Drs. Novello and Le Chevalier have reviewed the subject of chemotherapy for non-small-cell lung cancer (NSCLC) in great detail, organized under numerous subheadings. I will systematically comment on each section of this excellent overview, which deals with most of the published or recently presented data on the subjects discussed. In some cases, trials of multimodality therapies, and not just chemotherapy, are included in the review.
As the authors point out, almost all the published trials show no benefit to the use of adjuvant chemotherapy after complete surgical resection. However, they also point out that several large adjuvant trials of newer cisplatin(Drug information on cisplatin)-based regimens have been completed but not yet presented or published, and these trials may show benefits with this approach. Giving modern supportive care such as potent antiemetics should greatly improve compliance to the regimens being evaluated. Hopefully, with more patients actually receiving treatment, improved survival results will be seen in this very common cancer.
As the authors infer and I would like to emphasize, adjuvant therapy with old or new regimens should not be part of routine care in patients with completely resected NSCLC. Whether the results of the completed and not-yet-analyzed studies will change our practice remains to be seen. A North American Intergroup trial testing ZD1839 (Iressa)-an oral potent inhibitor of an epidermal growth factor receptor (EGFR)-associated tyrosine kinase (TK)-vs placebo as adjuvant therapy in this patient population will soon begin, and a similar Japanese trial has already begun.
Neoadjuvant Therapy
Neoadjuvant therapy with chemotherapy, with or without radiotherapy, seems to be a popular approach in some patients with stage IIIA disease. Despite the small size of the US and Spanish pivotal trials of this strategy,[1,2] the unexpectedly poor outcome in the surgical arms of these two studies, and the fact that the survival difference in the US study has lost its statistical significance, this approach remains virtually standard in 2003. However, as suggested by the authors, we need larger and better studies to confirm the original data and to evaluate more recent chemotherapy regimens as potentially better options in this setting.
Advanced Disease
The treatment of locally advanced disease (stage IIIB) has changed substantially in the past decade. A small but significant survival advantage has been achieved with chemotherapy plus radiotherapy compared to radiotherapy alone. Concurrent chemotherapy and radiotherapy is also probably superior to sequential therapy with these two modalities and may improve quality of life.
Phase II trials of many of the newer agents that are active in NSCLC (many have radiosensitizing properties) in combination with cisplatin or carboplatin(Drug information on carboplatin) (Paraplatin) and radiation therapy have been completed only recently. This should allow phase III studies to proceed safely, albeit with lower drug doses due to the increased toxicity of concurrent chemotherapy and radiation therapy. Hopefully, this approach will further improve the results of combined-modality therapy. Other drugs such as tirapazamine and erythropoietic agents may improve the results of treatment in areas of hypoxic cells and should also be studied in this patient population.
The authors point out that cisplatin-based combination chemotherapy and even single-agent chemotherapy with the newer agents clearly prolongs survival compared to best supportive care in patients with stage IV NSCLC, but only by about 6 to 8 weeks. Perhaps the newer agents combined with platinum derivatives would produce an even larger survival benefit, but such studies are not likely to be performed because best supportive care is no longer really an option. Although all of the new drug combinations produce superior results compared to older combinations such as cisplatin/ etoposide(Drug information on etoposide), none has emerged as the clearly superior regimen.
In fact, clinicians in different parts of the world tend to choose different regimens. For example, in the United States, paclitaxel(Drug information on paclitaxel) plus carboplatin is the most popular regimen because it may be less toxic and only requires administration once every 3 weeks. Gemcitabine(Drug information on gemcitabine) (Gemzar) and cisplatin (given on a day 1 and 8 schedule) is a popular combination in Europe, and vinorelbine (Navelbine)/cisplatin (also mainly given on a day 1 and 8 schedule) is popular in France and Canada.
Docetaxel (Taxotere) is emerging as another option in combination with a platinum derivative, based on preliminary results from an as yet unpublished study in 1,200 patients. Single agents are particularly useful in frail and elderly patients, who frequently cannot tolerate the toxicity of the platinum combinations. Nonplatinum combinations are probably slightly less effective but possibly less toxic than cisplatin combinations, and triplets have not proven to be superior to doublets in any study to date.
Future Directions
Among the new drugs discussed, targeted therapies seem to be the most exciting for future studies. The oral EGFR-TK inhibitors ZD1839 and erlotinib (OSI-774, Tarceva) are among the most interesting new drugs because they have activity even as third-line agents in patients with NSCLC and are generally well tolerated (except for significant skin rash and diarrhea).
Unfortunately, when administered concurrently with newer chemotherapy combinations in two large randomized trials, ZD1839 did not improve survival compared to chemotherapy alone. (Preliminary results were presented in October 2002 at the European Society of Medical Oncology meeting in Nice, France.) The explanation for this is still unclear. Similar trials of OSI-774 are ongoing. Obviously, we need to clarify the optimal use of these new drugs along with standard chemotherapy if they are to significantly change outcomes in these patients.
Five years ago, we would never have suggested that the standard of care in advanced NSCLC would involve routine use of second-line chemotherapy, but now we recommend it for patients with good performance status. Docetaxel(Drug information on docetaxel) is the single agent of choice in this situation, based on the results of two positive randomized trials.[3,4] Many other agents are being studied in this setting but are being compared to the established standard (docetaxel) before they can be approved for this indication.
Conclusions
It is clear from the excellent review article by Novello and Le Chevalier that much progress has been made over the past decade in the use of chemotherapy to treat patients with all stages of NSCLC. However, much work still needs to be done. New and ongoing trials evaluating new single agents and combination chemotherapy regimens will hopefully continue to improve the quality of life of these patients and perhaps also prolong survival. To this end, it is important to encourage eligible patients to enter clinical trials.
