Raymond P. Abratt

Phase III Study Comparing Oral Topotecan to Intravenous Docetaxel in Patients With Pretreated Advanced Non–Small-Cell Lung Cancer

PURPOSE This open-label, randomized, multicenter, phase III study compared oral topotecan versus intravenous (IV) docetaxel in patients with previously treated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with stage III or IV NSCLC, performance status < or = 2, who had received only one prior chemotherapy regimen, were randomly assigned to treatment with oral topotecan 2.3 mg/m2/d on days 1 to 5 or IV docetaxel 75 mg/m2 day 1 every 21 days. RESULTS A total of 829 patients were randomly assigned. In intent-to-treat analysis, 1-year survival rates were 25.1% with topotecan and 28.7% with docetaxel. The difference of -3.6% (95% CI, -9.59% to 2.48%) met the predefined criteria for noninferiority of topotecan relative to docetaxel because the lower limit of the 95% CI was above -10%. Median survival was 27.9 weeks with topotecan and 30.7 weeks with docetaxel. Although not statistically significant (log-rank P = .057), the higher survival rate with docetaxel was maintained across the entire treatment period. The median time to progression was 11.3 weeks with topotecan versus 13.1 weeks with docetaxel (log-rank P = .02). The overall response rate was 5% in each group. Grade 3/4 neutropenia occurred more frequently with docetaxel (60% v 50%). Grade 3/4 anemia and thrombocytopenia occurred more frequently with topotecan (26% v 10% and 26% v 7%, respectively). CONCLUSION Oral topotecan provides activity in the treatment of relapsed, locally advanced, unresectable NSCLC. Both regimens were well tolerated with differing safety profiles. Topotecan may provide an option for patients who desire an orally available treatment after relapse.

Palliative radiation for stage 3 non-small cell lung cancer — A prospective study of two moderately high dose regimens

Eighty four patients from Groote Schuur Hospital and Frere Hospital East London were entered into a prospective randomised trial between January 1990 and December 1993. All the patients possessed non-small cell carcinoma (NSCLC) of the lung too extensive for radical irradiation and World Health Organization performance status 0-2. The patients were randomised to receive either 35 Gy in 10 fractions (43 patients) or 45 Gy in 15 fractions (41 patients). In the patients treated to 35 Gy and 45 Gy, the median survival was 8.5 months in both groups, the symptomatic response rate was 68% and 76% and the incidence of moderate to severe radiation oesophagitis was 23% and 41% respectively. The latter approached statistical significance (P = 0.07, chi square). There was no evidence of a dose response effect on survival in the moderate dose range in patients treated palliatively for locally advanced NSCLC.

Pretreatment minimal staging and prognostic factors for non-small cell lung cancer

aDepatiment of Medical Oncology, Princess Margaret Hospital, Toronto, Canada bDepartment of Radiation Oncology, Groote Schuur Hospital, South Africa ‘Department of Medicine, Division of Hemoc, SUNY-Health Science Center, Syracuse, New York, USA ‘Department of One-Rad, Medical University, Gdansk, Poland eDepartment of Thoracic and Cardiac Surgery, Nymegen, The Netherlands ‘St. Pierre University Hospital, Brussels, Belgium gUnit~ de Biostatitique, Institute J. Bordet, Belgium h Hospital Erasme, Brussels, Belgium ‘Deparmtent of Radiolo@, Olive V?ew-UCLA Medical Center, Los Angeles, Calgomia, USA iUniversity Hospital, Division of Oncology, Zurich, Switzerland kStatistician, MRC Cancer Trials Of&e, Cambridge, UK

The cancer burden in Africa.

Cancer is currently responsible for more than 7 million deaths per year worldwide, more than malaria, tuberculosis and HIV / AIDS combined.

Phase II study of oral vinorelbine in combination with carboplatin followed by consolidation therapy with oral vinorelbine as single-agent in unresectable localized or metastatic non-small cell lung carcinoma.

INTRODUCTION This phase II study assessed the efficacy and safety of oral vinorelbine given weekly in combination with carboplatin (CBDCA) AUC 5 once every 3 weeks for four cycles in chemonaive patients with advanced non-small cell lung carcinoma (NSCLC), followed by consolidation therapy with single-agent oral vinorelbine in non-progressive patients. METHODS Chemonaive advanced NSCLC patients received four cycles of combination therapy with CBDCA AUC 5 day 1 and oral vinorelbine, 60 mg/m2 on days 1, 8 and 15 (cycle 1), dose increased to 80 mg/m2 (cycles 2-4) in absence of grades 3-4 neutropenia (NCI-CTCv2). Consolidation therapy with oral vinorelbine was continued (cycle 5) at same dosage; if dose was decreased during combination therapy, it was given at 60 mg/m2, then increased at 80 mg/m2 (cycle 6) in absence of grades 3-4 neutropenia until PD, toxicity or patients refusal. RESULTS A total of 57 patients were registered and 56 patients were treated (ITT population), median age was 61 years (37-71). Objective response evaluated by RECIST was 17.9% (95% confidence interval, CI [8.9-30.4]) and disease control (CR, PR, NC) 73.2% (95% CI [59.7-84.2]), median progression-free survival 4.3 months (95% CI [3.1-5.1]) with median overall survival 9.7 months (95% CI [7.7-11.9]) and 1-year survival 37.1% (95% CI [24.4, 49.9]). Grades 3-4 neutropenia occurred in 67.9% of patients during combination and 20% during consolidation; febrile neutropenia occurred in 4 patients (7.1%) during combination therapy. Non-hematological toxicities occurred primarily during combination (grade 3 nausea and grade 3 vomiting in 7.1% of patients). CONCLUSIONS The combination of oral vinorelbine given weekly in 3-week cycles in combination with carboplatin followed by consolidation therapy with oral vinorelbine as a single-agent was able to achieve efficacy results in line with other doublets including carboplatin in terms of response as well as survival. This regimen reported a good profile of tolerability in the treatment of advanced NSCLC, allowing that this combination can be easily proposed for the palliative care of NSCLC patients where the advantages of carboplatin over cisplatin are still appreciated.

Phase II Trial of Gemcitabine-Carboplatin-Paclitaxel as Neoadjuvant Chemotherapy for Operable Non-small Cell Lung Cancer

Background: The aim of this single-arm phase II study was to evaluate the efficacy, feasibility, and safety of the gemcitabine-carboplatin-paclitaxel combination as neoadjuvant chemotherapy in patients with operable non-small cell lung cancer (NSCLC). Methods: Patients with stage IB, II, or IIIA NSCLC were given three cycles of chemotherapy followed by tumor resection. Each 21-day cycle consisted of gemcitabine 1000 mg/m2 on days 1 and 8, carboplatin AUC 5 on day 1, and paclitaxel 175 mg/m2 on day 1. Results: Forty-four patients were enrolled: 18.2% of patients had stage IB, 15.9% had stage II, and 65.9% had stage IIIA NSCLC. All patients received three cycles of treatment. The clinical tumor response rate was 76.2% (32 of 42 patients; 95% CI, 60.5–87.9%). Thirty-six patients had a complete tumor resection, five of whom had a complete pathological response with no viable tumor cells in the resected tumor on histological examination. Median time to progression was 13.6 months (95% CI, 8.9, >16 months), and 26 of 44 patients (59.1%) had progressed. The 1-year disease-free survival rate was 53.6% (95% CI, 38.7–68.5%), and the 1-year survival rate was 86.0% (95% CI, 75.7–96.4%). Grade 3 and 4 neutropenia each occurred in 38.6% of patients, and grade 3 infection occurred in 2.3% of patients; grade 3 and 4 thrombocytopenia occurred in 25.0% and 0% of patients, respectively. Conclusion: The gemcitabine-carboplatin-paclitaxel combination showed promising efficacy and seemed to be safe and feasible as neoadjuvant chemotherapy in patients with operable-stage NSCLC.

Docetaxel as neo-adjuvant therapy for radically treatable stage III non-small cell lung cancer: early results of an international phase III study

During the last decade, neo-adjuvant chemotherapy has shown the potential to improve the survival of patients with stage III non-small cell lung cancer (NSCLC) [1–3]. A meta-analysis performed by the Non-small Cell Lung Cancer Collaborative Group has demonstrated a small survival advantage for patients who had received cisplatin-based neo-adjuvant therapy before definitive radical radiotherapy [4]. In this analysis, neo-adjuvant therapy was associated with a 13% reduction in mortality and a 5% increase in 5-year survival. There is a clear rationale for using neo-adjuvant chemotherapy before definitive local treatment of NSCLC by improving delivery of the chemotherapeutic agent to the tumour site through an intact blood supply that has not been disrupted by prior surgery or radiotherapy. Initially unresectable tumours may be transformed into operable ones, and the frequent occult extra-thoracic micrometastases in patients with stage III NSCLC may be eradicated. This approach may also reduce the extent of surgical resection and improve the degree of local control achieved with radiotherapy. The significant toxicity associated with cisplatin has led to the evaluation of other agents, including docetaxel, for the neo-adjuvant treatment of NSCLC. Single-agent docetaxel has been shown to be active in NSCLC. Four phase II trials, involving a total of 180 patients with advanced or metastatic NSCLC, have demonstrated that first-line therapy with docetaxel is associated with an objective overall response rate of 30% and a median overall survival of 9 months [5–8]. Docetaxel is one of the several chemotherapeutic agents that have recently received approval, in the USA and Europe, for second-line treatment of locally advanced or metastatic NSCLC. In view of its encouraging activity in advanced NSCLC, docetaxel is currently being investigated in the neo-adjuvant setting.

Overt hypoadrenalism is uncommon in patients with stage 3 and 4 bronchogenic carcinoma

INTRODUCTION Lung cancer is the leading cause of cancer mortality in most countries. The adrenal glands are common sites of metastatic lung cancer as approximately 40% of subjects with stage 4 bronchogenic carcinoma have adrenal metastases. The prevalence of biochemical hypoadrenalism is, however, remarkably poorly documented. OBJECTIVES Our study aimed to determine the prevalence of primary hypoadrenalism, as defined by a subnormal cortisol response to the 250 micrograms adrenocorticotrophic hormone (ACTH) stimulation test, in patients with stage 3 and 4 lung cancer. METHODS Thirty patients with stage 3 and 4 bronchogenic carcinoma were prospectively recruited from the bronchus clinic. Demographic data and electrolytes were recorded and each patient had a 250 micrograms ACTH stimulation test to determine the prevalence of overt adrenal insufficiency, defined as a +30 minute cortisol of less than 550 nmol/l. RESULTS The median age and quartile deviation was 62 (10) years and the median basal cortisol was 429.5 (321) nmol/l. The median peak cortisol was 828.5 (342) nmol/l (range 536-1,675 nmol/l). Twenty-eight patients (93.3%) had an appropriate rise of cortisol to greater than 550 nmol/l following 250 micrograms ACTH stimulation. Two patients (6.7%) had mild primary adrenal failure with a peak cortisol between 500 and 550 nmol/l associated with a raised plasma ACTH concentration (131.4 and 10.5 pmol/l, normal 2.2-10 pmol/l). Twenty-eight patients (92.9%) were normonatraemic, while the two hyponatraemic patients had biochemical evidence of the syndrome of inappropriate antidiuretic hormone secretion. CONCLUSION In conclusion, despite evidence that the adrenal glands of patients with disseminated bronchogenic carcinoma are frequently affected by metastatic disease, biochemical evidence of clinically significant hypoadrenalism is relatively uncommon and is not accurately predicted by electrolyte abnormalities.

Concurrent radiation and weekly cisplatin for non-small-cell lung cancer-a phase I/II study

SummaryA total of 20 patients with loco-regional nonsmall-cell lung carcinoma wereentered into a study of irradiation (3.0 Gy×15 doses to a total dose of 45 Gy given in 4 fractions per week on days 1, 2, 4 and 5 of each week) and cisplatin given at a dose of 40 mg/m2 on day 3 of each week for a total of three infusions. One patient who had stage 1 disease showed a complete response to therapy and is alive and clear of disease at 35 months. In 19 patients with stage 3 disease, the complete response rate was 16% and the partial response rate was 42%. The rate of 1-year survival was 42% and the rate of 2-year survival was 11%; the median survival of these patients was 11 months. Relapse occurred, mostly at metastatic sites, in 10 of the 11 patients who responded to therapy. Acute toxicity was modest and tolerable by our patients. No severe late toxicity was encountered, and none of the patients developed grade 3 dyspnoea (an inability to walk 100 yards because of breathlessness) while clear of recurrent disease. Changes in lung function observed at follow-up examinations were similar to those seen after irradiation alone. Weekly administration of cisplatin is therefore feasible in patients receiving a continuous course of irradiation. The high relapse rate observed in responding patients indicates the need for evaluation of the efficacy of combination chemotherapy in the adjuvant or neo-adjuvant setting.

Randomized phase II studies and their ethics.

TO THE EDITOR: Randomized phase II studies are being conducted more frequently and have recently been reviewed from a scientific perspective. These reviews of these important studies need to be complemented by some of the associated ethical considerations. Randomized phase II studies have come into being with two different aims. Randomization may be between different experimental arms so as to efficiently identify the most promising experimental treatments for further phase III study. Alternatively, a control group may be included to address some of the problems associated with a comparison to historical controls caused by selection bias. In practice however, there is overlap in the conduct and interpretation of different approaches to phase II studies, as well as phase III trials. Data on survival or other indicators of patient benefit are collected and statistical comparisons made, despite the fact that most randomized phase II studies are not powered to demonstrate statistically significant differences. This is valid provided that the prospectively defined comparative scale (eg, hazard ratio or odds ratio) and population (eg, all randomized patients) are still used, even if the power on that scale was low. These comparative statistics, along with their confidence intervals, then provide unbiased estimates of treatment effects and are, in fact, more appropriate than within-arm summary statistics, such as median survival or response. Indeed, statisticians generally argue that trials must stress comparisons. Low power is irrelevant to validity, and indeed should significant differences be found, they will not and should not be ignored. It is noted that comparative statistical analyses are not in themselves unbiased and may be biased when they are the best of several secondary and/or different comparative analyses. Ethical codes and good clinical practice guides do not differentiate between phase II and III studies. Ethical guidelines, which have been applied routinely in phase III trials, need to be considered when conducting a randomized phase II study. These ethical questions are in the realm of good science and differ from the concerns expressed at misinterpretation or over interpretation of phase II studies, as cited in a recent journal editorial. The nature of a possible control arm needs to be clarified in randomized phase II studies. Article 29 of the Helsinki Declaration of 2004 states, “The benefits, risks, burdens and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.” This requires careful attention with designs that do not include the current standard of care as a treatment arm, particularly when an unequivocal commitment to evaluate encouraging findings with a phase III trial cannot be made. In addition, the well known ethical commitment to patient care at the conclusion of a clinical study holds for all studies. Patients should have access to the best proven therapeutic methods identified by the study (Helsinki Declaration, article 30).