Treatment for Stage 3 Non small Lung Cancers, from Lung Cancer and Mesothelioma

CHAPTER 19: STAGE 3 NON-SMALL CELL LUNG CANCER

19.1 STAGE 3 IS DIVIDED INTO 3A AND 3B

One website explains how stage 3 non-small cell cancer came to be subdivided into two categories:

“Stage III lung cancer originally included patients with locally advanced disease, without distant metastasises. In 1986, the International Staging System for Lung Cancer further divided this group into two subgroups — IIIA and IIIB.4 These subgroups attempted to separate patients with tumors that were potentially resectable (stage IIIA) from patients with tumors clearly beyond the scope of surgical extirpation (stage IIIB). Stage IIIA originally included tumors of any size within the lung with limited extension of the primary site to the pericardium, mediastinal pleura or fat, or chest wall and without lymph node metastasises or with lymph node metastasises confined to the ipsilateral mediastinal lymph nodes. Experience has demonstrated that patients with this classification form a very heterogeneous group, with a long-term survival following surgical resection that ranges from 10 to 50%. Consequently,this classification has recently been modified.” Chestnut (1)

One of the main differences between stage 3 A and B non-small cell cancer is that surgery is part of 3A treatment. Surgery in stage 1 patients is designed to remove all of the tumor. In stage 3A, while that may not be the goal, it can at least remove enough tumor to make the risks of surgery and reduction of lung capacity make sense. In stage 3B where the tumor has extended beyond the immediate area into the mediastinum and adjoining structures, it is felt that the risk does not make sense. Since one group with different treatment plans is confusing, the groups are divided into 3A and 3B. Note that within each category are tumors with different characteristics, but the intra-category treatments are essentially the same.



19.2 CHEMOTHERAPY, RADIATION AND SURGERY IS STANDARD TREATMENT WITH THE BEST MIX STILL UNDER INVESTIGATION

A pharmaceutical site provides a good overview of Stage 3 A treatment:

“Historically, patients with stage III NSCLC (locally advanced disease) were managed with radiation therapy, but long-term survival was poor (5%–10%). The development of active chemotherapy regimens for NSCLC has led to the use of combined modality therapy for the management of stage III disease. Surgery and radiation are effective at controlling local disease, while chemotherapy works to control distant metastatic disease. Any two of these modalities or all three could be combined to treat stage III disease. However, patients with stage IIIb disease are generally not candidates for surgical resection and will most commonly receive combination chemotherapy, plus or minus radiation therapy.”

“Numerous trials comparing combined chemotherapy/radiation to radiation alone have been conducted in patients with stage III NSCLC. The chemotherapy regimens and radiation schedules have varied greatly among the studies, and conflicting results have emerged.... When two different meta-analyses were conducted with the data from all of the published randomized trials comparing chemotherapy/radiation with radiation alone, a small improvement in survival was reported for combined modality therapy. All of these studies utilized the older generation of chemotherapy regimens (cisplatin or cisplatin-based) in combination with radiotherapy. The improved activity of the newer combination chemotherapy regimens used in stage IV disease could lead to improved results when combined with radiation for the treatment of stage III disease.” USPharmasist (2).

19.21 Chemotherapy Before Surgery or NeoAdjuvant Surgery

Chemotherapy and radiation are also, with research continuing as to what combination of these three forms of treatment will achieve the best results. Recall that Stage III A tumors involve either large T2 or 3 tumors or situations of significant lymph node involvement. Many physicians believe in chemotherapy before surgery:

“Neoadjuvant chemotherapy with or without radiation therapy followed by surgery is another combined modality treatment for stage III (primarily stage IIIa) disease that is under investigation. Neoadjuvant chemotherapy is administered to patients with bulky disease prior to surgery in an attempt to decrease tumor size and increase surgical resectability. Two randomized studies have {favorably} compared chemotherapy followed by surgery with surgery alone.” U.S. Pharmacist (2).

A recent article discusses the purposes of neoadjuvant chemotherapy:

“The purpose of neoadjuvant chemotherapy is the eradication of micrometastatic disease, which is almost invariably manifest when ipsilateral mediastinal or subcarinal lymph nodes (N2) are involved. A chest computed tomography (CT) imaging study may show lymph nodes extending throughout many mediastinum regions, including the aortopulmonic window, the paratracheal region, and the precarinal and subcarinal areas.... Three randomized phase III trials reported that administering cisplatin-based chemotherapy before surgery to patients with resectable stage IIIA lung cancer improved survival results over those obtained with surgery alone or surgery plus radiotherapy. The MD Anderson investigators have recently updated the long-term follow-up of a selected high-risk population of patients with advanced but still resectable non-small cell lung cancer (NSCLC), T1-3N2M0 or T3-4N0M0.... This study shows that a preresectional chemotherapy regimen of cisplatin in combination with ifosfamide and mitomycin does improve the clinical outcome in comparison with surgery alone.” Rosell (3).

19.3 STAGE IIIB NON-SMALL CELL LUNG CANCER

Chemotherapy is the primary treatment for Stage 3B and Stage 4 non small cell lung cancer. We can note the following:

1. In the 80's and early 90's, there was some debate about whether chemotherapy improved survival, and whether multiple agents helped. That debate has probably ended. Studies have demonstrated a consistent (if relatively modest) benefit to chemotherapy over other treatments, and have also shown that multi-modal chemotherapy is better than single agent. If different drugs can fight cancer and work in different ways, it would make sense that a combination would achieve better results so long as significant side effects were not created.
2. No one combination has demonstrated markedly better results throughout different clinical trials than others. Clinical trials continue to test various combinations against one other to determine rates of tumor diminution, partial and complete response rate (partial meaning at least 50% reduction of the tumor and complete meaning no visible tumor at a certain point in time), survival rates, and side effects. To call such clinical trials “experimental” is a little misleading. The clinical trials are generally using the same drug combinations that practitioners use, only in a defined clinical setting.
3. The term non-small cell lung cancer includes adenocarcinoma, squamous cell, and large cell cancers. While we have grouped these three types together, it is possible that each type acts a little differently. Conceivably, one drug could be better for squamous and another for large cell. The fact that people with different types of tumors are grouped together, and different ages and health has made it more difficult to distinguish which drug is most effective.
4. The platinum-drugs, cisplatin and carboplatin have been the mainstays of chemotherapy for stage 3B patients, with the above list concentrating on platinum drug combinations. Taxol and Carboplatin appear in practice to be the most frequently used combination, though the literature does not clearly indicate better results with this combination.
5. Gemcitabine and Gemcitabine combinations have been showing results almost comparable to these platinum combinations, with Gemcitabine sometimes reported to have fewer side effects- “Kosimidis showed that a nonplatinum-containing regimen was equivalent to standard carboplatin/paclitaxel for the treatment of advanced disease. The results of this study are also consistent with the recent South West Oncology Group (SWOG) and Eastern Cooperative Oncology Group (ECOG) studies presented at the American Society for Clinical Oncology (ASCO) over the past 2 years.” Kosmidis (4).

6. Gene and angiogenic therapy is debated and investigated. Tarceva and Iressa appear to benefit non-smokers and light former smokers with adenocarcinoma and its subtypes. Initial studies indicate Avastin provides a modest benefit in survival though side effects are increased.

There are difficult issues of medical choice which might ultimately have to be made by the patients themselves. Is a slightly longer projected life-span worth additional side effects. Chemotherapy presents the problem of killing cancer cells, while preserving normal cells and bodily functions. How do we eliminate the rapidly dividing cells we call cancer, but preserve the other rapidly dividing cells necessary for different life functions?

19.31 Stage 3 B Chemotherapy and Radiation

NCI states,

“Patients with stage IIIb non-small cell lung cancer (NSCLC) do not benefit from surgery alone and are best managed by initial chemotherapy, chemotherapy plus radiation therapy, or radiation therapy alone, depending on sites of tumor involvement and performance status. [6].

For a subgroup, adenocarcinoma patients who are nonsmokers or former light smokers, EGFR drugs Tarcev and Iressa appear to provide a benefit. These patients’ tumors appear to be driven at least in part by a malfunctioning EGFR tyrosine kinase which can be identified in a recent EGFR test. (See 15.7. Harvard Laboratories Gene Test). For others, Avastin is showing promise, and cox-2 inhibitors like Celebrex are being evaluated.


REFERENCES

1. www.chestnet.org/education/pccu/vol12/lesson18.html.
2. Current Treatment of Non-Small Cell Lung Cancer, U.S. Pharmacist Continuing Education, www.uspharmacist.com.
3. Rosell, Preresectional chemotherapy in stage IIIA non-small-cell lung cancer: a 7-year assessment of a randomized controlled trial Lung Cancer, Vol. 26 (1) (1999) pp. 7 - 14.
4. Kosmidis (4) A randomized phase III trial of paclitaxel plus carboplatin versus paclitaxel plus gemcitabine in advanced non-small cell lung cancer (NSCLC): a preliminary analysis. Lung Cancer. 2000;29(Suppl 2):147, cited in Lynch, 9th World Conference on Lung Cancer, Presidential Symposium, (2000), www.medscape.com.

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