Radiation and chemotherapy for patients with stage III non-small cell lung cancer.

Nearly 50,000 people in the United States will be diagnosed with stage III non-small cell lung cancer during the year 2000. Over the past 10 years, combined modality therapy has become the standard of care for primary treatment of most of these patients. Numerous studies and meta-analyses document an improvement in survival for patients with stage III disease treated with sequential chemotherapy followed by chest radiation, compared with radiation alone. Some more recent studies have shown a further improvement in survival when the chemotherapy and full-dose radiation are given concurrently. Acute toxicity is increased compared with sequential chemotherapy followed by radiation, but late toxicities seem similar. A current question under study is whether the use of initial chemotherapy followed by concurrent chemoradiotherapy will further improve median and overall survival compared with immediate concurrent therapy alone.

The treatment of limited small cell lung cancer: a report of the progress made and future prospects.

The improvements in the treatment of small cell lung cancer over the last 30 years have been realised by understanding that it is a systemic disease, but that areas of bulk and sanctuary require a complementary therapy. Despite successful strategies using combinations and thoracic radiotherapy, there remains uncertainty about what the best regimens are, their timing and their intensity. However, earlier concurrent therapy and rather brief intense chemotherapy and radiotherapy seem to produce the best results in moderately fit patients of all ages. How to select the fit patients and what to do about the less fit ones remains controversial and have economic consequences for governments and payers. Despite a meta-analysis demonstrating the success of prophylactic cranial irradiation (PCI), doubts linger about its safety, despite nothing more than anecdotal evidence from a previous era. The role of surgery continues to be explored, more in Europe than North America or Asia. Strategies for treatment of minimum residual disease seem a focus. New drugs, molecular targeted therapy, immunotherapy and other molecular therapies offer promise and theory, but there is little evidence about their place in the treatment protocols of today.

Single-agent gemcitabine and gemcitabine/irinotecan combination (irimogem) in non-small cell lung cancer.

Gemcitabine is a fluoridated pyrimidine related to cytosine arabinoside that has significant activity in solid tumor models. Irinotecan is a camptothecin analog with an active metabolite, SN-38, which inhibits topoisomerase I activity by stabilizing the topoisomerase I-DNA cleavable complex. Gemcitabine studies in non-small cell lung cancer conducted in the United States, as well as an international collaboration and clinical trials from Europe and Japan, found overall response rates of 20% to 26%, a median duration of response between 5 to 9 months, and a median duration of survival ranging from 7 to 12.3 months. Gemcitabine also has been shown to be more effective than best supportive care in non-small cell lung cancer. In a phase I trial of irinotecan (50, 75, 100, and 115 mg/m2) in combination with 1,000 mg/m2 gemcitabine, three patients had documented partial responses: one with pancreas cancer at irinotecan 100 mg/m2, one with pancreas cancer, and one with metastatic carcinoma of unknown primary at irinotecan 115 mg/m2. Three of five non-small cell lung cancer patients had stable disease for four or more cycles at irinotecan doses of 50, 75, and 100 mg/m2; no non-small cell lung cancer patients were treated at irinotecan 115 mg/m2. We recommend that a combination of gemcitabine 1,000 mg/m2 and irinotecan 100 mg/m2 given on days 1 and 8 every 3 weeks be used as the starting dose in future phase II studies. Furthermore, based on the absence of severe nonhematologic toxicity or grade IV hematologic toxicity in the majority of patients treated at the highest dose, escalation of irinotecan to 115 mg/m2 may be considered for subsequent cycles in patients who do not experience > or =grade I hematologic or non-hematologic toxicity during the first cycle of gemcitabine/irinotecan combination chemotherapy.

The 1997 International Staging System for non-small cell lung cancer: have all the issues been addressed?

The International Staging System for Lung Cancer has been revised recently. Important changes have been made to allow better correlation of prognoses and direction of management. The classification of synchronous pulmonary nodules in the same lobe as the primary tumor as T4 stage IIIB may imply a poorer outcome than is warranted, while the designation of a similar stage for malignant pleural effusion may not be reflective of the very poor prognosis associated with this extent of disease.

Changes in providers' views and practices about emergency contraception with education.

OBJECTIVE: To assess changes in the prescribing practices, knowledge, attitudes, and perceptions of health care providers after an educational program about emergency contraception. METHODS: Health care providers completed self-administered questionnaires before and 1 year after full implementation of the project. The 102 providers who completed both questionnaires were physicians (64%) and mid-level professionals from 13 San Diego County Kaiser Permanente medical offices working in departments such as obstetrics and gynecology, primary care, and emergency medicine. RESULTS: The frequency of prescription for emergency contraceptive pills increased significantly from baseline to follow-up. There was an increase of almost 20% in the percentage who prescribed emergency contraception at least once a year. Knowledge also improved significantly, and perceptions of barriers to prescribing emergency contraceptive pills within the health maintenance organization decreased significantly. In contrast, attitudes about emergency contraception showed little change. CONCLUSION: This study suggests that providers who participate in in-service training and other aspects of a demonstration project show changes in perceptions, knowledge, and behavior. However, findings also suggest that significant gaps remain in knowledge about medications, side effects, and mode of action. It is likely that many providers in other health care settings also need additional information and training concerning protocols of emergency contraception provision and its modes of action and effects.

Regulated splicing of the amyloid precursor protein gene during postnatal development of the rat basal forebrain.

The expression of the amyloid precursor protein (APP) gene has been examined in the basal forebrain of rats from birth to adulthood. Levels of total APP mRNA are highest at birth and at postnatal day 15 (P15). The most abundant transcript in rat brain is APP-695, whose expression has previously been found to be largely restricted to the central nervous system. Comparison of the developmental profiles of APP-695 mRNA with that of Kunitz-protease inhibitor (KPI)-containing APP mRNA shows that the greatest difference in expression occurs at P15, when APP-695 message levels are over 6-fold higher than KPI-containing APP mRNA (APP-751, APP-770). This is the largest difference in the APP-695/KPI-APP ratio observed during postnatal development and coincides with the period of maximal neurotrophic responsiveness in the basal forebrain. These results suggest that the APP gene is alternatively spliced during postnatal development and that regulated expression of APP-695 may be influenced by neurotrophic factors in vivo.

Limited small-cell lung cancer: a potentially curable disease.

Patients with limited-stage small-cell carcinoma of the lung are treated with combined-modality therapy with the intent to cure. Standard therapy consists of platinum-based combination chemotherapy, thoracic irradiation, and for responders, prophylactic cranial irradiation. Despite this aggressive approach, too few patients achieve 5-year survival. In the past several years, new chemotherapeutic agents, including the taxanes and the topoisomerase I inhibitors, have demonstrated substantial activity against small-cell carcinoma. These agents are now being incorporated into clinical trials for patients with limited-stage disease. The best combination of these agents with platinum-based regimens is yet to be determined, and data supporting increased survival are awaited. Other studies are exploring thoracic radiation issues. Questions remain regarding optimal timing, dose, volume, and fractionation schemes. The most effective combination of thoracic irradiation and the newer chemotherapy agents also remains to be determined. The current approach to limited-stage small-cell carcinoma is reviewed, ongoing trials are described, and future directions are explored.

Advances in treatment of inoperable NSCLC: gemcitabine doublets--a promising alternative.

Gemcitabine (Gemzar) was originally approved for use in combination with cisplatin (Platinol) for the treatment of advanced non-small-cell lung cancer (NSCLC). Research began to focus on combining gemcitabine with newer drugs, such as carboplatin (Paraplatin), vinorelbine (Navelbine), the taxanes, and the camptothecins, when it became clear that these agents had potentially increased efficacy and fewer side effects than the standard treatment. This article will briefly review the original experience with the gemcitabine/cisplatin doublet and then examine the experience to date with non-cisplatin-based gemcitabine doublet combinations in the treatment of advanced NSCLC.

Docetaxel followed by gemcitabine and irinotecan in solid tumors.

Docetaxel (Taxotere), gemcitabine (Gemzar), and irinotecan (Camptosar, CPT-11) are active single agents in a variety of solid tumors. In combination, synergism may be schedule dependent. Preclinical studies suggested synergistic interactions when docetaxel was administered 24 hours before gemcitabine or irinotecan. The objective of this phase I trial in patients with refractory solid tumors was to determine the maximum tolerated dose of docetaxel followed 24 hours later by gemcitabine and irinotecan. Two different schedules were tested: docetaxel escalated by 5 mg/m2/cohort from an initial dose of 20 mg/m2 on days 1 and 8 (schedule A) or escalated by 15 mg/m2/cohort from 45 mg/m2 on day 8 only (schedule B). In both schedules, docetaxel was given over 1 hour. Gemcitabine and irinotecan were given on days 2 and 9 (arm A) or 1 and 9 (arm B) at fixed doses of 1,000 mg/m2 over 30 minutes and 100 mg/m2 over 90 minutes, respectively. Escalation of docetaxel was planned in groups of three patients, with three additional patients added at the first indication of dose-limiting toxicity. Four dose levels in arm A and one dose level in arm B have been tested. Seventeen patients were evaluable in arm A; one died of an unrelated cause on cycle 1, and another withdrew consent before beginning treatment. Five of six patients were evaluable in arm B; one patient inadvertently received G-CSF on cycle 1. Forty-two cycles have been delivered in arm A (mean; 2.2 cycles/patient), and 25 cycles in arm B (mean, 4.2 cycles/patient); the maximum tolerated dose of docetaxel on arm A was 20 mg/m2. The dose-limiting toxicities were grade 3 diarrhea in one patient, grade 3 infection in two patients, and grade 4 neutropenia for > 4 days in one patient at the 25 mg/m2 level. The dose-limiting toxicities on arm B occurred at the first dose level and included grade 3 diarrhea in one patient, grade 4 diarrhea in one patient, and grade 4 neutropenia for 4 days in another patient. Accrual to schedule B was closed after testing the cohort 1 dose level because testing of a single deescalated docetaxel dose given on day 8 was not considered clinically relevant.

Irinotecan/gemcitabine combination chemotherapy in pancreatic cancer.

Gemcitabine (Gemzar) and irinotecan (CPT-11, Camptosar) are active cytotoxic drugs against pancreatic cancer. Preclinical data evaluating the combination of gemcitabine and irinotecan suggest dose-dependent synergistic interactions in SCOG small-cell lung cancer and MCF-7 breast cancer cell lines. Two phase I trials of this combination have been reported to date: the day 1 and 8 every-3-week schedule (IrinoGem trial), and the day 1, 8, and 15 every-4-week schedule (MSKCC trial). Both trials aimed to determine the maximum tolerated dose of irinotecan when administered as a 90-minute i.v. infusion either immediately after (IrinoGem) or before or immediately after (MSKCC) gemcitabine at 1,000 mg/m2 by 30-minute i.v. infusion in patients with solid tumors. The achieved maximum tolerated dose of IrinoGem has a higher dose intensity of irinotecan (100 mg/m2 on days 1 and 8, every-3-week cycle) compared with the MSKCC schedule (60 mg/m2 on days 1, 8, and 15, every-4-week trial). In IrinoGem, two of three previously untreated metastatic pancreas cancer patients had durable radiologic partial responses. The third had stable disease with clinical benefit for eight cycles. In addition, a patient with metastatic adenocarcinoma of unknown primary--potentially pancreatic--has had a durable response and is alive more than 30 months after the diagnosis. Preliminary results of a 45-patient multicenter phase II trial with IrinoGem in advanced and metastatic pancreas cancer were recently reported. Toxicity was modest, with no toxic deaths or neutropenic fever. Radiologic response rate was 20% of patients (9 out of 45), and a CA 19-9 decrease of more than 50% from baseline values occurred in 32.5% of patients (13 out of 40). Median survival was 6 months (range: 0.9 to 12.2+ months) and median time to treatment failure was 2.9 months (range: 0.1 to 11.3+ months). A pivotal international multicenter phase III trial comparing IrinoGem to single-agent gemcitabine in advanced and metastatic pancreas cancer is ongoing.

Irinotecan in the management of patients with pancreatic cancer.

Synergy with no overlapping toxicities has been demonstrated for the combination of irinotecan (Camptosar, CPT-11) and gemcitabine (Gemzar) in vitro. Results of a single-institution phase I study in which patients with previously untreated pancreatic cancer were given irinotecan and gemcitabine were promising, with two of three patients achieving a partial response. Because of the favorable outcome of the phase I study, a multicenter phase II trial was undertaken in previously untreated patients with pancreatic carcinoma. Data from other sites entering patients in this phase II study have been analyzed, and a multicenter phase III trial of single-agent gemcitabine vs the irinotecan combination in first-line treatment of patients with locally advanced or metastatic pancreatic cancer is underway.

Emergency contraception: knowledge and attitudes of health care providers in a health maintenance organization.

One hundred sixty-four health care providers in a health maintenance organization were surveyed in 1996 regarding their knowledge of, attitudes toward, and perception of barriers regarding emergency contraceptive pills (ECPs), as well as their ECP prescribing practices. Providers reported primarily positive attitudes regarding ECPs. Only 42% reported having ever prescribed ECPs; those who had prescribed had more positive attitudes about ECPs. Knowledge of ECP provision was incomplete, with 40% believing treatment had to be initiated in 48 hours or less. Barriers identified by providers included lack of a dedicated product, lack of awareness of ECPs among providers, and liability issues.

Improving golf performance with a warm up conditioning programme.

OBJECTIVES: To determine whether a golf specific warm up programme (both immediately prior to play and after performing it five times a week for 5 weeks) improved performance in 10 male golfers compared with 10 controls matched for age, sex, and handicap. METHODS: Twenty male golfers were matched for age (+/-2 years) and handicap (+/-1 stroke). Club head speed was assessed by two dimensional video analysis in a laboratory setting. In week 1, all golfers performed 10 strokes. In weeks 2 and 7, the controls underwent the same procedure as in week 1. The exercise group performed the golf specific warm up followed by their 10 strokes. Between weeks 2 and 7, the exercise group performed the specially designed warm up five times a week for 5 weeks. RESULTS: The mean club head speeds of the exercise group improved at each testing week. Between weeks 1 and 2, golfers in the exercise group improved their club head speed on average by 3-6 m/s (12.8%), and between weeks 1 and 7, they increased their club head speeds by 7-10 m/s (24.0%). With the exception of one golfer whose club head speed varied by 1.7 m/s, the mean club head speeds of the golfers in the control group hardly varied over the testing period (range: 0.3-0.8 m/s). A significant difference (p = 0.029) was found between the mean club head speeds of the exercise and control groups over the duration of the study, and a significant interaction over time (p<0.001) was also found. CONCLUSIONS: This study has shown that golfers' performances will be significantly improved by undertaking a golf specific warm up programme compared with not performing the warm up.

Preventing injuries to competitive and recreational adult golfers: what is the evidence?

Although injuries to golfers are not common, both survey studies and hospital emergency department records have provided objective evidence that golfers are sometimes at risk of injury. While many golf injury studies describe the associated mechanisms and types of injuries, less attention has been given to research relating to the various injury prevention measures for this sport. This paper provides a critical review of the range of countermeasures to prevent golf injuries and highlights areas to be considered for future research, development, and implementation. In particular, it focuses on the strength of the evidence for the effectiveness of these measures. This review concludes that there needs to be more formal evaluation of the suggested countermeasures to prevent golf injuries. Particular attention should be given to evaluations of the golf swing and its relationship to particular injuries such as low-back, wrist, and shoulder problems. These countermeasures and associated strategies are recommended to reduce the incidence of injury in this popular and accessible sport.

How well does club head speed correlate with golf handicaps?

The velocity at which a golf club impacts with a golf ball is known as club head speed. Although club head speed has been used to measure performance changes in a number of golf studies, it has not been validated as a golf performance measure. As handicap is the usual measure of performance, the purpose of this study was to investigate the relationship between club head speed and handicap, and to determine whether club head speed at impact is a valid measure of golfing performance. Forty-five male golfers aged 18-80 years, all with registered golfing handicaps (2-27), participated in this study. Each golfer performed 10 golf swings captured by a high-speed camera. Golfers' club head speeds were determined using Video Expert 2, a biomechanical computer program. Golfers with a lower handicap (i.e., a better skill level) had faster club head speeds than higher handicap golfers. Linear regression analysis found club head speed to be highly correlated with handicap (r = 0.950). This relationship was described by the equation: In (club head speed)= 4.065 - 0.0214 x handicap. In conclusion, this study has shown that club head speed is a valid indicator of performance in golfers and may therefore be a useful performance measure in future laboratory-based studies.

Warm-up attitudes and behaviours of amateur golfers.

Although it is widely recommended that golfers warm-up before play/practice to enhance their physical performance and to prevent injuries, few actually undertake this activity. The reasons why golfers do/do not warm-up are not known. The aim of this study was to determine the self-reported behaviours and attitudes of adult golfers towards warming-up. A survey of 1040 randomly selected golfers was conducted over a 3-week period in July 1999. Information about golf participation, usual warm-up habits and reasons for these warm-up behaviours was obtained by a verbally administered self-report survey. Over 70% of the surveyed golfers stated that they never or seldom warm-up, with only 3.8% reporting warming-up on every occasion. The most common reasons why golfers warmed-up included to play better (74.5%), to prevent injury (27.0%), and because everyone else does (13.2%). Common reasons for not warming-up were the perception that they don't need to (38.7%), don't have enough time (36.4%) and can't be bothered (33.7%). These findings suggest that in order to increase the proportion of golfers who warm-up, education programs focussing on the benefits of warming-up, including injury prevention, need to be developed and implemented. Different strategies may need to be adopted to accommodate golfers' differing attitudes and baseline behaviours.

Warm up practices of golfers: are they adequate?

BACKGROUND: Although it is widely recommended that golfers warm up before play or practice to enhance their physical performance and reduce their injury risk, it is not known to what extent they actually undertake such warm up procedures. OBJECTIVE: To collect information about the proportion of golfers who actively warm up and to determine the types of warm up behaviours. METHODS: This study was conducted over three weeks at three different golfing venues: a private golf course, a public golf course, and a golf driving range. Golfers' warm up behaviours, defined as any form of preparative exercise, were recorded by direct observation by two independent observers. RESULTS: The sample consisted of 1040 amateur golfers (852 men and 188 women) aged at least 18 years. Only 54.3% (95% confidence interval 49.8 to 58.8) performed some form of warm up activity. Air swings on the tee were the most commonly observed warm up activity, with 88.7% (95% confidence interval 85.9 to 91.5) of golfers who warmed up performing these. CONCLUSIONS: Only a small proportion of amateur golfers perform appropriate warm up exercises. To improve on this, golfers should be educated about the possible benefits of warming up and be shown how to perform an appropriate warm up routine.

Hepatic extraction of bile salts in conscious dogs.

The enterohepatic circulation of cholic acid conjugates (CAC) was studied in three conscious dogs by comparing the relationship of the concentration of CAC in portal, hepatic, and peripheral venous plasma samples collected simultaneously. The pool of CAC in each dog was labeled with 14C. Catheters were surgically placed in the jugular, left hepatic, and portal veins. Each dog was studied on 2 consecutive days, and each study consisted of a series of samples withdrawn from each catheter at 15-min intervals before and after gallbladder contraction with cholecystokinin. The concentration of CAC in the portal vein ranged from 3 micron (fasting) to 235 micron (after gallbladder contraction). In individual studies, the concentration of CAC increased four to sixfold. A linear relationship exists between the concentration of CAC in the portal vein to that in the hepatic and jugular veins. Thus, the fractional hepatic extraction of CAC is constant over the physiological range of the concentration of CAC in portal venous plasma. Mean extraction varied among the six studies from 0.618 +/- 0.072 (+/- 1 SD) to 0.983 +/- 0.010.

Are squash players protecting their eyes?

OBJECTIVE: To determine factors associated with adult squash players' protective eyewear behaviours. METHODS: A survey of 303 players (aged >or =18 years) was conducted at three squash venues in Melbourne, Australia over a three week period in June 2000 to obtain information about protective eyewear use. RESULTS: Of 303 participants the response rate was 98.1%; 66.1% were males, with a mean age of 40.5 years. The majority (68.4%) had played squash for 10 years or more. Although 18.8% of players reported using protective eyewear, only 8.9% reported wearing approved eyewear. Both age group (p<0.05) and years of squash experience (p<0.01) were significantly associated with any eyewear use. The two main influences were personal experience of eye injuries (50.0%) and knowledge of eye injury risk (33.9%). A commonly reported barrier was restriction of vision (34.2%). CONCLUSION: These findings demonstrate a low prevalence of voluntary use of appropriate protective eyewear. Future prevention strategies incorporating education campaigns should focus on increasing players' knowledge of risks. The barriers to use and misconceptions about which types of eyewear is most protective need to be addressed as a priority.