CHAPTER EIGHT: NON_SMALL CELL LUNG CANCER-

STAGES 1 Approach

In this and the next chapters, we take our knowledge of lung anatomy, chemotherapy, surgery, and radiation, and apply it to non-small cell lung cancer, the most common form of lung cancer. Treatment is divided by stage, and each chapter reviews treatment of a particular stage.

The material can still be challenging, though I believe a good knowledge of this will be important for the patient or family member seeking to understand the nature of treatment and any options presented.

1.02 Suggestions to Make the Material Easier

Try to read each section, consult the definitions at the end of the book, and have a medical dictionary on hand. If you become confused about different stages, review the discusssion of different stages. If you are able to digest the information here, you may be able to reduce the general information which takes up time in doctor_patient conferences, better understand your condition and the treatment which is proposed, and be able to ask your physician knowledgeable questions about treatment procedures and alternatives.

1.21 This chapter deals with three substages of lung cancer, occult, also called stage 0, the very earliest type of tumor, stage 1A, and stage 1B. An occult cancer is a microscopic tumor which cannot be seen on a chest x-ray. Tumors discovered in this fashion are very early stage and given their limited area and lack of metastasis, usually cured by surgery.

1.22 Why Most Occult Tumors are Squamous Cell

One text states, " 90% of occult lung cancers are squamous carcinomas, and 10% are either adenocarcinomas or large cell carcinomas." (1) Martini, et. al. Treatment of Stage 1 and II Disease 339 in Aisner, Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996). Squamous cell tumors are usually in the main bronchus. Sputum cytology is gathering sputum from a cough. These small central tumors can sometimes be detected during an analysis of cells from a cough while deeper tumors in the smaller airways are not so easily found. The 90% figure means that of early cancers diagnosed, 90% are squamous cell, not that 90% of all tumors are squamous cell.

1.23 Sputum Cytology as a Tool for Early Detection

Diagnostic tools like sputum cytology need to be used more often, so we can treat certain lung cancer in its early stage when treatment is most effective. Since sputum cytology is less effective at revealing adenocarcinomas, it is not an all-inclusive diagnostic tool. Nonetheless with a cost of less than $100.00 per administration and date of detection critical, it needs to be utilized more frequently.

1.24 Treatment Similarities to Stage 1a tumors.

An occult tumor detected by sputum cytology, and a small tumor detected on a CT Scan which has not metastasises to a lymph node and has a limited area, are generally treated in the same fashion. If the patient is in good enough shape for surgery, the tumor is surgically removed and the patient has an excellent prognosis, with five year survival rates ranging from 70-85%, depending upon the study.

1.25 Phototherapy

Phototherapy has been described as an alternative to surgical resection in carefully selected patients. This investigational treatment seems to be most effective for very early central tumors. A recent article discusses photodynamic therapy and its use with Stage 0 patients:

Photodynamic  therapy uses a photosensitizing agent, which becomes activated when  exposed to light of the appropriate wavelength (1) and produces toxic oxygen radicals, resulting in cell death....Tissue penetrations is limited to a few millimeters in this method. This fact and the relatively low power prohibit complete eradication of large obstructing airway lesions. However, successful eradication of superficial (penetration less than 5 millimeters) bronchial wall tumors has been demonstrated. Superficial tumors are usually squamous cell carcinomas that are radiographically occult. They are often detected through cytological examination of sputum.

Surgical resection remains the best treatment for early_stage lung cancer. However, photodynamic therapy may be considered for some operable cancers, for cancers that are inoperable because of high surgical risk or limited pulmonary function or because they are multi centric, and for cancer in patient who refuse surgery. To be a candidate for photodynamic therapy, a patients must have a superficial stage 1 lesion (I/e. no evidence of nodal metastasis) that has a surface area estimated to be less than 3cm.Midthun, Endobronchial Techniques in Lung Cancer, Options for Nonsurgical Care. Vol. 101, No. 3, March 1997 Postgraduate Medicine

Note that this photodynamic surgery is generally an option only for those patients who cannot tolerate surgery. For example, if an 84 year old man with previous heart problems and poor health were diagnosed with in-situ lung cancer, photodynamic therapy could be used. For others, given the overall good results achieved through surgery, that is the preferred form of treatment.

References:

1. Omitted

2. Furuse K, Fukuoka M, Kato H, et al.: A prospective phase II study on photodynamic therapy with photofrin II for centrally located early_stage lung cancer. Journal of Clinical Oncology 11(10): 1852_1857, 1993.

3. Edell ES, Cortese DA: Photodynamic therapy in the management of early superficial squamous cell carcinoma as an alternative to surgical resection. Chest 102(5): 1319_1322, 1992.

1.3 SURGERY AND STAGE I NON_SMALL CELL LUNG CANCER

1.31 Surgery is the Preferred Option leading to Impressive Five Year Survival Prospects

Surgery, specifically a lobectomy- removal of the affected lobe of the lung and surrounding tissue, is the preferred option for stage 1 patients. Stage 1 patients whose tumors have been surgically removed have an excellent prognosis, with five year survival rates ranging from 55% to 85%, depending upon the study. (Since the occult tumors are even smaller, the survival rate is even higher).

1.32 Surgery and Pulmonary Reserve

The main consideration for surgery is whether the patient has sufficient pulmonary reserve. That is, can his pulmonary or respiratory system tolerate the removal of substantial parts of a lung. Surgery involves removal of not only the tumor, but surrounding tissue. For the average person, removal of a part of one lung would not present significant problems. However if a patient’s lungs have not only cancer but other disease such as emphysema, a physician may decide against surgery. Pulmonary function tests assess the patient’s breathing capacity in various contexts.

 

1.33 Wedge Resection Surgery Instead of Lobectomy Is Recommended Only for Stage 1 Patients with Impaired Pulmonary Function

1.34 Radiation is Used for Stage 1 Patients with Poor Pulmonary Reserve

NCI states, "Patients with stage I disease for whom surgery is deemed inappropriate may be considered for radiation therapy with curative intent. In one report of patients older than 70 years of age who had resectable lesions smaller than 4 centimeters but who were medically inoperable or who refused surgery, survival at 5 years following radiation therapy with curative intent was comparable to a historical control group of patients of similar age resected with curative intent. In the two largest retrospective radiation therapy series, inoperable patients treated with definitive radiation therapy achieved 5_year survival rates of 10% and 27%. Both series found that patients with T1, N0 tumors had better outcomes, with 5_year survival rates of 60% and 32% in this subgroup..... Careful treatment planning with precise definition of target volume and avoidance of critical normal structures to the extent possible is needed for optimal results and requires the use of a simulator.

1.4 POST SURGICAL OPTIONS OR THE STAGE 1 LUNG CANCER PATIENT

1.41 The Argument for Chemotherapy and or Radiation Following Surgery

Even though stage 1 patients have a good prognosis and the surgery has apparently removed the tumor, a significant number of patients will develop metastasises to lymph nodes and other organs. As the tumor spreads, it becomes increasingly more difficult to treat. Would it not make sense to provide some type of prophylactic chemotherapy or radiation designed to kill any cancer cells not visible to the human eye, to prevent relapse. At least that is the question scientists are confronting.

1.42 The Argument Against Post-surgical chemotherapy or radiation.

Chemotherapy is a serious treatment which causes side effects based upon its impact upon normal cells. A physician should not begin damaging normal tissue without clear medical justification.

1.43 Adjuvant Chemotherapy

Chemotherapy following surgery is called adjuvant chemotherapy. Thus if adjuvant chemotherapy was given to a patient, that means that surgery was first performed and chemotherapy later given. (Giving chemotherapy first to reduce tumor size, and then performing surgery is called neoadjuvant chemotherapy).

1.44 1970's and 1980's Studies Did not Show a Survival Increase for Adjuvant Chemotherapy

The book Lung Cancer reports that studies in the 70's and 80's showed little benefit to adjuvant chemotherapy:

"The Veterans Administration Surgical Adjuvant Group conducted a series of adjuvant chemotherapy studies... long-term follow-up revealed no benefit in overall survival.... Data from the Swiss Group for Clinical Cancer Research.... concluded that treatment with intermittent courses of cyclophosphamide over a two year period seemed to increase the recurrence and death rates.... In 1985, Gerling reported that prolonged cytoxic chemotherapy... did not improve survival over surgery alone." Pisters, Surgery and Chemotherapy, 770, in Pass, Lung Cancer (2000) citing, Girling, Fifteen-year Follow-up of all patients in a study of postoperative chemotherapy for bronchial carcinoma," Br. J. Cancer 1985; 52:867, Shields, Prolonged intermittent adjuvant chemotherapy... after resection of carcinoma of the Lung, Cancer, 1982; 50: 1713.

The National Cancer Institute states, "Trials of adjuvant chemotherapy regimens have failed to demonstrate a consistent benefit." NCI.net. Thus, most physicians do not prescribe chemotherapy for stage 1 patients whose tumors have been successfully removed and no evidence of cancer is seen on x-ray or other tests.

8.46 Why Doctors Do Not Always Consider New Studies or Utilize New Forms of Treatment

As we discuss below, there is some recent evidence that chemotherapy does provide a survival benefit. Putting aside the issue of side effects, why wouldn’t doctors utilize the research in these new studies. Has my doctor failed to consider the latest research. The question is more complex than that.

There is a maxim in medicine, first do no harm. That is, the physician’s intervention should not do damage to the patient. Without a sound medical foundation, most physicians are reluctant to undertake new forms of treatment until they are generally accepted in the particular area of practice. At this point while studies are favorable, they are not sufficiently widely accepted to constitute the standard of care or accepted practice. Most physicians would still consider adjuvant chemotherapy experimental.

8.47 The Malpractice Danger

Another reason is the concern about professional liability claims. From my perspective, that is unreasonable, the number of chemotherapy-related claims is rather low. When physicians are diagnosing many patients at advanced stages, it would seem the real danger is delayed diagnosis. Nonetheless, there is a concern, realistic or not, about using new treatments, finding out they went beyond the standard of care, and even with the best of intentions, the physician would face liability.

8.48 Accessibility to New Forms of Treatment

Where does the patient go to obtain new forms of treatment, or more accurately, known treatment given in a new context. First, there are clinical trials which assess and evaluate new forms of treatment. (Clinical trials are the subject of another chapter). Some University hospitals where clinical trials are being given may be somewhat more aggressive in providing new forms of treatment even outside the context of a clinical trial.

8.5 RECENT STUDIES OF ADJUVANT CHEMOTHERAPY FOR STAGE 1 PATIENTS AND THE IMPACT UPON PRACTICE

Some studies in the 80's and 90's, using more effective forms of chemotherapy have shown a benefit to chemotherapy. In a study from Finland, "survival in the chemotherapy arm was significantly better than control (61%versus 48%." Pisters, Surgery and Chemotherapy, 771-772, in Pass, Lung Cancer (2000). A recent study abstract said the following:

"The trial was designed as a randomized, two-group study with postoperative adjuvant chemotherapy versus surgery alone as control group. All patients had stage IB disease (pT2N0) assessed after a radical surgical procedure. Chemotherapy consisted of treatment with cisplatin (100mg/m(2) on day 1) and etoposide (120mg/m(2) on days 1-3) for a total of six cycles. Results: Between January 1988 and December 1994, 66 patients were included in the study. Thirty-three belonged to the adjuvant chemotherapy group and 33 to the control group. Patients were followed for a minimum period of 5 years.... The rates of locoregional recurrence and distant metastasises were 18 and 30%, respectively, in the adjuvant chemotherapy group and 24 and 43%, respectively, in the control group. The 5-year disease-free survival rates were 59% in the adjuvant group and 30% in the control group (P=0.02)... Conclusions: Our results suggest that adjuvant chemotherapy may reduce recurrences and prolong overall survival in patients at stage IB NSCLC deemed radically operated. Despite being difficult to accept, the use of adjuvant chemotherapy might have better long-term results."

Mineo, Postoperative adjuvant therapy for stage IB non-small-cell lung cancer, Eur J Cardiothorac Surg 2001 Aug;20(2):378-84

Distinguishing the successful results here from prior studies is not easy. Taxol and carboplatin were used here, which many believe to be the optimal combination. Did prior studies fail to utilize the optimum chemotherapy mix. Or is the fact that this subgroup was stage 1B patients, with a higher potential for metastasis the decisive factor. Another recent study showed a slight survival advantage for chemotherapy, using different chemotherapy drugs, 76% in the chemotherapy and surgery group versus 71% in the surgery group alone. Wada, Postoperative adjuvant chemotherapy with PVM... Eur J Cardiothorac Surg 1999 Apr;15(4):438-43 .

1.5 POST-OPERATIVE RADIATION FOR STAGE 1 TUMORS

A 1999 article in the journal Lung Cancer states, "There is no place for routine postoperative thoracic radiotherapy after complete resection of a stage 1 tumour. " Rodrigues, The Impact of Surgical Adjuvant Thoracic Radiation for different Stages of Non Small Cell Lung Cancer: the Experience from a Single Institution, Lung Cancer 23 (1999) 11-17.

1.6 NEW TECHNIQUES OF MOLECULAR DETECTION OF EARLY DETECTION OF RECURRENCE OR SPREAD

One could also conclude that routine use of chemotherapy should not be recommended for stage 1 patients, but that they should be intensively watched so that any signs of spread or metastasis can be timely treated. That is not what occurs today. Most physicians prescribe a yearly or bi-yearly chest x-ray and wait until tumor spread manifests itself on such on an x-ray before recommending additional treatment. The difficulty here is that the chest-ray is an imprecise tool, detecting tumors only of diameter of a centimeter, we lose precious time in treating the patient.

1.61 Ct Scan

One plausible alternative is the use of post-operative Ct Scans. The CT is approximately five times more accurate than the chest x-ray in detecting small tumors. Low does Ct presents limited risk of exposure. The primary difficulty is that this does not yet represent the standard of care. Additionally, some insurers might balk at paying for such CT’s if they were regarded as experimental.

1.63 Micro-Vessel Density

Angiogenesis is the formation of new blood vessels. While it is a normal process in wound healing and other areas, in cancer, it is the primary way that metastasis occurs and the cancer spread. A recent article explains:

"Angiogenesis is a complex regulated process, forming new blood vessels from pre-existing vessels.... The determination os microvessel density constitutes a measure for tumor Angiogenesis. According to investigations by Fontanini et. al. high vessel density is a negative prognostic factor for the overall survival of patients suffering non-small cell lung cancer. In these tumors, increased microvessel density was also associated with a higher incident of lymph node metastasises and distant metastasises. In their study on 227 patients with surgically treated stage I non-small cell lung cancers, Lucchi et. al. confirmed the prognostic significance of microvessel count regarding both overall and disease-free survival." Junker, Prognostic Factors in Stage 1/II Non-Small Cell Lung Cancer, Lung Cancer Suppl. 1 (2001) S17-24 quoting. Fontanini, Microvessel Count Predicts Metastatic Disease and Survival in Non-Small Cell Lung Cancer, J Pathol 1995; 177: 57-63. Lucchi, et. al, Tumor Angiogeneis and Biologic Markers in Resected Stage I NSCLC, Eur J. Cardiothorac Surg, 1997; 12: 535-41.

The theory is not free from challenge. One study of "69 stage I-II non small lung cancers failed to demonstrate the prognostic relevance of microvessel density." Junker at S 20, citing, Decaussin, Expression of Vascular Endothelial Growth Factor and its two receptors in Non-Small Cell Lung Carcinomas... J. Pathol 1999; 188: 369-77.

1.64 P-53.

P 53 is a potent tumor suppressor. P-53 has been measured, and the absence of normal P53 and the presence of mutated P53 has been shown to negatively impact survival.

1.65 Erb-2

C-erb is associated with the epidermal growth factor. The epidermal growth factor is one of the proteins which prompt cell proliferation.

1.651 Iressa,

Iressa is a new drug has shown substantial success in patients with advanced cancer, with few side effects. Iressa inhibits the epidermal growth factor. Significantly, because if targets a narrow group of cells, it has shown few side effects. It is conceivable that scientists could measure levels of C-erb 2, or epidmeral growth and prescribe Iressa (or similar drugs) at an earliest stage.

1.66 Measure Cell Death or Apoptosis

A properly working system in the body provides for cell death, and this is one way of preventing unlimited proliferation. One study measured rates of Apoptosis and found that patient’s prognosis was correlated with that. This measurement may show at an earliest stage where the cancer is reoccurring, and direct us to early intervention for those patients with a poorer prognosis. Junker, Prognostic Factors in Stage 1/II Non-Small Cell Lung Cancer, Lung Cancer Suppl. 1 (2001) S17-24.

Conclusions

In the upcoming years, oncologist will examine ways of detecting those patients whose tumors have or are likely to spread, and arrange for either prompt or prophylactic treatment. While we cannot suggest a particular course of treatment, patients and their families may well wish to discuss options with their oncologist.

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