Phase II study of 4′-deoxydoxorubicin in advanced colorectal cancer

Summary Thirty-three patients with advanced colorectal cancer were entered on a phase II study of 4'-deoxy-doxorubicin (esorubicin) (30–35 mg/m² q 3 weekly). Objective response was documented in 4 of 25 previously untreated patients and in none of 8 previously treated patients. Toxicity was acceptable with grade 3 or 4 leukopenia occurring in 8 patients. Complete alopecia occurred only in 4 patients and gastro-intestinal toxicity was mild. A significant decrease (> 10%) of the left ventricular ejection fraction occurred in 8/23 patients who received > 2 courses of treatment.     

Phase II trial of 4′-epi-doxorubicin in metastatic colorectal carcinoma

Summary Twenty-three patients with metastatic colorectal carcinoma were treated with 4-epi-doxorubicin (Epirubicin, 4-epi-DX) 90 mg/m² i.v. every 4 weeks. Out of 18 patients evaluable for response, 11 were previously untreated. One complete response of 21 + months was observed in a patient with rectosigmoid carcinoma. Furthermore there was one minor response in pretreated rectosigmoid series, and 6 patients had stabilization of disease. Median survival for all patients, including early deaths, was 4 months. For patients who were not pretreated and who received at least 2 cycles of therapy, median survival was 15 months. Further studies in patients with rectosigmoid carcinoma are warranted.     

Inhibition of NO synthase induction by an anticancer drug 4′-epi-doxorubicin in rats

• 1.1. Nitric oxide (NO) plays various physiological roles in tumour tissues. Herein, we examined the effects of an anticancer drug 4′-epi-doxorubicin on NO synthase and the related responses in rat thoracic aorta, rat cerebellum and lung homogenates.
• 2.2. Treatment with an anticancer drug 4′-epi-doxorubicin in vitro or in vivo had little effect on the relaxation response to acetylcholine or nitroprusside in rat thoracic aorta.
• 3.3. Treatment with 4′-epi-doxorubicin in vitro or in vivo did not alter the constitutive NO synthase activity of rat cerebellum ([³H]-citrulline production from [³H]-arginine).
• 4.4. After inducible NO synthase had been induced by lipopolysaccharide, 4′-epi-doxorubicin also neither affected the relaxation response to L-arginine in rat thoracic aorta nor the enzyme activity of rat lung.
• 5.5. Coincubation with lipopolysaccharide and 4′-epi-doxorubicin in vitro prevented the development of relaxation response to L-arginine in rat thoracic aorta. Pretreatment with 4′-epi-doxorubicin in vivo also prevented the induction of inducible NO synthase by lipopolysaccharide in rat thoracic aorta and lung.
• 6.6. These results suggest that 4′-epi-doxorubicin selectively inhibits the induction of NO synthase without affecting constitutive and inducible NO synthase activities. This effect was discussed in relation to the anticancer and side effects of the drug.

     

Phase Ⅱ trial of gemcitabine plus cisplatin in patients with advanced non-small cell lung cancer

Aim:

To investigate the pharmacodynamics and pharmacokinetics of gemcitabine (dFdC) administered on d 1 and 5 plus cisplatin administered on d 1 in chemonaive patients with stage IIIB or IV non-small cell lung cancer (NSCLC).

Methods:

In each combination cycle, gemcitabine was administered at a dose of 1250 mg/m² as a 30 min intravenous (iv) infusion on d 1 and 5 followed by cisplatin at a dose of 75 mg/m² as a 3 h iv infusion on d 1 every 3 weeks. There was an interval of 1 h between the two infusions. Clinical response and toxicity of the regimen were observed. Furthermore, the plasma concentrations of gemcitabine (dFdC) and its metabolite (dFdU) at different time points were detected during the first cycle of infusion. Pharmacokinetic software (PKS) was used to estimate the pharmacokinetic parameters of gemcitabine and its metabolite dFdU.

Results:

A total of 28 patients was enrolled in the study. The median age was 54 years (range 27–75 years), and most patients were in good clinical condition. Twenty-seven patients received two or more treatment cycles. The overall clinical response rate was 33.3%. The median overall survival time was 13 months. The estimated median time to tumor progression (TTP) was 6.2 months, and the 1-year survival rate was 55.6%. Toxicities were tolerated. The main toxicity was myelosuppression; 35.7% of patients had grade 3/4 hematologic toxicities and 28.6% had grade 3/4 non-hematologic toxicities, which were commonly gastrointestinal responses. The pharmacokinetic parameters of dFdC and dFdU were not different between pre- and post-administration of gemcitabine on d 1 and 5. dFdU was minimal (0.729±0.637 μg/mL) before gemcitabine was infused on d 5, and gemcitabine was not present.

Conclusion:

The regimen is active and well tolerated in chemonaive patients with advanced NSCLC. After gemcitabine was administered on d 1 and 5, the pharmacokinetic parameters of dFdC and dFdU showed no difference from those before the infusion, and dFdU was minimal before gemcitabine was administered on d 5.     

Paclitaxel: a hope for advanced non-small cell lung cancer?

Recent studies have shown that paclitaxel (Taxol); Bristol-Myers Squibb Co., Princeton, NJ) is an active agent in the treatment of advanced non-small cell lung cancer (NSCLC). Early trials in patients with advanced NSCLC utilised a 24 h infusion schedule and reported objective tumour responses in 21 - 24% of patients. Shorter infusion schedules have equivalent efficacy, and combined results from 14 separate trials of single agent paclitaxel in advanced NSCLC show an overall tumour response rate of 26%. Alternative schedules of paclitaxel from the traditional regimen every three weeks are under active investigation, but it is premature to assess whether these will yield improved efficacy for patients with advanced NSCLC. A single multicentre randomised trial of paclitaxel versus best supportive care in advanced NSCLC showed a significant survival advantage for the chemotherapy arm. Two large randomised Phase III trials have shown that paclitaxel and cisplatin is modestly more effective than cisplatin and podophyllotoxin combinations. The addition of cisplatin or carboplatin to paclitaxel results in higher response rates than for each of the drugs as single agents, but it is unclear whether the combinations yield superior survival or quality of life compared to single agent paclitaxel, or to other paclitaxel-containing regimens.     

Phase II trial of esorubicin (4′deoxydoxorubicin,DxDx) in patients with small cell lung cancer

Summary Esorubicin (4-deoxydoxorubicin or DxDx) is an analog of doxorubicin with preclinical antitumor activity and no significant cardiotoxicity in model systems. Eleven patients with small cell lung cancer who had previously received chemotherapy were given esorubicin (25 mg/m² intravenously) every 3 weeks. No major objective responses were observed (95% confidence limits: 0–25%). Nine of the 11 patients had grade 2 or greater toxicity, with 55% of the patients experiencing grade 3 or greater toxicity [myelosuppression (4/11), anemia (2/11) or elevated liver enzymes (3/11)]. Nausea, vomiting, alopecia and intravenous site phlebitis were also seen. Three of the 11 patients received 3 or more course of esorubicin without evidence of significant cardiotoxicity. At this dose and shedule, no significant antitumor response were seen in this population of patients. Esorubicin, with this low response rate and significant toxicity, appears to be of limited utility in this disease.     

A phase II trial of oral 4′ demethoxydaunorubicin (DMDR) in inoperable non small cell lung cancer

Summary 4 Demethoxydaunorubicin, an orally active daunorubicin analogue, was administered to 22 patients with inoperable non small cell lung cancer (NSCLC). Patients were stratified into good and poor risk categories and received doses of 45 mg/m² and 40 mg/m² respectively at 28 day intervals. All 22 patients were evaluable for response: No tumour responses occurred. Therapy was well tolerated. Mild gastrointestinal toxicity occurred in 41% of patients. Leucopenia with a wcc < 3 × 10⁹/L occurred in 33% of patients and thrombocytopenia < 100 × 10⁹/L in 9%. Severe marrow toxicity was rare and there appeared to be no difference in terms of toxicity between the different dose levels. DMDR appears to have no useful clinical activity in NSCLC.     

Resveratrol analogue 3,4,4′-trihydroxy-trans-stilbene induces apoptosis and autophagy in human non-small-cell lung cancer cells in vitro

Aim:

To investigate the effects of 3,4,4′-trihydroxy-trans-stilbene (3,4,4′-THS), an analogue of resveratrol, on human non-small-cell lung cancer (NSCLC) cells in vitro.

Methods:

Cell viability of NSCLC A549 cells was determined by MTT assay. Cell apoptosis was evaluated using flow cytometry and TUNEL assay. Cell necrosis was evaluated with LDH assay. The expression of apoptosis- or autophagy-associated proteins was measured using Western blotting. The formation of acidic compartments was detected using AO staining, neutral red staining and Lysotracker-Red staining. LC3 punctae were analyzed with fluorescence microscopy.

Results:

Treatment with 3,4,4′-THS (10-80 μmol/L) concentration-dependently inhibited the cell viability. It did not cause cell necrosis, but induced apoptosis accompanied by up-regulation of cleavaged PARP, caspase3/9 and Bax, and by down-regulation of Bcl-2 and surviving. It also increased the formation of acidic compartments, LC3-II accumulation and GFP-LC3 labeled autophagosomes in the cells. It inhibited the mTOR-dependent pathway, but did not impair autophagic flux. 3,4,4′-THS-induced cell death was enhanced by the autophagy inhibitors 3-MA (5 mmol/L) or Wortmannin (2 μmol/L). Moreover, 3,4,4′-THS treatment elevated the ROS levels in the cells, and co-treatment with 3-MA further elevated the ROS levels. 3,4,4′-THS-induced apoptosis and autophagy in the cells was attenuated by NAC (10 mmol/L)

Conclusion:

3,4,4′-THS induces both apoptosis and autophagy in NSCLC A549 cells in vitro. Autophagy inhibitors promote 3,4,4′-THS-induced apoptosis of A549 cells, thus combination of 3,4,4′-THS and autophagy inhibitor provides a promising strategy for NSCLC treatment.     

Patients with advanced lung cancer: is there scope to discontinue inappropriate medication?

Background Polypharmacy—taking five or medications per day—is common in lung cancer patients. This patient group is prescribed medication to control acute symptoms associated with cancer and also to prevent or treat other long-term conditions. These medications increase the pill burden for the patient and also the probability of developing a drug-related toxicity. Objective To assess the prevalence of inappropriate medication in patients taking erlotinib for the treatment of advanced non-small cell lung cancer. Method This was a multicentre study across three sites in the North of England. Medication histories for patients receiving erlotinib were retrospectively extracted from medical notes and assessed by the clinical team (a consultant pharmacist, nurse specialist and clinical oncologist) to determine if the medication was appropriate or inappropriate. The clinical team considered the following factors when deciding if the medication was appropriate or inappropriate: remaining life expectancy of the patient, time until benefit of the treatment, goals of care and treatment targets. Results Among the 20 patients assessed, 19 (95 %) according to the clinical team were taking medications that were inappropriate. The mean number of medications the patients were taking was 8 (range 1–16) and the most common class of medication used were drugs affecting the Central Nervous System. In addition, there were 11 patients (55 %) who were taking erlotinib in combination with a proton pump inhibitor (PPI)—a clinically significant drug interaction that impairs the absorption of erlotinib. Conclusions Patients taking erlotinib for the treatment of advanced non-small cell lung cancer take many inappropriate medications for the treatment or prevention of long-term conditions. These patients should have their medications reviewed in the context of their original therapeutic goals.     

Phase II study of docetaxel alternating with cisplatin in chemotherapy-naïve patients with advanced non-small cell lung cancer

The objective of this study was to evaluate a regimen of full doses of docetaxel and cisplatin, using an alternating schedule, as first-line therapy for patients with inoperable non-small cell lung cancer (NSCLC). The standard concomitant schedule does not allow full doses of both drugs to be administered. We wanted to see if there was an advantage to be gained by administering full doses of both docetaxel and cisplatin, using a different schedule. Docetaxel 100 mg/m2 was given once every 6 weeks from week 1 and cisplatin (120 mg/m2 for two doses and 100 mg/m2 thereafter) once every 6 weeks from week 4, for six cycles (three docetaxel and three cisplatin). Thirty-six of the 44 patients enrolled were evaluable for efficacy. Forty-eight percent of the patients had good (KPS 90-100%) performance status. A median of five cycles was administered, for which no dose reductions were necessary. There were 13 of 36 partial responses (36%; 95% CI 21-54%) and 15 of 36 patients achieved stable disease (42%). The median duration of response was 10.5 months, the median time to progression was 4.5 months and the median survival was 9 months. The 1 and 2 year survival rates were 39 and 16%, respectively. The most frequent grade 3-4 toxicities were nausea (23% of patients), vomiting (18%) and neutropenia (77%). Infections were also common, but not severe. The alternating schedule produced response, toxicity and survival figures that compared favorable with those using the concomitant schedule. This study could serve as a model for future studies of non-cisplatin-containing regimens, in which full doses of docetaxel could alternate with full doses of other new agents active against NSCLC.     

First-line bevacizumab,cisplatin and vinorelbine plus maintenance bevacizumab in advanced non-squamous non-small cell lung cancer chemo-naïve patients

Objective: The aim of this study was to evaluate efficacy and safety of first-line treatment with bevacizumab, cisplatin and vinorelbine and bevacizumab maintenance in non-squamous, non-small cell lung cancer (NSCLC).

Research design and methods: Forty-nine patients with stage IIIB plus pleural effusion or stage IV NSCLC were included in a Phase II clinical trial. Treatment consisted of 3-week cycles of bevacizumab (15 mg/kg on day 1), cisplatin (80 mg/m² on day 1) and vinorelbine (25 mg/m² on days 1 and 8). After 6 cycles, non-progressing patients received bevacizumab maintenance therapy. The primary end point was progression-free survival (PFS), calculated using the Kaplan–Meier method.

Results: Thirteen (29%) of 45 evaluable patients presented a partial response. PFS and overall survival were 6.0 months (95% confidence interval (CI) 4.5 – 7.5) and 14.7 months (95% CI 8.4 – 21), respectively. Fourteen patients (28%) experienced grade 3 – 4 neutropenia and 7 (14%) experienced febrile neutropenia during the combination treatment. During the maintenance phase, the most frequent grade 3 – 4 adverse event was hypertension. Neither grade 3 – 4 thrombocytopenia nor toxic death was observed.

Conclusions: The studied regimen achieved a similar efficacy to other regimens containing platinum doublets. The data provide further evidence that bevacizumab may be used in combination with multiple standard platinum-based doublets in this setting.     

The management of skin toxicity during erlotinib in advanced non-small cell lung cancer: how much does it cost?

Abstract

Introduction: The aim of this study is to estimate the costs for the foreseeable management of skin toxicity (papulo-pustular reactions) in patients treated with erlotinib for non-small cell lung cancer (NSCLC) in order to value the direct medical economical impact. No studies like the above have been published until now.

Materials and methods: We retrospectively analyzed all consecutive patients with NSCLC treated with erlotinib at Clinical Oncology Unit of University Hospital of Ferrara, Italy from June 2007 to May 2011. We evaluated severity and median duration of papulo-pustular reactions for each grade and we identified costs for the different therapeutic interventions.

Results: We evaluated 25 patients. Median time follow-up was 18.65 months (range 5.69–88.36). Finally, follow-up 7 patients (28.0%) were alive with metastases and 18 patients (72.0%) were deceased. Nineteen patients (76.0%) developed papulo-pustular reactions: 2 patients (10.5%) mild rash, 11 patients (57.9%) moderate rash and 6 patients (31.6%) severe rash; no case of hospitalization was observed. Median duration of mild rash was 97 days (costs-range: 157.7–452.2 €), median duration of moderate rash was 89 days (costs-range: 438.7–1035.6 €) and median duration of severe rash was 34 days (costs-range: 460.3–1057.2 €).

Conclusions: Our experience, though the analysis of not selected case study, showed that management of skin toxicities related to erlotinib is not so expensive, especially for low grade; therefore, we also recommended to give particular attention to low grade of toxicities for reducing progression to high grade and consequent risk of hospitalization, which really impact on costs.     

Tobacco smoke-induced lung cancer in animals--a challenge to toxicology (?)

Tobacco smoke is a known human carcinogen that primarily produces malignant lesions in the respiratory tract, although it also affects multiple other sites. A reliable and practical animal model of tobacco smoke-induced lung cancer would be helpful for in studies of product modification and chemoprevention. Over the years, many attempts to reproduce lung cancer in experimental animals exposed to tobacco smoke have been made, most often with negative or only marginally positive results. In hamsters, malignant lesions have been produced in the larynx, but not in the deeper lung. Female rats and female B6C3F1 mice, when exposed over lifetime to tobacco smoke, develop tumors in the nasal passages and also in the lung. Contrary to what is seen in human lung cancers, most rodent tumors are located peripherally and only about half of them show frank malignant features. Distant metastases are extremely rare. Male and female strain A mice exposed to 5 months to tobacco smoke and then kept for another 4 months in air respond to tobacco smoke with increased lung tumor multiplicities. However, the increase over background levels is comparatively small, making it difficult to detect significant differences when the effects of chemopreventive agents are evaluated. On the other hand, biomarkers of exposure and of effect as well as evaluation of putative carcinogenic mechanisms in rats and mice exposed to tobacco smoke allow detection of early events and their modification by different smoke types or chemopreventive agents. The challenge will be to make such data broadly acceptable and accepted in lieu of having to do more and more long term studies involving larger and larger number of animals.