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Background: Between 1982 and 1990 the Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial in high-risk pre- and postmenopausal (

Bacterial mono-ADP-ribosyltransferases (ARTs) catalyze the singular transfer of an ADP-ribose moiety from an NAD+ molecule onto a target molecule. ARTs contain an ancient and highly conserved tertiary structure and have a wide variety of intracellular targets and effects. Some, but not all, bacterial ARTs have an AB5-type multimeric structure consisting of an enzymatically active subunit non-covalently situated atop of a non-toxic pentamer. The active, or A, subunit of AB5-type toxins has a catalytic action that contributes to bacterial pathogenicity, and it is sometimes, but not always, an ART. ArtAB is an ART with AB5-type structure from the virulent and highly antibiotic resistant Salmonella Typhimurium DT104. In the studies described here, we tested the hypothesis that the active subunit of ArtAB is structurally and enzymatically homologous to that of the well-characterized AB5-type ART pertussis toxin. ArtAB was purified from E. coli and was used to characterize ArtAB’s cellular effects, predicted structure, and biophysical properties. In addition, a set of single-residue mutants was constructed and purified to probe ArtAB’s active site. AB5-type toxins have long been studied for their immunogenic properties, and some of these bacterial munitions have been harnessed and repurposed as vaccines or vaccine adjuvants to prevent infectious disease. Their receptor-binding pentamer, abbreviated as B5, binds to, and facilitates entry into, host cells. In additional work presented here, we tested the hypothesis that the B5 subunit of cholera toxin (CTB) from Vibrio cholerae could be used to construct a safe and effective mucosal vaccine against Staphylococcus aureus-caused mastitis. We constructed a bovine vaccine by conjugating Staphylococcus aureus antigens to the CTB-based adjuvant platform, and the immunogenicity of the vaccine was characterized in a bovine clinical trial. Finally, clinical isolates of caprine S. aureus were screened for the presence of surface antigens that could be use in a caprine version of the vaccine against mastitis. The work on bacterial AB5-type ARTs presented here contributes to a growing global understanding of the bacterial ART family, lays a foundation for the potential incorporation of ArtAB in a vaccine against Salmonella, and advances the development of bovine and caprine vaccines against S. aureus-caused mastitis.

Following the DAHANCA 5 trial [1], which demonstrated the benefit of the hypoxic radiosensitizer Nimorazole, and the DAHANCA 6&7 trial, which demonstrated that accelerated fractionation added signi...

PURPOSE: To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC).PATIENTS AND METHODS: Patients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl.RESULTS: Following a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events. The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16-2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event-free survival (HR: 1.36 [1.09-1.69]), disease-specific death (HR: 1.43 [1.08-1.90]), and overall survival (HR: 1.30 [1.02-1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting.CONCLUSION: Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival.

The Wadden Sea Region is comprised of the embanked coastal marshes and islands in the Wadden Sea near Denmark, Germany, and the Netherlands. This area retains an exceptional common history in all its aspects: archaeologically, economically, socially, and culturally. Its settlement history of more than two thousand years is unrivalled and still mirrored in the landscape. Even though it has never constituted a political unity, it still shares a landscape and cultural heritage. For example, the approaches to water management and associated societal organization developed in the region during the last millennium have set significant world standards. This book offers an overview of current research on history, landscape and cultural heritage of the Wadden Sea region.

BACKGROUND: The DBCG-IMN is a nationwide population-based cohort study on the effect of internal mammary node radiotherapy (IMN-RT) in patients with node positive early breast cancer. Due to the risk of RT-induced heart disease, only patients with right-sided breast cancer received IMN-RT, whereas patients with left-sided breast cancer did not. At seven-year median follow-up, a 3% gain in overall survival with IMN-RT has been reported. This study estimates IMN doses and doses to organs at risk (OAR) in patients from the DBCG-IMN. Numbers needed to harm (NNH) if patients with left-sided breast cancer had received IMN-RT are compared to the number needed to treat (NNT).MATERIAL AND METHODS: Ten percent of CT-guided treatment plans from the DBCG-IMN patients were selected randomly. IMNs and OAR were contoured in 68 planning CT scans. Dose distributions were re-calculated. IMNs and OAR dose estimates were compared in right-sided versus left-sided breast cancer patients. In six left-sided patients, IMN-RT was simulated, and OAR doses were compared to those in the original plan. The NNH resulting from the change in mean heart dose (MHD) was calculated using a published model for risk of RT-related ischemic heart death.RESULTS: In original plans, the absolute difference between right- and left-sided V90% to the IMNs was 38.0% [95% confidence interval (5.5%; 70.5%), p < 0.05]. Heart doses were higher in left-sided plans. With IMN-RT simulation without regard to OAR constraints, MHD increased 4.8 Gy (0.9 Gy; 8.7 Gy), p < 0.05. Resulting NNHs from ischemic heart death were consistently larger than the NNT with IMN-RT.CONCLUSION: Refraining from IMN-RT on the left side may have spared some ischemic heart deaths. Assuming left-sided patients benefit as much from IMN-RT as right-sided patients, the benefits from IMN-RT outweigh the costs in terms of ischemic heart death.

In 2003, the Danish Breast Cancer Cooperative Group (DBCG) initiated DBCG-IMN, a prospective study on the effect of adjuvant internal mammary lymph node radiotherapy (IMN-RT) in patients with early lymph node positive breast cancer (BC). In the study, standard DBCG IMN-RT was provided only to patients with right-sided BC. We provide estimates of doses to IMNs and organs at risk (OARs) in patients treated with the non-CT-based RT techniques used during the DBCG-IMN study. Material and methods. Five DBCG RT regimens were simulated on planning CT scans from 50 consecutively scanned BC patients, 10 in each group. Intended target volumes were chest wall or breast and regional lymph nodes ± IMNs. Field planning was conducted in the Eclipse(TM) RT treatment planning system. Subsequently, IMN clinical target volumes (CTVs) and OARs were delineated. Estimates on doses to the IMN-CTV and OARs were made. Results. IMN dose coverage estimates were consistently higher in right-sided techniques where IMN treatment was intended (p

Purpose: Several small studies have indicated that the ATM rsl 801516 SNP is associated with risk of normal tissue toxicity after radiotherapy. However, the findings have not been consistent. In order to test this SNP in a well-powered study, an individual patient data meta-analysis was carried out by the International Radiogenomics Consortium. Materials and methods: The analysis included 5456 patients from 17 different cohorts. 2759 patients were given radiotherapy for breast cancer and 2697 for prostate cancer. Eight toxicity scores (overall toxicity, acute toxicity, late toxicity, acute skin toxicity, acute rectal toxicity, telangiectasia, fibrosis and late rectal toxicity) were analyzed. Adjustments were made for treatment and patient related factors with potential impact on the risk of toxicity. Results: For all endpoints except late rectal toxicity, a significantly increased risk of toxicity was found for carriers of the minor (Asn) allele with odds ratios of approximately 1.5 for acute toxicity and 1.2 for late toxicity. The results were consistent with a co-dominant pattern of inheritance. Conclusion: This study convincingly showed a significant association between the ATM rs1801516 Asn allele and increased risk of radiation-induced normal tissue toxicity. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

Background and purpose: The aim of this report was to describe the incidence and prevalence of acute and late morbidity in the DAHANCA 6&7 multicentre randomised trial with accelerated radiotherapy for squamous cell carcinoma of the head and neck. Materials and methods: The DAHANCA 6&7 study included 1476 patients eligible for primary radiotherapy alone. Patients were randomised between five or six weekly fractions of conventional radiotherapy. The prescribed dose was 66–68 Gy in 33–34 fractions. All patients were seen weekly during treatment and at regular intervals after completion where detailed morbidity recording was done. Reports from 1468 patients were available for analysis of treatment related morbidity. Results: Accelerated radiotherapy caused a significant (p < 0.05) increase in the peak incidence of: use of analgesics (53% vs. 65%), dysphagia (35% vs. 45%), mucosal oedema (52% vs. 59%), and mucositis (33% vs. 53%). All acute reactions were reversible and healed within three months after radiotherapy. Loss of taste, xerostomia, and acute skin reaction was not different between the two groups. For all late endpoints except fibrosis and atrophy a decline in prevalence was observed in the years after radiotherapy, there was no significant difference between randomisation arms in any of the late endpoints. Conclusions: Six fractions per week, resulting in a one-week reduction in overall treatment time relative to conventional radiotherapy increased acute but not late morbidity. Since acceleration improves locoregional tumour control, the schedule represents a significant improvement of the therapeutic ratio for head and neck radiotherapy and might be close to the maximal gain possible with accelerated fractionation alone.

The main objective of the present study aims at comparing the long-term efficacy of breast conserving surgery (BCS) vs. mastectomy (M) based on a randomized design. The Danish Breast Cancer Cooperative Group (DBCG) conducted the trial (DBCG-82TM) from January 1983 to March 1989 recruiting 1154 patients with invasive breast carcinoma. Follow-up time ended 1(st) May 2006 with a median follow-up time of 19.6 years (time span 17.1-23.3 years). Eligibility criteria included a one-sided, unifocal, primary operable breast carcinoma, patient age below 70 years, probability of satisfactory cosmetic outcome with BCS, and no evidence of disseminated disease. The patients accrued were grouped into three subsets: correctly randomized, suspicion of randomization error, and declining randomization. The main analyses focus on the subgroup of 793 correctly randomized patients representing 70% of the complete series. 10-year recurrence free survival (RFS) and 20-year overall survival (OS) based on intent to treat did not reveal significant differences in outcome between breast conserving surgery vs. mastectomy, p=0.95 and p=0.10, respectively. Including the complete series comprising 1133 eligible patients based on treatment in fact given similarly no significant difference between surgical options could be traced in outcome of 10-year RFS and 20-year OS, p=0.94 and p=0.24, respectively. The pattern of recurrences as a first event in breast conservation vs. mastectomy did not differ significantly irrespective of site, p=0.27. Looking into the type of local relapse, viz., new primaries vs. true recurrences, it appeared that new primaries were significantly associated to BCS, while true recurrences dominated among M treated patients (p

Udgivelsesdato: 2008-null BACKGROUND: Randomised studies have shown that breast conserving surgery followed by radiotherapy is associated with a prognosis similar to mastectomy alone. This formed the basis for recommending breast conserving surgery combined with radiotherapy as a standard treatment for suited breast cancer patients in Denmark. PATIENTS AND METHODS: To evaluate the results of this treatment, we performed a nationwide population-based follow-up study of patients aged less than 75 years treated in Denmark from 1989 to 1998 based on the database of Danish Breast Cancer Cooperative Group. RESULTS: At 15 years of follow-up, the Kaplan-Meier estimate of overall survival was 69% among 3 758 patients who received the recommended treatment. Within the first 10 years of follow-up, the cumulative incidences of loco-regional recurrences, distant metastases or other malignant disease, or death as a first event were 9.0, 19.9, and 6.0% respectively, when analysed in a competing risk setting. The risk of loco-regional recurrences was significantly decreased in patients aged 50 years or more and increased with increasing tumour size. There was a pronounced beneficial effect of adjuvant radiotherapy with those not receiving radiotherapy having a hazard ratio of 3.52 (95% CI 2.21-5.61). The effect of resection margins was significant for loco-regional recurrences only in node negative patients. CONCLUSION: In conclusion, the present study shows that results similar to those from randomised clinical trials can be obtained when breast conserving treatment is applied as a standard treatment in an entire population.

INTRODUCTION: Axillary dissection in combination with radiation therapy is thought to be the main reason why patients surgically treated for breast cancer may develop decreased shoulder mobility on the operated side. The surgery performed on the breast has not been ascribed any considerable importance. In order to evaluate the influence of the surgical technique and the adjuvant oncological therapy on the development of shoulder morbidity, we assessed the physical disability in 132 breast cancer patients with a median follow-up time of 3 years after surgery. METHODS AND METHODS: Eighty nine (67%) patients had been subjected to modified radical mastectomy and 43 (33%) to breast conserving therapy (BCT). All patients had axillary dissection of level I and II. The shoulder function was assessed by the Constant Shoulder Score including both subjective parameters on pain and ability to perform the normal tasks of daily living, and objective parameters assessing active range of motion and muscle strength. RESULTS: Shoulder disability seems to be a frequent late complication to the treatment of early breast cancer (35%). When equal axillary dissection and radiation therapy had been applied, BCT patients were found to suffer less frequent from this complication than patients treated with mastectomy.

BACKGROUND.: The benefit of a complementary fluorodeoxyglucose-positron emission tomography (FDG-PET) scan to standard workup for carcinoma of unknown primary (CUP) and metastatic neck lesions was prospectively studied. METHODS.: Sixty-seven patients underwent standardized diagnostic workup according to national guidelines including panendoscopies, multiple mucosal biopsies, and diagnostic CT/MRI scans. Median follow-up was 40 months (range, 2-65 months). RESULTS.: In 60 eligible patients, FDG-PET indicated a primary tumor or metastatic disease in 30 patients (50%). Additional investigations confirmed a primary tumor in 18 patients: hypopharynx in 5, oropharynx in 5, nasopharynx in 2, lung in 1, axilla in 1, bone in 1, rectum in 1, as well as multiple metastatic lesions from CUP in 2 patients. In retrospect, MRI was able to detect 1 of the PET-detected primaries, leading to an overall detection rate of PET of 29% in CUP. A therapeutic change of treatment was made in 25% as a consequence of FDG-PET. PET before panendoscopy demonstrated fewer false-positive pathological foci. CONCLUSION.: FDG-PET is a valuable tool in addition to conventional extensive workup in CUP and neck metastases. Consequently, FDG-PET is now recommended as an early diagnostic modality in the workup of these patients. (c) 2007 Wiley Periodicals, Inc. Head Neck, 2007.

Purpose It is unknown whether irradiation of the internal mammary lymph nodes improves survival in patients with early-stage breast cancer. A possible survival benefit might be offset by radiation-induced heart disease. We assessed the effect of internal mammary node irradiation (IMNI) in patients with early-stage node-positive breast cancer. Patients and Methods In this nationwide, prospective population-based cohort study, we included patients who underwent operation for unilateral early-stage node-positive breast cancer. Patients with right-sided disease were allocated to IMNI, whereas patients with left-sided disease were allocated to no IMNI because of the risk of radiation-induced heart disease. The primary end point was overall survival. Secondary end points were breast cancer mortality and distant recurrence. Analyses were by intention to treat. Results A total of 3,089 patients were included. Of these, 1,492 patients were allocated to IMNI, whereas 1,597 patients were allocated to no IMNI. With a median of 8.9 years of follow-up time, the 8-year overall survival rates were 75.9% with IMNI versus 72.2% without IMNI. The adjusted hazard ratio (HR) for death was 0.82 (95% CI, 0.72 to 0.94; P = .005). Breast cancer mortality was 20.9% with IMNI versus 23.4% without IMNI (adjusted HR, 0.85; 95% CI, 0.73 to 0.98; P = .03). The risk of distant recurrence at 8 years was 27.4% with IMNI versus 29.7% without IMNI (adjusted HR, 0.89; 95% CI, 0.78 to 1.01; P = .07). The effect of IMNI was more pronounced in patients at high risk of internal mammary node metastasis. Equal numbers in each group died of ischemic heart disease. Conclusion In this naturally allocated, population-based cohort study, IMNI increased overall survival in patients with early-stage node-positive breast cancer.

INTRODUCTION: Radiotherapy for oropharyngeal cancer often causes severe side effects. If the primary tumour is localized to the tonsillar region, elective irradiation may be limited to the ipsilateral neck, sparring the contralateral normal tissues. We wanted to study the consequences of volume sparring on all prospectively registered morbidity endpoints. METHODS AND PATIENTS: Medical records, treatment charts and database information were collected for all 158 oropharynx cancer patients treated from 1998 to 2002 at Aarhus University Hospital. Of the 139 patients treated with curative intent 40 were treated with an ipsilateral technique. RESULTS: Primary tumour extension outside the tonsillar fossa and T-stage were the only patient-, disease- and treatment related factors that differed between ipsilaterally and bilaterally treated patients. Loco-regional control and survival were not negatively influenced by the volume sparring technique. Side effects were reduced, in the ipsilaterally treated group, for all endpoints: xerostomia, dysphagia, hoarseness, atrophy, fibrosis and oedema. The number of patients experiencing moderate to severe toxicity was more than halved with ipsilateral treatment for all endpoints except fibrosis. CONCLUSION: For selected patients with tonsillar cancer without involvement of midline structures, ipsilateral treatment is safe and reduces morbidity compared with bilateral treatment. Udgivelsesdato: 2007-Oct

Background and aim: Numerous consensus reports recommend that postmastectomy radiotherapy (RT) in addition to systemic therapy is indicated in high-risk patients with 4+ positive nodes, but not in patients with 1–3 positive nodes. A subgroup analysis of the DBCG 82 b&c trials was performed to evaluate the loco-regional recurrence rate and survival in relation to number of positive nodes. Materials and methods: In the DBCG 82 b&c trials 3083 pre- and postmenopausal high-risk women were randomized to postoperative RT in addition to adjuvant systemic therapy. Since many patients had relatively few lymph nodes removed (median 7), the present analysis was limited to 1152 node positive patients with 8 or more nodes removed. Results: The overall 15-year survival rate in the subgroup was 39% and 29% (p = 0.015) after RT and no RT, respectively. RT reduced the 15-year loco-regional failure rate from 51% to 10% (p < 0.001) in 4+ positive node patients and from 27% to 4% (p < 0.001) in patients with 1–3 positive nodes. Similarly, the 15-year survival benefit after RT was significantly improved in both patients with 1–3 positive nodes (57% vs 48%, p = 0.03) and in patients with 4+ positive nodes (21% vs 12%, p = 0.03). Conclusion: The survival benefit after postmastectomy RT was substantial and similar in patients with 1–3 and 4+ positive lymph nodes. Furthermore, it was not strictly associated with the risk of loco-regional recurrence, which was most pronounced in patients with 4+ positive nodes. The indication for RT seems therefore to be at least equally beneficial in patients with 1–3 positive nodes, and future consensus should be modified accordingly. c 2007 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 82 (2007) 247‐253.

Purpose Postmastectomy radiotherapy (RT) in high-risk breast cancer patients can reduce locoregional recurrences (LRRs) and improve disease-free and overall survival. The aim of this analysis was to examine the overall disease recurrence pattern among patients randomly assigned to receive treatment with or without RT. Patients and Methods A long-term follow-up was performed among the 3,083 patients from the Danish Breast Cancer Cooperative Group 82 b and c trials, except in those already recorded with distant metastases (DM) or contralateral breast cancer (CBC). The end points were LRR, DM, and CBC, and the follow-up continued until DM, CBC, emigration, or death. Information was selected from medical records, general practitioners, and the National Causes of Death Registry. The median potential follow-up time was 18 years. Results The 18-year probability of any first breast cancer event was 73% and 59% (P < .001) after no RT and RT, respectively (relative risk [RR], 0.68; 95% CI, 0.63 to 0.75). The 18-year probability of LRR (with or without DM) was 49% and 14% (P < .001) after no RT and RT, respectively (RR, 0.23; 95% CI, 0.19 to 0.27). The 18-year probability of DM subsequent to LRR was 35% and 6% (P < .001) after no RT and RT, respectively (RR, 0.15; 95% CI, 0.11 to 0.20), whereas the probability of any DM was 64% and 53% (P < .001) after no RT versus RT, respectively (RR, 0.78; 95% CI, 0.71 to 0.86). Conclusion Postmastectomy RT changes the disease recurrence pattern in high-risk breast cancer patients; fewer patients have LRR as first site of recurrence, and overall fewer patients have DM.

Background and purpose In the DBCG 82 b&c trials, 3083 patients with stages II and III breast cancer were randomised to receive post-mastectomy radiotherapy (RT) versus no RT in addition to systemic therapy. The study showed a decrease in loco-regional recurrences and an improved survival in patients receiving RT. The aim of the present study was to identify risk factors for loco-regional recurrence (LRR), to evaluate the treatment of LRR and to examine the prognosis after LRR. Patients and methods The 18-year probabilities of LRR were calculated for different prognostic factors using the Kaplan–Meier method. The efficacy of different LRR treatments was compared. The 5-year survival and distant metastases (DM) probability after LRR was calculated with regard to initial randomization group, primary tumor and recurrence related variables. Results Of the 3083 patients, 535 had a LRR alone as first site of failure. In univariate analyses, large primary tumor size, ductal carcinoma, high malignancy grade, fascia invasion, few removed nodes, many positive nodes and extracapsular invasion were all risk factors for developing LRR. Combined treatment with surgery and RT at the time of LRR increased the persistent loco-regional control. The 5-year probability of subsequent DM was 73% irrespective of initial randomization group. In multivariate analysis, large primary tumor size, many positive nodes, extracapsular invasion, supra/infraclaviculary failures, multiple LRR and a short interval less than 2 years to first LRR were poor prognostic factors for survival. Conclusions Twenty-seven percent of LRR patients had no DM 5 years after failure. Initial randomization group did not alter the prognosis after LRR. Combined treatment of the LRR with surgery and RT improved persistent loco-regional control compared with surgery or RT alone.

Introduction In the DBCG 82 b&c trials 3083 patients with stages II and III breast cancer were randomised to receive postmastectomy radiotherapy (RT) versus no RT in addition to systemic therapy. The study showed a decrease in loco-regional recurrences and an improved survival in patients receiving RT. The aim of the present study was to describe the delivered RT for the 1538 patients who were randomised to RT, and to evaluate the compliance with the RT guidelines. Patients and methods Basic information about the given RT was recorded in the DBCG datacentre. For the current study, missing and additional information was collected from individual RT treatment charts. We defined some criteria for complying with the DBCG RT guidelines regarding target coverage and dose and fractionation and based on that we also defined some criteria for having clinically acceptable RT treatments. Results Of the 1538 patients, 87% received megavoltage RT, 8% had orthovoltage RT and 5% never began or completed RT. Of the 1341 megavoltage irradiated patients, the guideline compliance regarding target coverage of the axillary/periclaviculary region, internal mammary nodes and chest wall was 88, 79 and 85%, respectively. Only 0, 0.2 and 0.4% did not have clinically acceptable target coverage. The dose and fractionation was according to the guidelines in 96% and none had clinically unacceptable dose and fractionation schedules. Conclusion The guideline compliance for megavoltage RT was high with 88, 79 and 85% complying with the guidelines regarding target coverage of the axillary/periclaviculary region, internal mammary nodes and chest wall, respectively, and with 96% complying with the guidelines regarding dose and fractionation schedules. Less than 1% had clinically unacceptable target coverage and none had unacceptable dose and fractionation schedules.

OBJECTIVE: In 1998, the Danish Society for Head and Neck Oncology decided to conduct a nationwide survey at the five head and neck oncology centers with the aim of evaluating the surgical outcome of salvage laryngectomy after radiotherapy with special emphasis on identifying factors that could contribute to the development of pharyngocutaneous fistulae. PATIENTS: A total of 472 consecutive patients undergoing postirradiation salvage laryngectomy in the period July 1, 1987-June 30, 1997 were recorded at the five head and neck oncology centers in Denmark. Age ranged from 36 to 84 years, median 63 years, 405 men and 67 women. Primary tumor site was glottic larynx (n = 242), supraglottic larynx (n = 149), other larynx (n = 45), pharynx (n = 27), and other (n = 9). All patients had received prior radiotherapy. RESULTS: Median time between radiotherapy and laryngectomy was 10 months (range, 1-348 months). A total of 89 fistulae lasting at least 2 weeks were observed, corresponding to an overall average fistulae risk of 19%. The number of performed laryngectomies per year decreased linearly (from 58 to 37), whereas the annual number of fistulae increased slightly (from 7 to 11), which meant that the corresponding estimated fistulae risk increased significantly from 12% in 1987 to 30% in 1997. Other significant risk factors for fistulae in univariate analysis included younger patient age, primary advanced T and N stage, nonglottic primary site, resection of hyoid bone, high total radiation dose, and large radiation fields. Multiple logistic regression analysis of these parameters suggested that nonglottic tumor site, late laryngectomy period (1987-1992 vs 1993-1997), and advanced initial T stage were independent prognostic factors for fistulae risk. Surgical parameters like resection of thyroid/tongue base/trachea or radiotherapy parameters like overall treatment time or fractions per week did not influence fistulae risk. CONCLUSIONS: The risk of fistulae is especially high in patients initially treated with radiotherapy for nonglottic advanced stage tumors. A significant decrease in the number of performed salvage laryngectomies over the 10 years was seen. Over the same time period, the annual number of fistulae remained almost constant. The resulting more than doubling of fistulae rate could thus in part be explained by less surgical routine.

A total of 266 recurrence-free breast cancer patients from the randomized DBCG-82TM breast conservation trial were called in for a follow-up investigation to study the impact of surgical and radiation treatment factors on the cosmetic and functional outcome after breast conservation. The patients were interviewed and examined after a median follow-up time of 6.6 years, and 194 of them (73%) regarded the cosmetic result as excellent or good. Morbidity assessments showed that breast fibrosis, skin telangiectasia, and breast retraction were significantly associated with a less satisfactory cosmetic result. On univariate analysis, it was found that treatment with a direct anterior electron field produced more morbidity and inferior cosmetic outcomes compared with tangential photon treatment, while increasing breast size was associated with increased breast retraction and breast fibrosis. Treatment characteristics that emerged as independent prognostic factors of a poor cosmetic outcome on multivariate analysis were the use of a direct anterior electron field (OR = 2.15, CI 1.25-3.70) and adjuvant systemic therapy (OR = 2.13, 1.22-3.71). A significant but relatively low level of concordance was found between the patients' and the clinician's evaluations of cosmetic results but self-assessments of breast morbidity and psychological distress were significantly related to the observed treatment-induced side effects after breast-conserving treatment, indicating that subjective perceptions and observations as reported by the patients are relevant for the identification of treatment factors that impact on normal tissue reactions.

PURPOSE: Risk factors for local and distant recurrence after breast-conserving therapy and mastectomy were compared to define guidelines for the decision making between both treatments. PATIENTS AND METHODS: The data of two randomized clinical trials for stage I and II breast cancer patients were pooled. The total number of patients in the study was 1,772, of whom 879 underwent breast conservation, and 893, modified radical mastectomy. Representative slides of the primary tumor were available for histopathologic review in 1,610 cases (91%). RESULTS: There were 79 patients with local recurrence after breast-conservation and 80 after mastectomy, the 10-year rates being 10% (95% confidence interval [CI], 8% to 13%) and 9% (95% CI, 7% to 12%), respectively. Age no more than 35 years (compared with age >60: hazard ratio [HR], 9.24; 95% CI, 3.74 to 22.81) and an extensive intraductal component (HR, 2.52; 95% CI, 1.26 to 5.00) were significantly associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion was predictive of the risk of local recurrence, irrespective of the type of primary treatment (P < .01). Tumor size, nodal status, high histologic grade, and vascular invasion were all highly significant predictors of distant disease after breast-conserving therapy and mastectomy (P < .01). Age no more than 35 years and microscopic involvement of the excision margin were additional independent predictors of distant disease after breast-conserving therapy (P < .01). CONCLUSION: Age no more than 35 years and the presence of an extensive intraductal component are associated with an increased risk of local recurrence after breast-conserving therapy. Vascular invasion causes a higher risk of local recurrence after mastectomy as well as after breast-conserving therapy and should therefore not be used for deciding between the two treatments.

Following modified radical mastectomy, pre- and perimenopausal (amenorrhoea for5 years) patients with stage II or III breast cancer received CMF (cyclophosphamide 600, methotrexate 40, 5-fluorouracil 600 mg/m2 intravenously (i.v.) every 4 weeks, 9 cycles). The effect on recurrence-free survival (RFS) and overall survival (OS) of the addition of adjuvant tamoxifen (TAM) to adjuvant chemotherapy was examined by randomisation either to no additional treatment (n = 314), or concurrently TAM 30 mg daily for 1 year (n = 320). 40% had positive, 12% negative and 48% unknown receptor status. One year after surgery 21% versus 35% (CMF + TAM versus CMF) were still menstruating (P0.01). With a median follow-up of 12.2 years there was no difference in RFS (10-year RFS 34% versus 35%, P = 0.81) or OS (45% versus 46%, P = 0.73). In a Cox proportional hazards model, tumour size, number of metastatic lymph nodes, frequency of metastatic nodes in relation to total number of nodes removed, degree of anaplasia, age, and menostasia within the first year after operation were significant independent prognostic factors for RFS, and the same factors except age for OS. No significant interactions with TAM were seen. Thus, in this group of pre- and perimenopausal high-risk early breast cancer patients with heterogeneous receptor status given CMF i.v., concurrent TAM for 1 year did not improve the outcome. These results do not exclude that receptor positive patients may benefit from adjuvant TAM for longer periods given sequentially to chemotherapy.

Summary Background Radiotherapy in addition to systemic treatment after mastectomy prolongs survival in high-risk breast-cancer patients. However, adjuvant radiotherapy has a potential association with ischaemic heart disease. We assessed morbidity and mortality from ischaemic heart disease in patients treated with postmastectomy radiotherapy. Methods Between 1982 and 1990, we randomly assigned 3083 women at high risk of breast cancer, after mastectomy, adjuvant systemic treatment with (n=1538) or without (n=1545) radiotherapy. An anterior photon field was used against the periclavicular region and the axilla. The chest wall was treated through two anterior shaped electron fields, one including the internal mammary nodes. The intended dose was 48–50 Gy in 22–25 fractions, at four to five fractions per week. We obtained information on morbidity and mortality of ischaemic heart disease over a median of 10 years. Analysis was by intention to treat. Findings More women in the no-radiotherapy group than in the radiotherapy group died of breast cancer (799 [52·5%] vs 674 [44·2%]), whereas similar proportions of each group died from ischaemic heart disease (13 [0·9%] vs 12 [0·8%]). The relative hazard of morbidity from ischaemic heart disease among patients in the radiotherapy compared with the no-radiotherapy group was 0·86 (95% CI 0·6–1·3), and that for death from ischaemic heart disease was 0·84 (0·4–1·8). The hazard rate of morbidity from ischaemic heart disease in the radiotherapy group compared with the no-radiotherapy group did not increase with time from treatment. Interpretation Postmastectomy radiotherapy with this regimen does not increase the actuarial risk of ischaemic heart disease after 12 years.

Postmastectomy irradiation has been analyzed in several randomized trials, usually without the presence of systemic therapy. Overview analysis of these studies has shown that, although postmastectomy irradiation generally reduces the locoregional recurrence rate by a factor of 3, this is not transferred into a general long-term survival benefit. Recently, a clinically relevant survival gain from adjuvant radiotherapy has been shown in high-risk premenopausal patients also treated with adjuvant chemotherapy. There are now 11 published trials, including more than 6000 patients, in which the effect of postmastectomy radiotherapy has been evaluated in the presence of adjuvant systemic therapy. This article reviews the available data from these trials, as well as problems in their design, sample size, inclusion criteria, quality, and extent of treatments, and length of follow-up time.

Purpose : To investigate the prognostic value of T POT , S-phase time ( T S ), iododeoxyuridine (IdUrd) labelling index ( LI ) and DNA index with loco-regional tumour control as the end-point. Materials and methods : Iododeoxyuridine was given to 99 patients with squamous cell carcinomas of the head and neck before the start of radiotherapy. The analysis included FCM parameters ( LI , T S , T POT and DNA index, n =87) and LI determined by immunohistology (IHC, n =45). A hybrid T POT was determined by combining the FCM T S and the IHC LI ( n =45). In diploid tumours ( n =39), the FCM LI was underestimated and the FCM T POT was overestimated because the flow cytometer was unable to distinguish between tumour and normal cells. The `tumour LI ' was defined as the IHC LI or the FCM LI of aneuploid tumours when a biopsy for IHC evaluation was not available and similarly the `tumour T POT ' was determined by the hybrid T POT or the FCM T POT of aneuploid tumours ( n =63). Results : There was good agreement between the IHC LI and the FCM LI for aneuploid tumours, but there was disagreement for diploid tumours. The median tumour T POT was 4.1 days (range 0.6–19.5 days) and the median tumour LI was 12.9% (range 3.1–46.0%). In a univariate analysis there was no prediction of loco-regional tumour control by the LI , the T S or the T POT determined by either of the methods. T-classification, N-classification, clinical stage and tumour diameter were related with loco-regional tumour control, whereas clinical stage was the only parameter that yielded independent prognostic significance in a multivariate analysis. Conclusions : This study does not confirm the significant prognostic value of T POT as indicated in some previous reports. Larger clinical studies are needed to draw final conclusions.

Sentinel node biopsy (SN) in breast cancer treatment was introduced in the mid-1990s in order to be able to stage patients before decision of definitive surgery. Since then, both the pathological examinations of the SN and the systemic adjuvant treatment have improved and cause new challenges in the correct decision making regarding whether or not to radically treat the axilla in case of a positive SN. In SN positive patients, current St. Gallen guidelines support no completion ALND (axillary lymph node dissection) in clinically node-negative patients with 1-2 macrometastatic sentinel nodes operated with breast conservation and receiving tangential field adjuvant radiotherapy (RT). ALND is being questioned due to increased morbidity compared with SN biopsy alone, and to limited long term benefit on disease free survival in selected patients. An alternative to ALND is treating the axilla with nodal RT although this treatment is mostly used as adjuvant treatment after ALND in high risk patients. Few studies have investigated the benefit of nodal RT compared to ALND, and no consensus has yet been reached. Clinical decision making regarding treating the axilla should be based on relevant data, and in this review studies aiming at deciding whether or not and how the axilla should be treated in SN positive patients will be discussed. Furthermore treatment choice will be discussed, since besides ALND, both breast irradiation and nodal irradiation might cure residual disease after SN. Also the issue of improved systemic adjuvant treatment will be discussed in relation to eventually no regional axillary treatment.

Background: Tamoxifen is an antiestrogen with proven efficacy and low toxicity in the treatment of breast cancer. However, tamoxifen has been shown to exert a number of nonhormonal as well as hormonal effects. One nonhormonal effect of tamoxifen is the induction of transforming growth factor-p (TGF-p) secretion. TGF-P has been implicated in the pathogenesis of radiation-induced fibrosis. Purpose: We investigated the development of lung fibrosis in breast cancer patients who were treated after mastectomy with radiotherapy, with or without simultaneous adjuvant treatment with tamoxifen. Methods: Data from 196 women were included in the analysis. Eighty-four women were postmenopausal patients who participated in a randomized trial testing tamoxifen as an adjuvant to postmastectom y radiotherapy. The radiotherapy technique employed an 8-MV photon field covering the axillary and the infraclavicular and supraclavicular regions of the affected side of the chest; the chest wall was treated with an abutted electron field. Optical density changes in pretreatment and post-treatment chest x-ray Films were used to monitor the development of lung fibrosis; lung reactions were assessed in the photonirradiated field only. Logistic regression analysis was used to explore relationships between radiation dose and the development of lung fibrosis in patients either receiving or not receiving tamoxifen. All P values are from two-sided tests. Results: Among the 84 women who participated in the randomized trial of radiotherapy plus tamoxifen (n = 38) versus radiotherapy alone (n = 46), there was a significant association between tamoxifen treatment and the incidence of marked lung fibrosis (relative risk = 2.0; 95% confidence interval [CI] = 1.2-3.5; P = .01). When logistic regression analysis was used to evaluate data from all 196 patients, a highly significant relationship was found between the incidence of lung fibrosis and total radiation dose (P = .0005). In the full analysis, an increased risk of marked lung fibrosis was found again for patients who received tamoxifen simultaneously with radiotherapy (with patients receiving radiotherapy alone as the referent, odds ratio = 2.9; 95% CI = 1.3-63; P = .007). Patient age and menopausal status did not significantly influence the results. Conclusion: Tamoxifen treatment during postmastectomy radiotherapy enhances the risk of radiation-induced lung fibrosis. Implications: In view of pre-existing data, we hypothesize that tamoxifen mediates the enhancement of radiation-induced lung fibrosis through the induction of TGF-P secretion. If this hypothesis is correct, new strategies might be devised for preventing or reducing radiation-induced fibrosis. Because we studied a relatively small portion of the irradiated lung, we cannot recommend changes in current therapeutic measures; however, we strongly encourage additional studies of lung fibrosis in patients receiving tamoxifen and radiotherapy. [J Natl Cancer Inst 1996;88:918-22]

Background and purpose: Hypoxic tumor cells are known to be relatively radioresistant. The aim of the study was to correlate oxygenation status and radiation response in advanced squamous cell carcinomas of head and neck. Methods and patients: Pretreatment oxygenation status was measured in 34 lymph nodes and one primary tumor neck using oxygen electrodes. The primary oxygenation endpoint was the fraction of pO2 values less than 2.5 mmHg. Patients received standardized, conventional, external radiotherapy 66–68 Gy in 33–34 fractions. Results: Sixteen patients had loco-regional failure. Among these 16 patients the median of the fraction of pO2 values less than 2.5 mmHg was 22% (range 0–95%) as compared to 6% (range 0–51%) among patients with loco-regional tumor control. When separating all 35 patients by the median of the fraction of pO2 values less than 2.5 mmHg and comparing the 2 years actuarial tumor control probability using Kaplan-Meier estimates, the most hypoxic subgroup had significantly lower loco-regional tumor control (P=0.013, Logrank test). By univariate regression analysis the fraction of pO2 values less than 2.5 mmHg was found to be significant as continuous variable (P=0.010). Finally, by Cox multiple regression analysis the fraction of pO2 values less than 2.5 mmHg was found to be the strongest independent variable in predicting radiation response when using tumor control in the site of pO2 assessment as treatment endpoint (P=0.018). Conclusion: These results suggest that pretreatment tumor oxygenation status is predictive of radiation response, when using the fraction of pO2 values less than 2.5 mmHg as endpoint.

A colony-forming assay of human skin fibroblast radiosensitivity was established in our laboratory and applied to primary skin biopsies from 12 women belonging to an unselected group of patients who received postmastectomy radiotherapy 10-12 years prior to this study. The aim was to investigate the relationship between in vitro radiosensitivity and the occurrence of subcutaneous fibrosis after radiotherapy. Early generations of normal skin fibroblasts in exponential growth were irradiated at room temperature at a high dose-rate to estimate the surviving fraction of colony-forming cells after single doses ranging from 1 to 8 Gy. A linear-quadratic cell survival curve was fitted to the data and from these fits the surviving fraction at 3.5 Gy (SF3.5) was estimated. Replicate experiments of different cell generations were made to validate the assay, and the between-patients variability was significantly larger than the assay variability for both SF2(p = 0.002) and SF3.5 (p = 0.04). Patients were treated in the period 1978-1982 with a dose per fraction between 2.7 and 3.9 Gy, a total of 12 fractions at two fractions per week. They were evaluated with respect to the occurrence of marked subcutaneous fibrosis in a total of 36 independent treatment fields. In each treatment field the total dose and dose per fraction at the relevant dosimetric reference depth as well as the length of follow-up were recorded. A previously derived LQ mixture model was applied to these data in order to determine the probability of marked fibrosis in that particular field. From this probability and the actually observed fibrosis, the excess risk of fibrosis was calculated, and this was averaged over the three treatment fields to obtain a single measure of clinical radiosensitivity. Increasing values of SF3.5 were statistically significantly correlated with decreasing probabilities of developing subcutaneous fibrosis (p = 0.014, Spearman's rank correlation test). Thus, this pilot study has demonstrated a positive correlation between in vivo radiosensitivity and normal skin fibroblasts and the clinical expression of subcutaneous fibrosis.

BACKGROUND AND PURPOSE: Tumour HPV-positivity is a favourable prognostic factor in the radiotherapy of HNSCC, but the optimal radiotherapy regimen for HPV-positive HNSCC is not yet defined. Reducing overall treatment time is known to improve outcome in the radiotherapy of HNSCC as was also demonstrated in the randomised DAHANCA 6&7 trial. We aimed to assess the influence of tumour HPV-status, expressed by p16, on the response to accelerated fractionated radiotherapy in HNSCC through evaluation of the DAHANCA 6&7 trial.MATERIALS AND METHODS: Immunohistochemical detection of HPV-associated p16-expression was performed on FFPE-pre-treatment tumour-tissues from 794 patients enrolled in the DAHANCA 6&7 trial. The influence of tumour p16-status on loco-regional tumour control and survival as a function of fractionation schedule (5Fx/week vs 6Fx/week) was evaluated 5years after the completion of radiotherapy.RESULTS: The significant and independent prognostic value of tumour p16-positivity in HNSCC radiotherapy was confirmed, with adjusted hazard ratios (HR) of 0.58 [0.43-0.78], 0.47 [0.33-0.67] and 0.54 [0.42-0.68] for loco-regional control, disease-specific and overall survival, respectively. Accelerated radiotherapy significantly improved loco-regional tumour control compared to conventional radiotherapy, adjusted HR: 0.73 [0.59-0.92] and the benefit of the 6Fx/week regimen was observed both in p16-positive (HR: 0.56 [0.33-0.96]) as well as in p16-negative tumours (HR: 0.77 [0.60-0.99]). Disease-specific survival was also significantly improved with accelerated radiotherapy in the group of p16-positive tumours (adjusted HR: 0.43 [0.22-0.82]).CONCLUSION: Accelerated radiotherapy significantly improves outcome in HNSCC compared to conventional fractionation. The observed benefit is independent of tumour p16-status and the use of a moderately accelerated radiotherapy regimen seems advantageous also for HPV/p16-positive HNSCC.

than in more recent trials. The heart mortality has decreased in more recent trials as demonstrated by data from the US Surveillance Epidemiology and End Results (SEER) cancer registries. They have documented in a cohort of more than 115,000 irradiated breast cancer patients with known tumour laterality that for patients treated during 1973–1982 the cardiac mortality ratio (left versus right tumour) was 1.20 (95% CI, 1.04–1.38) less than 10 years after irradiation, 1.42 (1.11–1.82) 10–14 years after irradiation, and 1.58 (1.29–1.95) after 15 years or more [5]. For women irradiated during 1983–1992 the corresponding figures were 1.04 (0.91–1.18) less than 10 years afterwards and 1.27 (0.99–1.63) 10 years or more after irradiation. The cardiac mortality ratio was 0.96 (0.82–1.12) for patients treated 1993–2001 and followed for less than 10 years. These figures thus may reflect the improvements in planning breast radiotherapy and the attempts to lower the dose to the heart. In the Danish Breast Cancer Cooperative Group (DBCG) 82 b&c post-mastectomy radiotherapy protocols no excess cardiac mortality was seen after median 12 year follow up comparing patients with left and right-sided breast cancer [6]. The patients treated according to these two protocols were irradiated with techniques designed to almost avoid doses to the heart. The patients also received systemic therapy [7].

The indication for adjuvant postmastectomy radiotherapy (PMRT) in breast cancer patients with small tumors and 1–3 macrometastases in the axilla remains a controversial issue, despite the recommendation that PMRT should be applied in these patients in the most recent overview by the Early Breast Cancer Trialists’ Collaborative Group. In this report, we discuss the available data on the benefit from PMRT in patients diagnosed with N1 breast cancer. Based on this, we recommend adjuvant PMRT to the chest wall and regional lymph nodes in patients diagnosed with early node-positive breast cancer.

Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of hemoglobin often have a poor response to radiation that may be related to hypoxia-induced radioresistance. We have previously published the importance of hemoglobin level and the effect of transfusion by the results from the randomized DAHANCA 5 trial, including 414 patients in the analysis. Aim of the current analysis was to gain additional power by adding patients from the continued subrandomization in the DAHANCA 7 trial, now including a total of almost 1200 patients.Patients were randomized to treatment in the DAHANCA 5 and 7 study (nimorazole vs. placebo and five fx/week vs. six fx/week), and in addition, patients with "low" pre-irradiation hemoglobin values (females13 g/dl; males14.5 g/dl) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a hemoglobin level in the "high" value range.A total of 1166 patients were included, 701 patients had high hemoglobin levels and 465 had low hemoglobin levels. Among the low hemoglobin patients, 235 were randomized to receive transfusion. Patient characteristics and treatment arms were well balanced. In the majority of patients, transfusion resulted in increased hemoglobin levels although this decreased slightly throughout treatment as in the non-transfused patients. Overall, the patients with low hemoglobin level had a significant reduced probability of locoregional control, disease-specific and overall survival. In the low hemoglobin group, transfusion did not improve the outcome in locoregional control, disease-specific or overall survival. In multivariate analyses, HPV/p16 status, T and N classification were significant factors for all outcome measures, whereas there was no significant influence of transfusion or hemoglobin level on endpoints.Transfusion prior to and during radiation treatment did not improve the outcome in patients with HNSCC and low hemoglobin values, but may have a negative impact on survival.

Patients with head and neck squamous cell carcinoma (HNSCC) and a low level of haemoglobin (Hb) often have a poor response to radiation which may be related to hypoxia induced radioresistance. The aim of the study was to evaluate the prognostic significance of low Hb level and its modification by transfusion in HNSCC patients treated with radiotherapy. The study was performed as a subrandomization in the DAHANCA 5 trial.Patients were randomized to treatment with the hypoxic radiosensitizer nimorazole or placebo, and in addition, patients with "low" pre-irradiation Hb values (females13 g/dL; males14.5 g/dL) were subrandomized to plus or minus transfusion. Transfusion was given with packed red blood cells with the aim to achieve a Hb level in the "high" value range.A total of 414 patients were included, 243 patients had high Hb levels and 171 patients had low Hb levels. Of the low Hb patients, 82 were randomized to receive transfusion and 89 not to receive transfusion. The treatment arms were well balanced. In the majority of patients, transfusion resulted in increased Hb levels although this tended to decline throughout treatment. Patients with high Hb levels had a significantly better probability of locoregional control, disease-specific survival and overall survival compared to 'low Hb no transfusion' patients. In the low Hb group, transfusion did not improve the outcome in locoregional control, disease-specific survival or overall survival. In multivariate analyses, T and N classifications were significant for all outcome measures, whereas there was no significant influence of transfusion or Hb level on endpoints.The univariate prognostic significance of high Hb level was demonstrated in patients with HNSCC treated with radiotherapy; however, transfusion prior to and during treatment did not improve the outcome in patients with low Hb values.

The effect of radiotherapy alone or given simultaneously with 5-FU in the treatment of locally recurrent or inoperable colorectal carcinoma was investigated in a randomized feasibility trial. Twenty-nine patients were randomized to radiotherapy alone (50 Gy/5 weeks + 10-20 Gy boost), and 30 patients to the same radiotherapy with weekly 5-FU (600 mg/m2) given before treatment every Monday during the first 5 weeks. The two groups were comparable with regard to age, sex, previous treatment, symptoms, tumour size and performance status. Treatment compliance to radiotherapy was the same in both groups with 87% receiving at least 50 Gy. Drug treatment was completed in 18/30 patients. Overall the treatment resulted in a significant palliative effect in 73% of evaluable patients with a median duration of 26 months, and objective response in 32% (8 CR, 11 PR), with a median duration of 18 months. The 3-year actuarial survival rate was 9% (median 12 months). Only patients who achieved CR became long-time survivors (63% 3-year actuarial survival). Similarly, performance status had a strong association with survival. Multivariate analysis showed complete response and high performance status to be the only parameters having prognostic influence on survival. Addition of 5-FU did neither influence the objective or symptomatic response, nor the development of distant metastases. However, addition of the drug resulted in an apparent increase in the frequency of severe acute radiation complications (33% vs. 13% after irradiation alone).

The impact of treatment duration on survival and progression-free survival is uncertain in metastatic breast cancer. In this trial 359 patients were randomised to receive cyclophosphamide, epirubicin and 5-fluorouracil (CEF) once every 3 weeks for a maximum of 18 months or identical chemotherapy for a maximum of 6 months. Following progressive disease (PD) or severe toxicity CEF was discontinued before the scheduled maximum duration. A second series of CEF continued for a maximum of 12 months was offered to patients with PD more than 3 weeks after completing a maximum of 6 months of CEF. Both groups received tamoxifen (30 mg daily) until PD, and premenopausal patients also received ovarian irradiation. After 6 months 254 evaluable patients were unprogressive. Survival and progression-free survival were significantly longer in 127 patients continuing CEF than in 127 patients interrupting CEF at 6 months (χ 2 = 17.6, P = 0.00003 and χ 2 = 4.7, P = 0.03, respectively). The results of the second series of CEF were discouraging with only one complete response in 44 evaluable patients. In conclusion, prolonged chemotherapy for 18 months is superior to identical chemotherapy for 6 months in the treatment of metastatic breast cancer.

The discovery that certain genetic syndromes are associated with a high cellular radiosensitivity has stirred interest in the concept that radiosensitivity of persons in general should have a genetic component. This has motivated research into assays for prediction of cellular normal tissue radiosensitivity. If such an intrinsic factor were a major factor in the development of late normal tissue injury, this should be detectable as a correlation between the probability of developing injury in different tissues. This hypothesis is tested in a series of 229 patients treated with postmastectomy radiotherapy and evaluated with respect to a number of late endpoints 16 to 71 months after the end of treatment. In each patient, the presence of marked subcutaneous fibrosis and telangiectasia were evaluated in two different treatment areas: in a photon field underneath a 5-mm wax bolus and in an abutted electron field used for treating the chest wall. The use of two different doses per fraction and the fact that a single anterior photon field was used with the dose prescribed at the level of the mid-axilla, led to a substantial variation in total dose and dose per fraction in these patients. A non-tissue-specific patient-to-patient difference in radiosensitivity would cause higher than expected reactions in one treatment area to be correlated with higher than expected reactions in the other area. For each of the two endpoints, telangiectasia or subcutaneous fibrosis, patients experiencing stronger than expected reactions in one treatment area tended to do so in the other area as well. Thus, a strong host factor appears to exist for a specific endpoint. It is an open question whether this is explained by individual variability in intrinsic radiosensitivity, progression rate of injury or other. Contrary to this, no significant correlation was seen when pairing the two late end-points, fibrosis and telangiectasia. Thus, patients showing stronger than expected fibrosis developed on average marked telangiectasia with a probability well predicted from their total dose and dose per fraction. These findings suggest that an assay for clinical expression of late injury would have to be specific for that type of injury.

Udgivelsesdato: 2009-May-20 BACKGROUND: Lymphovascular invasion has been associated with poor prognosis in women with breast cancer, but it is unclear whether the presence of lymphovascular invasion should be considered sufficient to reclassify breast cancer patients who are at a low risk of recurrence into a high-risk category. METHODS: Of the 16,172 patients with operable breast cancer who were entered into the Danish Breast Cancer Cooperative Group Registry from January 1, 1996, to December 31, 2002, lymphovascular invasion was classified at primary diagnosis in 16,121 patients as present (n = 2453, 15%) or as absent (n = 13,206, 82%). Patients with at least one of the risk criteria (positive lymph nodes, tumor size > 2 cm, high grade, hormone receptor-negative tumor, or younger than 35 years) were assigned to the high-risk group; the other patients were assigned to the low-risk group. All procedures, including report forms, central review, and querying, were specified in advance. Kaplan-Meier analyses were used to estimate disease-free intervals and overall survival rates among patients with and without lymphovascular invasion, and multivariable analysis was used to adjust for differences in baseline characteristics and therapy. All statistical tests were two-sided. RESULTS: Complete follow-up was achieved for 15,659 patients. The median estimated potential follow-up was 6.4 years for invasive disease-free interval and 7.7 years for overall survival. Invasive disease-free interval and overall survival were statistically significantly associated with lymphovascular invasion within the high-risk group (hazard ratio [HR] for invasive disease = 2.29, 95% confidence interval [CI] = 2.14 to 2.45, P < .001; and HR for death = 2.42, 95% CI = 2.25 to 2.61, P < .001) but not within the low-risk group. At 5 years after surgery, 65.4% (95% CI = 63.5% to 67.3%) and 85.2% (95% CI = 84.5% to 85.9%) of those in the high-risk group with and without lymphovascular invasion were alive; 98.1% (95% CI = 87.6% to 99.7%) and 94.1% (95% CI = 93.2% to 94.8%) of those in the low-risk group with and without lymphovascular invasion were alive. These differences persisted in a multivariable analysis, and for overall survival, a statistically significant interaction (P = .03) was observed between lymphovascular invasion and risk group. CONCLUSIONS: In this prospective population-based study, lymphovascular invasion was not an independent high-risk criterion. Lymphovascular invasion should not by itself be considered sufficient to move patients from a low-risk group to a high-risk group.

New strategies for adjuvant radiotherapy of early breast cancer are being investigated in several phase III randomised trials at the present time. Accelerated partial breast irradiation (APBI) is a way to offer an early breast cancer patient, who has had breast conservative surgery, an adjuvant radiotherapy of short duration aimed at the tumour bed with a certain margin. The rationale of this strategy is that most local recurrences appear close to the tumorectomy cavity and a wish to spare the patient late radiation morbidity. This review discusses the background for APBI, the different techniques, and we highlight possible pitfalls using these techniques. A systematic overview of all phase I and II studies is provided. Patient selection for this therapy is pivotal and based on evidence from previous studies on patient/tumour characteristics and pattern of local recurrences we propose inclusion criteria for patients in APBI protocols.