Who Needs Neighbors? PKS8 Is a Stand-Alone Gene in Fusarium graminearum Responsible for Production of Gibepyrones and Prolipyrone B.

Genome sequencing of the genus Fusarium has revealed a great capacity for discovery of new natural products of potential economical and therapeutic importance. Several of these are unknown. In this study, we investigated the product of the PKS8 gene in Fusarium graminearum, which was recently linked to gibepyrones in F. fujikuroi. Genomic analyses showed that PKS8 constitutes a stand-alone gene in F. graminearum and related species. Overexpression of PKS8 resulted in production of gibepyrones A, B, D, G and prolipyrone B, which could not be detected in the wild type strain. Our results suggest that PKS8 produces the entry compound gibepyrone A, which is subsequently oxidized by one or several non-clustering cytochrome P450 monooxygenases ending with prolipyrone B.

CT-planned internal mammary node radiotherapy in the DBCG-IMN study: benefit versus potentially harmful effects.

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.

Quality assurance of conventional non-CT-based internal mammary lymph node irradiation in a prospective Danish Breast Cancer Cooperative Group trial: the DBCG-IMN study.

UNLABELLED: 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 < 0.0001). Estimated doses to cardiac structures were low regardless of whether IMNs were treated or not. Post-lumpectomy patients had the highest estimated lung doses. CONCLUSION: Overall, simulator-based treatment using the DBCG RT techniques resulted in satisfactory coverage of IMNs and acceptable levels of OAR irradiation.

Factors associated with acute and late dysphagia in the DAHANCA 6 & 7 randomized trial with accelerated radiotherapy for head and neck cancer.

BACKGROUND: Dysphagia is a common and debilitating side effect in head and neck radiotherapy (RT). Prognostic factors are numerous and their interrelationship not well understood. The aim of this study was to establish a multivariate prognostic model for acute and late dysphagia after RT, based on information from a prospective trial. MATERIAL AND METHODS: The DAHANCA 6&7 randomized study included 1476 patients with head and neck cancer eligible for primary RT alone. Patients were randomized between 5 and 6 weekly fractions of conventional RT, and received 62-70 Gy in 31-35 fractions. Patients were scored for dysphagia weekly during treatment and at regular intervals until five years after treatment. Dysphagia scores were available from 1461 patients. RESULTS: Acute dysphagia according to DAHANCA grades 1, 2, 3 and 4 occurred in 83%, 71%, 43% and 23%, respectively. Severe dysphagia occurred in 47% and 38% of patients receiving accelerated or conventional radiotherapy, respectively (p = 0.001). At one, two, three, four and five years the prevalence of chronic dysphagia above grade 0, was 46%, 32%, 29%, 24%, 23%, respectively with no difference between 5 and 6 fractions. In multivariate analysis, the following parameters were independent factors for severe acute dysphagia: T3-T4 tumors, N-positive disease, non-glottic cancer, age> median, baseline dysphagia > 1 and accelerated radiotherapy. The following factors were prognostic factors for late dysphagia: non-glottic cancer, T3-T4, N-positive disease and baseline dysphagia > 1. The data confirmed previously published predictive models, as it was possible to separate patients in groups with low, medium and high risk of dysphagia, respectively, based on pre-treatment risk scores. CONCLUSION: Prognostic models were established to characterize patients at risk of developing acute or late dysphagia in the DAHANCA 6&7 trial. The results may be useful to identify patients at risk of dysphagia and thus candidates for prophylactic measures against swallowing dysfunction.

Postmastectomy radiotherapy in high-risk breast cancer patients given adjuvant systemic therapy. A 30-year long-term report from the Danish breast cancer cooperative group DBCG 82bc trial.

BACKGROUND: Between 1982 and 1990 the Danish Breast Cancer Cooperative Group (DBCG) conducted a randomized trial in high-risk pre- and postmenopausal (<70 years) breast cancer patients comparing mastectomy plus adjuvant systemic therapy alone versus the same treatment plus postoperative irradiation. AIM: To present a comprehensive analysis of the complete DBCG 82bc study with a 30-year long-term follow-up of the cancer therapeutic effect and survival, together with an additional focus on the potential long-term life-threatening morbidity related to cardiac irradiation and/or the risk of secondary cancer induction. METHODS: A total of 3083 patients with pathological stage II and stage III breast cancer were after mastectomy randomly assigned to receive adjuvant systemic therapy and postoperative irradiation to the chestwall and regional lymph nodes (1538 pts), or adjuvant systemic therapy alone (1545 pts). Pre- and menopausal patients (DBCG 82b) received 8-9 cycles of CMF with an interval of 4 weeks, whereas postmenopausal patients (DBCG 82c) received tamoxifen 30 mg daily for one year. The median follow-up time was 34 years. The primary endpoints were loco-regional recurrence (LRR) and overall mortality, and the secondary endpoints were distant metastasis, breast cancer mortality, and irradiation related late morbidity. RESULTS: Overall the 30-year cumulative incidence of loco-regional recurrence was 9% in irradiated patients versus 37% in non-irradiated patients who received adjuvant systemic therapy alone (HR: 0.21 [95% cfl 0.18-0.26]). Distant metastasis probability at 30 years was 49% in irradiated patients compared to 60% in non-irradiated (HR: 0.77 [0.70-0.84]). Consequently, these figures resulted in a reduced breast cancer mortality: 56% vs 67% (HR: 0.75 [0.69-0.82], and overall mortality (81% vs 86% at 30 years (p < 0.0001), HR: 0.83 [0.77-0.90] in favor of irradiation. Radiotherapy did not result in any significant excess death of other courses, such as ischemic heart disease, HR: 0.82 [0.58-1.18]; nor secondary lung cancer HR: 1.44 [0.92-2.24], or other non-cancer related death HR: 1.15 [0.92-1.45]. CONCLUSION: The study definitely demonstrate that optimal long-term treatment benefit of high-risk breast cancer can only be achieved if both loco-regional and systemic tumor control are aimed for. Therefore, radiotherapy has an important role in the multidisciplinary treatment of breast cancer. The PMRT treatment did not result in excess ischemic heart damage, nor in other non-breast cancer related death.

Internal Mammary Node Irradiation in Patients With Node-Positive Early Breast Cancer: Fifteen-Year Results From the Danish Breast Cancer Group Internal Mammary Node Study.

PURPOSE: The Danish Breast Cancer Group Internal Mammary Node study demonstrated improved 8-year overall survival (OS) with internal mammary node irradiation (IMNI) in patients with node-positive early breast cancer. Here, we present long-term results from the Danish Breast Cancer Group Internal Mammary Node study cohort. PATIENTS AND METHODS: This nationwide, prospective cohort study allocated patients with node-positive early breast cancer to adjuvant radiotherapy with or without IMNI depending on cancer laterality. Patients with right-sided cancer received IMNI. Patients with left-sided cancer were treated without IMNI because of risk of radiation-induced heart disease. Other treatment was independent of laterality. The primary study end point was OS. Secondary end points were distant recurrence and breast cancer mortality. Analyses were by intention to treat. RESULTS: During 2003-2007, 3,089 women were allocated to IMNI (right-sided, n = 1,491) or no IMNI (left-sided, n = 1,598). With a median follow-up of 14.8 years, 589 patients with and 701 patients without IMNI had died. The corresponding 15-year OS rates were 60.1% and 55.4%. The adjusted hazard ratio (HR) for death was 0.86 (95% CI, 0.77 to 0.96; P = .007) in favor of IMNI. The 15-year risk of developing distant recurrence was 35.6% (523 recurrences) and 38.6% (602 recurrences) with vs. without IMNI (adjusted HR, 0.88 [95% CI, 0.79 to 0.99; P = .04]). The 15-year breast cancer mortality with IMNI was 31.7% (467 deaths) compared with 33.9% (537 deaths) without IMNI (adjusted HR, 0.88 [95% CI, 0.78 to 1.00; P = .05]). The distribution of other deaths was similar across groups. CONCLUSION: In patients with node-positive early breast cancer treated with IMNI or without IMNI depending on breast cancer laterality, IMNI reduced the risk of distant recurrence and death from breast cancer, thereby improving long-term survival.

Does transfusion improve the outcome for HNSCC patients treated with radiotherapy? - results from the randomized DAHANCA 5 and 7 trials.

BACKGROUND: 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. MATERIAL AND METHODS: 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 (females <13 g/dl; males <14.5 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. RESULTS: 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. CONCLUSION: 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.

Accelerated partial breast irradiation as part of breast conserving therapy of early breast carcinoma: a systematic review.

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.

High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of DBCG 82 b&c.

BACKGROUND AND PURPOSE: International consensus reports recommend postmastectomy radiotherapy only to patients at high risk of a local recurrence (LR). MATERIALS AND METHODS: The present analysis included 1000 out of 3083 high-risk breast cancer patients randomly assigned to postmastectomy radiotherapy in the DBCG82 b&c trials. Tissue microarrays had been constructed and sections stained for estrogen, progesterone and HER2 receptors. Median potential follow-up time was 17 years. Endpoints were LR as isolated first event, breast cancer mortality and overall mortality. RESULTS: Among patients randomly assigned to not receive radiotherapy, three prognostic subgroups of LR risk were found. "The good" defined by at least four out of five favorable criteria (3 positive nodes, tumor size <2cm, Grade 1 malignancy, estrogen or progesterone receptor positive, HER2 negative), "the Poor" defined by at least two out of three un-favorable criteria (>3 positive nodes, tumor size >5cm, Grade 3 malignancy) and finally "the Intermediate" the group in between. The smallest absolute reduction in 5-year LR probability (11%) after radiotherapy was seen for the good prognosis group. A similar absolute reduction in 15-year breast cancer mortality after radiotherapy (11%) was seen. The largest absolute reduction in 5-year LR probability after radiotherapy was seen for the poor prognosis group (36%). However, this large LR reduction did not translate into any reduction in 15-year breast cancer mortality (0%). CONCLUSION: Translation of LR reduction into breast cancer mortality reduction after postmastectomy radiotherapy to high-risk breast cancer patients seems to be heterogeneous, with the largest translation occurring within the good prognosis group.

Carbonic anhydrase IX and response to postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of the DBCG82 b and c trials.

INTRODUCTION: A significant survival improvement after postmastectomy radiotherapy was identified in the Danish Breast Cancer Cooperative Group (DBCG82) b and c studies and in the British Columbia Randomized Radiation Trial. Recently, potential predictive value regarding response to postmastectomy radiotherapy was reported for carbonic anhydrase (CA) IX in a study (reported in abstract form) that included 160 patients. The purpose of the present study was to examine the importance of CA IX to response to postmastectomy radiotherapy in the larger scaled DBCG82 b and c studies. METHODS: The DBCG82 b and c studies included 3,083 high-risk Danish breast cancer patients. The women were randomly assigned to postmastectomy radiotherapy plus systemic therapy (cyclophosfamide, methotrexate and fluorouracil in premenopausal women; and tamoxifen in postmenopausal women) or to systemic therapy alone. Cores from invasive tumour-containing paraffin blocks from 1,000 patients (more than seven nodes surgically removed) were transferred to tissue microarrays. Tissue microarray sections were stained immunohistochemically for CA IX (M75). The median follow up for patients remaining alive was 17 years. Clinical end-points were loco-regional recurrence, distant metastases, disease-specific survival and overall survival. Statistical analyses included kappa statistics, chi2 or exact tests, Kaplan-Meier probability plots, Log-rank test and Cox regression analyses. RESULTS: CA IX was assessable in 945 cores. The percentage of tumours positive for CA IX was 16% (> or = 10% invasive tumour staining). CA IX was not an independent prognostic marker for survival, distant metastases, or locoregional recurrence in the subgroup of 945 patients or within either of the two randomization arms. In subgroup analyses, however, CA IX was an independent prognostic marker for overall survival among postmenopausal women (P = 0.001), women with one to three positive nodes (P = 0.02) and hormone receptor positive women (P = 0.001). Fifteen-year probabilities of overall survival were improved by 9% and 7% after postmastectomy radiotherapy for the subgroups of CA IX negative and CA IX positive patients, respectively. CONCLUSION: Within this series of 945 high-risk premenopausal and postmenopausal women, positivity for CA IX was not overall an independent prognostic marker for survival; only in subgroup analyses was it found to have prognostic value. The improvement in 15-year survival after postmastectomy radiotherapy was of similar magnitude in the two subgroups of CA IX positive and CA IX negative patients.

Postoperative radiotherapy in DBCG during 30 years. Techniques, indications and clinical radiobiological experience.

During the time period 1977-2007 postoperative radiotherapy in DBCG has varied considerably with regard to techniques and indications together with changes in the extent of surgery and adjuvant systemic therapy. The radiation treatment has been developed on the basis of clinical, radiophysical and radiobiological principles, encompassing also practical problems such as available equipment in the different centres and at times lack of sufficient machine capacity. The paper focus especially on the comprehensive work done prior to the DBCG 82 b&c studies, in order to optimize radiotherapy in all aspects prior to the evaluation of the efficacy of this treatment modality. The results from these trials did succeed in clear evidence that radiotherapy has an important role in the multidisciplinary treatment of early breast cancer. In parallel to these studies a new and challenging use of radiotherapy after breast conserving surgery was evaluated in the DBCG TM 82 protocol. The experience obtained with different techniques in this study formed the basis for the current principles of radiotherapy after lumpectomy. Reduction of radiation related morbidity has been a major issue for the DBCG radiotherapy group, and in this aspect several studies, including quality control visits, have been carried out to make the relevant modifications and to evaluate deviations from the guidelines between the centres. The background for the changes in radiotherapy is described for each of the programme periods as well as future perspectives which will include further refinements of the target and adjustments of dose and fractionation in selected patients.

Shoulder disability and late symptoms following surgery for early breast cancer.

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.

Long-term results of breast conserving surgery vs. mastectomy for early stage invasive breast cancer: 20-year follow-up of the Danish randomized DBCG-82TM protocol.

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<0.001). In conclusion, long-term data indicate that BCS in eligible patients proves as effective as mastectomy both regarding local tumour control, RFS and OS. Local failures as a first event consistent with new primaries are strongly associated with BCS, whereas true recurrence predominates after mastectomy.

Breast conserving treatment in Denmark, 1989-1998. A nationwide population-based study of the Danish Breast Cancer Co-operative Group.

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.

Post-mastectomy radiotherapy in Denmark: from 2D to 3D treatment planning guidelines of The Danish Breast Cancer Cooperative Group.

This paper describes the procedure of changing from 2D to 3D treatment planning guidelines for post-mastectomy radiotherapy in Denmark. The aim of introducing 3D planning for post-mastectomy radiotherapy was to optimize the target coverage and minimize the dose to the normal tissues. Initially, it was investigated whether it was possible to find a treatment technique alternative to the one recommended by the Danish Breast Cancer Cooperative Group (DBCG). A dosimetric comparison of a combined photon/electron 3-field technique (3F) and a partial wide tangent technique (PWT) was carried out on individual planning CT-scans from seven patients selected to represent a wide range of sizes and shapes of chest walls. The heart dose was lower for PWT than for 3F, however, for both techniques the dose was within the accepted constraints. The lung dose was higher but acceptable for six of the seven patients with PWT. The dose to the internal mammary nodes (IMN) was not satisfactory for five of the seven patients for 3F, whereas only two of the seven patients had a minimum dose lower than 95% of the prescribed dose with PWT. Finally, the dose to the contralateral breast was increased when using PWT compared to 3F. It was concluded that PWT was an appropriate choice of technique for future radiation treatment of post-mastectomy patients. A working group was formed and guidelines for 3D planning were developed during a series of workshops where radiation oncologists and physicists from all radiotherapy centres participated. This work also included a definition of the tissue structures needed to be outlined on the planning CT-scan. The work was initiated in 2003 and the guidelines were approved by the DBCG Radiotherapy Committee in 2006. The first of January 2007 the 3D guidelines had been fully implemented in five of the seven radiotherapy centres.

A Non Platinum Regimen for the Treatment of Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Region. Results From an Extended Phase II Study With Paclitaxel and Capecitabine.

BACKGROUND: This study presents the results of an extended phase II study originally published in 2007, regarding the antitumor activity and toxicity of a non-platinum containing regimen with paclitaxel and capecitabine for the treatment of recurrent or disseminated squamous cell carcinoma of the head and neck region. Fifty patients were included in the original study. MATERIALS AND METHODS: A total of 183 patients with recurrent or disseminated squamous cell carcinoma were eventually included in the extended study. There were 37 women and 146 men. The mean age was 56 years. Performance status (WHO) was as follows: WHO 0:31, WHO 1:107, and WHO 2:45 patients. The treatment consisted of paclitaxel 175 mg/m2, once every third week and capecitabine 825 mg/m2 p.o. b.i.d for 2 weeks. RESULTS: The overall response rate (complete response and partial response) according to the WHO criteria was: 33% (CI 26-40). The median progression-free survival was 4.8 (CI 4.2-5.4) months. The median overall survival (OS) was 8.9 (CI 7.6-9.5) months. Compliance was good. Of the 1,131 cycles, only 13% had to be administered with a reduced dose and/or postponed to a later date. Toxicity was mild and grades 3 and 4 toxicities were uncommon. Two toxic deaths were registered though. CONCLUSION: The response rate and the OS for this low toxicity regimen makes it a feasible alternative for not cisplatin eligible patients.

DAHANCA 10 - Effect of darbepoetin alfa and radiotherapy in the treatment of squamous cell carcinoma of the head and neck. A multicenter, open-label, randomized, phase 3 trial by the Danish head and neck cancer group.

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.

Morbidity after ipsilateral radiotherapy for oropharyngeal 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.

Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials.

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.