Long-term results of a randomized trial comparing breast-conserving therapy with mastectomy: European Organization for Research and Treatment of Cancer 10801 trial.

BACKGROUND: Breast-conserving therapy (BCT) has been shown to be as effective as mastectomy in the treatment of tumors 2 cm or smaller. However, evidence of its efficacy, over the long term, in patients with tumors larger than 2 cm is limited. From May 1980 to May 1986, the European Organization for Research and Treatment of Cancer carried out a randomized, multicenter trial comparing BCT with modified radical mastectomy for patients with tumors up to 5 cm. In this analysis, we investigated whether the treatments resulted in different overall survival, time to distant metastasis, or time to locoregional recurrence. METHODS: Of 868 eligible breast cancer patients randomly assigned to the BCT arm or to the modified radical mastectomy arm, 80% had a tumor of 2.1-5 cm. BCT comprised lumpectomy with an attempted margin of 1 cm of healthy tissue and complete axillary clearance, followed by radiotherapy to the breast and a supplementary dose to the tumor bed. The median follow-up was 13.4 years. All P values are two-sided. RESULTS: At 10 years, there was no difference between the two groups in overall survival (66% for the mastectomy patients and 65% for the BCT patients; P =.11) or in their distant metastasis-free rates (66% for the mastectomy patients and 61% for the BCT patients; P =.24). The rate of locoregional recurrence (occurring before or at the same time as distant metastasis) at 10 years did show a statistically significant difference (12% of the mastectomy and 20% of the BCT patients; P =. 01). CONCLUSIONS: BCT and mastectomy demonstrate similar survival rates in a trial in which the great majority of the patients had stage II breast cancer.

Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European Organization for Research and Treatment of Cancer Randomized Phase III Trial.

PURPOSE: To assess the long-term contribution of adjuvant chemotherapy (CT) and hormonal therapy (HT) in patients with locally advanced breast cancer, and to evaluate the impact of time of analysis on the results during accrual and up to 8 years after closure of a randomized phase III trial. MATERIALS AND METHODS: In a trial using a factorial design, 410 patients were randomized between radiotherapy (RT) alone, RT plus CT, RT plus HT, and RT plus HT plus CT. RESULTS: CT and HT each produced a significant prolongation of the time to locoregional tumor recurrence and to distant progression of disease, with the combined treatments providing the greatest therapeutic effect. At the time of trial closure, a significant improvement of survival was observed in patients who received CT (P = .004); however, with a longer follow-up duration, this effect disappeared (P > .05). HT did not initially appear to improve survival (P = .16); however, in the latest analysis with a long-term follow-up duration, a significant improvement of survival was seen (P = .02). A consistent 25% reduction in the death hazards ratio has been seen at all evaluations since trial closure in patients who received HT. The best survival results were observed in patients who received RT, HT, and CT (P = .02), with a reduction of 35% in the death hazards ratio. CONCLUSION: An improvement in survival attributable to HT has been shown in patients with locally advanced breast cancer. The greatest therapeutic effect was seen in the treatment group that received both CT and HT. The improvement obtained with HT became apparent only after long-term follow-up evaluation.

Clinical stages I and II Hodgkin's disease: a specifically tailored therapy according to prognostic factors.

The H5 program in clinical stage (CS) I to II supradiaphragmatic Hodgkin's disease (HD) was tailored to prognostic factors identified in former European Organization for the Research and Treatment of Cancer (EORTC) studies. Among the 494 adult patients included in the study, the 237 patients belonging to the favorable group (H5F) underwent a staging laparotomy (Sx) in order to select the patients who could be treated with limited radiotherapy (RT) only. Thus, 198 patients (84%) with negative laparotomy were treated with RT alone and randomized to either mantle irradiation (M) or extended field mantle plus para-aortic (M + PA) irradiation. Complete remission (CR) was achieved in 99% of the patients. There was no difference in the 6-year relapse-free survival (RFS) rate (74% and 72%, respectively) or survival rate (96% and 89%). Therefore, Sx helped to define those patients who could be treated with M alone in contrast to those who required more aggressive therapy. The 39 patients with positive laparotomy were treated as the unfavorable group (H5U) from onset and randomized to either total/subtotal nodal irradiation (TNI/STNI) or a sandwiched mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) X 3, M irradiation, MOPP X 3 protocol (3M). Although the RFS rate was higher in the 3M arm (100% v 53%; P = .002), the 6-year survival was not significantly different between the two arms (overall, 92%). In the 257 patients with initial unfavorable disease, the Sx was avoided. They were randomized to either TNI/STNI or 3M. In complete responders (96%), the 6-year RFS was 91% in the 3M arm and 77% in the TNI/STNI arm (P = .02). The pattern of failure differed in the two arms: the inverted Y and spleen irradiation controlled occult infradiaphragmatic disease better than MOPP; conversely, less patients begun on MOPP recurred in the involved mantle areas. The difference in 6-year actuarial total survival (TS) (89% and 82%; P = .05 in favor of the 3M arm) was not retrieved after exclusion of the unrelated deaths from the analysis. The two arms produced similar TS in patients under 40 years of age. TNI retains interest, especially in young men wishing to preserve fertility. The overall result shows that when treatment is tailored to initial prognostic factors, excellent results can be obtained in all patient subgroups at minimal morbidity and toxic cost.

Arabidopsis thaliana genes expressed in the early compatible interaction with root-knot nematodes.

In the compatible interaction between Arabidopsis thaliana and the endoparasitic nematode Meloidogyne incognita, galls are formed on the roots of the host plant. Differential display was used to identify alterations of gene expression in young A. thaliana root galls caused by M. incognita. Six genes were confirmed as plant genes by DNA gel blot hybridizations. Significant homology was found with a trypsin inhibitor, peroxidase, mitochondrial uncoupling protein, endomembrane protein, 20S proteasome alpha-subunit, and diaminopimelate decarboxylase. The cellular and temporal expression of each of the six genes was analyzed by mRNA in situ hybridizations.

Acute side effects and late complications after radiotherapy of localized carcinoma of the prostate.

In the last two decades, many authors have treated prostatic carcinoma by radiation therapy. Accumulated data have been updated, after 10 and 15 years of follow-up. In stage A and B, the reported survival and local control rates after irradiation (20, 22, 30, 34, 35, 39, 42) are as good as in selected patients treated by radical prostatectomy (9, 18, 23). In stage C, the results after irradiation (20, 22, 30, 42) are better than after radical surgery (23, 43). However, patients are nonrandomly selected and the methods of statistical analysis differ. Therefore, a valid comparison cannot be made. The therapeutic ratio is determined by survival and local control, and also by therapy related complications. It is therefore of interest to find out from radiotherapy series if their incidence is related to the treatment technique. Unfortunately, relatively few studies accurately describe treatment technique and complications. Gastro-intestinal radiation injury becomes significant when the dose at the posterior rectal wall is 65-76 Gy and the length of the treated rectum is at least 10 cm. A hot spot of 80-84 Gy needs to be only 2 to 3 cm to increase the risk of late bowel stenosis. Genito-urinary complications are influenced by local extension of the tumor and by previous surgical manipulations. A dose at the prostatic area exceeding 70 Gy should be avoided, as it does not improve local control (22, 35) and apparently increases the risk of late urethral stricture and penile/scrotal edema (12, 39). The dose at the anterior bladder wall correlates with other types of genito-urinary complications. Therefore, the anterior bladder wall should not receive a dose higher than 65 Gy. Incidence of impaired potency after irradiation is usually 30 to 40%, which is much less than after radical surgery. As many data in the literature dealing with radiation treatment of the prostate are still inadequate a more standardized reporting is recommended to make comparison of effectiveness and side effects possible.

Randomized clinical trial to assess the value of breast-conserving therapy in stage I and II breast cancer, EORTC 10801 trial.

In a prospective randomized clinical trial conducted by the European Organization for Research and Treatment of Cancer (EORTC), mastectomy was compared with breast-conserving therapy in 903 stage I and stage II breast cancer patients entering the study between 1980 and 1986. The main participating centers were: Guy's Hospital, London; The Netherlands Cancer Institute, Amsterdam; University Hospital, Leuven; Radiotherapy Institute, Rotterdam; Breast Unit, Tijgerberg, S.A. The data were collected in the EORTC Data Center, Brussels. Treatment in the study arm consisted of lumpectomy, axillary clearance, and radiotherapy to the breast (50 Gy external irradiation in 5 weeks followed by boost with iridium implant of 25 Gy). Important in this study is the large number of TNM stage II patients (755). Most patients were stage II because of the size of the tumor (2-5 cm). The patient and tumor characteristics in the study and control groups were well balanced. So far the survival curves and local recurrence rates are not statistically different for the two study arms. Tumor size was found in univariate analysis to be a significant risk factor for local recurrence in the breast-conserving therapy group but not in the mastectomy group. Results of salvage treatment for local recurrence were not better for the breast-conserving therapy group compared with the mastectomy group. Measurements of quality of life and cosmesis show a clear benefit for the breast-conserving therapy group.

Federation of European Cancer Societies. Full report. Economic evaluation in cancer care: questions and answers on how to alleviate conflicts between rising needs and expectations and tightening budgets.

All Western countries have experienced a fast growth in their healthcare expenses over recent decades. It is expected that pressure for such growth will continue in the future. But spending an ever larger share of our nation's resources on healthcare cannot be afforded. As a consequence, making choices will become more and more inevitable, even in cancer care. Economic evaluation is a very supportive tool for such decisions. This position statement concludes with recommendations for providers and healthcare policy-makers, to safeguard and further improve good clinical decision making and healthcare policy in cancer care under tightening budgets.

Changes of lymphocyte subsets after local irradiation for early stage breast cancer and seminoma testis: long-term increase of activated (HLA-DR+) T cells and decrease of "naive" (CD4-CD45R) T lymphocytes.

Blood lymphocyte subsets of early breast cancer patients and of men with stage I seminoma of the testis were studied up to 6 years after radiotherapy. Similar results were obtained in the two patient groups. After a temporary decrease, the CD4-w29 or "memory" T cells recovered completely, while the CD4-45R or "naive" T cells remained decreased up to 6 years after irradiation. The number of CD8 T lymphocytes did not change during or after treatment. Because of the decrease of a subset of CD4 cells, and the unchanged values of CD8 cells, the CD4/CD8 ratio decreased significantly after irradiation, and remained lower than before treatment up to 5-6 years after radiotherapy. The number of both HLA-DR positive CD4 and HLA-DR positive CD8 T cells ("activated" T cells) increased significantly after irradiation. The natural killer (NK) cells were not affected by treatment. We propose that the recovery of the CD4 cells is limited to the CD4-w29 ("memory") population because of thymic dysfunction in older humans. The impact of the observed immune modulation on the low susceptibility for infections after local irradiation, and on putative antitumour immune responses is discussed.

Local control of operable breast cancer after radiotherapy alone.

221 patients with operable breast carcinoma stage Tis, T1, T2, T3, N0N1 were treated with radiotherapy alone without tumorectomy. The mean follow-up time was 15.5 years (range 5-22). The annual risk for local recurrence was 3% during the first 5 years and 1% during the following 10 years, resulting in an actuarial local control rate of 75.4% after 15 years. The risk for local recurrence was assessed in multivariate analysis and was significantly related to the size of the tumour measured on mammography (P = 0.0002), the radiation dose administered (P = 0.0018), the length of the split-course intervals being longer than 75 days (P = 0.001) and age (P = 0.019). Dose was related to response over a wide range as a function of tumour volume. All 18 patients with minimal tumour load (T0 and Paget's disease) treated with doses above 55 Gy in 6 weeks achieved local control. 5-year local control rates ranged from 40 to 100% for T1 carcinomas treated with 45-110 Gy, and from 0 to 95.3% for T2 carcinomas at the same dose. For T3 carcinomas local control varied between 50 and 83% at 60-110 Gy. The risk for local failure increased by 8% per cm tumour diameter. With exclusive radiotherapy, the doses needed to provide local control rates similar to those obtained after tumorectomy and irradiation are 10 Gy higher for T1 (95% 5 year control) and 35 Gy higher for T2 (90% 5 year control).

Factors influencing local relapse and survival and results of salvage treatment after breast-conserving therapy in operable breast cancer: EORTC trial 10801, breast conservation compared with mastectomy in TNM stage I and II breast cancer.

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

In vivo cell kinetic measurements in human oesophageal cancer: what can be learned from multiple biopsies?

The importance of intratumour variability of cell kinetics was studied in 60 patients with cancer of the oesophagus. Five biopsies per tumour were taken. The labelling index, S-phase duration and potential doubling time (Tpot) were measured using flow cytometry. The mean Tpot value was 5.56 +/- 4.43 days (+/- 1S.D.) for adenocarcinomas and 4.40 +/- 2.45 days (+/- 1S.D.) for squamous cell carcinomas. These values were statistically significantly different. Although intratumour variation in Tpot measurements occurred, the intertumour variability was more important (P < 0.00001). This feature permits classification of tumours into slow and fast proliferating groups, leaving an intermediate group of tumours that could not be unequivocally categorised. The relative distribution of tumours into these three categories depends on the intratumour and intertumour variability of Tpot, and on the cut-off values used. Increasing the number of biopsies from one to five reduces the number of non-classifiable tumours.

The Quality Assurance programme of the Radiotherapy Group of the European Organization for Research and Treatment of Cancer (EORTC): a critical appraisal of 20 years of continuous efforts.

In 1982, the European Organization for Research and Treatment of Cancer (EORTC) Radiotherapy Group established the Quality Assurance (QA) programme. During the past 20 years, QA procedures have become a major part of the activities of the group. The methodology and steps of the QA programme over the past 20 years are briefly described. Problems and conclusions arising from the results of the long-lasting QA programme in the EORTC radiotherapy group are discussed and emphasised. The EORTC radiotherapy group continues to lead QA in the European radiotherapy community. Future challenges and perspectives are proposed.

Characterisation of complete responders to combination chemotherapy for advanced breast cancer: a retrospective EORTC Breast Group study.

This retrospective study was undertaken to characterise the natural history of women achieving complete response (CR) following standard dose combination chemotherapy for metastatic breast cancer (MBC), and to analyse the significance of various patient, disease and treatment characteristics in determining survival and time to disease progression. 75 patients achieving a CR following standard dose combination chemotherapy or combined chemoendocrine therapy for MBC have been studied. At a median follow-up of 6 years, 28% of patients are still alive, with 18 of 21 patients showing no evidence of disease. 15 (20%) patients, with median follow-up of 61 months from start of chemotherapy, have never experienced relapse. Median overall survival is 32.5 months. Multivariate analysis for survival identified inclusion of anthracyclines and WHO performance status as significant predictors of good long-term outcome. Concomitant hormonotherapy almost reached statistical significance in our multivariate analysis. Neither dominant site of disease nor disease-free interval were significant determinants of complete remission. With conventional dose combination chemotherapy, approximately 20% of women with MBC who have achieved a clinical CR have been shown to be expected to remain alive and free of disease at 5 years. Inclusion of an anthracycline appears to be an important determinant of durability of CR and patient survival.

Prognosis after treatment for loco-regional recurrence after mastectomy or breast conserving therapy in two randomised trials (EORTC 10801 and DBCG-82TM). EORTC Breast Cancer Cooperative Group and the Danish Breast Cancer Cooperative Group.

The aim of this study was to investigate and compare the prognosis after treatment for loco-regional recurrences (LR) after (modified) radical mastectomy (MRM) or breast conserving therapy (BCT), in terms of overall survival and time to subsequent LR, in patients originally treated in two European randomised trials. In EORTC trial 10801 and DBCG trial 82-TM, 1,807 patients with stage I and II breast cancer were randomised to receive MRM or BCT from 1980 to 1989. All patients with a LR in these trials were analysed for survival and time to subsequent LR after salvage treatment. Of these, 133 patients had their LR as a first event, the majority within 5 years after initial treatment. The prognostic significance for survival and time to subsequent LR after salvage treatment was analysed in uni-, and multivariate analyses for a number of original tumour- and recurrence-related variables. After salvage treatment of LR after MRM or BCT, actuarial survival curves and the actuarial locoregional control curves were similar. The 5-year survival rates were 58% and 59% and the 5-year subsequent loco-regional control rates 62% and 63%, respectively. In a multivariate analysis, pN category (P = 0.03), pT category (P = 0.01) and vascular invasion (P = 0.02) of the primary tumour were the only independent prognostic factors for survival, whereas extensive LR (P < 0.001), interval < or = 2 years (P < 0.002) and pN+ at primary treatment (P = 0.004) were significant predictive factors for time to subsequent LR. The type of original treatment (MRM or BCT) did not have any prognostic impact. It is concluded that the survival and time to subsequent LR after treatment for an early loco-regional recurrence after MRM or BCT was similar in these two European randomised trials. This suggests that both after MRM and BCT an early LR is an indicator of a biologically aggressive tumour; early loco-regional relapse carries a poor prognosis and salvage treatment only cures a limited number of patients, whether treated by MRM or BCT originally.

International Clinical Trials in Radiation Oncology. Lung sites.

The lung studies of the RTOG have been among the most productive of any in the group. The development of studies has been predicated upon failure pattern analyses from previous trials. Multiple approaches to attacking these diseases have been taken, including dose/fraction studies and high LET irradiations to improve local-regional control, prophylactic irradiation of sites of frequent, distant metastases, systemic chemotherapy and radioimmunoglobulins to control distant metastases, and biologic response modifiers to restore or enhance host defense mechanisms. All studies have been predicated upon making incremental advances in improving treatment outcome in these common disease, based on the philosophy that small improvements in survival will save thousands of lives.

The tolerance to multiple daily fractionated radiotherapy for the treatment of prostatic and bladder carcinoma: a feasibility study.

A modified fractionation schedule was designed with the purpose of reducing the treatment burden. Three fractions of 2 Gy with four hours interval were given during 5 days. The whole scheme was repeated after a rest period of 4 weeks. This makes it possible to deliver a dose of 60 Gy in 10 treatment days and over a total time of 6 weeks. A total of 30 patients, 22 with prostatic cancer and 8 with invasive bladder carcinoma, have been treated. The feasibility has been found to be very good. Forty-seven percent of the patients had acute morbidity, although it was mild in all patients. One patient had a persistent, another had a transient delayed symptom, and one had a severe late complication. The tolerance to this schedule is better than that observed with conventional fractionation schedules. Together with the drastic reduction of the total treatment days, this multiple daily fractionation (MDF) schedule has already been shown to improve the therapeutic ratio by diminishing the burden on the patients. Longer follow-up necessary for the assessment of the efficacy of this schedule for local tumor control. However, with a follow-up period of 7 to 16 months no recurrence of the prostate cancer in the pelvis has been observed. These results warrant further exploration of the possible benefits of modifications in time-dose-fractionation schedules.

Influence of thorax irradiation on the survival of mice with spontaneous or artificial lung metastases from a transplantable mammary adenocarcinoma.

The effect of thorax irradiation on lung metastases, either occurring spontaneously from a primary mammary adenocarcinoma (M8013X) transplanted on the leg or artificially induced by intravenous injection of tumor cells was studied. Increasing the interval between the moment at which lung metastases are supposed to originate and the thorax irradiation resulted in a rapid decrease of the effectiveness of this treatment in preventing the development of lung metastases. Early treatment of the mice not only resulted in a considerable number of animals that were cured, but also in a significant decrease in the number of tumor localizations in the lung of those animals still developing metastases. Thorax irradiation performed later was much less effective; at autopsy the lung showed a large number of small metastases. Increasing the radiation dose led to an increased number of cures; however, an increased number of mice dying of lethal lung damage was also observed. Irradiation of the lungs of mice with 5 or 10 Gy, 24 hours, 7 days or 14 days prior to i.v. injection with tumor cells, did not significantly increase the number of mice with lung metastases. Immunological resistance against the tumor played a role in our experiments with both spontaneous and artificial lung metastases.

Immunologic changes after loco-regional radiotherapy and fractionated total body irradiation (TBI) in mice.

The immunologic effects of fractionated irradiation to both hind limbs and the tail of adult (2.5-3 months old) male Balb/c mice were investigated. A dose of 34 Gy given in 17 fractions of 2 Gy, 1 fraction per day, 5 days per week, was delivered with a 60Co source. A significant decrease of the total splenocyte count (29% of control value) and of the PHA(phytohemagglutinin)-induced proliferation of T cells (22% of control value) was found immediately after irradiation. Both parameters normalized within 30 days after irradiation. Immediately after irradiation, the MLC (mixed lymphocyte culture) was supranormal (126% of control value), dropped to 45% 1 week later, and normalized within 1 month after radiotherapy. The NK (natural killer) activity was significantly decreased only the first week after loco-regional irradiation, while the LAK (lymphokine activated killer) activity was not altered at all. The percentage of goat-anti-mouse+ cells (mainly B lymphocytes) was not changed immediately after loco-regional irradiation, but rose to supranormal values (175% of control level) 3 months after irradiation. A persistent decrease of the percentage and the absolute numbers of the Lyt2+ cells (= CD8+ cells, suppressor/cytotoxic phenotype) was observed up to 3 months after irradiation, while the percentage of L3T4+ cells (= CD4+ cells, helper phenotype) remained normal for the total follow-up. No differences in allogeneic skin graft survival could be demonstrated between irradiated and control animals. The observed immunological effects could not be explained by the scatter irradiation to the whole body as total body irradiation (TBI) administered in a dose and dose rate similar to the scatter dose did not result in persistent immunologic changes. No dose-rate effect could be demonstrated in a low dose fractionated total body irradiation schedule. A total body irradiation similar to the scatter dose in humans did not result in significant immunologic changes.

Evaluation of mouse lip mucosa reactions after combinations of cis-diammine-1,1-cyclobutanedicarboxylate platinum (II) (CBDCA) and irradiation: single and fractionated treatments.

The influence of CBDCA (JM8) on the radiation-induced mouse lip mucosal reactions has been tested. Both single and fractionated drug doses were used intraperitoneally at 60 mg/kg and 5 X 25 mg/kg respectively. A single injection of CBDCA did not alter the response to a single radiation dose, whether the drug was given at different time intervals from 24 hr prior, to 96 hr after irradiation. A concomitant treatment of daily CBDCA injections and irradiations for 5 consecutive days demonstrated no change of the capacity to repair sublethal radiation damage. When two equal sized radiation doses were separated by 10 days and CBDCA was administered daily from day 3 to 7, the ability to repopulate the lip mucosa epithelium during the radiation-free period was not influenced.

The significance of extension and impaired mobility in cancer of the vocal cord.

The criteria for T2 glottic cancer staging in the UICC classification are extension to the supra- or subglottic region combined or not with impaired mobility of the vocal cord. The prognostic significance of these factors is examined in this study. Patients with T2A lesions (normal mobility, 33 patients) have an uncorrected actuarial 5 year survival of 54%, and a local control rate with radiotherapy alone of 62%. Patients with T2B lesions (impaired mobility, 28 patients) have a survival of 40% and a local control rate of 65% with radiation only. After rescue surgery, local control is obtained in 81% of T2A patients and 68% of T2B patients. While local control rates with radiotherapy alone were the same in T2A and T2B patients, final survival was lower for T2B patients because of less successful salvage surgery. While no significant differences in local control were found for different mucosal spread patterns, local control was excellent (87%) with radiotherapy alone in eight patients with mobility impairment without extension beyond the true cord, indicating that impaired mobility by itself is not a bad prognostic factor, but only when it is combined with tumor extension. In 9 patients with T2B tumors, a laryngectomy was performed immediately after initial radiotherapy (40 or 50 Gy) when the tumor persisted or the vocal cord mobility did not return to normal. None of these patients had a local recurrence after surgery. The total local control in all 37 T2B patients together was 78% (compared with 81% in T2A patients). The adverse prognostic influence of impaired mobility seems to have been eliminated by the treatment policy of surgery for those patients with poor regressions after radiotherapy. A dose-response relation can not be demonstrated in T2 glottic cancer for the dose range between 50 and 70 Gy.