Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer.

Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group of patients.

Randomized phase II study of cyclophosphamide, doxorubicin, and vincristine compared with single-agent carboplatin in patients with poor prognosis small cell lung carcinoma.

BACKGROUND: Information on the effect of chemotherapy in a group of patients with poor prognosis, poor performance status small cell lung carcinoma (SCLC) is scarce. A randomized study comparing single-agent carboplatin with combination chemotherapy in this largely unreported population of SCLC patients was undertaken. METHODS: One hundred nineteen patients were allocated to four cycles of either cyclophosphamide, doxorubicin, and vincristine (CAV) or single-agent carboplatin. Patients had either a Karnofsky performance score < or = 50 and/or a prognostic score indicative of a 1-year survival rate < or = 15%. RESULTS: Grade 3-4 neutropenia and intravenous antibiotic use were significantly more common with the CAV regimen (P < 0.005). Conversely, Grade 3-4 thrombocytopenia was more common (P < 0.0009) and platelet transfusion was more frequent (P < 0.05) with carboplatin therapy. Nonhematologic toxicity was similar in both treatment arms, except for alopecia with CAV therapy (P < 0.0007). Symptom relief occurred in 48% and 41% of patients in the CAV and carboplatin treatment arms, respectively. Dyspnea was improved in 66% and 41% of patients and cough was improved in 21% and 7% of patients in the CAV and carboplatin treatment arms, respectively. CAV therapy produced a higher response rate than carboplatin (38% vs. 25%), but this was not statistically significant (P = 0.15). The median overall survival for patients in the CAV and carboplatin treatment arms was 17 weeks and 15.9 weeks, respectively, with 1-year survival rates of 12% and 6%. CONCLUSIONS: Single-agent carboplatin is a feasible treatment in patients with poor prognosis SCLC and produces response rates, relief of tumor-related symptoms, and survival similar to what is seen in patients who receive CAV chemotherapy. The lower risk of life-threatening sepsis and less need for hospitalization or intravenous antibiotic courses is advantageous in this susceptible patient population.

Use of hematopoietic progenitors in whole blood to support dose-dense chemotherapy: a randomized phase II trial in small-cell lung cancer patients.

PURPOSE: Small-cell lung cancer (SCLC) is exquisitely chemosensitive, but few patients are cured by conventional chemoradiotherapy. Recent studies suggest that increased cytotoxic dose-intensity might improve survival. In this randomized phase II study, we tested the feasibility of dose intensification using sequential reinfusion of hematopoietic progenitors in whole blood. PATIENTS AND METHODS: SCLC patients with a favorable prognosis were treated with six cycles of ifosfamide, carboplatin, and etoposide (ICE), at 4-week (standard treatment) or 2-week (intensified treatment) intervals. Intensified treatment was supported by daily subcutaneous filgrastim injections and reinfusion of 750 mL of autologous blood collected immediately before each cycle. RESULTS: Fifty consecutive patients were randomized to standard (n = 25) or intensified (n = 25) ICE. A total of 94% completed at least three treatment cycles, and 70% completed six cycles; 96% of treatments were given at full dose. The planned dose-intensity was 1.0 for standard and 2.0 for intensified ICE. The median received dose-intensity for cycles 1 through 3 was 0.99 (range, 0.33 to 1.02) for the standard treatment arm and 1.80 (range, 0.99 to 1.97) for the intensified treatment arm (P <.001). Over all six cycles, the median received dose-intensity was 0.95 (range, 0.17 to 1.03) for the standard treatment arm and 1.60 (range, 0.60 to 2.01) for the intensified treatment arm (P <.001). Febrile neutropenia was more common on the standard treatment arm (84% v 56%), resulting in more days of intravenous antibiotics (median, 10 v 3 days; P =.035). Transfusion requirements were similar in the two groups. CONCLUSION: Sequential reinfusion of hematopoietic progenitors in whole blood can safely support substantial increases in dose-intensity of ICE chemotherapy for SCLC.

Gemcitabine plus best supportive care (BSC) vs BSC in inoperable non-small cell lung cancer--a randomized trial with quality of life as the primary outcome. UK NSCLC Gemcitabine Group. Non-Small Cell Lung Cancer.

Three hundred patients with symptomatic, locally advanced or metastatic NSCLC not requiring immediate radiotherapy were enrolled into this randomized multicentre trial comparing gemcitabine + BSC vs BSC alone. Patients allocated gemcitabine received 1000 mg/m2 on days 1, 8 and 15 of a 28-day cycle, for a maximum of six cycles. The main aim of this trial was to compare patient assessment of a predefined subset of commonly reported symptoms (SS14) from the EORTC QLQ-C30 and LC13 scales. The primary end-points were defined as (1) the percentage change in mean SS14 score between baseline and 2 months and (2) the proportion of patients with a marked (> or = 25%) improvement in SS14 score between baseline and 2 months sustained for > or =4 weeks. The secondary objectives were to compare treatments with respect to overall survival, and multidimensional QL parameters. The treatment groups were balanced with regard to age, gender, Karnofsky performance status (KPS) and disease stage (40% had metastatic disease). The percentage change in mean SS14 score from baseline to 2 months was a 10% decrease (i.e. improvement) for gemcitabine plus BSC and a 1% increase (i.e. deterioration) for BSC alone (P = 0.113, two-sample t-test). A sustained (> or = 4 weeks) improvement (> or =25%) on SS14 was recorded in a significantly higher proportion of gemcitabine + BSC patients (22%) than in BSC alone patients (9%) (P = 0.0014, Pearson's chi-squared test). The QLQ-C30 and L13 subscales showed greater improvement in the gemcitabine plus BSC arm (in 11 domains) than in the BSC arm (one symptom item). There was greater deterioration in the BSC alone arm (six domains/items) than in the gemcitabine + BSC arm (three QL domains). Tumour response occurred in 19% (95% CI 13-27) of gemcitabine patients. There was no difference in overall survival: median 5.7 months (95% CI 4.6-7.6) for gemcitabine + BSC patients and 5.9 months (95% CI 5.0-7.9) (log-rank, P = 0.84) for BSC patients, and 1 -year survival was 25% for gemcitabine + BSC and 22% for BSC. Overall, 74 (49%) gemcitabine + BSC patients and 119 (79%) BSC patients received palliative radiotherapy. The median time to radiotherapy was 29 weeks for gemcitabine + BSC patients and 3.8 weeks for BSC. Patients treated with gemcitabine + BSC reported better QL and reduced disease-related symptoms compared with those receiving BSC alone. These improvements in patient-assessed QL were significant in magnitude and were sustained.

Treatment of endobronchial metastases with intraluminal radiotherapy.

Metastasis to the lung occurs quite commonly from certain types of extrapulmonary primary carcinoma. Spread to the bronchial lumen is relatively rare. When this does occur, symptoms resembling those of primary bronchial carcinoma are often present, in association with partial or complete obstruction of the bronchial lumen. Palliation of such symptoms is possible with the use of intraluminal radiotherapy (ILT). Between 1990 and 1998, 37 patients with endobronchial metastases were treated using this modality; a single fraction of radiation was delivered by the remote afterloading high dose rate microSelectron system. Data regarding these patients' characteristics and outcome are presented, following a retrospective review of case notes. The commonest symptoms were dyspnoea, cough and haemoptysis; the commonest primary tumour sites were breast, colorectum, oesophagus and kidney. Twenty-four (64.9%) patients had some improvement in symptoms following treatment. Mean overall survival was 280 days, range 9-1145 days. No serious adverse effects occurred. ILT is a relatively simple, safe and effective treatment in the palliation of symptoms due to endobronchial metastases.

Radical radiotherapy for carcinoma of the oesophagus: an effective alternative to surgery.

BACKGROUND AND PURPOSE: Despite advances in operative and postoperative care, long term survival rates following radical oesophagectomy are poor. Surgery remains the mainstay of radical treatment despite various series reporting similar results for treatment with radiotherapy, in particular in the upper third of the oesophagus. We have studied a cohort of patients treated with definitive radiotherapy to examine the influence on survival of changes in diagnostic scanning and radiotherapy computer planning as well as various patient and disease related prognostic factors. PATIENTS AND METHODS: From 1985 to 1994, 101 patients with clinically localised carcinoma of the oesophagus were treated at the Christie Hospital with definitive radiotherapy. This included 11 patients with oesophageal adenocarcinoma. Diagnostic and planning techniques changed over the period studied, with increasing use of both diagnostic and radiotherapy planning CT scanning. Radiotherapy doses ranged from 45 to 52.5 Gy in 15 or 16 fractions over 3 weeks. RESULTS: The 3- and 5-year survival figures were 27% and 21%, respectively, corrected for intercurrent deaths. Survival was better for adenocarcinoma than squamous cell carcinoma, though not statistically significantly. The only significant prognostic factor (P = 0.01) was the use of diagnostic CT scanning (42% versus 13% 5-year survival with or without diagnostic CT scanning, respectively) which was associated with an increase in field size. Radiotherapy was well tolerated with no acute mortality or significant morbidity. Late stenosis requiring oesophageal was seen in five of 20 patients surviving 3 years or more. CONCLUSIONS: Survival following well planned radiotherapy is an effective alternative to surgery for both squamous cell and adenocarcinoma. Advances in staging and three-dimensional planning and the use of multimodality treatment may further improve survival.

Changes in the cellularity of the cortex of human hairs as an indicator of radiation exposure.

Growing hair follicles with their rapid cell proliferation would be expected to be sensitive organs to cytotoxic agents such as radiation. Various abnormalities in the hair and hair follicles have been reported in the past. Changes in the number of cells in the newly forming hair cortex have been shown in the mouse to be one of the more sensitive assays for radiation effects, and this approach could provide a basis for a biological dosimeter. Here we show for the first time using hair cortex cell counts some preliminary data indicating that the number of cell nuclei in a unit of length (140 microns) of the cortex of human hairs from the chest and scalp of patients undergoing fractionated radiotherapy falls significantly (P = 0.005) by 5%-10% 3 days after the first dose in a fractionated sequence of irradiations. The first dose was delivered on a Friday, and no further exposures were delivered until after the hair sample was taken on the 3rd day (Monday). No significant effect of radiation dose could be detected over the available. limited range of doses studied (5-6.5 Gy with one exit dose sample at 2.6 Gy). Also, the width varies from hair to hair. If the width of the hair is taken into account and the cortical nuclei counts are normalised to the width of each hair, the effects seen at day 3 become slightly more significant (P = 0.002), and those at day 5 also become significant (P = 0.012). Samples taken on the 5th day after the first (Friday) exposure were also 2 days after the second exposure and 1 day after the third exposure. However, little expression of damage attributable to the 2nd and 3rd exposures was anticipated since their effects would take some time to be expressed in the cortical region examined, which is some distance from the proliferative region of the follicle.

Massive haemoptysis death and other morbidity associated with high dose rate intraluminal radiotherapy for carcinoma of the bronchus.

Four hundred and six patients with primary non-small cell carcinoma of the bronchus causing symptoms due to endobronchial disease, were treated with intraluminal radiotherapy (ILT) using the microSelectron-HDR machine at the Christie Hospital, Manchester, between April 1988 and the end of 1992. An assessment of morbidity for this treatment is presented, particularly with regard to the risk factors and causes of massive haemoptysis death. The most common early side-effect was a mild transient exacerbation of cough which usually resolved within 2-3 weeks. At various times following ILT treatment 83 bronchoscopies were carried out randomly in 55 patients. In bronchoscopies carried out within the first 3 months following ILT, no tumour was visible in 80% of cases. A mucosal radiation reaction score (RRS) was used to grade bronchoscopic appearance after ILT treatment. Overall, 55% of bronchoscopic examinations showed some degree of mucosal radiation reaction. The majority of radiation reactions from 6 months onwards after ILT demonstrated a degree of fibrosis. A radiation reaction was seen more frequently after treatment with 2000 cGy as opposed to 1500 cGy at 1 cm from the central axis of the radiation source. Thirty-two patients were identified who had died from massive haemoptysis (MH) as a terminal event. A Cox multivariate regression analysis showed that the treatment-related factors of increased dose at first ILT (P = 0.004), prior laser treatment at the site of ILT (P = 0.020) and second ILT treatment in the same location as the first ILT treatment (P = 0.047), all significantly increased the relative risk of MH death compared with their effect on the relative risk of death from other causes (OC). (In addition a fourth treatment-related factor, namely the concurrent use of ILT and external beam radiotherapy (EB) had a P value of 0.08). Twenty out of 25 assessable MH-death patients (80%) had evidence of recurrent or residual tumour before death but 5 patients (20%) did not. For surviving patients the instantancious risk of death at any one time (the cause-specific death rate expressed as deaths per 100 cases per month), showed a sharp peak for MH deaths between 9 and 12 months post ILT in contradistinction to OC death where the peak was between 3 and 6 months post ILT. These findings may imply a role for late radiation reaction in the treatment-related risk factors identified as increasing the relative risk of MH death and possible mechanisms are discussed. The results have implications for treatment regimes that use a dose of 2000 cGy at 1 cm in a single fraction technique, that have a high frequency of previous laser treatment, that use multiple, repeated ILT treatments in the same location and that use ILT concurrently with EB.

Long-term survival and symptom palliation in small primary bronchial carcinomas following treatment with intraluminal radiotherapy alone.

Between April 1988 and December 1992, 37 patients with small, previously unirradiated, primary non-small cell carcinomas of the bronchus causing symptoms due to endobronchial disease were treated at the Christie Hospital, Manchester, with a single fraction of high dose rate intraluminal radiotherapy (ILT) using the microSelectron-HDR machine. Small primary (SP) lesions were defined as being less than 2 cm in diameter in a direction perpendicular to the central axis of the iridium-192 treatment source. Fifteen patients (41%) were treated to a dose of 15 Gy and 22 patients (59%) to 20 Gy at a distance of 1 cm from the central axis of the source. At 6 weeks following ILT, improvement in symptoms was seen in the following percentages of patients: haemoptysis 96%, pulmonary collapse 69%, cough 55% and dyspnoea 52%. The magnitude of improvement in these symptoms was largely maintained in patients surviving to 4 months and then 12 months post-ILT. Median actuarial survival was 709 days, 2-year survival 49.4% and 5-year survival 14.1%. Overall, there was no significant difference in survival after treatment with 20 Gy compared with 15 Gy at 1 cm. At the close of study, there were four patients still alive without disease recurrence with survivals of 38, 48, 49 and 63 months. All had had biopsy-proven squamous cell carcinomas and all had been treated with 20 Gy at 1 cm. Five patients died from massive haemoptysis as a terminal event at 4, 9, 9, 10 and 11 months post-ILT, well below the median survival for this group of patients. Again, all had been treated with 20 Gy as opposed to 15 Gy at 1 cm. Over the same time period, 287 patients with non-small cell carcinomas of more than 2 cm in diameter (large primary lesions, LP), were treated with a single fraction of ILT only, as their initial treatment. A consistently greater percentage of patients with SP lesions showed an improvement in the symptoms of haemoptysis and pulmonary collapse when compared with patients with LP lesions. Patients with LP lesions demonstrated a decreased actuarial survival when compared with SP lesions, with median survival being 156 days, 2-year survival 3.1% and no survivors beyond 39 months. This study demonstrates that, in patients with small endobronchial carcinomas a single fraction of ILT can give efficient palliation of symptoms and lead to long term disease-free survival, but that a dose of 20 Gy may be at the limit of bronchial radiation tolerance for a single dose technique employing a high dose rate source.

Technical note: the efficacy of megavoltage imaging in the radical radiotherapy of non-small cell lung cancer.

Megavoltage imaging (MVI) has been used to obtain digital images of treatment fields during therapy for non-small cell lung cancer. Tumours were seen in all 33 cases studied and in three cases MVI was used to improve the set-up. It is concluded that in the setting of radical radiotherapy for non-small cell lung cancer this is an appropriate technique for the verification and correction of field position and is an aid to quality assurance.

The intrinsic radiosensitivity of cervical carcinoma: correlations with clinical data.

PURPOSE: The aims of the work were to study the intrinsic radiosensitivity of tumor biopsies from patients with cervical carcinoma and to correlate the data with information on patient age, disease stage, differentiation status, tumor volume, and tumor ploidy. METHODS AND MATERIALS: Radiosensitivity was assessed for 145 tumors in vitro as surviving fraction at 2 Gy (SF2) using a clonogenic assay. RESULTS: Although the clonogens in tumors classified as Stage I or II tended to be more radiosensitive than in Stage III or IV disease, the difference was not statistically significant (p > 0.15). There was also no significant difference in the intrinsic radiosensitivity of well, moderately, or poorly differentiated tumors or between squamous cell carcinoma and adenocarcinoma (p > 0.53). There was no correlation between patient age and tumor radiosensitivity (p = 0.49). Large volume (> or = 4 cm) disease was more radioresistant than small volume (< 4 cm) disease, but the difference was not significant (p = 0.08). Finally, diploid tumors tended to be more radioresistant than aneuploid tumors (p = 0.07). CONCLUSION: The intrinsic radiosensitivity of cervix tumors is independent of disease stage, tumor grade, and patient age. Weak trends, however, were observed of increased tumor radioresistance for large volume disease and diploid tumors, suggesting that tumor SF2 may not be a completely independent parameter.

Single fraction prophylactic cranial irradiation for small cell carcinoma of the lung.

The effectiveness of a single 8-Gy fraction prophylactic cranial irradiation regime was assessed in 106 patients with small-cell carcinoma of the lung. All patients had limited stage disease and received combination chemotherapy consisting of either cisplatin or carboplatin with ifosfamide, etoposide, and vincristine (VICE). Cranial irradiation was administered 48 h after the first cycle of chemotherapy and was well tolerated. Actual 2-year survival was 35% and cranial relapse occurred in 22% of those patients who achieved complete remission. This compares favourably with a cranial relapse rate of 45% incomplete remitters previously reported with the same chemotherapy regime after a minimum follow-up of 2 years where PCI was not used. Formal psychometric testing was performed retrospectively on a series of 25 long-term survivors of whom 14 were taken from this reported series. Whilst 75% of patients were impaired on at least one test with 68% performing badly in the most complex task, this was not associated with clinically detectable neurological damage and the patients did not complain of memory or concentration difficulties. In conclusion, single fraction PCI, when used with platinum based combination chemotherapy, appears to be equally effective but may be less neurotoxic than the more standard fractionated regimes.

Intraluminal brachytherapy using the high dose rate microSelectron in the palliation of carcinoma of the oesophagus.

A total of 197 patients, who presented to the Christie Hospital with advanced carcinoma of the oesophagus, were treated with the high dose rate microSelectron between June 1988 and June 1992. In 54%, a single intraluminal brachytherapy treatment resulted in useful palliation, which was sustained for a substantial part of the patient's remaining life. The simplicity of the treatment, which could be completed as a day case procedure and did not cause significant morbidity, commends itself in the palliation of these patients who have poor overall survival and quality of life. Approaches that might improve the response rate in those patients who did not gain significant palliation after a single treatment are discussed.

High dose rate intraluminal radiotherapy for carcinoma of the bronchus: outcome of treatment of 406 patients.

In April 1988 the Christie Hospital started using the microSelectron-HDR machine to deliver intraluminal radiotherapy (ILT) to inoperable bronchial carcinomas causing symptoms due to endobronchial disease. Results of treatment in the first 406 patients with primary non-small-cell carcinoma are presented. Three main categories of patient were defined. Category 1 consisted of 324 patients (79.8%) who were previously unirradiated and received a single fraction of ILT as their primary treatment, mostly to a dose of 1500 cGy (76%) or 2000 cGy (23%) at 1 cm from the centre of the iridium-192 treatment source. The percentage of these patients whose symptoms or signs were improved at 6 weeks following ILT were as follows: stridor 92%, haemoptysis 88%, cough 62%, dyspnoea, 60%, pain, 50% and pulmonary collapse, 46%. Approximately two-thirds of these patients (67.3%) derived long lasting palliation and required no further treatment during their lifetime. The other third of patients needed subsequent treatment at some stage because of recurrence of their symptoms and in this situation external beam radiotherapy (EB) or a repeat ILT treatment was effectively utilised. Category 2 consisted of 65 patients (16%) who had previously received EB but required ILT when their tumour recurred. At 6 weeks post-ILT levels of symptom palliation were broadly similar to those obtained if ILT was used in previously unirradiated individuals, although the improvement was not so well sustained with time and only 7% showed improvement in pulmonary collapse at 6 weeks. Category 3 consisted of 17 patients (4.2%) in whom ILT was used concurrently with EB as a combined initial treatment. Similar levels of palliation were seen when compared with patients who received a single ILT treatment only. Overall, ILT was well tolerated in terms of early and late morbidity. In conclusion, the efficiency of a single ILT treatment in palliating symptoms due to endobronchial tumour in previously unirradiated individuals is comparable with that reported in series where treatment for advanced lung cancer combines a prolonged course of EB concurrently with several ILT treatments.

Intraluminal irradiation for the palliation of lung cancer with the high dose rate micro-Selectron.

Fifty patients with inoperable, symptomatic endobronchial carcinoma were treated by a single exposure of intraluminal radiotherapy. A high dose rate afterloading system (the micro-Selectron-HDR) was used to minimise radiation exposure for staff. Haemoptysis was relieved in 24 of 28 patients, breathlessness in 21 of 33 patients, and cough in nine of 18 patients. Radiological collapse resolved in 11 of 24 patients. Treatment was given on an outpatient basis and was well tolerated. Intraluminal radiotherapy appears to offer an effective alternative to conventional fractionated external beam radiotherapy.

Radical radiotherapy for carcinoma of the bronchus: an equal alternative to radical surgery?

A retrospective study of 175 patients with T1-T3N0M0 carcinoma of the bronchus treated by radical radiotherapy at the Christie Hospital and Holt Radium Institute, Manchester between 1971 and 1980, is presented. Survival corrected for intercurrent death was 60.3% at 1 year and 19.6% at 5 years. Excluding T3 tumours which were all fatal by 5 years, corrected survival was 64.6% at 1 year and 26.0% at 5 years. A definition of the type of tumour suitable for radical radiotherapy is given.