Avid Bioservices Inc (CDMO)

[pharmboy21]

here is also some info concerning NSLC and its treatments from the BC Cancer Agency, which is recognized as one of the leading cancer institutes in North America

http://www.bccancer.bc.ca/HPI/CancerManagementGuidelines/Lung/6ManagementPolicies/641NonSmallCellLungCancer/14PalliativeChemotherapyofAdvancedNSCLC.htm

Palliative Chemotherapy of Advanced NSCLC




Updated February 2008


Guideline: There is evidence from meta-analyses of a small survival benefit of chemotherapy over best supportive care in performance status 0-2 NSCLC patients.1 If symptom control and quality-of-life are the outcomes of interest, chemotherapy appears to be of benefit based on randomized trials analyzing chemotherapy for this purpose.2-6 Chemotherapy is an option for palliative therapy of patients with NSCLC provided there is a full discussion of the benefits, limitations and toxicities of the treatment.

Level of Evidence: I (survival benefit), I (quality-of-life, symptom control)

Grade of Recommendation: A (survival), A (quality-of-life, symptoms)

Chemotherapy modestly improves median and one year survival in patients with distant metastatic NSCLC compared with best supportive care, but is not curative. The results of three recently published meta-analyses indicate that cisplatin-based chemotherapy yields an improvement in median survival of approximately 6 to 8 weeks in stage IV disease. One year survival improves from 10-15% to 25-35%. The evidence supporting chemotherapy is based on patients entered on clinical trials with good performance status and other selection criteria that may not be representative of typical clinical practice. Many recent randomized trials assessing aggressive regimens allow only patients with ECOG performance status of 0 and 1. Survival results of such trials appear superior to older trials but the patient populations are not comparable.

Patient Selection for Palliative Chemotherapy

Palliative chemotherapy patients should have performance status of ECOG 0, 1, or 2. Extensive previous radiotherapy is associated with increased chemotherapy toxicity and symptomatic disease within a previous radiotherapy volume may be less chemosensitive. Renal, hematologic and hepatic function must be adequate.

Active patient participation in decision-making is crucial. Outcome measurements should reflect more than just the selected disease measures (e.g. survival), but other concerns as well, including symptom control and quality-of-life, patients’ value or meaning of life, their feelings about themselves, and their perceptions and attitudes about a specific treatment.

Palliative Chemotherapy Regimens

Of the chemotherapeutic agents with activity against NSCLC, platinum-based chemotherapy has historically been considered the most effective and remains the "backbone" of current chemotherapy. It is recognized that doublet therapy provides the best balance of benefit and toxicity in comparison to single agent or triplet treatment. Multiple trials have established that platinum combinations with vinorelbine, gemcitabine, docetaxel and paclitaxel were equivalent with respect to response rate and survival benefit.7-10 Fit patients with advanced NSCLC therefore should be offered first line doublet platinum-based chemotherapy.

Comparisons of the two commonly used platinum agents in NSCLC, cisplatin and carboplatin, have been undertaken. A meta-analysis of abstracted data comparing the platinum agents indicated that cisplatin plus a new agent yielded an 11% longer survival than the same carboplatin doublet.11 When older chemotherapeutic regimens were included, the survival benefit was not statistically significant. Toxicity was noted to be lower with carboplatin-based chemotherapy. Subsequently, the CISCA meta-analysis looked at individual patient data and found an improvement in response rate with cisplatin over carboplatin. However, the survival benefit was not statistically significant (HR for death, carboplatin vs cisplatin 1.07 p=0.101).12 Again, carboplatin was better tolerated. For patients with good performance status and limited co-morbidities, cisplatin is the preferred agent for palliative therapy.

Non-platinum third-generation regimens have been compared to platinum doublets in the phase II and III setting. Meta-analyses suggest that outcomes are similar for both groups, but the toxicity profiles differ depending on the combination.13 Platinum doublets remain the mainstay of advanced NSCLC therapy.

Efforts have been made to combine doublet chemotherapy with biologic agents to improve first line outcomes. Combinations with epidermal growth factor tyrosine kinase inhibitors, matrix metalloproteinase inhibitors and hypoxic cytotoxins have all failed to demonstrate an improvement over standard therapy.

ECOG 4599 was the first trial to show a survival benefit with the addition of a targeted therapy. Patients were randomized to carboplatin and paclitaxel with or without bevacizumab, an antibody directed against vascular endothelial growth factor.14 Due to risk of bleeding and toxicity with this agent, patients with squamous-cell tumors, brain metastases, clinically significant hemoptysis, or inadequate organ function or performance status were excluded. The median survival of chemotherapy alone was 10.3 months in comparison to 12.3 months in the bevacizumab group. While this represented a significant improvement, it was tempered by the fact that there were 15 treatment related deaths in the bevacizumab arm of which 5 were pulmonary hemorrhage. A second phase III trial comparing cisplatin and gemcitabine with or without bevacizumab at two different doses was conducted in chemo naïve NSCLC patients.15 The preliminary results of this trial were presented at ASCO 2007. There was a small but statistically significant improvement in progression free survival (approximately 2 weeks). Overall survival data is anticipated in 18 months. The apparent limited benefit of adding bevacizumab in this trial may have been impacted by the frequency of evaluation (every 3 months as opposed to 2 months in ECOG 4599). However, this is speculative. Current practice at the BCCA does not incorporate bevacizumab in standard therapy as the results of confirmatory trials are awaited.

Chemotherapy Duration

There is no evidence that continuing chemotherapy beyond 3-4 months in responding patients prolongs survival, and cumulative treatment toxicity is a concern and should be minimized.


References:


1. Anonymous: Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. Bmj. 311:899-909, 1995

2. Cullen MH, Billingham LJ, Woodroffe CM, et al: Mitomycin, ifosfamide, and cisplatin in unresectable non-small-cell lung cancer: effects on survival and quality of life. J Clin Oncol 17:3188-94, 1999

3. Helsing M, Bergman B, Thaning L, et al: Quality of life and survival in patients with advanced non-small cell lung cancer receiving supportive care plus chemotherapy with carboplatin and etoposide or supportive care only. A multicentre randomised phase III trial. Joint Lung Cancer Study Group. Eur J Cancer 34:1036-44, 1998

4. Thongprasert S, Sanguanmitra P, Juthapan W, et al: Relationship between quality of life and clinical outcomes in advanced non-small cell lung cancer: best supportive care (BSC) versus BSC plus chemotherapy. Lung Cancer 24:17-24, 1999

5. Gridelli C: The ELVIS trial: a phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer. Elderly Lung Cancer Vinorelbine Italian Study. Oncologist 6 Suppl 1:4-7, 2001

6. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. The Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst 91:66-72, 1999

7. Schiller JH, Harrington D, Belani CP, et al: Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. New England Journal of Medicine. 346:92-8, 2002

8. Fossella F, Pereira JR, von Pawel J, et al: Randomized, Multinational, Phase III Study of Docetaxel Plus Platinum Combinations Versus Vinorelbine Plus Cisplatin for Advanced Non-Small-Cell Lung Cancer: The TAX 326 Study Group. J Clin Oncol 21:3016-3024, 2003

9. Scagliotti GV, De Marinis F, Rinaldi M, et al: Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. Journal of Clinical Oncology. 20:4285-91, 2002

10. Kelly K, Crowley J, Bunn PA, Jr., et al: Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial. Journal of Clinical Oncology. 19:3210-8, 2001

11. Hotta K, Matsuo K, Ueoka H, et al: Meta-analysis of randomized clinical trials comparing Cisplatin to Carboplatin in patients with advanced non-small-cell lung cancer. J Clin Oncol 22:3852-9, 2004

12. Ardizzoni A, Tiseo M, Boni L, et al: CISCA (cisplatin vs. carboplatin) meta-analysis: An individual patient data meta-analysis comparing cisplatin versus carboplatin-based chemotherapy in first-line treatment of advanced non-small cell lung cancer (NSCLC). ASCO Meeting Abstracts 24:7011-, 2006

13. D'Addario G, Pintilie M, Leighl NB, et al: Platinum-based versus non-platinum-based chemotherapy in advanced non-small-cell lung cancer: a meta-analysis of the published literature. J Clin Oncol 23:2926-36, 2005

14. O'Brien M SA, Popovish A, et al.: Xyotax vs. gemcitabine or vinorelbine for the treatment of performance status 2 patients with chemotherapy naive non small cell lung cancer (NSCLC): the STELLAR 4 phase III study. Lung Cancer 2005;49(suppl 2):S37, 2006

15. Manegold C, von Pawel J, Zatloukal P, et al: Randomised, double-blind multicentre phase III study of bevacizumab in combination with cisplatin and gemcitabine in chemotherapy-naive patients with advanced or recurrent non-squamous non-small cell lung cancer (NSCLC): BO17704. ASCO Meeting Abstracts 25:LBA7514-, 2007