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2006 - Lung Cancer Update Information
Editor: Ernest H. Rosenbaum, MD

Treatment for lung cancer has been advancing more rapidly in recent years with the advent of Platinum-containing doublets (Carboplatin and Cisplatin) and newer drugs, such as Gemcitabine, Taxol (Paclitaxel and Docitaxel) and Navelbine.

One can divide lung cancer into two groups: early, with limited stage or early advanced disease, Stage I and II, or more advanced disease, Stage IIIA and advanced disease, IIIB and metastatic cancer..

There was an analysis of 52 research studies that showed that Cisplatinum-based chemotherapy produced a 10% increase in one-year survival and a 27% reduction in the risk of death compared to the best supportive therapy (Non-small Cell Lung Cancer Collaborative Group, Chemotherapy in Non-small Cell Lung Cancer, (BMJ 1995; 311: 899-909). More recent reports of four different platinum-containing doublets (two drugs) found that they were all comparable, and there was no difference between Carboplatinum and Cisplatinum doublets. A combination of Cisplatinum and Paclitaxel improved median survival. Also, using Cisplatinum with Gemcitabine or Paclitaxel improved survival 11%; although, Cisplatinum was seen to have more side effects, such as nausea, vomiting, and kidney toxicity, while Carboplatin had more myelosuppression and thrombocytopenia.

There has also been a question whether three drugs (a triplet) is better than two drugs (a doublet). Three-drug programs showed more toxicity but did not have significantly better results.

Looking at various studies, median survival varied between six and twelve months; although, six to seven months appeared to be the average. The one-year survival varied between 24 and 51%; although, 25-30% seemed to be the average. The side effects varied between fatigue, nausea, anemia, kidney toxicity, low white counts and low platelet counts.

Thus, in summary, comparing the various combinations of Paclitaxel/Carboplatin to Gemcitabine/Carboplatin to Gemcitabine/Paclitaxel, they were all comparable as far as survival, but toxicities varied depending on the drugs. Thus, in first-line therapy, comparing Cisplatinum doublets to Cisplatinum doublets, there was a slight edge for the Cisplatinum; although, one has to rate the toxicities. Adding a third agent did not improve the overall survival, and an average of four to six cycles of chemotherapy with any regimen appeared to be satisfactory and optimal. 

The Elderly Person with a Reasonable Performance Status with Advanced Non-small Cell Lung Cancer
Corey J. Langer, MD
Fox Chase Cancer Center, Philidelphia,Pa
From: Cancer Congress, June 2005, Kauai.

Elderly persons are usually considered to be over age 70, and many studies have been done showing that there is value for chemotherapy as long as there is a reasonable performance status. In elderly patients, studies have been done showing that single-drug therapy was acceptable, such as Vinorelbine (Navelbine). There is a significant improvement in one-year survival and quality of life in patients with the treatment arm compared to best supportive therapy. In the MILES study (Multicenter Italian Lung Cancer in Elderly Study), when comparing single agents to combination agents, such as Vinorelbine and Gemcitabine, there was no major advantage seen in the combination compared with single drug therapy, but the toxicity was greater.

In the ECOG E1594, E5094 phase three trial, which compared Gemcitabine/ Cisplatinum to Docitaxel/Cisplatinum and Paclitaxel/Carboplatinum to Paclitaxel/Cisplatinum, there were 1155 eligible patients, and 20% were over age 70. There was no significant statistical difference in the response rate or survival in patients less than 70, and those greater than 70 had about 30% completion of six cycles of therapy. In those less than 70 versus those greater than 70, there was a similar grade IV toxicity of about 60-70%. The overall response rate was the same, 22 versus 24%, and time to progression averaged 3.7 months for both groups. Median survival was 8 months in both groups, and the median one-year overall survival was 33% in less than 70 and 35% in more than 70. The two-year overall survival was 11% versus 14%.

More recent studies are comparing Docitaxel with and without Gemcitabine in patients over age 65 with a performance status of 2. Programs with weekly versus every three weeks Docitaxel are also effective. 

In the ECOG E5094 outcome sub analysis of 68 patients on various combinations, the time to progression averaged between one-and-a-half to five months, with a median survival between four and eight months, and a one-year overall survival for the various programs varying between 19 and 38%. Gemcitabine/Carboplatinum appeared to be the most optimal with 38% one-year overall survival, and the Docitaxel was 10.5% one-year survival.

The CALGB 9730 study of 99 patients showed an overall response rate between 10 and 24%, comparing single-drug Paclitaxel versus Paclitaxel/Carboplatinum, which had a better response rate of 24% versus Taxol with 10%. The median survival varied between 2.0 and 4.7 months, with a one-year survival varying between10-18%, and a two-year survival of 0-9%.  Thus, age should not be the basis in denying elderly patients the potential benefits of chemotherapy, as there is improvement in quality of life, time to progression, and median survival; although, patients older than 80 had a reduced tolerance to treatment and more toxicity. Platinum-based combinations also yielded greater toxicity versus the younger person. 

Second-line Chemotherapy for Progressive and Advanced Non-Small Cell Lung Cancer
Angela M. Davis, MD
University of California Davis Davis, California
From: Cancer Congress, June 2005, Kauai. 

When first-line therapy fails with tumor progression, second-line therapy is often considered. This, in part, depends on how much toxicity was incurred during the first four to six rounds of therapy and also the person's performance status. Often when treatment fails, the body is also failing, and people are not in good enough condition to continue therapy, palliative care has to be considered.

It is of note that patients, who do respond to first-line therapy, are more likely to respond to second-line therapy. There are many agents involved, and drugs such as Docitaxel, pemetrexed, and Erlotinib are to be considered. In a phase III study, TAX317b, showed that compared to best supportive care, Docitaxel 75mg/m2 every three weeks significantly improved the median survival to 7.5 months versus 4.6 months, and one-year survival of 37% versus 12% for patients with advanced non-small cell lung cancer. Docitaxel also improved quality of life in terms of lower rates of pain medicines used for control, as well as less weight loss and less fatigue. There was also improvement in the one-year survival.

Pemetrexed in a study using 500 mg/m2 versus Docitaxel 75 mg/m2 every three weeks showed good results. Folic acid 350-1000 mg per day and vitamin B12 1000 mcg every nine weeks gave protection with pemetrexed to reduce hemorrhage and non-hematologic toxicities. Fewer patients with pemetrexed were hospitalized because of febrile neutropenia (white blood counts).

The recent use of Tyrosine Kinase Inhibitors (TKI) and Erlotinib 150 mg/day (Tarceva) showed significant improved overall survival of 6.7 versus 4.7 months and a one-year survival of 31 versus 22% compared to placebo. Of note is that those who responded were mainly non-smokers, and, also of note, there was a decrease in symptoms, such as shortness of breath, pain, cough and improved quality of life in those who responded! Patients with adenocarcinoma expressing EGFR tumor cells was found in over 10% of the study patients. An alternate agent, gefitinib, also showed activity but no significant improvement in overall response or one-year overall survival, and is no longer approved for therapy.

Of note is that Docitaxel, pemetrexed and Erlotinib have similar efficacies for second-line treatment; therefore, one has to individualize patients with specific drug programs. Pemetrexed is less toxic than Docitaxel, but both are very costly. Erlotinib is an oral pill and costs less than Docitaxel and pemetrexed and is a feasible choice for selected patients.

Hopefully, new molecular tests will be able to discriminate which are the best drugs or TK inhibitors to offer optimal therapy. 

Reference: Joan Schiller, University of Wisconsin
From: Lung Cancer Congress, June 2005, Kauai.

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