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Pulmonary & Critical Care Bulletin
Vol. VII, No. 3, July 15, 2001
In this issue :

From Editor's Desk

(Dr. Uma Maheswari,)

(R. S. Bedi & U.S. Bedi)

16th Annual Meeting on Pulmonary and Critical Care Medicine
(Dr. S. K. Jindal)

Publihed under the auspices of:
Pulmonary C. M. E. Programme

Editorial Board :

Department of Pulmonary Medecine
Post Graduate Institute of Medical Education & Research (PGIMER) Chandigarh. INDIA-160012

Subscription :

Newer Agents for Lung Cancer

The incidence of lung cancer each year worldwide is over six hundred thousand cases. The cure rate is very low, around 14%. Except for patients with stage I non small cell lung cancer (NSCLC) and limited disease small cell lung cancer (SCLC), all require systemic chemotheraphy.

At diagnosis, 50% NSCLC have detectable metastases and another 15% have non-resectable locally advanced disease. Additionally, 50% of those who are operated, require post operative systemic therapy for local infiltration or distant metastases. Thus, 75% of all patients require systemic therapy.

During early chemotherapeutic era, non small cell cancer was considered resistant to all chemotherapeutic agents. Still, drug treatment for NSCLC is most controversial issue in oncology. Prolonged evaluation and controlled trials show that : (1) Cisplatin based regimens improve survival in advanced NSCLC as compared to best supportive care; (ii) It improves five year survival by 50% in respectable lung cancer.

Single agent chemotherapy had a response rate of over 15% but seldom reached 25%. Cisplatin/Etoposide combination improves the response to 25-40% and 1 year survival to 30%. There are several other agents such as Ifosfamide, Mitomycin, Vinblastine and Vindesine. Of several combinations used, Cisplatin based regimens have advantage in response rate and median survival.

Important Questions

(i) What chemotherapy has to offer in advanced cancer ? The four criteria regarding the activity of an anti-cancer drug are ? subjective improvement in performance status, objective response and increase in length of remission and prolongation of life. A response rate of 15% or more is considered a significant response. Al Cisplatin based regimens have significant response of more than 15%.

(ii) Who should receive chemotherapy ? Studies have shown that patients with performance status of more than 60% respond well. There are no studies in patients with performance status of 50% or less.

(iii) Do these new drugs improve survival in NSCLC ?

The meta-analysis of 808 patients with Cisplatin based regimens showed median survival advantage of 3 months (4 versus 7 months) and 1 year survival advantage by 5% (20% vs 25%) over best supportive care.

New drugs for NSCLC

1. Gemcitabine

It is a new antimetabolite with good action against solid tumours. It is pyrimidine analogue similar to Cytosine arabinoside. It is metabolized into Gemcitabine phosphates by pyrimidine nucleoside, phosphorylase. These Gemcitabine mono, di and triphosphates are active in inhibition of DNA synthesis. Gemcitabine disphosphate inhibits ribonucleotide reductase enzyme thus inhibiting DNA repair. Gemcitabine triphosphate, actively incorporated into DNA strands, inhibits further prolongation by DNA polymerase. The toxicities include myelosuppression which is dose limiting but short lived, fever with rash and derangement of liver enzymes.

Gemcitabine in NSCLC has been evaluated extensively. Eight trials evaluated single agent; the response rate was 19-25% with median survival of 6.4 ? 9.4 months and 35-44% one year survival. When continued with Cisplatin, the response rate improved to 38-42% with median survival of 33-60 months and 1 year survival of 40-60%. Gemcitabine-Cisplatin combination had significantly better response rate and median survival when compared with other Cisplatin based therapies. These studies suggested that Cisplatin-Gemcitabine combination can be considered as standard therapy in NSCLC.

2. Taxols

These are deterpenoid compounds containing taxene ring isolated from the bark of Western Yew tree. These agents promote microtubule formation in absence of GTP. Thy bind specifically to beta tubulin subunit of microtubules and antagonize disassembly of cytoskeleton, leading to the formation of aberrant structure. Arrest of mitosis follows. These agents have low solubility and have to be dissolved in castor oil and ethanol mixture. So, the hypersensitivity reactions are more. Both Paclitaxel and its analogue, Docetaxel have been evaluated for non small cell lung cancer. Toxicities include neutropenia (about 36%), myalgias, glove stocking sensory neuropathy, mucositis and hypersensitivity reactions.

Single agent Docetaxel showed response rate of 29% in pooled six trials and individual response rate ranging between 21-38% which was significantly higher than conventional therapy. Docetaxel ? Cisplatin combination had response rate and median survival comparable to Docetaxel alone. Use of Docetaxel as a second line drug showed response rate of 16-21% and median and 1 year survival better than best supportive care.

Docetaxel is also shown to have good response as adjuvant thereapy in post radiotherapy and post surgery patients.

3. Camptothecan analogues

These are plant alkaloids from Camptotheca acuminate and include Topotecan, and Rinotecans. They damage G 2 phase or S. phase of cell cycle. Action totally depends on DNA synthesis. These agents act by inhibiting the enzyme Topoisomerase I. The toxicities include myelosuppression, diarrhoea, mucositis and nausea. When single agent Rinotecan was used in NSCLC, 31% partial response and 42 week median survival was seen. It is comparable with other new agents. Rinotecan, Cisplatin combination resulted in partial response of 48-54% in phase II studies. Further reports regarding its efficacy are being evaluated.

4. Vinorelbine

It is a semi synthetic compound derived from Vinca alkaloids, similar to Vincristing, Vinblastine and Vindesine, Vinblastine and Vindesine. It binds to the tip of micro-tubules and causes disruption of mitotic spindles. It acts both on malignant and normal cells in G and S. phase of cell cycle. Its toxicity includes neurotoxicity, neutropenia, mucositis and gastro-intestinal side effects.

Vinorelbine has a response rate of 12-14% in NSCLC as a single agent. It is also being evaluated as second line agent in NSCLC.

5. Multitargetted Folate Antagonist (MTA)

Many antifolate agents were evaluated for lung cancer in the past without significant benefit. MTA has a definite role in NSCLC. It inhibits thymidylate synthase, dihydrofolate reductase and glycinamide ribonucleotide formyl transferate killing the malignant cells. Multiple actions bring advantage against development of resistance. Single agent has a response rate of 14-23%; when combined with Cisplatin, it increases to 42%. It is also being evaluated as a 2nd line drug in previously treated lung cancer.

6. Tirazapamine

It is a benzotriazine compound and acts on hypoxic cells. Under hypoxic conditions, it undergoes reduction releasing oxygen free radicals. Oxygen free radicals cause DNA cleavage and death of malignant cells. Toxicities include severe diarrhoea and unusual ototoxicity. Phase I and II studies evaluating the drug are still in progress.

There are several other drugs being evaluated for NSCLC which include NB 506, KLN 5500, ULN 01, KW 2149 and DX 8951 F. The ideal drug combination for non small cell lung cancer is yet to develop.

Gene Therapy

The identification of genetic aberration that leads to carcinogenesis presented the opportunity for this new mode of therapy. The tumour suppressor gene P53 has a role in cell cycle regulation and apoptosis. P53 replacement was a noble theoretical basis of gene therapy.

A phase I study conducted on 21 patients showed favourable response. It was well tolerated and local progression of lesion was delayed. Side effects were fever, chills, rashes and fatigue. Further trials are awaited.

Small Cell Lung Cancer

Contrary to NSCLC, SCLC respond better with chemotherapy. With standard therapy, the response rate varies between 70-90% although recurrence is very high. Newer agents are under trial and early results show response of 40-60%.

Dr. C.P. Sharma, MD, DM
Deptt. Of Pulm. Medicine
PGI, Chandigarh

Dr. C.P. Sharma

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