Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: satellite--a phase II study from the Swedish Lung Cancer Study Group.

BACKGROUND: Several attempts to increase the locoregional control in locally advanced lung cancer including concurrent chemotherapy, accelerated fractionation and dose escalation have been made during the last years. As the EGFR directed antibody cetuximab has shown activity concurrent with radiotherapy in squamous cell carcinoma of the head and neck, as well as in stage IV NSCLC combined with chemotherapy, we wanted to investigate radiotherapy with concurrent cetuximab in locally advanced NSCLC, a tumour type often over expressing the EGF-receptor. METHODS: Between February 2006 and August 2007 75 patients in stage III NSCLC with good performance status (PS 0 or 1) and adequate lung function (FEV1>1.0) were enrolled in this phase II study at eight institutions. Treatment consisted of 2 cycles of induction chemotherapy, docetaxel 75 mg/m² and cisplatin 75 mg/m² with 3 weeks interval. An initial dose of cetuximab 400 mg/m² was given before start of 3D-CRT to 68 Gy with 2 Gy per fraction in 7 weeks concurrent with weekly cetuximab 250 mg/m². TOXICITY was scored weekly during radiotherapy (CTC 3.0), and after treatment the patients were followed every third month with CT-scans, toxicity scoring and QLQ. RESULTS: Seventy-one patients were eligible for analysis as four were incorrectly enrolled. HISTOLOGY: adenocarcinoma 49%, squamous cell carcinoma 39% and other NSCLC 12%. The majority had PS 0 (62.5%), median age 62.2 (42-81), 50% were women and 37% had a pre-treatment weight loss>5%. TOXICITY: esophagitis grade 1-2: 72%; grade 3: 1.4%. Hypersensitivity reactions grade 3-4: 5.6%. Febrile neutropenia grade 3-4: 15.4%. Skin reactions grade 1-2: 74%; grade 3: 4.2%. Diarrhoea grade 1-2: 38%; grade 3: 11.3%. Pneumonitis grade 1-2: 26.8%; grade 3: 4.2%; grade 5: 1.4%. The median follow-up was 39 months for patients alive and the median survival was 17 months with a 1-, 2- and 3-year OS of 66%, 37% and 29% respectively. Until now local or regional failure has occurred in 20 patients and 22 patients have developed distant metastases. Weight loss, PS and stage were predictive for survival in univariate as well as in multivariate analysis. CONCLUSION: Induction chemotherapy followed by concurrent cetuximab and RT to 68 Gy is clearly feasible with promising survival. TOXICITY, e.g. pneumonitis and esophagitis is low compared to most schedules with concurrent chemotherapy. This treatment strategy should be evaluated in a randomised manner vs. concurrent chemoradiotherapy to find out if it is a valid treatment option.

How to improve loco-regional control in stages IIIa-b NSCLC? Results of a three-armed randomized trial from the Swedish Lung Cancer Study Group.

BACKGROUND: A combination of chemotherapy and radiotherapy is the treatment base for locally advanced non-small cell lung cancer (NSCLC). However, both loco-regional and distant failure is frequent. Attempts to improve the loco-regional control were made in three separate phase II studies in Swedish University Hospitals, where accelerated radiotherapy or concurrent daily or weekly chemotherapy with conventional radiotherapy were tested. Comparatively good results from these studies lead to this national randomized phase II study, the RAKET-study, where the different concepts were investigated on a wider basis for further phase III studies. METHODS: Inoperable stage III non-small cell lung cancer patients in good performance status (PS<2) were equally randomized to either of three arms in eight institutions. All arms started with two cycles of induction chemotherapy: paclitaxel 200 mg/m2 and carboplatin AUC6. Arm A: a third identical cycle was given concomitant with start of accelerated radiotherapy, 1.7 Gy BID to 64.6 Gy in 4.5 weeks. Arm B consisted of daily concomitant paclitaxel 12 mg/m2 with conventionally fractionated radiotherapy: 2 Gy to 60 Gy in 6 weeks. Arm C: weekly concomitant paclitaxel 60 mg/m2 and identical radiotherapy to 60 Gy. Primary endpoint: TTP. Secondary: OS, toxicity, QL and relapse pattern. RESULTS: Between June 2002 and May 2005 152 patients were randomized and of them 151 were evaluable: 78 men and 73 women, median age 62 years (43-78), 55% had performance status 0 and 45% PS 1. Thirty-four percent had stage IIIa and 66% IIIb. HISTOLOGY: adenocarcinoma 48%, squamous cell carcinoma 32% and 20% non-small cell carcinoma. The three arms were well balanced. Toxicity was manageable with 12% grades 3-4 esophagitis, 1% grades 3-4 pneumonitis and there was no clear difference between the arms. The QL data did not differ either. Median time to progression was 9.8 (8.3-12.7) months (8.8, 10.3 and 9.3 months for arms A, B and C, respectively). Median survival was 17.8 (14.4-23.7) months (17.7, 17.7 and 20.6 months for A, B and C, respectively). The 1-, 3- and 5-year overall survival was 63, 31 and 24%. Sixty-nine percent of the patients relapsed with distant metastases initially and 31% had loco-regional tumor progression, without significant differences between treatment arms. Thirty-four percent developed brain metastases. CONCLUSIONS: Treatment results are quite equal by intensifying the loco-regional treatment either by accelerated fractionated radiotherapy or daily or weekly concomitant chemo-radiotherapy both in terms of survival, toxicity and quality of life. The optimal treatment schedule for patients with locally advanced NSCLC is still to be decided and investigated in future clinical studies. Relapse pattern with distant metastases and especially brain metastases is a great problem and need further research for better therapy options and higher cure rate for this patient group.

Single-agent gemcitabine: an active and better tolerated alternative to standard cisplatin-based chemotherapy in locally advanced or metastatic non-small cell lung cancer.

This randomized study was designed to determine the response rates, survival and toxicities of single-agent gemcitabine (GEMZAR) and a combination of cisplatin/etoposide in chemonaive patients with non-resectable, locally advanced or metastatic non-small cell lung cancer (NSCLC). Gemcitabine 1000 mg/m2 was given as a 30-min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin 100 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 (following cisplatin), 2 and 3. Major eligibility criteria included histologically confirmed non-small cell lung cancer, measurable disease, Zubrod performance status 0-2, no prior chemotherapy, no prior radiation of the measured lesion, and no CNS metastases. One hundred and forty-seven patients were enrolled, 72 in the gemcitabine and 75 in the cisplatin/etoposide arm. Patient characteristics were well-matched across both arms. Sixty-seven gemcitabine and 72 cisplatin/etoposide patients were qualified for efficacy analysis. There were no complete responses, but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response but 12 partial responses in the gemcitabine arm and 11 in the cisplatin/etoposide arm, for protocol-qualified response rates of 17.9% (95%, CI: 9.6-29.2%,) and 15.3% (95% CI: 7.9-25.7%,), respectively. Median survival times were 6.6 months (95% CI: 4.9-7.3 months) for gemcitabine and 7.6 months (95% CI: 5.4-9.3 months) for cisplatin/etoposide. The 1-year survival probability estimate was 26% for gemcitabine and 24% for cisplatin/etoposide. There were no statistically significant between-group differences in time-to-event measures, but patients in the gemcitabine arm had a greater probability of achieving a tumour response after 2 months (probability estimate: 8 vs. 0%,) and of the response lasting at least 6 months (73 vs. 45%,). Clinical and haematologic toxicity was more pronounced in the cisplatin/etoposide arm. Quality-of-life measures indicated a significant worsening of symptomatology in the cisplatin/etoposide arm for hair loss, nausea and vomiting, and appetite loss. This randomized study provides further evidence that single-agent gemcitabine is an active and effective therapy for patients with non-resectable. locally advanced or metastatic NSCLC and good performance status, and that it is better tolerated than the combination cisplatin/ etoposide.

Treatment with paclitaxel 1-h infusion and carboplatin of patients with advanced non-small-cell lung cancer: a phase II multicentre trial. Joint Lung Cancer Study Group.

The primary aim of this phase II study was to determine the response rate of a combination of paclitaxel and carboplatin in advanced non-small cell lung cancer (NSCLC) in a multicentre setting. The secondary aim was to determine time to progression (TTP), 1-year survival rate and toxicity. 65 patients were treated and all of them were included in the follow up for survival and toxicity. 60 patients were followed for response rate and time to progression. 55% were stage IV patients and 45% stage IIIB patients. The treatment consisted of paclitaxel 200 mg/m2 given as a 1-h i.v. infusion and carboplatin given as a 30 min i.v. infusion and the latter was dosed by using the Calvert formula at an area under the concentration time curve (AUC) of 5. The glomerular filtration rate (GFR) was determined by iohexol clearance and was not calculated from the serum creatinine level. The chemotherapy courses were given every third week with a maximum number of six or eight courses for patients who responded late. As premedication we used 8 mg betamethasone 40 min prior to infusion and then 10 min later clemastin and cimetidine. One complete response and 18 partial responses were seen giving a response rate of 29%. 40% of the patients progressed during the treatment and 28% had stable disease. The median TTP was 22 weeks. At a minimum follow up of 1 year, the 1-year survival rate was 38% and the median survival rate was 41 weeks. Haematological toxicity was mild with no grade 4 leucopenia and only seven patients (11%) had grade 3 leucopenia. There was no grade 4 toxicity. Grade 3 toxicity was seen as myalgia 5%, allergic reaction 3% and peripheral neuropathy 6%. 15% of the patients had a dose reduction due to neurotoxicity. The haematological toxicity was much milder than we expected, probably because of more exact determination of the GFR. This trial confirms the results of earlier reported trials of the efficacy and the ease of the regimen as an out-patient treatment option in advanced NSCLC. The main problem with this treatment is peripheral neuropathy.

Single-agent gemcitabine versus cisplatin-etoposide: early results of a randomised phase II study in locally advanced or metastatic non-small-cell lung cancer.

BACKGROUND: This randomised study was designed to determine the response rate survival and toxicity of single-agent gemcitabine and cisplatin-etoposide in chemo-naïve patients with locally advanced or metastatic non-small-cell lung cancer. PATIENTS AND METHODS: Gemcitabine 1,000 mg/m2 was given as a 30 min intravenous infusion on days 1, 8, 15 of a 28-day cycle, cisplatin 100 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1 (following cisplatin), 2 and 3. Major eligibility criteria included histologically confirmed non-small-cell lung cancer, measurable disease, Zubrod PS 0-2; no prior chemotherapy, no prior radiation of the measured lesion, and no CNS metastases. RESULTS: 146 patients were enrolled, 71 patients on gemcitabine and 75 patients on cisplatin-etoposide. Patient characteristics were well matched across both arms. Sixty-six gemcitabine patients and 72 cisplatin-etoposide patients were evaluable. Partial responses were seen in 12 gemcitabine patients (18.2%; 95% CI: 9.8-30) and 11 cisplatin-etoposide patients (15.3%; 95% CI: 7.9-25.7). Early indications show no statistical differences between the two treatments with respect to time to disease progression or survival. Haematological and laboratory toxicity were moderate and manageable. However, hospitalisation because of neutropenic fever was required for 6 (8%) cisplatin-etoposide patients but not for any gemcitabine patients. Non-haematological toxicity was more pronounced with significant differences in nausea and vomiting (grade 3 and 4: 11% gemcitabine vs. 29% cisplatin-etoposide; despite the allowance for 5-HT3 antiemetics during the first cycle of cisplatin-etoposide), and alopecia (grade 3 and 4:3% gemcitabine vs. 62% cisplatin-etoposide). CONCLUSIONS: In this randomised study, single-agent gemcitabine was at least as active but better tolerated than the combination cisplatin-etoposide.

A randomized study of gemcitabine monotherapy versus etoposide/cisplatin in the treatment of locally advanced or metastatic non-small cell lung cancer.

This randomized, multinational, multicenter study was designed to determine the response rate of gemcitabine monotherapy and cisplatin/etoposide combination therapy in chemotherapy-naive patients with advanced, recurrent, and/or metastatic non-small cell lung cancer (stage IIIA [if inoperable], IIIB, or IV). One group of patients received gemcitabine 1,000 mg/m2 intravenously once a week for 3 weeks (days 1, 8, and 15) followed by a 1-week rest period. The second group received cisplatin 100 mg/m2 intravenously on day 1 of each 28-day cycle in combination with etoposide 100 mg/m2, administered on days 1, 2, and 3 following the cisplatin infusion. Each patient was allowed to remain on study up to a maximum of six cycles. The planned interim analysis was based on the 117 patients in the study, 116 of whom were randomized up until November 20, 1995. The efficacy analysis was performed on the 107 patients who had data from a minimum of two cycles, whereas the safety analysis was based on data from all 116 randomized patients. In the gemcitabine arm there were 10 of 52 (19%) partial responders; in the cisplatin/etoposide arm there were four (7%) of 54 partial responders. There was a statistically significant difference in the response rates between the two arms, with a 95% confidence interval of 0.6% to 32.1% (P = .040). The median time to progressive disease was 4.2 months for gemcitabine patients and 3.7 months for cisplatin/etoposide patients. There was significantly more alopecia and nausea and vomiting in the cisplatin/etoposide arm compared with the gemcitabine arm, as well as two cases of neutropenic sepsis in the cisplatin/etoposide arm. These data indicate that single-agent gemcitabine is at least as effective as the combination of cisplatin/etoposide in the treatment of advanced non-small cell lung cancer and has an improved safety profile.

Fas receptor is expressed in human lung squamous cell carcinomas, whereas bcl-2 and apoptosis are not pronounced: a preliminary report.

We report a pilot study on the Fas receptor (APO-1, CD95) in vivo in 15 human squamous cell (non-small) carcinomas and ten normal bronchial specimens. The principal aim was to investigate whether the so-called death receptor, Fas, is present in these tumours. Ligation of Fas promptly induces apoptosis, particularly in T Jurkat cells in vitro, and expression of Fas on human cancer would thus theoretically be of great interest. The immunoreactivity for the anti-apoptotic protein Bcl-2 was also investigated, and the degree of apoptosis was evaluated by TdT dUTP nick end labelling (TUNEL) and conventional morphological criteria. Fas was present in all initial tumours but absent in control tissue, that is in the potential precursor cells of bronchial epithelium (P = 0.001). Fas was not detectable after radiotherapy (P = 0.03). We propose that radiotherapy induces an early selection of tumour cells rather than a down-regulation of Fas. Both Bcl-2 and apoptosis (TUNEL) were generally expressed at a modest level. In agreement with other studies, we did not find any significant correlation between Bcl-2 and prognosis, or between Bcl-2 and TUNEL. Hence, in this preliminary report, we have demonstrated Fas receptor in human squamous cell carcinomas in vivo. This is a novel finding, and the apparent absence of Fas after radiotherapy may have important therapeutic implications.

A new diagnostic approach to the patient with severe pneumonia.

36 patients with severe community-acquired pneumonia, treated in an intensive care unit (ICU), were examined in a prospective study using a comprehensive diagnostic program to establish an early etiological diagnosis. The resulting prompt and adequate antimicrobial therapy may have decreased the number of fatal cases. Special emphasis was placed on the use of a method incorporating fiberoptic bronchoscopy, together with protected brush sampling and bronchial lavage. An etiological diagnosis was established in 81% (29/36) of the cases. This etiological diagnosis was established within 48-72 h in 53% (19/36) of the patients, S. pneumoniae being the most frequent agent found (12 patients). This information, however, was poorly utilized since in only 11/19 of these patients was the antimicrobial therapy changed from a broad-spectrum antibiotic to a more specific narrow spectrum agent. The overall mortality rate was 22% (8/36). 7/8 patients who died had compromising factors. Most deaths in community-acquired pneumonia are still associated with pneumococcal infection. We conclude that fiberoptic bronchoscopy with brush samples via a plugged double lumen catheter provides the least misleading information concerning the etiological agent in pneumonia; sampling should be done as soon as possible after admission to the hospital, ideally before the need for ICU treatment; factors other than prompt antimicrobial therapy may influence the outcome of severe community-acquired pneumonia.

The snuff-induced lesion. A clinical and morphological study of a Swedish material.

Snuff-induced oral lesions were studied clinically, histologically and by electron microscopy. The material was collected from 21 male snuff users. The lesions had a characteristic whitish appearance with a wrinkled swollen texture and the most common localization was in the vestibular area of the upper jaw. In two cases gingival retraction was observed. The light-microscopical examination showed a mild epithelial dysplasia in five cases. No carcinoma in situ or invasive carcinoma was recognized. In some of the cases ultrastructural changes in the basement lamina region, such as defects of the basement lamina and the occurrence of basal cell processes in the connective tissue, were observed. Odland bodies were seen in the epithelium. In the connective tissue filamentous material of unknown nature was found. The ultrastructure of the filamentous material suggested that it might be amyloid. In summary, snuff-induced lesions should be diagnosed, patients should be informed and made to quit the habit, and remaining lesions should be followed up regularly.