Paul A Burt

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.

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/m2on 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 (≥ 25%) improvement in SS14 score between baseline and 2 months sustained for ≥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 (≥ 4 weeks) improvement (≥25%) on SS14 was recorded in a significantly higher proportion of gemcitabine + BSC patients (22%) than in BSC alone patients (9%) (P = 0.0014, Pearsons 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.

Neurological and cognitive impairment in long-term survivors of small cell lung cancer

Despite its effectiveness in reducing the rate of brain metastases, the role of prophylactic cranial irradiation (PCI) in the management of small cell lung cancer (SCLC) remains controversial because of concern about radiation-induced neurological morbidity. In order to evaluate morbidity and its impact on quality of life 64 patients surviving > or = 2 years in remission were recalled for assessment. 52 had received PCI. Most of the patients were well: 95% had performance status < or = 1 and nine out of 37 neurological examinations were abnormal. On neuropsychometric testing, only 19% of patients performed at the level expected for their age and intellectual ability on all four tests used. Fifty-four per cent of patients were impaired on two or more of the tests, suggesting a significant degree of measurable cognitive dysfunction. The number of patients who had not received PCI was insufficient for comparative analysis with the number who had, but among those treated with PCI, patients receiving 8 Gy in 1 fraction appeared less impaired than those receiving higher radiation doses in multiple fractions. The study showed that neuropsychometric testing is acceptable to patients, can be administered by non-psychologists in the clinic and is sensitive to otherwise undetected deficits of cognitive function in this patient population. Prospective evaluation of PCI should include neuropsychometric testing.

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.

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.

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.

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.

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.

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 patients 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.

Randomized Phase II Study of Two Gemcitabine Schedules for Patients With Impaired Performance Status (Karnofsky performance status ≤ 70) and Advanced Non–Small-Cell Lung Cancer

PURPOSE This randomized phase II study compared two treatment schedules of gemcitabine in patients with non-small-cell lung cancer (NSCLC) and impaired Karnofsky performance status (KP). Primary objectives were to record changes from baseline KP and to assess symptom palliation. Secondary objectives were overall survival, tumor response, and toxicity. PATIENTS AND METHODS Patients with stage IIIb and IV NSCLC and KP </= 70 were randomly assigned to receive gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 of each 28-day cycle (3w4) or gemcitabine 1,500 mg/m(2) on days 1 and 8 of each 21-day cycle (2w3), both for up to six cycles. KP, toxicity, and SS14 lung cancer specific questions were recorded before each cycle of treatment. Response was evaluated 4 weeks after the last cycle. RESULTS One hundred seventy-four patients were enrolled. There was significant early attrition due to disease progression; only 61.5% of patients were alive at 2 months. There was a significant improvement in KP from baseline to pre-cycle 3 in both arms, with a trend in favor of the 3w4 regimen for duration and faster onset of improvement. Eight of the 17 quality-of-life (QOL) variables assessed showed an improvement of more than 10% between baseline and the start of the third cycle of treatment. Response rate, survival, and duration were similar in both arms. CONCLUSION There was no significant difference between the two schedules examined in terms of improvement in KP or QOL, but there seemed to be a trend in favor of the 3w4 schedule.