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Purpose: To analyse the prognostic impact of isolated local recurrence (ILR) on long-term outcome for early-breast cancer patients treated with breast-conserving therapy., Material and Methods: The data of the EORTC 22881-10882 'boost-no boost' and 22922-10925 'IM-MS' trials were used to analyse the prevalence and outcome following ILR. A multistate model described the impact of intermediate events on long-term outcomes, taking into account various prognostic factors. This model was used to predict long-term outcomes after ILR., Results: Of the 8367 patients included, 726 experienced an ILR, 11.6% of them within the first 2 years and 30.0% after 10 years. Ten-year cumulative breast cancer mortality rates after ILR were 58.2% in patients with an ILR within 2 years, 31.0% for ILR between 2 and 4 years, 17.6% in patients with an ILR between 4 and 10 years, and 29.7% for ILR after year 10 (p < 0.001). The multistate model showed that when tumour-free, younger breast cancer patients had a higher probability of developing ILR compared to older patients. Shorter time to ILR was associated with a higher chance to develop distant metastases (DM), and a shorter time to development of DM were associated with an increased hazard of breast cancer-related death. The multistate model enabled prediction of long-term outcome based on individual patient covariates, length of follow-up without recurrence and timing of ILR since randomisation., Conclusions: Outcome of early-breast cancer changed not only according to baseline risk factors but also according to the presence of intermediate events, time to these events, and subsequent follow-up without any further events., Competing Interests: Conflict of interest statement PP is medical advisor of Sordina IORT Technologies Spa since April 2020., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Locoregional recurrence (LRR) after breast-conserving therapy is a well-known independent risk factor associated with unfavourable long-term outcome. Controversy exists concerning the prognostic impact of a LRR after a very long event-free interval., Method: Patients who underwent breast-conserving therapy for early stage breast cancer were pooled from four European Organisation for Research and Treatment of Cancer (EORTC) Breast Group trials. Only LRR as a first event was taken into account. Risk factors such as tumour size, nodal status, young age and chemotherapy were assessed in multivariate Cox regression analysis. LRR was used as a time-dependent variable in the landmark analysis for distant disease-free survival (DFS) and overall survival (OS). Patients were categorised as having at least 0, 5 or 10 years event-free survival., Results: In total, 7751 early stage breast cancer patients were included with a median follow-up of 10.9 years. Tumour size, nodal status, young age and chemotherapy are strong independent prognostic factors with a significant impact on long-term outcome, but lose their power and significance over time. Including all patients, LRR was the strongest prognostic factor for OS and distant DFS (resp. HR 5.01 and HR 5.31, p<0.001). In the subgroup of patients developing a LRR after at least 5 or 10 years, LRR remained the strongest independent prognostic factor for OS (resp. HR 3.98, HR 4.96, p ≤ 0.001) and distant DFS (HR 4.42, HR 7.57 p<0.001)., Conclusion: This is the first study which shows LRR after breast-conserving therapy is a very strong, time-independent prognostic factor for long term outcome in early stage breast cancer patients. These findings suggest that a LRR after a long event-free interval seems to be an indicator rather than an instigator of subsequent distant disease., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The EORTC 22881-10882 trial in 5178 conservatively treated early breast cancer patients showed that a 16 Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. To investigate predictors for the long-term risk of fibrosis, Cox regression models of the time to moderate or severe fibrosis were developed on a random set of 1797 patients with and 1827 patients without a boost, and validated in the remaining set. The median follow-up was 10.7 years. The risk of fibrosis significantly increased (P<0.01) with increasing maximum whole breast irradiation (WBI) dose and with concomitant chemotherapy, but was independent of age. In the boost arm, the risk further increased (P<0.01) if patients had post-operative breast oedema or haematoma, but it decreased (P<0.01) if WBI was given with >6 MV photons. The c-index was around 0.62. Nomograms with these factors are proposed to forecast the long-term risk of moderate or severe fibrosis.

The EORTC 22922/10925 trial randomly compares irradiation or no irradiation of the internal mammary and medio supraclavicular (IM-MS) nodes for stage I-III breast cancer. We report on the characteristics of 4004 participating patients, aspects of quality assurance and compliance to protocol treatment. The actual population has intermediate-risk disease: 51.8% stage II, 56% positive axillary nodes. The allocated treatment was not followed in 3.2% in the IM-MS irradiation arm versus 2% in the no IM-MS irradiation arm. In the IM-MS arm, there were major deviations for dose in 0.8%, surgery-to-radiotherapy time interval in 3.9% and in overall treatment time in 0.9% cases. Major deviations were found in 7.9% patients in the IM-MS group and in 2% patients in the no IM-MS group. In the final trial analysis, a sensitivity analysis should evaluate the subgroup of patients receiving an optimal treatment to verify the robustness of the results and the true impact of IM-MS irradiation.

Unlabelled: A randomised phase III study was performed comparing sequential (S) and concurrent (C) chemo-radiotherapy (CRT) in non-small cell lung cancer (NSCLC) patients., Methods: One hundred and fifty-eight patients were randomised to receive two courses of Gemcitabine (1250mg/m(2) days 1, 8) and Cisplatin (75mg/m(2) day 2) prior to, or daily low-dose Cisplatin (6mg/m(2)) concurrent with radiotherapy, consisting of 24 fractions of 2.75Gy in 32 days, with a total dose of 66Gy., Results: Acute haematological toxicity grade 3/4 was more pronounced in the sequential (S) (30% versus 6%), oesophagitis grade 3/4 more frequent in the concurrent (C) arm (5% versus 14%). Late oesophagitis grade 3 was 4% (S and C), pneumonitis grade 3/4 14% (S) and 18% (C). Because of the poor power of the study no significant differences in median survival (MS), overall survival (OS) and progression-free survival (PFS) could be detected. MS was 16.2 (S) and 16.5 (C) months, 2-year OS was 34% (S) and 39% (C), 3-year OS was 22% (S) and 34% (C)., Conclusion: Radiotherapy 66Gy given concurrently with daily low-dose Cisplatin or after two courses of Gemcitabine/Cisplatin was well tolerated. Due to early closure no conclusions can be reached on the relative merits; both arms showed good OS.

The aim of this study was to evaluate prognostic factors for isolated loco-regional recurrence in patients treated for invasive stage I or II breast cancer. The study population comprised 3602 women who had undergone primary surgery for early stage breast cancer, who were enrolled in European Organisation for Research and Treatment of Cancer (EORTC) trials 10801, 10854, or 10902, by breast conservation (55%) and mastectomy (45%). The median follow-up time varied from 5.3 (range: 0.6-9.5) to 11.9 years (range: 0.6-17.4). Main outcome was the occurrence of isolated loco-regional recurrence. The results of multivariate analysis showed that younger age and breast conservation were risk factors for isolated loco-regional recurrence (breast cancer under 35 years of age versus over 50 years of age: hazard ratio 2.80 (95% CI 1.41-5.60)); breast cancer age 35-50 years versus over 50 years: hazard ratio 1.72 (95% CI 1.17-2.54); breast conservation (hazard ratio: 1.82 (95% CI 1.17-2.86)). After perioperative chemotherapy, less isolated loco-regional recurrences were observed (hazard ratio 0.63 (95% CI 0.44-0.91)). No significant interaction effects were observed. It is concluded that young age and breast conserving therapy are both independent predictors for isolated loco-regional recurrence. As an isolated loco-regional recurrence is a potentially curable condition, women treated with breast conservation or diagnosed with breast cancer at a young age should be monitored closely to detect local recurrence at an early stage.

In this work, we have studied the response rates and duration of response after low-dose (4 Gy) involved field radiotherapy (LD-IF-RT) in relapsed or chemotherapy refractory indolent and aggressive lymphoma patients. 71 patients (177 symptomatic sites) received LD-IF-RT consisting of 39 males and 32 females with a median age of 69 years (range 43-93). Patients included were those with small lymphocytic lymphoma/chronic lymphocytic leukaemia (n=23), marginal zone lymphoma, nodal type (n=18), mantle cell lymphoma (n=17), and diffuse large B-cell lymphoma (n=13). Bulky disease (5 cm) was present in 73% of all patients. A median of two prior chemotherapy regimens (range 0-10) preceded LD-IF-RT. Median time since diagnosis was 31 months (range 1-216 months). Time to (local) progression was calculated according to the Kaplan-Meier method. Differences in response rates were compared using the chi2-test. The results showed that overall response rate was 87%; complete remission (CR) was reached in 34 patients (48%) and a partial remission (PR) in 28 patients (39%). Stable disease (SD) was maintained in nine patients (13%). The median time to progression (TP) was 12 months and the median time to local progression (TLP) was 22 months. The 34 CR patients showed a median TP of 16 months and a median TLP of 23 months. None of the factors studied (age, sex, lymphoma subtype, radiotherapy regimen, number of prior regimens or time since diagnosis, number of positive sites or largest lymphoma diameter) were found to relate to response. At time of death 70% of patients were without in-field progression after LD-IF-RT. It appears that LD-IF-RT is a valuable asset in the management of relapsed disease in both indolent and aggressive lymphoma and should be considered to palliate symptoms in patients with recurrent and/or chemotherapy refractory disease.

The present study evaluated the outcome of salvage treatment for women with local or local-regional recurrence after initial breast conservation treatment with radiation for mammographically detected ductal carcinoma in situ (DCIS; intraductal carcinoma) of the breast. The study cohort consisted of 90 women with local only first failure (n=85) or local-regional only first failure (n=5). The histology at the time of recurrence was invasive carcinoma for 53 patients (59%), non-invasive carcinoma for 34 patients (38%), angiosarcoma for one patient (1%), and unknown for two patients (2%). The median follow-up after salvage treatment was 5.5 years (mean=5.8 years; range=0.2-14.2 years). The 10-year rates of overall survival, cause-specific survival, and freedom from distant metastases after salvage treatment were 83%, 95%, and 91%, respectively. Adverse prognostic factors for the development of subsequent distant metastases after salvage treatment were invasive histology of the local recurrence and pathologically positive axillary lymph nodes. These results demonstrate that local and local-regional recurrences can be salvaged with high rates of survival and freedom from distant metastases. Close follow-up after initial breast conservation treatment with radiation is warranted for the early detection of potentially salvageable local and local-regional recurrences.

Patients treated for head and neck tumours with local radiotherapy (RT) on the neck harbour an increased risk of stroke. This may be due to accelerated atherosclerotic changes within the RT-field; however, the real impact of local RT on the carotid artery remains debatable. The aim of the present study was to assess the difference in carotid wall thickness (intima-media thickness) in 42 unilaterally irradiated parotid tumour patients by performing B-mode ultrasonography. A mean difference in intima-media thickness (IMT) of the irradiated compared with the non-irradiated carotid artery of 0.30 mm (P=0.031) was found. A significant correlation was established with a longer post-RT interval (P=0.008). RT on the neck is associated with increased thickening of carotid IMT. Screening and treatment of additional cerebrovascular risk factors which contribute to further IMT thickening and stroke development is recommended, especially in radiotherapy patients with a favourable prognosis.

Lymphatic mapping has become a frequently used technique for staging the axilla in patients with breast cancer. In addition to sentinel nodes in the axilla, lymphoscintigraphy depicts sentinel nodes outside the axilla in up to 34% of patients. An increasing number of surgeons are now pursuing these extra-axillary nodes and are able to harvest them with limited morbidity in up to 87% of the patients concerned. Improved accuracy of staging is the result. Surgeons, radiotherapists and medical oncologists should consider the implications of the presence or absence of metastatic disease in such nodes. Incorporating the tumour status of these extra-axillary sentinel nodes in the management of patients will lead to a better selection of those who may benefit from postoperative radiotherapy to the internal mammary lymph node chain and from adjuvant systemic treatment.

Although adequate locoregional treatment improves local and regional control in early-stage breast cancer, uncertainty still exists about the role of locoregional therapy with respect to survival. To study the impact of surgery and radiotherapy on locoregional control and survival, we combined the data of three European Organisation for Research and Treatment of Cancer (EORTC) Breast Cancer Group trials including early-stage breast cancer patients with long-term follow-up. Risk ratios (RR) were estimated for locoregional recurrence and overall survival using Cox regression models. All analyses were adjusted for tumour size, nodal status, age, adjuvant radiotherapy, adjuvant chemotherapy and trial. The combined data-set consisted of 3648 patients. The median follow-up period was 11 years. 5.9% of the patients who underwent mastectomy and 10.8% of the patients who underwent breast-conserving therapy had a locoregional recurrence (P<0.0001). The risk of death after breast-conserving therapy was similar compared with mastectomy (RR 1.07, P=0.37). Adjuvant radiotherapy after mastectomy was associated with a lower risk for locoregional recurrence (RR 0.43, P<0.001) and death (RR 0.73, P=0.001). Patients with 1-3 positive nodes benefited the most from radiotherapy after mastectomy. Breast-conserving therapy was associated with an impaired locoregional control. However, breast-conserving therapy was not associated with a worse overall survival. Adjuvant radiotherapy in mastectomised patients was associated with both a significantly superior locoregional control and overall survival. The effect of adjuvant radiotherapy was most profound in patients who had 1-3 positive nodes.

The aim of this study was to identify patient-, tumour- or treatment-related factors associated with young age that might explain the higher risk of ipsilateral breast recurrence that occurs after breast-conserving therapy (BCT) in young breast cancer patients. In the 'boost versus no boost trial', 5569 early-stage breast cancer patients were entered. All patients underwent tumorectomy followed by whole breast irradiation of 50 Gy. Patients having a microscopically complete excision were randomised between receiving no boost or a 16-Gy boost, while patients with a microscopically incomplete excision were randomised between receiving a boost dose of 10 or 26 Gy. The 5-year local control rate was 82% for patients 60 years of age (P<0.0001). In young patients, the tumour was significantly larger and more often oestrogen and progesterone receptor-negative. Invasive carcinoma and the intraductal component were more often of a high grade. The intraductal component was more frequently incompletely resected in young patients. Re-excisions were performed more often (most probably due to a more frequent incomplete excision at the first attempt). The total volume of breast tissue removed at the tumorectomy was smaller in the younger patient group, even after including the volume removed during re-excision. When relating all these parameters (including age itself) to local control, the multivariate analysis stratified by treatment showed that age was the only independent prognostic factor for local control (P=0.0001). Including the boost treatment as a separate covariate, the analysis retained age and boost treatment as significant factors related to local control (P<0.0001). It was shown that the boost dose significantly reduced the 5-year local recurrence rate from 7 to 4% for patients with a complete excision (P<0.001). For patients 40 years of age or younger, the boost dose reduced the local recurrence rate from 20 to 10% (P=0.002). This large European Orgnaization for Research and Treatment of Cancer (EORTC) trial demonstrated an increased local recurrence rate in young patients. Although several associations between patient, tumour and treatment factors and age were found, that might explain the high local recurrence rate in the younger patients, it appears that age itself and the boost dose were the only factors that were independently related to local control.

A randomised phase II trial was initiated to explore the feasibility of concomitant cisplatin and radiotherapy with conventional fractionation (CF) or multiple fractions per day (MFD) for patients with locally advanced head and neck malignancies. The MFD schedule was designed to achieve higher tumour concentrations of cisplatin at the time of irradiation by reducing the number of radiation treatment weeks from 7 to 3, allowing recovery from side-effects of both irradiation and cystostatic drugs during the rest periods, while keeping the same total dose and overall treatment time. Patients were randomised between a conventional fractionation scheme (CF) of 70 Gy in 7 weeks with 2 Gy per fraction with a daily dose of 6 mg/m(2) cisplatin and a modified fractionation scheme (MFD) delivering three fractions of 1.6 Gy per day, in weeks 1, 4 and 7, keeping the same overall treatment time and total dose. In the modified treatment regime, a daily dose of 10 mg/m(2) cisplatin was administered. 53 patients were entered in this trial and radiotherapy was given according to the schedule to all patients in both treatment arms. Cisplatin was given during the whole course of radiotherapy to only one quarter of the patients in the CF arm, stopping mostly after 5-6 weeks due to bone marrow depression and kidney toxicity, while patients in the MFD arm received it according to schedule. No difference was observed in acute and late toxicity in both treatment arms, while a similar or even better tumour response was obtained with MFD. A 67% higher daily dose of cisplatin concomitant with irradiation could be given in a 3-week multiple fractionation per day schedule, as opposed to the cisplatin given in the conventional daily fractionation schedule of 7 weeks with the same total radiation dose. Similar acute and late toxicities were seen in both treatment arms.

Several clinical trials carried out during the last decade clearly show that concomitant radiotherapy and chemotherapy significantly improves local control in a variety of advanced solid tumours. In most of these trials, cisplatin alone or in combination with other drugs has been used. This has led to improved survival rates in head and neck, lung and cervical cancer. The interaction of radiotherapy with chemotherapy for these solid tumours appears to be schedule-dependent, as no such an improvement was observed with neo-adjuvant chemotherapy followed by radiotherapy in eight out of nine clinical trials in cervical cancer. A major advantage of this combined modality treatment is organ preservation possible for patients with advanced larynx or anal cancer. Major further improvement can be expected from the design and exploration of drugs that influence the pathways leading to cell death after irradiation. Examples include topoisomerase 1 (topo1) inhibitors, alkyl-lysophospholipids, epidermal growth factor receptor (EGFR) receptor inhibitors.

The latest dramatic progress in the technologies of the computer industry is likely to increasingly influence the oncologist's daily routine. Besides well known and established telemedical services such as videoconferencing, the most influential trends are the spread of digital hospital infrastructures with unlimited, secured access to all relevant patient information. This article seeks to summarise the most imminent influences of telemedical developments on the future of the oncologist: the effects of telemedical services and electronic infrastructures on clinical workflow and on medical quality management. In addition, the history of telemedicine, recent technologies and the performance of electronic patient records are described.

The purpose of this work was to study the feasibility of concurrent chemoradiation in patients with inoperable non-small cell lung cancer (NSCLC). 40 patients with inoperable NSCLC were treated with escalating doses of radiotherapy and cisplatin (cDDP). The radiation dose was increased step by step from 60.5 to 66 Gy in daily fractions of 2.75 Gy. Chemotherapy was also increased step by step from 20 to 24 daily doses of cDDP 6 mg/m(2) and given concurrently with radiotherapy. A dose of 40 Gy/2 Gy/20 fractions (fx) was given to the EPTV (elective planning target volume) which included the gross tumour volume with a margin of 2 cm and part of or the entire mediastinum. During each session a boost dose of 0.75 Gy was given simultaneously to the BPTV (boost planning target volume), which encompassed the GTV (gross tumour volume) with a margin of 1 cm, for the first 20 fx, so the total dose to the tumour was 55 Gy. Cisplatin 6 mg/m(2) was given 1 h prior to radiotherapy at each fraction. From then on the dose of radiation to the BPTV and the dose of cDDP were increased step by step. In group I the BPTV was irradiated with two extra fractions of 2.75 Gy to a total dose of 60. 5 Gy without cDDP. In group II the same total dose of 60.5 Gy was given but the last two fractions were combined with cDDP. In group III four extra fractions of 2.75 Gy were given to the BPTV to a total dose of 66 Gy, only two of these fractions combined with cDDP. Finally, in group IV a total dose of 66 Gy was given in 24 fractions, all fractions combined with cDDP. All patients were planned by means of a CT-based conformal treatment planning. The maximal length of the oesophagus receiving >/=60.5 Gy was 11 cm. 40 patients were evaluable for acute and late toxicity and for survival. Acute toxicity grade >/=3 (common toxicity criteria, CTC) was rarely observed; nausea/vomiting in 3 patients (8%), leucopenia in 2 patients (5%), thrombocytopenia in 2 patients (5%), whilst 2 patients (5%) suffered from severe weight loss. Late side-effects (European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group, EORTC/RTOG) were: oesophageal toxicity >/=grade 3 in 2 patients (5%) and radiation pneumonitis grades 1 (3%) and 2 (3%) in 1 patient each. Overall actuarial 1- and 2-year survival was 53% and 40%, respectively. The 1- and 2-year local disease-free interval was 65% and 58% respectively. Radiotherapy at a dose of 66 Gy/2.75 Gy/24 fx combined with daily cDDP 6 mg/m(2) given over 5 weeks is feasible and results in a good local disease-free interval and a good survival rate. This treatment schedule is at present being tested as one of the two treatment arms of EORTC phase III study protocol 08972/22973.

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.

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.

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.

Dermatofibrosarcoma protuberans (DFSP), a fibrohistiocytic tumour of intermediate malignancy, has a strong tendency to recur locally. Wide local excision is the recommended treatment modality. A retrospective analysis was performed on 38 consecutive DFSP patients presenting to The Netherlands Cancer Institute, to define the role of radiotherapy. Of the 21 patients treated surgically (all with negative resection margins) seven recurred, a local control probability of 67%. Combined modality treatment was given to 17 patients. Prior to radiotherapy, these patients experienced 33 occurrences of DFSP, but after irradiation only three recurrences were seen, a local control probability of 82%. These results are in keeping with the recent literature where increasing value is being given to both adjuvant and curative radiotherapy in the local management of DFSP. We recommend radiotherapy in DFSP patients where repeated surgery may cause mutilation or functional impairment.

The aim of this study was to determine whether it is feasible to reduce the overall treatment time from 7 to 4 weeks in patients with non-small cell lung cancer (NSCLC) receiving radiotherapy with cisplatin. This follows an EORTC phase III randomised trial (08844) in which cisplatin given before each radiation dose resulted in improved local control and survival, but which had a relatively long treatment period of 7 weeks [Schaake-Koning et al., N Engl J Med 1992, 326, 524-530]. 38 patients with confirmed NSCLC (2 stage I, 1 stage II, 18 stage IIIA, 17 stage IIIB) received a total tumour dose of 55 Gy/20 fractions/26 days, from January 1992 to March 1994. Daily fractions of 2 Gy (5 times/week) were given to the macroscopic tumour and the non-involved adjacent lymph node areas. During the same session, a dose of 0.75 Gy was given to the macroscopic tumour (simultaneous boost). Cisplatin 6 mg/m2 was administered 1-2 h before each fraction, in an escalating total dose, during week 1 in 3 patients, during weeks 1 and 2 in 6 patients, during weeks 1, 2 and 3 in 5 patients and during the whole treatment in 24 patients. 38 patients were evaluable for acute side-effects (WHO). Maximal therapy-related toxicity (WHO) was grade 3 (nausea/vomiting in 2 patients, oesophagitis in 3 patients, dyspnoea in 3 patients, cough in 1 patient). Late side-effects were evaluated in 34 patients. There was grade 2 oesophagitis in 2 patients; grade 3 toxicity in 8 patients (tiredness in 3 patients, dyspnoea in 3 patients, oesophagitis in 2 patients); grade 4 toxicity in 4 patients (dyspnoea in 3 patients, cough in 1 patient). Pulmonary fibrosis grade 3 occurred in 4 and grade 4 in 6 patients. One patient developed a severe (grade 3) radiation pneumonitis. The low incidence of acute and late side-effects with this treatment, combining daily administration of 6 mg cisplatin with radical radiotherapy using a simultaneous boost technique, indicates that escalation of the radiation dose seems feasible.

To evaluate the prognostic significance of the axillary apex biopsy and its impact on clinical practice, a retrospective analysis was performed in 875 patients with clinically operable breast cancer who underwent this procedure from 1977 to 1985 (165 TNM stage I; 512 TNM stage II; 198 TNM stage IIIA). Apex biopsy is performed as a staging procedure. Apex biopsy positive patients are treated by radiotherapy alone, while apex biopsy negative patients are treated with breast conserving therapy or mastectomy, both including complete axillary dissection. The apex biopsy was tumour positive in 4% of TNM stage I patients; 17% of stage II patients and 40% of stage IIIA patients. Among patients with clinically node-negative disease, the apex biopsy was positive in 12%; in patients with palpable suspected lymph nodes this figure was 45%. Actuarial 8 y survival rates for patients with stage I, II and III disease and a negative apex biopsy were 83, 70 and 50%, respectively. The corresponding figures for patients with a positive apex biopsy were 60, 28 and 14%. In a multivariate analysis, a positive apex biopsy, clinical N classification and T classification were independent prognostic factors for survival (P < 0.0001). We conclude that a positive apex biopsy is rare in clinical stage I breast cancer, and that in patients with TNM stage II and III disease the procedure is an important tool to assess prognosis pre-operatively.

During the last two decades, radiotherapy has become an integral part of the multidisciplinary approach in the treatment of patients with colorectal cancer. Currently, radiotherapy is seen mainly as an adjuvant therapy, sometimes in combination with chemotherapy, in a pre- or postoperative setting. Adjuvant radiotherapy alone leads to a significant reduction of local recurrence rates, but an impact on survival is seen only in subset analyses. Combined modality treatment can reduce local recurrence rates even further, and can also reduce the rate of distant relapses and increase survival. The acute toxicity of combined modality is considerably higher. Local radiation can also be use as a component of organ conserving local treatment for selected early lesions. Radiotherapy has been an important palliative treatment modality, diminishing symptoms in cases of inoperable primary rectal cancers or pelvic recurrences. The timing of radiation, surgery and chemotherapy has been under evaluation for years. For patients with locally advanced primary or recurrent malignancies (unresectable due to fixation), the preferred sequence is pre-operative irradiation with or without chemotherapy, followed by surgical resection. For mobile resectable lesions, sequencing issues are being tested in phase III randomised trials.

Risk factors for local recurrence (LR) in a univariate analysis had a significant correlation with survival. Local and distant failure could not be regarded as independent events. We undertook a multivariate survival analysis to study the relation between LR and survival. In a retrospective study of 1026 patients treated with tumorectomy, axillary dissection and radiotherapy, factors associated with disease-specific survival (DSS) were analysed. Actuarial estimates for DSS are 91% at 5 years and 86% at 10 years. The multivariate analysis revealed five factors: clinical stage, number of affected axillary nodes, histological grade, degree of tubule formation and left-sided primary tumour. Controlling for these factors, LR appeared to be significantly correlated with DSS. The hazard rate of DSS was estimated to increase by a factor 8.8 (95% confidence interval 4.6-16.8) upon occurrence of a LR. Local recurrence per se, apart from the identified prognostic factors, is a risk factor for DSS. The exact mechanism by which LR has an influence on survival cannot be clarified from these data.

The changing composition of the patient population in breast cancer, which has been reported over the last decade, has important consequences for prognosis. In the present trial, an analysis of the population in an EORTC trial (22881/10882) on breast-conserving therapy was conducted. A shift towards earlier stages has been seen stage per stage, therefore better survival and local control rates are likely to be expected in comparison to previously published series. The majority of tumours in this trial were small, with a median clinical size of 2 cm and a median pathological size of 1.5 cm. A substantial number of lesions were detected in a pre-clinical stage (17.8%). Nodal involvement was present in only 19% of all patients and usually in only a low number of nodes (only 4% of all patients had four or more nodes invaded). The median number of nodes examined was 12, the difference between institutions was large. There was a significant correlation between the number of nodes examined, the percentage of patients with positive nodes (P = 0.03) and the percentage of patients with massive axillary invasion (P = 0.003). The correlation between clinical evidence and pathological invasion of the axillary nodes showed that 15% of the clinical examinations were false-negative and 51% were false-positive. Pathological nodal invasion could be clinically predicted in only 31% of patients, and consequently clinical examination of the axilla was a poor predictor of prognosis in this study. Pathological invasion of axillary lymph nodes was better correlated to pathological tumour size than clinical or radiological size.

We investigated the feasibility of breast conserving treatment (BCT) in patients with large (T2, T3) breast cancers, by combining preoperative radiotherapy and tissue replacement after wide excision by a myosubcutaneous flap transposition. The treatment consisted of 50 Gy whole breast irradiation followed by a 15-25 Gy iridium implant to the primary tumour with 2 cm margins. Four weeks after completion of the radiotherapy, wide excision of the original tumour area with a 1 cm margin and an axillary dissection was performed. In the same session the breast was reconstructed with an ipsilateral latissimus dorsi transposition flap. The treatment results in the first 6 patients are encouraging with respect to treatment toxicity and cosmetic outcome. The clinical tumour response after radiotherapy was difficult to evaluate. However, microscopic evaluation showed residual tumour in all specimens with (focal) involvement of the surgical margins in two. With a minimum follow-up of over 2.5 years no tumour recurrences in the breast have occurred.

A (modified) radical mastectomy (RM) was compared with breast-conserving therapy (BCT) in stage I and stage II breast cancer patients. Treatment of the study arm comprised lumpectomy, axillary clearance and radiotherapy to the breast (50 Gy in 5 weeks external irradiation and a boost with iridium implant of 25 Gy). 902 patients were included. There were 734 TNM stage II patients. Patients with microscopically incomplete excision of the tumour were not excluded. After a median follow-up of 6 years, overall survival and local recurrence rates do not differ significantly between the two study arms. Actuarial survival at 8 years was 73% after RM and 71% after BCT; actuarial local recurrence at 8 years was 9% and 15%, respectively. In the mastectomy group tumour size did not affect local relapse, but after BCT the incidence of local recurrences was higher for tumours of 2-5 cm (16%) than for smaller tumours (7%) (at 8 years, P = 0.08). Results of salvage treatment for local recurrence so far were similar in both the BCT and the mastectomy group.

Between 1970 and 1990, 22 patients with 44 chemodectomas in the head and neck region were seen at the Netherlands Cancer Institute in Amsterdam. All patients were treated with radiation therapy (17 patients with radiation therapy only and 5 in combination with surgery). One patient was treated two times with an interval of 12 years at each side of the neck. Standard dose was 50 Gy in 25 fractions over 5 weeks. A radiation portal arrangement with oblique fields with paired wedges was used most frequently. The follow-up period ranged from 1 year to 20 years. Two recurrences at 2 and 9 years after treatment were observed. The actuarial local control rate was 88% at 10 years follow-up. Comparison of the results of surgery and radiotherapy demonstrates that radiation therapy is an effective treatment modality without mutilation or severe late morbidity for chemodectomas in the head and neck region.

A quality control study was performed during the EORTC phase III study 08844: radiotherapy combined with low dose cisplatin (cDDP) in inoperable non-metastatic non-small cell lung cancer. Radiation alone (55 Gy, split course) was compared to radiotherapy with 30 mg/m2 cisplatin once a week and to radiotherapy with 6 mg/m2 cisplatin daily. The purpose of the control study was to check to which degree protocol guidelines were followed and to measure the extent of differences in assessment of tumour response, recurrence and toxicities between the individual institutes. A review team, consisting of a data manager, a diagnostic radiologist, a chest physician and two radiotherapists reviewed entry criteria, treatment data, tumour responses, recurrences and late toxicity of 177 patients (a total of 300 patients was required for the trial). Only departments which had entered more than 5% of this number of patients were visited. There was a 15% difference in T staging of the patients and a 17% discrepancy in N stage scoring between the review team and the local investigators. Radiotherapy field sizes were insufficient in 15% of the eligible patients during a period of the radiotherapy; in another 17% patients the tumour free margin was less than 1 cm. Radiation doses were incorrectly given to 7% of the patients. The given doses of cisplatin deviated in 10% of the patients treated with combined modalities. The interpretation of chest X-rays and computed tomography (CT) showed important differences in tumour response, tumour recurrence and late toxicity. From these data it is concluded that immediate checks can detect errors in treatments as planned at the local level and will make corrections possible at an early stage in multicentre studies. The quality of trial results will thus be improved. Uniform assessment of treatment outcome, tumour progression and forms of toxicity will lead to more sound trial conclusions.