared to intermediate expression levels; the other genes show no or a linear relation.

Background High-resistance heat and moisture exchangers (HMEs) have been reported to increase transcutaneous oxygenation (tcpO2) values in laryngectomized individuals and to negatively influence patient compliance. The goal of the present study was to validate earlier published results on short-term transcutaneous oxygenation changes by high-resistance HMEs. Methods We conducted a randomized crossover study, monitoring the influence of an HME on tcpO2 over a 2-hour time interval in 20 subjects. Results No evidence of an immediate HME effect (95% CI: −14.9–13.3 mm Hg, p = .91), or a time-dependent HME effect (95% CI: −.121 – .172 mm Hg/minute, p = .74), on tcpO2 was found. After fitting the statistical model without time dependency, again no evidence of HME presence was seen (95% CI: −.5 mm Hg – 3.6 mm Hg, p = .15). Conclusion In contrast to earlier suggestions, there is no evidence of increased tcpO2 levels by high-resistance HMEs in laryngectomized individuals. Thus, using such HMEs has no added clinical value in this respect. © 2007 Wiley Periodicals, Inc. Head Neck, 2007

PURPOSE: To establish the alpha/beta ratio of bladder cancer from different radiotherapy schedules reported in the literature and provide guidelines for the design of new treatment schemes.METHODS AND MATERIALS: Ten external beam radiotherapy (EBRT) and five brachytherapy schedules were selected. The biologically effective dose (BED) of each schedule was calculated. Logistic modeling was used to describe the relationship between 3-year local control (LC3y) and BED.RESULTS: The estimated alpha/beta ratio was 13 Gy (95% confidence interval [CI], 2.5-69 Gy) for EBRT and 24 Gy (95% CI, 1.3-460 Gy) for EBRT and brachytherapy combined. There is evidence for an overall dose-response relationship. After an increase in total dose of 10 Gy, the odds of LC3y increase by a factor of 1.44 (95% CI, 1.23-1.70) for EBRT and 1.47 (95% CI, 1.25-1.72) for the data sets of EBRT and brachytherapy combined.CONCLUSION: With the clinical data currently available, a reliable estimation of the alpha/beta ratio for bladder cancer is not feasible. It seems reasonable to use a conventional alpha/beta ratio of 10-15 Gy. Dose escalation could significantly increase local control. There is no evidence to support short overall treatment times or large fraction sizes in radiotherapy for bladder cancer.

Purpose: To study the correlations between the dose distributions in the anorectal region and late GI symptoms in patients treated for localized prostate carcinoma. Methods and materials: Data from a randomized study were analyzed. In this trial, patients were treated with either rectangular or conformal fields with a dose of 66 Gy. Data concerning GI symptoms were collected from questionnaires of 197 patients. The distributions of the anorectal region were projected on maps, and the dose parameters were calculated. The incidences of complaints were studied as a function of the dose-area parameters and clinical parameters, using a proportional hazard regression model. Finally, we tested a series of dose parameters originating from different parts of the anorectal region. Results: Analyzing the total region, only a statistically significant dose-area effect relation for bleeding was found (p < 0.01). Defining subareas, we found effect relations for bleeding, soiling, fecal incontinence, and mucus loss. For bleeding and mucus loss, the strongest correlation was found for the dose received by the upper 70-80% of the anorectal region (p < 0.01). For soiling and fecal incontinence, we found the strongest association with the dose to the lower 40-50% (p < 0.05). Conclusion: We found evidence thatmore » complaints originate from specific regions of the irradiated lower GI tract. Bleeding and mucus loss are probably related to irradiation of the upper part of the rectum. Soiling and fecal incontinence are more likely related to the dose to the anal canal and the lower part of the rectum.« less

BACKGROUND: The influence of isolated limb perfusion (ILP) on the limb recurrence-free interval (LRFI) and the number of lesions per recurrence was studied for patients with frequently recurring regional in-transit metastases previously managed by excisional surgery. METHODS: All 43 patients who had their first ILP for a third or further limb recurrence were selected from our computer database of 451 patients who underwent therapeutic ILP for recurrent extremity melanoma in our centers. Eighteen patients had resectable and 25 had locally unresectable lesions at the time of ILP. The patients had a total of 269 intervals between treatment of their primary melanoma and last recurrence or last follow-up. Median follow-up was 35 months (interquartile range, 14-64 months). RESULTS: The median LRFI decreases over time from primary melanoma to the third or further recurrence for which ILP was performed (P < 0.001). The median LRFI is 4.7 times longer (95% confidence interval [CI], 2.8-7.9; P < 0.001) after ILP in comparison with the last interval before ILP. Patients with resectable lesions have a median LRFI that is 5.9 times longer (95% CI, 2.7-13; P < 0.001). In all patients, the number of lesions increases by 22% per recurrence number (95% CI, 10%-35%; P = 0.02). At the same recurrence number, patients before ILP have a 2.6-fold higher (95% CI, 1.6-4.5) mean number of lesions than do patients after ILP (P < 0.001). CONCLUSIONS: ILP lengthens the LRFI and decreases the number of lesions per recurrence significantly in patients with repeatedly recurrent limb melanoma. Therefore, ILP could be a valuable adjunct to excisional surgery for in-transit metastases in these patients whose LRFIs tend to shorten over time

Contains fulltext : 138550.pdf (Publisher’s version ) (Open Access) BACKGROUND: Successful treatment options for cancer result in more young long-term survivors prone for long-term complications. Carotid artery vasculopathy is a potential long-term complication after radiotherapy of the neck, resulting in cerebrovascular events and probably deficits in cognitive and motor functioning. Better insight into the underlying pathofysiology of radiotherapy induced carotid artery vasculopathy is needed for prognostic purposes and to develop preventive strategies. METHODS/DESIGN: The current study is a prospective cohort study on the long-term cerebral and vascular complications after radiotherapy of the neck, in 103 patients treated for head and neck cancer, included in our study database between 2002 and 2008. Baseline protocol (before radiotherapy) included screening for cerebrovascular risk factors and intima media thickness measurement of carotid arteries by ultrasonography. Follow-up assessment more than 5 years after radiotherapy included screening of cerebrovascular risk factors, cerebrovascular events, neurological examination with gait and balance tests, extensive neuropsychological examination, self-report questionnaires, ultrasonography of the carotid arteries with measurement of intima media thickness and elastography, magnetic resonance imaging of the brain and magnetic resonance angiography of the carotid arteries. DISCUSSION: The current study adds to the understanding of the causes and consequences of long-term cerebral and vascular changes after radiotherapy of the neck. These data will be helpful to develop a protocol for diagnostic and preventive strategies for long-term neurological complications in future head and neck cancer patients with anticipated radiotherapy treatment. 9 p.

Helicobacter pylori eradication is generally accepted as the first choice of treatment for stage IE low-grade gastric MALT lymphoma (mucosa-associated lymphoid tissue-type lymphoma). Treatment failure may be attributed to the extent of the disease and to progression into an antigen-independent phase. This study assessed the value of morphological grading and the expression of the co-stimulatory markers CD40, CD80 and CD86 and their ligands to predict clinical outcome in 23 consecutive low-grade MALT lymphoma patients treated with H. pylori eradication. Complete regression was achieved in 13/23 patients (56%), partial regression in two (9%), and no response in eight (35%). Histological grading was highly predictive of clinical response, especially in stage IE1 patients, with complete remissions in 10/12 tumours with purely low-grade (type A) morphology and 1/8 tumours with increased numbers of blasts (type B) (p=0.0046) and was related to the expression of costimulatory markers (p=0.0061). Moreover, CD86 as a single marker proved to be of predictive value for treatment outcome (p=0.0086). These results suggest that morphological grading and immunological criteria can be defined to recognize the transition into the antigen-independent phase of gastric MALT-NHL. In addition to clinical stage, these critera may in future serve as a practical pathological guide to the choice of therapy. Copyright © 2000 John Wiley & Sons, Ltd.

Background: The optimal toxic reaction of the normal tissues in perfused limbs after isolated limb perfusion (ILP) is unknown. Theoretically, more severe limb toxicity could reflect a concomitant increased toxic effect to the tumor and improved outcomes. We determined whether there is a relation between limb toxicity and treatment outcomes after ILP for recurrent limb melanoma. Study Design: Among 252 patients with recurrent melanoma of the limbs, treatment outcomes in 192 patients (76%) with no or mild acute limb toxicity were compared with those in 60 (24%) with more severe reactions. Multivariate analysis was used to identify prognostic factors for complete response, limb recurrence–free interval, and survival. Results: Among 112 patients with measurable disease, 65 patients (58%) had a complete response and 27 (42%) experienced a relapse in the perfused limb. For complete response, uninvolved regional lymph nodes (p = 0.0025) and ILP using tumor necrosis factor-α (p = 0.0076) appeared to be favorable prognostic factors in multivariate analysis. There was no evidence of a relation between limb toxicity and complete response either in univariate (p = 0.16) or multivariate analysis (p = 0.46). For limb recurrent–free interval, only the number of lesions was a significant prognostic factor (p = 0.047); limb toxicity was not (p = 0.095). In 140 patients with recurrent melanoma excised before or at the moment of ILP, independent prognostic factors for survival were gender, the number of positive nodes, and stage of disease. There was no relation between limb toxicity and survival in either univariate (p = 0.53) or multivariate analysis (p = 0.94). Forty-eight (34%) of the 140 patients had a relapse in the perfused limb. No prognostic factors for limb recurrent–free interval could be identified; limb toxicity was not related to relapse time in univariate or multivariate analyses (p = 0.16 and p=0.14, respectively). Conclusions: More severe acute limb toxicity is not associated with improved outcomes. One should aim at grade II toxicity (slight erythema or edema, compatible with complete recovery) at the most to increase the therapeutic ratio of ILP.

The Byk LIA-mat CA125 II assay was compared with the Centocor IRMA CA125 II. Serum samples studied (n = 1012) were obtained from 652 apparently healthy females, 61 pregnant women, and 299 patients with benign and malignant gynecological tumors. The CA125 II assay value at the 95th percentile of the total healthy group was 29 kU/L for the LIA-mat and 32 kU/L for the Centocor assay. For the LIA-mat assay the 95th percentile was 31 kU/L (Centocor 36 kU/L) for the group 55 years of age. By using ROC curves we found the optimal pretreatment Byk LIA-mat CA125 II value differentiating between benign and malignant ovarian tumors to be 95 kU/L. Pretreatment CA125 values >1000 kU/L were detected in serum samples of patients with advanced epithelial ovarian cancer.

Contains fulltext : 51878.pdf (Publisher’s version ) (Closed access) PURPOSE: To determine whether the effect of an additional "boost" radiation after breast conservative therapy (BCT) on local control depends on age and evaluate the impact of a treatment policy with a threshold for age. PATIENTS AND METHODS: We used data from EORTC 22881-10882 trial, with median follow-up of 77.4 months. Patients receiving BCT and 50Gy whole breast irradiation were randomized to no boost and 16Gy boost (N=5318). RESULTS: In univariate analysis, a boost reduced local failure by a factor of 2 (P

To identify dose-volume parameters related to late rectal bleeding after radiotherapy for prostate cancer.Clinical complication data from a randomized trial were collected and linked to the individual dose-volume data. In this trial, patients with prostate cancer were treated with either conventional (with rectangular fields) or three-dimensional conformal radiotherapy to a dose of 66 Gy. Patient complaints, including rectal blood loss, were collected for 199 patients, using questionnaires. Absolute and relative dose-volume histograms (DVHs) of the rectal wall (with and without the anal region) were calculated with and without rectal filling. A proportional hazard regression (PHR) model was applied to estimate the probability of any rectal blood loss within 3 years, as a function of several DVH parameters. In a multivariable analysis, dose-volume parameters were tested together with patient- and treatment-related parameters (age, smoking, diabetes, cardiovascular disease, tumor stage, neo-adjuvant androgen deprivation, conformal vs. conventional and rectal bleeding during treatment).The estimated incidence of any and moderate/severe rectal bleeding at 3 years was 33% and 8%, respectively. Differences between the conventional and conformal technique were small and not significant. The analysis of relative DVHs of the rectal wall (with and without the anal region), showed significant (p0.01) relations between the irradiated volume and the probability of rectal blood loss within 3 years for dose levels between 25 Gy and 60 Gy. This relationship was shown in subgroups defined by dose-volume cutoff points as well as in the PHR model, in which a continuously rising risk was seen with increasing volumes. For absolute DVHs and DVHs of the rectum including filling, less or no significant results were observed. The most significant volume-effect relation (p = 0.002) was found at 60 Gy for the rectum wall excluding the anal region. The probability of rectal bleeding increased from 10% to 63% when the irradiated rectum volume at 60 Gy increased from 25% to 100%. Other factors. including age, smoking, diabetes, cardiovascular disease, tumor stage, neo-adjuvant androgen deprivation, conformal vs. conventional, rectal bleeding during treatment, rectum length. and whole rectum volume. did not have a significant effect in the multivariable analysis. When controlling for the volumes at 60 Gy, the volumes at lower dose levels (25-55 Gy) were no longer significant (p = 0.5).For any rectal bleeding within 3 years, an overall incidence of 33% was observed for patients treated to 66 Gy. For this endpoint, a volume-effect relation was found for DVH parameters of the relative rectal wall volume. This relationship appeared to be most significant for the rectum without the anal region and for the higher dose levels (50-60 Gy).

Item does not contain fulltext During photodynamic therapy (PDT), low oxygenation levels, induced both by oxygen consumption and by vascular occlusion, can lead to an inefficient photochemical reaction that may compromise the efficacy of PDT. In the present studies, tumor oxygenation was measured before, during and after meta-tetrahydroxyphenylchlorin (mTHPC)-mediated PDT of murine RIF1 tumors and human mesothelioma xenografts (H-MESO1). Tumor pO2 was measured in real time with Eppendorf polarography, and the extent of relative hypoxia at specific times was measured by immunohistochemical staining. Significant decreases in median pO2 values, as well as an increase in the number of values below 2.5 mmHg, were seen during and after PDT in RIF1 tumors, although there was a large intertumoral variation. Tumor pO2 values did not change significantly in H-MESO1 tumors. Staining with antibodies against the hypoxia marker EF3 showed significant increases in relative hypoxia after PDT in both tumor types compared with separate groups of untreated controls. Our results are consistent with PDT-induced oxygen depletion (reduced pO2) leading to an increase in relative hypoxia in RIF1 tumors. Extensive necrosis in the H-MESO1 tumors may have prevented the detection of PDT-induced hypoxia using the Eppendorf polarographic needle, whereas immunohistochemistry did reveal increases in relative hypoxia.

PURPOSE: To determine the changes in pulmonary function tests (PFTs) 0 to 48 months after treatment for breast cancer and lymphoma. PATIENTS AND METHODS: The alveolar volume (VA), vital capacity, forced expiratory volume in 1 second, and corrected transfer factor of carbon monoxide (TL,COc) were measured in 69 breast cancer and 41 lymphoma patients before treatment and 3, 18, and 48 months after treatment with radiotherapy alone or radiotherapy in combination with chemotherapy (mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine; cyclophosphamide, epidoxorubicin, fluorouracil; cyclophosphamide, thiotepa, carboplatin; cyclophosphamide, methotrexate, fluorouracil). The three-dimensional dose distribution in the lung of each patient was converted to the mean lung dose. Statistical analysis was used to evaluate the changes in PFT values over time in relation to age, sex, smoking, chemotherapy, and the mean lung dose. RESULTS: After an initial reduction in PFT values at 3 months, significant recovery was seen at 18 months for all patients. Thereafter, no further improvement could be demonstrated. Reductions in spirometry values and VA were related to the mean lung dose only (0.9% per Gy at 3 months and 0.4% per Gy mean dose at 18 months). TL,COc decreased 1.1% per Gy mean dose and additionally decreased 6% when chemotherapy was given after radiotherapy. Chemotherapy administered before radiotherapy reduced baseline TL,COc values by 8% to 21%. All patients showed an improvement of 5% at 18 months. CONCLUSION: On the basis of the mean lung dose and the chemotherapy regimen, the changes in PFT values can be estimated before treatment within 10% of the values actually observed in 72% to 85% of our patients with healthy lungs.

Purpose: To study the effects on survival, disease-free survival, and locoregional control of adjuvant hormonal and chemotherapy in patients with locally advanced breast cancer after a minimal follow-up period of 14 years. Methods and Materials: A total of 118 patients were randomized between radiotherapy alone (arm I); radiotherapy, 12 courses of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF), and tamoxifen (arm II); adriamycine, vincristine (AV) alternated with CMF, then radiotherapy, followed by four cycles of chemotherapy (AV/CMF); and tamoxifen during the entire treatment period (arm III). Results: No improvement in survival, disease-free survival, or locoregional control was observed. After 6 years of follow-up, the overall survival curves grew apart, resulting in differences in 10-year survival rates: 15% (confidence interval—3%, 33%) between arms III and I. Conclusion: Owing to the relatively small numbers of patients involved, the relative value of the three treatment modalities cannot be established completely.

BACKGROUND & AIMS: Stomach-conserving therapy in primary gastric non- Hodgkin's lymphoma (mucosa-associated lymphoid tissue [MALT]-NHL) is increasingly gaining importance as an alternative to surgery. As a consequence, surgical pathologists have to define histological criteria in pretreatment endoscopic biopsy specimen samples not only to make the diagnosis but also to recognize minor tumor components that may infer a significantly adverse impact on prognosis. The aim of this study was to define histological criteria for clinically significant tumor progression in pretreatment endoscopic biopsy specimens. METHODS: In a consecutive series of 106 patients with gastric MALT-NHL, the prognostic impact of large cell components was assessed by semiquantitative analysis of clusters and diffusely intermingled malignant blasts. RESULTS: In low-grade MALT-NHL, a category with a diffuse large cell component of 1%-10% with or without nonconfluent clusters of blasts could be separated with a significantly worse prognosis (10-year disease-specific survival, 90% vs. 75%). No clinical parameters of known prognostic significance could account for this difference. CONCLUSIONS: It is possible to define criteria in endoscopic biopsy specimens to recognize clinically relevant tumor progression. To serve as a guideline in the choice of treatment, these criteria should be validated prospectively in future clinical trials. (Gastroenterology 1997 May;112(5):1466-74)

In order to gain some insight into the cause of acute regional toxicity after isolated perfusion using melphalan, 15 patient-related and perfusion-technique-related factors were tested in a logistic regression model. Acute toxicity was graded according to Wieberdink's grading system. In a group of 425 patients, 362 (85%) encountered no or slight toxicity with a grade I or II reaction, and 63 (15%) patients encountered more severe toxicity with a grade III, IV, or V reaction. Most patients were treated with a standard dose of 10 or 13 mg melphalan per liter of perfused tissue for leg and arm perfusions, respectively. Factors associated with a more severe toxicity reaction proved to be tissue temperatures of 40 degrees C or higher, female gender, a deterioration of the gas values of the venous perfusate during perfusion, and perfusion at a proximal level of isolation. Consideration of these prognostic factors may lead to a further decrease of acute regional toxicity in perfusion.

Between 1966 and 1985, 92 patients with local or locoregional tonsillar carcinoma were treated in the Netherlands Cancer Institute. Treatment consisted of radiotherapy in 79 patients, combination of surgery and postoperative radiotherapy in 10 patients, and surgery alone in 3 patients. The 5-year crude survival rate was 43% and the disease-free interval 57%. Patients were classified according to the UICC 1982 and the UICC 1987/AJCC 1988 criteria. The changes in the lymph node classification proposed in UICC 1987 lead to inversion in sizes of N1 and N2 groups, and of stages III and IV. The most important prognostic factor for disease-free interval is T stage (P = .03). Prognosis is significantly worse in stage IV (UICC 1982) compared to stages I to III (41% vs. 65%, respectively, P = .03). Crude survival is lower in males (P = .031) and in patients who smoked (P = .019).

A retrospective study was made of the results of high dose radiotherapy (greater than or equal to 50 Gy) given to 171 patients with inoperable, intrathoracic non small cell lung cancer from January 1971-April 1973. Local control was dependent on the total tumor dose: after one year local control was 63% for patients treated with greater than 65 Gy, the two year local control was 35%. If treated with less than 65 Gy the one year local control was less than or equal to 40%. Tumor doses correlated with the size of the booster field. If the size of the booster field was less than 100 cm2, the one year local control was 72%; the two year local control was 44%. Local control was also influenced by the performance status, by the localization of the primary tumor in the left upper lobe and in the periphery of the lung. Local control for tumors in the left upper lobe and in the periphery of the lung was about 70% after one year, and about 40% after two years. The one and two years survival results were correlated with the factors influencing local control. The dose factor, the localization factors and the performance influenced local control independently. Tumors localized in the left upper lobe did metastasize less than tumors in the lower lobe, or in a combination of the two. This was not true for the right upper lobe. No correlation between the TNM system, pathology and the prognosis were found.

A favourable influence of nutritional support on chemotherapy related toxicity and on tumour response remains to be established. This study was performed to investigate the effects of nutritional depletion and replenishment on cell kinetics of tumour and host. Flow cytometric (FCM) analysis of bone marrow in rhabdomyosarcoma bearing WAG/Rij rats showed a significant decrease of the percentage cells in S-phase (%S) after 2 weeks of protein deprivation (S%: 19.7 ± 1.6) compared to rats receiving a diet with a normal protein content (S%: 29.9 ± 0.7) and a diet rich in protein (%S: 32.5 ± 4.4) (p < 0.001) (study 1). Twenty-four hours of nutritional replenishment following a 5-day period of protein deprivation (study 2) quickly increased the %S-phase cells of the bone marrow (p < 0.001). Neither with FCM (study 1) nor with FCM and 3HT dR-autoradiography (study 2) significant differences in the %S-phase cells in the tumour were detected as a consequence of nutritional manipulation. This study suggest that host tissue is more susceptible to nutritional manipulation than tumour.

Some cancer types (e.g. breast cancers) are known to consist of mixed populations of cells which respond to hormones, and cells that do not. A theoretical model is proposed to investigate the proportion of these different cell types in experimental tumors. The model exploits the fact that when grafts are treated with hormones, both cell types form an outgrowth, whereas in the absence of hormones only the autonomous cell types can grow. Method 1 consists of serially transplanting the tumor to be investigated in castrated mice that are not treated with hormones, and comparing the growth rates of two consecutive transplant generations. Method 2 involves comparing the growth of the tumor in hormone treated and untreated castrated mice. The merits and limitation of each of these two methods are discussed.

Three chemically induced, mammary tumour virus (MMTV) and leukemia virus (MuLV) producing, baby mouse kidney (BMK) cell lines derived from respectively strains BALB c (-/HeA and -/CrglA) and C57BL LiA were investigated for their mammary tumour (MT) evoking potentials in syngeneic female hosts. An i.p. inoculated virus-enriched fraction from A3 cells (BALB/c/HeA) had a similar oncogenic effect as i.p. and s.c. inoculated whole A3 cells. The average MT ages were reduced in all 3 groups. Cell lines BBM (BALB/c/CrglA) and BB ( C57BL LiA ) were tested as i.p. inoculated whole cells. Again, the average MT age was reduced in thus treated BALB/c/Crgl females. In the case of C57BL LiA the percentage of animals with MT was strongly increased in the BB cell inoculated group (1 MT in control group). Bioassay results corrected for intercurrent death cases (including leukosis) were statistically significant. It is concluded that the endogenous MMTV variants of the 3 mouse (sub-)strains are virulent MT evoking viruses in autologous hosts when they are induced.

The incidence of spontaneous lung tumors in relation toH-2, the major histocompatibility complex, was studied in congenic strains of mice on the B10-, A-, and C3H-backgrounds. The most relevant results were obtained with congenic strains on the B10-background. The strains could be divided into two groups: one with a low frequency of spontaneous lung tumors carrying the haplotypesH-2 b ,H-2 h4 ,H-2 d ,H-2 i H-2 r and one with a higher incidence of lung tumors carrying the haplotypesH-2 f ,H-2 m ,H-2 h2 ,H-2 a . The differences between these two groups were highly significant. Analysis of the results obtained with the recombinant strains indicated that genes in theIB region determined the susceptibility to the development of spontaneous lung tumors. The comparison of the results in the B10, B10.A and A strain has shown that the incidence in the B10.A strain carrying the haplotypeH-2 a derived from the highly susceptible strain A (H-2 a ) on the resistant background strain B10 (H-2 b ) is intermediate between these two strains. This shows, that other genes of the background are also involved. The lung tumor incidence in (B10.A × B10)F1 hybrids was intermediate between the two parental strains. The results obtained in the strains C3H with the haplotypeH-2 k , C3H.B10 with the haplotypeH-2 b and C3H.NB with the haplotypeH-2 p , were inconclusive because of the early mortality which occurred among the animals of these strains. The strains A (H-2a) and A.SW (H-H-2 s ) were both equally susceptible.

A series of 34 B-cell lymphomas was studied for the presence of transferrin receptors by immunofluorescence on frozen tissue sections with a monoclonal antibody. These lymphomas were classified by light microscopic study and furthermore investigated by immunohistochemical and morphometric methods. There were diffuse centrocytic, diffuse centroblastic, and follicular and diffuse centrocytic/centroblastic lymphomas. Significant differences in log mean nuclear area in these four histologic groups were found, as well as a significant correlation between log nuclear area and transferrin receptors as measured semiquantitatively by fluorescence intensity of the cell membranes. In addition, it was found that there is a strong correlation between the transferrin receptor activity and malignancy grading on histologic and morphometric basis. Therefore, the transferrin receptor determination on frozen sections appears to be a good method of malignancy grading.

In this study the results of combined radiotherapy and surgery are compared with the results of surgery alone in patients with neck node metastases from squamous cell carcinomas of the head and neck region. Postoperative radiotherapy decreases the recurrence rate in the neck, especially in cases with histologically established extranodal spread. Results of preoperative radiotherapy were similar to those of irradiation after surgery. Postoperative radiotherapy is favored, because it allows a selection of patients for extra treatment on the base of prognostic information, provided by the histologic characteristics of the neck dissection specimen.

The results of radiotherapy alone in 233 patients with lymph node metastases of squamous cell carcinoma in the head and neck region were examined. It appeared that the recurrence rate in the neck was mainly related to: localization of the primary tumor; the recurrence of the primary tumor; the radiation dose; and the presence of a residual palpable tumor mass in the neck 6 weeks after radiation. The optimum radiation dose was about 2000 ret. An isoeffect curve was calculated, which differed only slightly with the nominal standard dose (NSD) formula. Elective irradiation of the contralateral neck appeared to diminish the outgrowth of neck node metastases at the side. Changes in the radiation treatment in the last treatment period, such as a higher radiation dose and a larger treatment area, resulted in a lower recurrence rate for the neck node metastases, and also in a higher survival rate.

A retrospective analysis of 1378 cases of urinary bladder tumor, showed that unilateral or bilateral ureteric obstruction seen on an intravenous urogram at presentation, was significantly associated with both decreased overall survival and tumor-free interval. A tumor shadow shown on standard projections did not correlate with survival. At 24 months only 35% of the ureteric obstruction group were tumor-free as compared with 65% of the unobstructed group. Survival at 5 years was 27% in the obstructed ureter group and 73% in the non-obstructed group. This difference although less marked, persists at 9-year follow-up.

Microscopically assessed changes observed in large sections of osteosarcomas from patients who had undergone pre-operative chemotherapy (PCT) (n = 22), or no chemotherapy (n = 22), were examined either quantitatively, semiquantitatively, or qualitatively. Eight tumour characteristics were associated with the treatment mode by way of a stepwise logistic analysis. Minimal amount of viable tumour tissue (less than 10 per cent) and strong fibroblastic proliferation were each proved to be associated with PCT. These two variables in combination indicated a good response to PCT. The discrimination between PCT and non-PCT patients based on statistical analysis was superior to discrimination based on 'overall impression'.

The alterations in serum levels, anti-tumor activity and host toxicity of methotrexate (MTX) were tested in tumor bearing rats following a period of dietary manipulation. A protein deprived (PD) diet or a diet containing a normal protein content (NP) was administered for 5 days and MTX injected intra-peritoneally (i.p.) at the end of the 5 day period. The MTX serum levels were significantly elevated in rats which received the PD diet, as compared to NP dietary rats. This elevation correlated with an enhanced tumor response to MTX administration. In addition, bone marrow toxicity and intestinal tract toxicity, measured with flow cytometry (FCM) of the bone marrow and morphometry of the jejunal mucosa respectively was increased in rats receiving the PD diet. These results indicate that the serum clearance of MTX is delayed in animals suffering from malnutrition, leading to both enhanced tumor response and increased host toxicity.

The effect of cis-diamminedichloroplatinum (II) (c-DDP) on the shape of the radiation dose-response curve for mouse duodenal crypt cells was investigated. A priming X-ray dose was followed 18 h later by graded test doses (single doses or five equal fractions at 3-h intervals) with or without c-DDP. Curves were fitted by a linear quadratic (LQ) relationship. The drug modified the dose-response curve by enhancing both the alpha and the beta terms. Repair kinetics were analyzed in split-dose experiments. c-DDP caused a minor, nonsignificant decrease in the rate of repair after irradiation. The survival ratio after split-dose irradiation, when the same X-ray doses were given, was actually slightly increased by the drug. This paradoxical effect can be explained by the fact that c-DDP mainly increased the beta term in the LQ relationship. There was no significant increase in crypt cell survival when split-drug doses were given alone at increasing intervals, suggesting no cellular repair after c-DDP treatment. The data are discussed in the light of the recently proposed "lethal and potentially lethal" (LPL) unified repair model of Curtis.

Pulmonary metastases have been irradiated with single and fractionated doses of fast neutrons and cobalt- 60 gamma rays. The response to radiation was measured on volume changes of the lesions and thus RBE values could be derived. A correlation was found between grading of the tumour and volume doubling time and also between RBE and volume doubling time. This suggests an advantage for high LET radiation of slowly growing, well differentiated tumours. Furthermore the RBE for multiple fractions tends to be higher than for single doses. Calculation of the N exponent of the Ellis formula indicated that hardly any shoulder exists when neutrons are applied.

Twenty-one patients with complaints of severe pain from disseminated breast cancer were treated with half body irradiation with a single dose of 600 to 800 rad. All of them had a relief of pain for periods ranging from 14 to 280 days, with a median duration of 101 days. The objective effects of a single radiation dose was studied in 15 patients with lung metastases. The growth delay observed in these patients was of the same order as the periods of pain relief observed in breast cancer patients after half body irradiation. In general a longer lasting palliation was obtained in patients with slowly growing tumors.

Between 1977 and 1980, 118 breast cancer patients with locally advanced disease, T 3B–4 , any N, M 0 or T 1−3 , tumor positive axillary apex biopsy, were randomized to one of three arms: I: radiotherapy (RT) to the breast and adjacent lymph node areas; II: RT followed by 12 cycles of cyclophosphamide, methotrexate, 5 fluorouracil (CMF) and tamoxifen during the chemotherapy period; III: 2 cycles of adriamycin and vincristine (AV), alternated with 2 cycles of CMF, then RT, followed by another 4 cycles of AV, alternated with 4 CMF; tamoxifen during the entire treatment period. The median follow-up period was 512 years. The adjuvant chemo- and hormonal therapy did not improve the overall survival; the 5-year survival was 37% for all three treatment arms. There was no statistically significant difference in RFS between the three modalities, nor when arm I was compared to arm II and III together, p = 0.11. Local recurrence (LR) was observed in 24 of the 86 patients (28%) who had reached complete remission (CR). LR was not statistically different over the three treatment arms. In 18 of the 24 patients with LR, distant metastases appeared within a few months from the local recurrence. In arm III, the CR rate after 4 cycles AV plus CMF and RT hardly changed after another 8 cycles of chemotherapy. The menopausal status did not influence the treatment results. Dose reduction in more than 4 cycles of chemotherapy was accompanied by better results, p = 0.04. In conclusion: adjuvant chemo- and hormonal therapy did not improve RFS and overall survival. These findings do not support the routine use of adjuvant chemo- and endocrine therapy for inoperable breast cancer.

For some small rectal cancers electrofulguration can be an attractive alternative to more extensive surgical procedures. This report is a review of 49 patients who, after careful selection, were considered ideal candidates for curative fulguration in the period 1959–1982. All had rectal adenocarcinomas and were clinically staged as Dukes' A tumors. To put the results of this analysis into perspective, they are compared to the results of those patients (34) who also had early clinical stage rectal adenocarcinomas, but for a variety of reasons underwent abdominoperineal excisions (APE, 11 patients) or low-anterior resections (LAR, 23 patients) instead of fulguration. Postoperative complications after fulguration were minimal, there were no postoperative deaths, and all patients retained anal continence. After APE or LAR there were two postoperative deaths (one myocardial infarction, one ruptured iliac aneurysm); postoperative morbidity was greater. All LAR-treated patients remained continent. Of the patients at risk 55% remained disease-free after fulguration, while 77% remained disease-free after APE or LAR (P = 0.023). This is due to a higher percentage of loco-regional recurrences occurring after fulguration than after APE or LAR (31% vs 9%, respectively, P = 0.021). The percentage of patients with distant metastases in both groups are similar. It seems that electrofulguration of rectal cancers, even in strictly selected patients in a specialized institution, can lead to an unacceptably high percentage of patients with loco-regional recurrences. Nearly all local failures occurred in patients with tumors that measured more than 3 cm in diameter and/or occupied more than one-third of the rectal circumference. Salvage operations for loco-regional failure were performed in 13 patients, 5 of whom are alive with no evidence of disease. Since there seems to be a direct relation between tumor size and the chance of loco-regional recurrence and since salvage operations for local failure are not uniformly successful, electrofulguration for cure must be reserved for the very rare patient with a very small early-stage rectal cancer.

Oral dietary protein-calorie malnutrition was used in rats to study the influence of malnutrition on the distribution of the dividing cells in the bone marrow (stem cells) over the compartments of the cell cycle. A 5 -day period of malnutrition induced an increase in the percentage of cells in the G 0 G 1 phase of the cell cycle while simultaneously inducing a statistically significant decrease in the percentage of cells in S phase. Similar results were obtained after a 14 -day period of malnutrition. Nutritional replenishment after 5 and 14 days of dietary deprivation induced a rapid recovery of the percentage of S phase cells and a decrease in the percentage of cells in the G 0 G 1 phase of the cell cycle. Malnutrition and nutritional replenishment did not influence hemoglobin concentration and platelet numbers in the peripheral blood, but leucocyte numbers increased significantly after short-term replenishment. These results demonstrate a decrease in the percentage of proliferating bone marrow cells after short periods of protein deficiency and general malnutrition. The results also demonstrate that bone marrow cells recover quickly after nutritional replenishment. In malnourished cancer patients, suspected of bone marrow insufficiency and receiving therapy that potentially impairs bone marrow proliferation, a short period of nutritional replenishment preceding treatment could possibly be marrow-protective.