Hanne Sand Hansen

Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6&7 randomised controlled trial

BACKGROUND Although head and neck cancer can be cured by radiotherapy, the optimum treatment time for locoregional control is unclear. We aimed to find out whether shortening of treatment time by use of six instead of five radiotherapy fractions per week improves the tumour response in squamous-cell carcinoma. METHODS We did a multicentre, controlled, randomised trial. Between January, 1992, and December, 1999, of 1485 patients treated with primary radiotherapy alone, 1476 eligible patients were randomly assigned five (n=726) or six (n=750) fractions per week at the same total dose and fraction number (66-68 Gy in 33-34 fractions to all tumour sites except well-differentiated T1 glottic tumours, which were treated with 62 Gy). All patients, except those with glottic cancers, also received the hypoxic radiosensitiser nimorazole. Analysis was by intention to treat. FINDINGS More than 97% of the patients received the planned total dose. Median overall treatment times were 39 days (six-fraction group) and 46 days (five-fraction group). Overall 5-year locoregional control rates were 70% and 60% for the six-fraction and five-fraction groups, respectively (p=0.0005). The whole benefit of shortening of treatment time was seen for primary tumour control (76 vs 64% for six and five fractions, p=0.0001), but was non-significant for neck-node control. Six compared with five fractions per week improved preservation of the voice among patients with laryngeal cancer (80 vs 68%, p=0.007). Disease-specific survival improved (73 vs 66% for six and five fractions, p=0.01) but not overall survival. Acute morbidity was significantly more frequent with six than with five fractions, but was transient. INTERPRETATION The shortening of overall treatment time by increase of the weekly number of fractions is beneficial in patients with head and neck cancer. The six-fractions-weekly regimen has become the standard treatment in Denmark.

A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85

PURPOSE A multicenter randomized and balanced double-blind trial with the objective of assessing the efficacy and tolerance of nimorazole given as a hypoxic radiosensitizer in conjunction with primary radiotherapy of invasive carcinoma of the supraglottic larynx and pharynx. PATIENTS AND TREATMENT Between January 1986 and September 1990, 422 patients (414 eligible) with pharynx and supraglottic larynx carcinoma were double-blind randomized to receive the hypoxic cell radiosensitizer nimorazole, or placebo, in association with conventional primary radiotherapy (62-68 Gy, 2 Gy per fraction, five fractions per week). The median observation time was 112 months. RESULTS Univariate analysis showed that the outcome (5-year actuarial loco-regional tumor control) was significantly related to T-classification (T1-T2 48% versus T3-T4 36%, P = 0.0008), neck-nodes (N- 53% versus N+ 33%), pre-irradiation hemoglobin (Hb) concentration (high 46% versus low 37%, P = 0.02) and sex (females 51% versus males 38%, P = 0.03). Overall the nimorazole group showed a significantly better loco-regional control rate than the placebo group (49 versus 33%, P = 0.002). A similar significant benefit of nimorazole was observed for the end-points of final loco-regional control (including surgical salvage) and cancer-related deaths (52 versus 41%, P = 0.002). This trend was also found in the overall survival but to a lesser, non-significant extent (26 versus 16%, 10-year actuarial values, P = 0.32). Cox multivariate regression analysis showed the most important prognostic parameters for loco-regional control to be positive neck nodes (relative risk 1.84 (1.38-2.45)), T3-T4 tumor (relative risk 1.65 (1.25-2.17)) and nimorazole (relative risk 0.69 (0.52-0.90)). The same parameters were also significantly related to the probability of dying from cancer. The compliance to radiotherapy was good and 98% of the patients received the planned dose. Late radiation-related morbidity was observed in 10% of the patients, irrespective of nimorazole treatment. Drug-related side-effects were minor and tolerable with transient nausea and vomiting being the most frequent complications. CONCLUSION Nimorazole significantly improves the effect of radiotherapeutic management of supraglottic and pharynx tumors and can be given without major side-effects.

Preoperative Staging of Lung Cancer with Combined PET–CT

BACKGROUND Fast and accurate staging is essential for choosing treatment for non-small-cell lung cancer (NSCLC). The purpose of this randomized study was to evaluate the clinical effect of combined positron-emission tomography and computed tomography (PET-CT) on preoperative staging of NSCLC. METHODS We randomly assigned patients who were referred for preoperative staging of NSCLC to either conventional staging plus PET-CT or conventional staging alone. Patients were followed until death or for at least 12 months. The primary end point was the number of futile thoracotomies, defined as any one of the following: a thoracotomy with the finding of pathologically confirmed mediastinal lymph-node involvement (stage IIIA [N2]), stage IIIB or stage IV disease, or a benign lung lesion; an exploratory thoracotomy; or a thoracotomy in a patient who had recurrent disease or death from any cause within 1 year after randomization. RESULTS From January 2002 through February 2007, we randomly assigned 98 patients to the PET-CT group and 91 to the conventional-staging group. Mediastinoscopy was performed in 94% of the patients. After PET-CT, 38 patients were classified as having inoperable NSCLC, and after conventional staging, 18 patients were classified thus. Sixty patients in the PET-CT group and 73 in the conventional-staging group underwent thoracotomy (P=0.004). Among these thoracotomies, 21 in the PET-CT group and 38 in the conventional-staging group were futile (P=0.05). The number of justified thoracotomies and survival were similar in the two groups. CONCLUSIONS The use of PET-CT for preoperative staging of NSCLC reduced both the total number of thoracotomies and the number of futile thoracotomies but did not affect overall mortality. (ClinicalTrials.gov number, NCT00867412.)

The Danish Randomized Lung Cancer CT Screening Trial—Overall Design and Results of the Prevalence Round

Introduction: Lung cancer screening with low dose computed tomography (CT) has not yet been evaluated in randomized clinical trials, although several are underway. Methods: In The Danish Lung Cancer Screening Trial, 4104 smokers and previous smokers from 2004 to 2006 were randomized to either screening with annual low dose CT scans for 5 years or no screening. A history of cigarette smoking of at least 20 pack years was required. All participants have annual lung function tests, and questionnaires regarding health status, psychosocial consequences of screening, smoking habits, and smoking cessation. Baseline CT scans were performed in 2052 participants. Pulmonary nodules were classified according to size and morphology: (1) Nodules smaller than 5 mm and calcified (benign) nodules were tabulated, (2) Noncalcified nodules between 5 and 15 mm were rescanned after 3 months. If the nodule increased in size or was larger than 15 mm the participant was referred for diagnostic workup. Results: At baseline 179 persons showed noncalcified nodules larger than 5 mm, and most were rescanned after 3 months: The rate of false-positive diagnoses was 7.9%, and 17 individuals (0.8%) turned out to have lung cancer. Ten of these had stage I disease. Eleven of 17 lung cancers at baseline were treated surgically, eight of these by video assisted thoracic surgery resection. Conclusions: Screening may facilitate minimal invasive treatment and can be performed with a relatively low rate of false-positive screen results compared with previous studies on lung cancer screening.

CT screening for lung cancer brings forward early disease. The randomised Danish Lung Cancer Screening Trial: status after five annual screening rounds with low-dose CT

Background The effects of low-dose CT screening on disease stage shift, mortality and overdiagnosis are unclear. Lung cancer findings and mortality rates are reported at the end of screening in the Danish Lung Cancer Screening Trial. Methods 4104 men and women, healthy heavy smokers/former smokers were randomised to five annual low-dose CT screenings or no screening. Two experienced chest radiologists read all CT scans and registered the location, size and morphology of nodules. Nodules between 5 and 15 mm without benign characteristics were rescanned after 3 months. Growing nodules (>25% volume increase and/or volume doubling time<400 days) and nodules >15 mm were referred for diagnostic workup. In the control group, lung cancers were diagnosed and treated outside the study by the usual clinical practice. Results Participation rates were high in both groups (screening: 95.5%; control: 93.0%; p<0.001). Lung cancer detection rate was 0.83% at baseline and mean annual detection rate was 0.67% at incidence rounds (p=0.535). More lung cancers were diagnosed in the screening group (69 vs 24, p<0.001), and more were low stage (48 vs 21 stage I–IIB non-small cell lung cancer (NSCLC) and limited stage small cell lung cancer (SCLC), p=0.002), whereas frequencies of high-stage lung cancer were the same (21 vs 16 stage IIIA–IV NSCLC and extensive stage SCLC, p=0.509). At the end of screening, 61 patients died in the screening group and 42 in the control group (p=0.059). 15 and 11 died of lung cancer, respectively (p=0.428). Conclusion CT screening for lung cancer brings forward early disease, and at this point no stage shift or reduction in mortality was observed. More lung cancers were diagnosed in the screening group, indicating some degree of overdiagnosis and need for longer follow-up.

Primary radiotherapy of larynx and pharynx carcinoma—An analysis of some factors influencing local control and survival

An analysis of 950 patients with carcinoma of the larynx and pharynx was performed to identify factors of importance for local control and survival other than the TNM-classification. All patients were treated with primary radiotherapy, with doses ranging between 60-68 Gy in 6-7 weeks. The achievement of local-regional control by primary radiotherapy was highly correlated with disease-free survival (98% actuarial 5 year probability), which was significantly better than in patients who failed in the primary treatment but were salvaged by radical surgery. Furthermore, occurrence of distant metastases were almost all associated with failure to control the primary tumor. Sex was found to be a dominant prognostic factor, and in all sites and stages, women had a significantly better prognosis both with regard to local control and survival. The degree of histopathological differentiation was not significantly correlated with local control but with the incidence of distant metastases, which was significantly higher in patients with poorly differentiated tumors. In both males and females the pre-treatment hemoglobin concentration was correlated with the probability of primary tumor control and survival but only in patients with pharyngeal and to a lesser degree supraglottic tumors. In these groups, patients with hemoglobin levels above 13 g% (females) and 14.5 g% (males) had a significantly better prognosis than comparable patients with lower hemoglobin values. Such correlation could not be detected in patients with glottic tumors. The influence of tumor size was analyzed in a larger group of 1,060 patients with laryngeal carcinoma. In this group a notable correlation between tumor size and prognosis was observed within the various T-categories, indicating the tumor size as a significantly important parameter related to both probability of local control and survival. The study reveals that head and neck cancer is a heterogeneous disease and it is demonstrated that attention should be given to the various prognostic parameters since important therapeutic achievement is otherwise lost.

A randomized study of radiotherapy versus radiotherapy plus chemotherapy in stage I-II non-hodgkin's lymphomas

In a randomized, prospective trial from 1974–1978, 73 patients with non‐Hodgkins lymphomas in clinical Stage I or II were treated with extended field radiotherapy alone (RT) or RT plus adjuvant chemotherapy with vincristine, streptonigrin, cyclophosphamide and prednisone (RT + CT). With a median follow‐up time of five years, 54% have relapsed in the RT group versus only 10% in the RT + CT group (P < 0.01). There is no statistical difference in the overall survival yet, but 13/14 deaths in the RT group versus only 3/12 in the RT + CT group were due to progressive disease. Among patients with unfavorable histology, 13/22 in the RT group have died from disease progression against 3/34 in the RT + CT group (P < 0.01). The results are in agreement with those from two other series published in detail. Based on these results we therefore recommend to use adjuvant CT with RT in all Stage I‐II patients with unfavorable histology. Further observation is necessary before a conclusion can be drawn for the lymphoma patients with more favorable histology. Cancer 52:1–7, 1983.

Preoperative radiotherapy in esophageal carcinoma: A meta-analysis using individual patient data (oesophageal cancer collaborative group)

PURPOSE The existing randomized evidence has failed to conclusively demonstrate the benefit or otherwise of preoperative radiotherapy in treating patients with potentially resectable esophageal carcinoma. This meta-analysis aimed to assess whether there is benefit from adding radiotherapy prior to surgery. METHODS AND MATERIALS This quantitative meta-analysis included updated individual patient data from all properly randomized trials (published or unpublished) comprising 1147 patients (971 deaths) from five randomized trials. RESULTS With a median follow-up of 9 years, the hazard ratio (HR) of 0.89 (95% CI 0.78-1.01) suggests an overall reduction in the risk of death of 11% and an absolute survival benefit of 3% at 2 years and 4% at 5 years. This result is not conventionally statistically significant (p = 0.062). No clear differences in the size of the effect by sex, age, or tumor location were apparent. CONCLUSION Based on existing trials, there was no clear evidence that preoperative radiotherapy improves the survival of patients with potentially resectable esophageal cancer. These results indicate that if such preoperative radiotherapy regimens do improve survival, then the effect is likely to be modest with an absolute improvement in survival of around 3 to 4%. Trials or a meta-analysis of around 2000 patients would be needed to reliably detect such an improvement (15-->20%).

Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation

PURPOSE Accelerated repopulation of tumor cells during radiotherapy has been suggested as an important cause of treatment failure in squamous cell carcinoma of the head and neck. Due to tumor heterogeneity, not all tumors may benefit from accelerated radiotherapy at the expense of a lower total dose. This analysis evaluates the impact of histological differentiation on loco-regional control in relation to treatment duration. PATIENTS AND METHODS A total of 501 patients with advanced supraglottic and pharyngeal squamous cell carcinoma with known histopathological grading were treated with planned split-course (191 patients) or continuous radiotherapy (310 patients) in two consecutive randomized controlled trials. Irradiation was given 2 Gy per fraction, 5 fractions per week to a dose of 66-68 Gy in 9.5 or 6.5 weeks, respectively. RESULTS Overall, split-course and continuous treatment resulted in a 5-year loco-regional control of 30% and 41% (P = 0.007), respectively. However, the detrimental effects of split-course were only found in moderately and well-differentiated tumors, where the 5-year tumor controls were 38% and 21% after continuous and split-course treatment, respectively (P = 0.001). In contrast, in poorly differentiated tumors loco-regional control was obtained in 44% of the cases for continuous and 40% for split-course treatment (P = 0.63). CONCLUSIONS It is suggested that the ability to accelerate repopulation may be lost by dedifferentiation, and that prolongation of the overall treatment time only lead to reduced loco-regional control in well to moderately differentiated tumors.

Melanomas of the mucosa in the oral cavity and the upper respiratory passages

Thirty‐eight patients with malignant melanoma of the mucosa in the nasal and oral cavity have been treated at the Radium Centres in Århus, Copenhagen and Odense in the years from 1956 to 1978. Twenty cases were localized to the nasal cavity and the nasal sinuses, and 18 cases to the oral cavity and oropharynx. Twenty‐nine patients had local tumors, eight had local lymph node metastases, and one patient had lung metastases. The primary treatment has been surgery, which was radical in 50% of the cases, whereas 14 patients received irradiation and combined treatment. Complete response was seen locally in five of six irradiated nasal tumors and in three of eight oral tumors. Only two patients with nasal and one patient with oral tumors had recurrence later. Active treatment for recurrence has had the result that 10 patients have survived for 2 additional years, and 1 patient for almost 5 additional years. Eight patients lived for more than 5 years; crude survival is 26%.