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 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.
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.
Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival.
Abstract 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 (5 Fx/week vs 6 Fx/week) was evaluated 5 years 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 6 Fx/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.
In the period 1963-1991, a total of 277 consecutive patients with malignant tumours of the nasal cavity and paranasal sinuses were treated at Aarhus University Hospital. The major histological types ...included squamous cell carcinoma (46%), lymphoma (14%), adenocarcinoma (13%), and malignant melanoma (9%). Kaplan-Meier estimates of 5-year corrected survival (death from cancer) showed the best prognosis for adenoid cystic carcinoma (87%), adenocarcinoma (65%) and lymphoma (56%), and the poorest prognosis for undifferentiated carcinoma (17%) and malignant melanoma (24%). The 5-year corrected survival for squamous cell carcinoma was 35%. Of the 180 patients with treatment failure, the vast majority occurred locally (n = 166); a minor proportion was regional (n = 23) or distant (n = 30). For the 195 patients with carcinoma, the following parameters were of statistical prognostic significance (5-year corrected survival): histological differentiation (moderate-well 65% vs. poor 22%), primary T-site (nasal cavity 56% vs. maxillary antrum 39% vs. other sinuses 24%), tumour stage (T2 68% vs. T3 37% vs. T4 29%), nodal stage (N0 48% vs. N1-3 21%), treatment (radiotherapy + surgery 56% vs. radiation alone 35%).
Abstract
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.
Abstract 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.
Abstract 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 loco-regional 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.
Abstract Background and purpose 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. Material and methods Patients were randomized to treatment with the hypoxic radiosensitizer nimorazole or placebo, and in addition, patients with “low” pre-irradiation Hb 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 Hb level in the “high” value range. Results 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. Conclusion 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 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 1st 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.
Abstract 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 <2 cm, 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 >5 cm, 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.
