Reading the prognosis of the individual with breast cancer.

AIM: To obtain better survival estimates for the individual than is provided by placement in an NPI group. METHOD: Consecutive primary operable breast cancers treated at Nottingham City Hospital 1990-1999. Ten year % actuarial survivals plotted for 10 ranges of NPI from 2.0 to 6.9. There is an excellent inverse correlation between median NPI value for each range and survival at 10 years. To enable estimation of survival for all individual values of NPI, a curve fitting technique applied to these results (by G.B.) gave the formula to estimate survival from the individual's NPI score: 10 year % survival for the individual=-3.0079 x NPI(2)+12.30 x NPI+83.84. This gave an r(2) of 0.98. RESULTS AND CONCLUSION: Greater accuracy in individual survival prediction is obtained by dividing women into 10 groups by NPI scores than in the originally described six groups; rank order of survival in relation to NPI score is preserved. A curve fitting technique has been applied to these data to give a formula for the prediction of 10 year survival for every 0.1 value of NPI.

Survival of invasive breast cancer according to the Nottingham Prognostic Index in cases diagnosed in 1990-1999.

UNLABELLED: The Nottingham Prognostic Index (NPI) is a well established and widely used method of predicting survival of operable primary breast cancer. AIMS: Primary: To present the updated survival figures for each NPI Group. Secondary: From the observations to suggest reasons for the reported fall in mortality from breast cancer. METHODS: The NPI is compiled from grade, size and lymph node status of the primary tumour. Consecutive cases diagnosed and treated at Nottingham City Hospital in 1980-1986 (n=892) and 1990-1999 (n=2,238) are compared. Changes in protocols towards earlier diagnosis and better case management were made in the late 1980s between the two data sets. RESULTS: Case survival (Breast Cancer Specific) at 10 years has improved overall from 55% to 77%. Within all Prognostic groups there are high relative and absolute risk reductions. The distribution of cases to Prognostic groups shows only a small increase in the numbers in better groups. CONCLUSION: The updated survival figures overall and for each Prognostic group for the NPI are presented.

The use of the Gompertz function to relate changes in life expectancy to the standardized mortality ratio.

BACKGROUND: Change in life expectancy may be more readily appreciated by a lay person as a measure of risk than the standardized mortality ratio (SMR). METHODS: The linear increase in the logarithm of the age-specific mortality rates with age (the Gompertz function) is used to deduce formulae connecting SMR with change in life expectancy. Their validity is checked by a comparison between the 1992 and 1952 mortality data for England and Wales, and between smokers and non-smokers in the American Cancer Society's second Cancer Prevention Study. RESULTS: It is shown that the Gompertz function is a good fit to mortality data for England and Wales from age 30 years upwards. Changes in life expectancy at ages 15, 25, 45 and 65 are presented for values of SMR from 0.5 to 3. A very simple formula connecting the two is valid at ages 15 and 25, and provides a reasonable approximation at age 45. CONCLUSIONS: The Gompertz relationship can be used to calculate the change in life expectancy corresponding to a particular SMR over a greater range than have previous methods, and, although subject to some uncertainties, can provide a quick method of judging the change in life expectancy that is associated with a given SMR value.

Life expectancy as a measurement of the benefit shown by clinical trials of treatment for early breast cancer.

Improvements in life expectancy could be a more readily appreciated measure of benefit from a clinical trial than relative risks, odds ratios or increases in survival rate at some arbitrary point in time. Parametric models of survival experience can be used to determine differences in life expectancy. Using the log-normal model, it is shown that the increases in 10-year survival rate found by the overviews of adjuvant systemic therapy trials in early breast cancer are consistent with only small overall increases in life expectancy of about 1 year for Stage I and about 2 years for Stage II. However, if adjuvant therapy transfers a patient from being not cured to being cured, then her life expectancy will have been improved by 16 years for Stage I disease and by 21 years for Stage II. Model analyses on large data sets, such as are available in overviews, could possibly provide some evidence on whether the effect of adjuvant systemic therapy is to increase the cure rate, with the consequent considerable increase in life expectancy for some patients, or whether the effect is only a small increase in life expectancy for those who are not cured.

Should years lost always be equated with life expectancy?

BACKGROUND: The 'years lost' by a person dying prematurely from some cause is usually equated with life expectancy at the age of death derived from a life table for either the general population or a population in which the cause does not operate. It is suggested that this procedure may not always be valid. METHODS: The calculation of years lost by individuals dying prematurely from smoking-related deaths is taken as an example using data from the American Cancer Society Cancer Prevention Study (ACS CPS II) and from Peto et al. An alternative hypothesis, whereby smoking advances the age of death by an amount considerably less than the life expectancy, is examined. RESULTS: It is shown that when smoking-related deaths are removed from the ACS CPS II data, the life expectancy of the smokers is still less than that of the non-smokers. Secondly, it is demonstrated that, if the alternative hypothesis is used to predict a survival curve in the absence of smoking, it would be incorrect to equate years lost with life expectancy calculated from that curve. CONCLUSIONS: Years lost cannot automatically be equated with life expectancy. In the case of smoking, estimates of years lost must still be subject to considerable uncertainty. Further research is needed to see if smokers dying at a given age have comparable physical and social characteristics to all smokers living at that age.

Role of radiotherapy following total mastectomy in patients with early breast cancer. The Closed Trials Working Party of the CRC Breast Cancer Trials Group.

Between June 1970 and April 1975 the CRC (King's/Cambridge) Trial for early breast cancer randomized 2800 patients following mastectomy to immediate prophylactic radiotherapy (DXT group, n = 1376) or control (WP group, n = 1424). Although no difference in overall survival has been demonstrated, there is an increase in mortality in the irradiated patients from nonbreast cancer causes beyond 5 years. It is because of an increase in the number of deaths due to new nonbreast malignancies [RR V 1.89 (1.18-3.05)] and to cardiac-related disease [RR = 1.52 (1.01-2.29)]. This increased cardiac death rate may be related to the use of orthovoltage, which has greater scatter. There was a significant increase in risk for those with left-sided rather than right-sided tumors in this subgroup [chi 2 (int) = 5.08; p = 0.02]. Local relapse was significantly reduced in those patients randomized to radiotherapy [RR = 0.44 (0.39-0.51)]. Median survival following local relapse was 1.35 years in the DXT group and 2.66 years in the WP group (logrank p < 0.001). Patients with the first relapse in the supraclavicular nodes had a particularly poor prognosis (median survival: DXT 0.69 years; WP 1.37 years). Almost 50% of patients who have had a recurrence on the chest wall or in the axilla and subsequently died have had disease at the same site at death, regardless of whether they had radiotherapy immediately following surgery. However, the actual number of patients dying with persistent disease is halved by the use of prophylactic radiotherapy (DXT 66; WP 143). Classic pathological features such as tumor size, tumor grade, and nodal involvement help define those patients at high risk of local failure who should be recommended for immediate radiotherapy.

Cardiac doses in post-operative breast irradiation.

Data were collected on radiation doses given to the heart and coronary arteries during primary breast irradiation in order to analyze factors which might be important in the aetiology of subsequent cardiac-related disease. Twenty eight patients with breast cancer were studied. Fourteen patients treated from 1957 to 1984 were studied retrospectively (group 1), and 14 treated from 1988 to 1989 were studied prospectively (group 2). All patients had stage I or II disease at presentation, and were under 70 years of age. None had chemotherapy as a primary form of treatment. Patients were given a computed tomography scan of the chest, and three-dimensional reconstruction was made of the heart, lung and body contour. Original dose distributions were super-imposed on these outlines, and doses to the total cardiac volume and three main coronary arteries were estimated using an alpha/beta ratio of 4 Gy. Nine out of 14 patients in group 1 had a mastectomy followed mainly by orthovoltage radiation with similar techniques used up until 1984. Thirteen out of 14 patients in group 2 had conservative surgery followed by a modern two- or four-field megavoltage technique. We found that for patients with left-sided tumours (n = 20), the heart volume irradiated to a minimum extrapolated target dose of 5 Gy is significantly decreased for patients treated with a modern technique (group 2) when compared with those treated with earlier techniques (group 1).(ABSTRACT TRUNCATED AT 250 WORDS)

LOPP alternating with EVAP is superior to LOPP alone in the initial treatment of advanced Hodgkin's disease: results of a British National Lymphoma Investigation trial.

PURPOSE: The purpose of this randomized trial was to compare the efficacy of eight cycles of chlorambucil, vincristine, procarbazine, and prednisone (LOPP) with four cycles of LOPP that alternate with four cycles of etoposide, vinblastine, Adriamycin (doxorubicin; Familitalia Carlo Erba, Ltd, UK), and prednisone (EVAP) in patients with advanced Hodgkin's disease. PATIENTS AND METHODS: Between June 1983 and December 1989, 594 patients were entered onto the study. Of the 594, 295 patients were allocated to receive LOPP, and 299 were allocated to receive LOPP/EVAP. RESULTS: The complete remission (CR) rates were 57% and 64%, respectively, after initial chemotherapy (difference not significant [NS]), and 65% and 75%, respectively, after the subsequent administration of radiotherapy to residual masses (P less than .01). The procedure associated mortality in the LOPP and LOPP/EVAP arms was 1% and 3%, respectively. The actuarial CR relapse-free survival was significantly greater in the LOPP/EVAP arm (P less than .001) as was the overall survival (P less than .05). The CR relapse-free rate, disease-free survival (DFS) rate, and overall survival rate at 5 years were 52%, 32%, and 66%, respectively, in the LOPP arm, compared with 72%, 47%, and 75% in the LOPP/EVAP arm, respectively. CONCLUSION: These results indicate that LOPP and EVAP is superior to LOPP alone as initial treatment for advanced Hodgkin's disease.

Salvage surgery following irradiation with different fractionation regimes in the treatment of carcinoma of the laryngo pharynx: experience gained from a British Institute of Radiology study.

The 10-year follow-up of patients in a clinical trial involving the comparison of treatment by three fractions per week versus five fractions per week in radiotherapy of squamous carcinoma of the larynx and hypopharynx has now been completed. The trial involved an intake of 734 patients between 1966 and 1975. No statistically significant differences have been found between the two trial arms in terms of overall survival, age corrected survival, local recurrence, laryngectomy-free rates or effects on the normal tissues. Local recurrence was found in 320 of the 713 evaluable patients (45 per cent). Salvage laryngectomy was performed in 151 of the 320 patients with recurrence (47 per cent). Survival at 10 years for all node negative patients was 50 per cent in those patients without primary recurrence, compared with 40 per cent in those undergoing salvage laryngectomy.

Normal tissue reactions in the British Institute of Radiology Study of 3 fractions per week versus 5 fractions per week in the treatment of carcinoma of the laryngo-pharynx by radiotherapy.

The radiobiological data obtained from a multicentre clinical trial of the British Institute of Radiology, which compared the treatment of carcinoma of the laryngo-pharynx by 3 fractions per week (3F/wk) with 5 fractions per week (5F/wk) radiotherapy, have been studied. The trial involved an intake of 734 patients between 1966 and 1975. The number of fractions, overall treatment time and total doses used by different treatment centres ranges from 9 to 40 fractions, 18 to 70 days and 3880 to 7800 cGy, respectively. An 11-13% reduction in the total radiation dose was applied for treatments with 3F/wk as compared with 5F/wk in centres treating over 6 weeks and 3 weeks, respectively. All patients were followed for 10 years from the start of treatment. Different types of early and late normal-tissue reactions were investigated, ranging from a low percentage incidence of perichondritis to 95% for slight early reactions. Greater than 80% of the late normal-tissue reactions seen were observed within the first year after the start of treatment, and 96% were observed within the first 5 years. There was no statistically significant difference in the normal-tissue event-free rates between the 3F/wk and 5F/wk treatment groups. This finding did not differ when different major treatment centres were studied separately. For a number of end-points, alpha/beta ratios and N- and T-exponents of a modified nominal standard dose (NSD) formula have been calculated.

The predictive value of histological classification into degrees of differentiation of squamous cell carcinoma of the larynx and hypopharynx compared with the survival of patients.

In the course of running two clinical trials between 1966 and 1985, data became available for 1315 patients, 713 in the first trial and 602 patients in the second trial, which has allowed comparison between histological findings in laryngeal and hypopharyngeal carcinoma, the observed survival and the tumour-free rates for these patients who were followed for up to 10 years. Extensive histopathology reviews have revealed over 98% agreement on tumour cell type between the initial report and that of the reviewer. Highly significant differences have been found for squamous cell carcinoma between the observed survival and the tumour-free rates for patients with well-differentiated and with anaplastic lesions. There was a statistically significant greater proportion of patients with well-differentiated tumours at larynx sites and in stage 1 when compared with patients with anaplastic tumours, but even when this was taken into account, multivariate analyses showed that tumour grading still made an independent significant contribution to the prediction of prognosis. For squamous cell carcinoma only very simple and rapidly assessed histopathological features need to be identified to classify tumours into the two grades employed in this study. The analyses have confirmed the prognostic significance of tumour grading in squamous cell carcinoma in the larynx and hypopharynx.

British National Lymphoma Investigation randomised study of MOPP (mustine, Oncovin, procarbazine, prednisolone) against LOPP (Leukeran substituted for mustine) in advanced Hodgkin's disease--long term results.

From 1979-1983, 299 patients with stage III or IV Hodgkin's disease (HD) were randomised to receive cyclical chemotherapy with MOPP (mustine, Oncovin, procarbazine, prednisone) or LOPP (Leukeran substituted for mustine). Two hundred and ninety patients were evaluable. There was no statistically significant difference between the complete remission (CR) rates (63% for MOPP, 57% for LOPP), percentage of patients remaining disease free at 5 years (38% for MOPP, 35% for LOPP) and overall survival at 5 years (65% for MOPP, 64% for LOPP). On multivariate analysis younger age, grade I histopathology, absence of systemic symptoms, and normal albumin level were favourable prognostic factors for survival. Acute toxicity in the form of nausea/vomiting, myelosuppression, and phlebitis were less with LOPP than MOPP. Deaths in both groups were usually due to disseminated Hodgkin's disease; there were no infective deaths in the absence of Hodgkin's disease. Second malignancies occurred in six patients treated with MOPP--three acute myeloid leukaemia (AML), one non-Hodgkin's lymphoma (NHL), two carcinomas (Ca); with LOPP, four second malignancies occurred (one AML, one NHL, two Ca). These long term results confirm that LOPP is as effective as MOPP, and less toxic, in the treatment of advanced Hodgkin's disease.

Curability of breast cancer.

Three concepts of cure are defined--statistical, clinical and personal. The evidence for the curability of female breast cancer according to each of these concepts is examined. It is concluded that the presence of statistically or clinically cured groups of patients is not convincingly demonstrated in past series of treated patients, but that a quarter of such patients have experienced personal cure in that they died from some other cause without overt signs of breast cancer present. The level of personal cure in currently treated series of patients should be higher, mainly due to their more favourable stage distribution.

Final report on the second British Institute of Radiology fractionation study: short versus long overall treatment times for radiotherapy of carcinoma of the laryngo-pharynx.

The second British Institute of Radiology trial of dose fractionation in radiotherapy compared two groups of prospectively randomized patients with squamous carcinoma of the laryngo-pharynx; one group was treated in a short (less than or equal to 4 weeks) and the other in a long (greater than 4 weeks) overall time. Treatment in any one centre could be given, with no planned gap in the course of treatment, either as a conventional, daily (5 fractions per week regime) or as 3 fractions per week. A total of 611 patients were allocated to treatment, of whom nine have had to be excluded from the analysis for a lack of information. Patients were admitted to the trial from January 1976 to December 1985 and were followed up for a maximum of 10 years and a minimum of 3 years. A reduction in total dose was made for use in the short compared with the long treatment regime. This reduction in total dose varied between 18% and 22% depending on whether 5 fractions or 3 fractions per week regimes were used. Overall, no statistically significant differences have been found between the two arms of the trial. The patients treated with 5 fractions per week in a short overall treatment time showed fewer late normal tissue effects. An analysis based on stratification by age, stage and anatomical site gave a relative risk (short/long overall treatment time) for deaths of 1.23 with a 95% confidence interval from 0.96 to 1.59. Analyses stratified for stage and site gave relative risks with 95% confidence intervals of 1 x 10 (0.84-1.44) for local recurrences/tumour persistence, and 1.01 (0.70-1.45) for laryngectomies.

Recruitment, follow-up and analysis times in clinical trials of cancer treatment: a case study.

A study has been made of the way in which the number of events available for analysis in a clinical trial was dependent on the recruitment period, the maximum follow-up time on individual patients and the length of time between the start of the trial and its analysis. The events considered were deaths, local recurrences and late radiation effects on normal tissue in patients treated for cancer of the laryngo-pharynx by two different fractionation regimes. The relationship is demonstrated between the number of events and the 95% confidence intervals that can be placed on differences between results in the two arms of the trial. It was found, in this particular trial, that no significant improvement in precision was gained by following up patients beyond 5 years or carrying out the analysis later than 2 years after the end of recruitment. The results are discussed in the context of the initial design of clinical trials, particularly those in which the aim is to test therapeutic equivalence.

The predictive value of tumor classification compared with results of the British Institute of Radiology fractionation trial in the treatment of laryngopharyngeal carcinoma.

Data from a clinical trial involving 734 patients have shown the value and the deficiencies of the current Union Internationale Contre le Cancer's tumor, node, and metastasis classification system for prognostic purposes. The tumor-category classification provides a good discriminant for both nodal involvement and survival; however, the previous node classification system only discriminated between node-negative and node-positive patients, as nodal fixity was not found to be a discriminator. The current anatomical site classification is ambiguous for some laryngeal and pharyngeal subsites, and modifications to the present system based on prognostic values are proposed. A difference in patient age between tumor categories has been shown, and various differences in incidence and survival data for the sexes have been demonstrated. Differences in observed and expected survival rates are related to continued late deaths from tumor. Multivariate analyses have shown that stage grouping is the most powerful prognostic discriminator, followed by anatomical site and age.

Final report of the general clinical results of the British Institute of Radiology fractionation study of 3F/wk versus 5F/wk in radiotherapy of carcinoma of the laryngo-pharynx.

The 10 year follow-up of a clinical trial involving the comparison of 3F/wk versus 5F/wk in radiotherapy of squamous cell carcinoma of the larynx and hypopharynx has now been completed. The trial involved an intake of 734 patients between 1966 and 1975. The classification of all patients has been revised to conform with the latest TNM publication. A reduction in total dose was made for 3F/wk compared with 5F/wk. This varied between 13% and 11% in centres treating over 3 weeks and 6 weeks, respectively. No statistically significant differences have been found between the two arms (3F/wk versus 5F/wk) of the trial in any of the main group analyses. A number of sub-group analyses relating to survival, tumour-free and laryngectomy-free rates and to the comparison of acute or late normal-tissue radiation damage have also been performed. No differences have been found that could be considered to be statistically significant in relation to the particular sub-group. Previous interim reports suggested minor differences in sub-group analyses between the 3F/wk and 5F/wk regimes in this trial; these have diminished now that the full follow-up data are available. This trial has provided evidence on which clinicians may base their choice between either a 3F/wk fractionation regime or a conventional 5F/wk treatment protocol in the treatment of carcinoma of the laryngo-pharynx.