TREATING NON-SMALL CELL LUNG CANCER- STAGE 1

17.0 OVERVIEW

In the next four 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, with each chapter reviewing 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.

17.01 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 discussion 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.

17.02 Division into Stages 0, 1a, 1B

Scientists divide stage 1 cancer into three substages: occult, also called stage 0, the very earliest type of tumor, stage 1A, a small discrete tumor with no involvement of the main bronchus or adjoining areas, and 1B, a tumor with no lymph node involvement or metastasis, but which is larger than 3cm, had made contact with the main bronchus, visceral pleura, or is associated with pneumonia or ateclasis.


STAGE 0 AND 1 NON SMALL CELL LUNG CANCER

STAGE TUMOR SIZE POSITIVE NODES FIVE YEAR
Occult Tumor Not visible on x-ray
microscopic 0 75-85%
Stage 1A 3 cms or less, no
involvement with adjoining areas 0 65-75%
Stage 1B More than 3cm or invasion to main bronchus or visceral pleura 0 55-65%


As the tumor increases in size, the patient’s long-term survival prospects decrease though they still remain excellent throughout stage 1. The division into three stages reflects increasing specificity and sophistication in the treatment of these early stage tumors. For all stages, surgery will be recommended if the patient is in good health, and specifically, has sufficient pulmonary reserve- enough breathing capacity to survive the removal of a sufficient part of the lung. The hot topic today is whether some type of treatment before or after surgery should be recommended before a recurrence is seen and to improve the patient’s prospects. Clinical trials are investigating whether chemotherapy before or after surgery should be prescribed, and before any evidence of spread of the tumor is observed.
Additionally, scientists are investigating whether molecular markers can detect a subset of patients whose tumors are likely to spread, and to prescribe therapy for those patients before the tumor does spread. Because these approaches are experimental, they are likely to be utilized only in a university setting.

17.1 OCCULT TUMORS

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.

17.11 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.” Martini, (1). 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.

17.12 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.

17.13 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.

17.14 Phototherapy

Phototherapy is an alternative to surgical resection in certain 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 penetration is limited to a few millimeters in this method. This fact and the relatively low power prohibit complete eradication of large airway obstructing 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.” Edell (2)

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 (3).
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.

17.2 SURGERY AND STAGE I NON-SMALL CELL LUNG CANCER

17.21 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).

17.22 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 been damaged not only by cancer but diseases such as emphysema, a physician may decide against surgery. Pulmonary function tests assess the patient’s breathing capacity in various contexts.

“The objective is to establish that after surgical resection of the lung for a tumor, there will be sufficient pulmonary reserve to keep the patient comfortable, and he will not become a respiratory cripple. You should always evaluate the patient to determine whether he could withstand pneumonectomy even if radiologically only a lobectomy or limited resection is contemplated. On thoracotomy, a surgeon may be forced to do pneumonectomy because of an unexpected node over the pulmonary artery. If you have decided the patient cannot withstand pneumonectomy, this should be addressed with the surgeon ahead of thoracotomy.”
Step 1: Routine PFTs. If the patient meets the following criteria, no further workup is necessary:
FEV1 > 2 liters
FEV1/FVC > 50%
MVV > 50% of predicted
RV/TLC <50%”

17.23 Radiation for Stage 1 Patients with Diminished 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.” NCI (3).


17.3 POST SURGICAL CHEMOTHERAPY FOR
STAGE 1 TUMORS

17.31 The Argument for Chemotherapy and or Radiation Following Surgery

Even though stage 1 patients have a good prognosis with the surgery having apparently removed the tumor, approximately 40% 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? That is the question scientists are confronting.
With occult tumors and stage 1A tumors, one may argue that the patient should not be put through the stress and physical changes chemotherapy or radiation may entail. However, by stage 1B, the long-term survival chances are just above 50%. Thus, there is a substantial group of patients whose tumors will recur.

17.32 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.

17.33 Adjuvant Chemotherapy

Chemotherapy following surgery is called adjuvant chemotherapy. 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.

17.34 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 (4) Girling (5).

The National Cancer Institute states, “Trials of adjuvant chemotherapy regimens have failed to demonstrate a consistent benefit.” NCI.net. (3). 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.

17.35 Recent Studies of Adjuvant Chemotherapy

Some studies in the 80's and 90's, using more effective forms of chemotherapy have shown a benefit to chemotherapy. In a Finnish study, “survival in the chemotherapy arm was significantly better than control (61% versus 48%).” A recent study 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 etopiside (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 (5).

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 (8).

17.36 Why Doctors Do Not Always Consider New Forms
of Treatment

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 latest research in their treatment? Is my doctor unaware of the latest research? The issue 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 have become generally accepted in a particular area of practice. At this point, while some 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.
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, that physician would face liability.

17.37 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). Many 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.

17.38 Differences between Stage 1A and 1B treatments

Medicine is moving towards some type of prophylactic treatment of stage 1B patients. The larger size of the tumor, and the number of patients who will have ultimately metastasises, between 40 and 50%, means that the risk of spread is real and substantial.

17.4 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 tumor.” Another article suggested:

“The Port meta-analysis found a detrimental effect of postoperative radiotherapy particularly for patients with stage 1/II disease.
At present, the use of postoperative radiotherapy should be restricted to those patients with incompletely resected disease (positive surgical margins or residual local disease) or selected patients with multiple lymph nodes involved at surgery.” Pisters, (6).

Yet investigation continues. An Italian study found beneficial results:

“Background and purpose: To evaluate the benefits and the drawbacks of post-operative radiotherapy in completely resected Stage I (a and b) non-small cell lung cancer... Overall 5-year survival (Kaplan--Meier) showed a positive trend in the treated group: 67 versus 58% (P=0.048). Regarding toxicity in G1, six patients experienced a grade 1 acute toxicity....”
“Radiological evidence of long-term lung toxicity, with no significant impairment of the respiratory function, has been detected in 18 of the 19 patients who have been diagnosed as having a post-radiation lung fibrosis. Conclusions: Adjuvant radiotherapy gave good results in terms of local control in patients with completely resected NSCLC with pathological Stage I. Overall 5-year survival and disease-free survival showed a promising trend. Treatment-related toxicity is acceptable.” Adjuvant therapy (10).

Whether radiation is effective for stage 1 patients continues to be debated. Absent clear proof of its benefits, few physicians will utilize it because of its effects and radiation for stage 1 patients is now reserved for clinical trials or other investigational settings. In the future, molecular markers may help us target a subgroup of stage 1 patients who would benefit from radiation or chemotherapy.


17.5 POST SURGICAL DIAGNOSTIC TECHNIQUES

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 an x-ray before recommending additional treatment. The difficulty here is that the chest-ray is an imprecise tool, detecting tumors of usually at least a centimeter, and the tumor has spread before it is identified.

17.51 Ct Scan

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

17.511 Studies of Ct Scan for Post-Surgical Stage 1 Patients

A recent study compared post-surgical evaluation with Ct Scan and x-ray. Seven smaller nodules were identified on Ct Scan while only the four larger nodules were seen on x-ray. Ray, (15).


17.6 DEFINING SUBGROUPS OF STAGE 1 PATIENTS WHO WOULD BENEFIT FROM CHEMOTHERAPY

While most stage 1 patients are cured, some are not. Scientists today are attempting to identify risk factors with stage 1 patients.

17.61 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:

“Angiogenesis is a complex regulated process, forming new blood vessels from pre-existing vessels.... The determination of 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, (3).

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 (9) (10).

17.611 Micro-Metastases

Stage 1 patients have no lymph node metastases measured by conventional diagnostic tools. However, a Japanese study measured micro-metastases, which would be undetected by conventional means. Not surprisingly, the extent of such metastases in the lymph nodes negatively impacted long-term survival. Osaki, (16). Similar findings were made in a 1996 study:

“Among the 67 patients available for follow-up with a histopathologic nodal stage of N0, 51 patients had disease classified without nodal micrometastases by our immunohistochemical assay. Their mean relapse-free survival and cancer-related survival were 41.1 months and 44.6 months, respectively. For the 16 patients with nodal micrometastases, the mean relapse-free survival and cancer-related survival were 29.0 months and 36.5 months, respectively. Patients with histopathologic stage N1 disease without further nodal micrometastases (n = 11) exhibited mean relapse-free survival of 34.8 months and cancer-related survival of 38.2 months, compared with six patients with nodal micrometastases who had mean relapse-free and cancer-related survivals of 18.0 months and 23.5 months, respectively.” Izbicki (17)

Measurement of nodal micro-metastases has a clear factual basis. We know the extent of metastasis directly impacts survival. Micro-vessel density, a similar marker, is also reliable. Other chemical markers are showing promise but a consensus is not seen as to which is most reliable or the best predictor. Measuring micro-metastases and micro-vessel density makes sense and should be tested in clinical trials.

17.62 VEGF Factor

Microvessel density measures preliminary indications of metastasis. The metastatic process involves production of VEGF, (vascular endothelial growth factor). Some scientists suggest measuring VEGF levels, and there is some correlation with VEGF levels and later metastasis. Again, patients could be measured following surgery, and consideration given to providing chemotherapy to those patients with high microvessel density and/or VEGF levels. Because there has been some variation in the studies, some scientists would like to see consistent results or some consensus within the medical community about what to measure before providing any recommendation.

17.621 P-53

P-53 is a potent tumor suppressor which has been measured with conflicting results:

“Interestingly, we found no evidence for an effect of P53 expression
level on prognosis. While some investigators have reported that P53 protein expression was a significant factor for poor prognosis in patients with lung cancer, other studies found that P53 expression had no impact on clinical outcome.” Minami (14).

17.622 Combination of VEGF and P-53 Measurement

One study found the prognostic value of either VEGF or P-53 to be limited. However, when both were elevated in stage 1 patients, survival rates markedly decreased. Five year survival with VEGF and P-53 negative was 64% compared with 38% in patients with both factors positive. That makes sense. The activation of VEGF combined with the suppression of P-53 means that a critical factor leading to metastasis is present while a critical regulator is absent. Research is continuing but it would make sense for patients in the dual positive group to consider post-surgical treatment.

17.63 BCL-2

Tumor cells manage to escape apoptosis, or cell death. Where cells are damaged or deficient, apoptosis generally occurs. That process is circumvented in cancer. BCL-2 protects cells from cell death and is therefore associated with various cancers, with its role in lung cancer being researched:

“We found Bcl-2-protein expression with statistically significant association with histology and clinical outcome in 30% of the tumors of this series. These results are in agreement with previous reports 10 and 11 showing that SCCs express Bcl-2 more frequently than adenocarcinomas. We also found in multivariate analysis that Bcl-2 protein expression emerged as a significant marker of poor long-term prognosis; only 7 of 37 patients with Bcl-2–negative tumors had recurrence. Moreover, Bcl-2 also appeared as a prognostic factor on univariate analysis regardless of the histopathologic type and stage subcategories. Bcl-2 is a human proto-oncogene located on chromosome 18 that encodes inhibitors of apoptosis and can act as oncogene by reducing the rate of cell death.”

17.64 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 the measurement did impact the patient’s prognosis. 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 (3).

17.65 Other Measurements

17.651 Cyclin B

Cyclin B1 is a key molecule for G2-M-phase transition during the cell cycle and is overexpressed in various tumor types. Soria (19). One can hypothesize that its presence indicates that cell duplication is occuring and at elevated levels are an indicator of cancer. Soria found:

“Patients with tumors that overexpressed cyclin B1 had significantly shorter survival times than patients with tumors that displayed low levels of cyclin B1 (P = 0.02, log-rank test). About 60% of the patients whose tumors had a low cyclin B1 expression were alive at 5 years compared with only 30% of the patients whose tumors had high cyclin B1 expression .” Soria (18).

Similar findings were made with other types of tumors.

17.652 Glut-1

One study found rates of glucose (sugar) metabolism (Glut-1) of the resected tumor relevant in determining the patient’s survival. Minami (14).
“The appearance of Glut-1 positive clones was associated with aggressive tumor behavior and Glut-1 was significant indicator of poor prognosis in cases of NSCLC.” Minami (14) at 56. Minami reports that “the state of Glut-1 may reflect the biologic behavior of tumor cells.... Brown reported that Glut-1 was the major glucose transporter expressed in NSCLC.” Minami (14) at 56.

17.653 CEA

CEA (Carinoembryonic antigen) is a commonly used tumor marker. Unlike many of the items above, CEA is easily and quickly tested. A recent study found:
“We studied 118 consecutive NSCLC patients who were clinically judged operable and were eventually operated upon... In tumors pathologically classified in stage Ia to IIb, a preoperative CEA level higher than 10 ng/mL was associated with a 67% probability of tumor relapse. In the same stages of disease, a CEA level less than 10 ng/mL increased the baseline probability of no recurrence from 80% to 88%. CONCLUSIONS: In operable patients with NSCLC the frequency of abnormal serum concentrations of CEA is low (17% in our series). However, it is important to identify such a small group of high-risk patients as many of them (in our study, 55% and 70% of those with a CEA value in excess of, respectively, 5 and 10 ng/mL) will develop an early postoperative recurrence. Such patients should be investigated preoperatively by mediastinoscopy or positron emission tomography in even in the absence of suspicious symptoms and signs. Then after an apparently successful operation, they should be carefully followed up. These patients could represent a suitable target for neoadjuvant clinical trials of selected high-risk groups.” Buccheri (18)

17.654 Cox 2 Levels

One oncologist writes, “If you look at all stage I cases there is a clear survival difference for stage I lung cancers for overexpression of COX-2 cases versus those that have negative expression.” Thus, it may make sense to test cox-2 and provide cox-2 inhibitors and other treatment to those with cox-2 positive tumors.

17.66 Conclusion

Various cell characteristics indicate whether the patient was cured by surgery or whether carcinogenic type processes are still occuring. Using one or more of these indicators, we can identify patients at enhanced risk and prescribe some type of post-surgical treatment. However, while many studies have and will be conducted, this analysis remains experimental as scientists struggle to identify which factors are most important and attempt to duplicate results in subsequent tests. One would not be surprised to see multi-faceted tests incorporating multiple factors since cancer itself involves multiple genetic changes.

17.7 POST-SURGICAL GENE THERAPY IRESSA

17.71 Response to Iressa

In a separate chapter, I review Iressa and epidermal growth factor (EGF) inhibitors. EGF is associated with the spread of lung cancer and worse prognosis. In 2004, scientists identified a subgroup of patients who responded particularly well to an anti-EGF drug called Iressa. EGF meets a receptor (EGFR) to create binding and then chemical changes in the tyrosine kinase portion of the cell. Iressa inhibits those chemical changes called.
Scientists found that patients with defects in the tyrosine portion of the EGFR responded particularly well to Iressa. Response rates in some studies exceeded 35% in particular subgroups. Iressa has limited side effects, generally significantly less than chemotherapy, because Iressa impacts only a specific cell, not a large group of dividing cells.
Thus it may make sense to test individuals for this defect and if the testing is positive prescribe Iressa to prevent possible spread of the tumor.

17.72 Who Should be Tested

Not all patients are likely to have this defect. Studies found that non-smokers and very light former smokers with adenocarcinoma or bronchoalveolar cancer were likely to have the defect. Certainly there is a strong argument for testing patients in this subgroup.
For others testing might make sense if only to exclude some patients. Those with normal (called wild) type EGFR are less likely to benefit. Those with some defects though not fitting the precise pattern of responders might still consider some treatment. EGFR treatment is evolving, and more is being learned each month.

17.73 Testing Cost and Procedure

Today EGFR testing can be performed at Harvard’s Center for Genetics and Genomics, in Cambridge, Massachusetts. The current cost if $850. As testing becomes effective, more testing laboratories will offer it, reductions will be negotiated by HMO’s and hospitals, and procedures will develop. Whether today’s insurance carriers will pay the cost remains unclear. Since most stage 1 patients have had surgery, obtaining samples for testing should be easy.

CONCLUSION

In the upcoming years, the stage 1 patient will be followed more closely at the major hospitals, with new forms of genetic testing used to identify potential recurrence or spread at early stages. Some of these institutions will begin utilizing newer drugs like Iressa for post-surgical treatment to inhibit the spread of tumors and improve the long-term survival of stage 1 patients.


REFERENCES

1. Martini, Treatment of Stage 1 and II Disease 339 in Aisner, Comprehensive Textbook of Thoracic Oncology (Williams & Wilkins 1996).
2. 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.
3. Midthun, Endobronchial Techniques in Lung Cancer, Options for Nonsurgical Care. Vol. 101, No. 3, March 1997 Postgraduate Medicine.
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5. Pisters, Surgery and Chemotherapy, 770, in Pass, Lung Cancer (2000).
6. Girling, Fifteen-year Follow-up of all patients in a study of postoperative chemotherapy for bronchial carcinoma,” Br. J. Cancer 1985; 52:867.
7. Mineo, Postoperative adjuvant therapy for stage IB non-small-cell lung cancer, Eur J Cardiothorac Surg 2001 Aug;20(2):378-84.
8. Wada, Postoperative adjuvant Chemotherapy with PVM... Eur J Cardiothorac Surg 1999 Apr;15(4):438-43.
8. 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.
9. Junker, Prognostic Factors in Stage 1/II Non-Small Cell Lung Cancer, Lung Cancer Suppl. 1 (2001) S17-24.
10. Decaussin, Expression of Vascular Endothelial Growth Factor and its two receptors in Non-Small Cell Lung Carcinomas... J. Pathol 1999; 188: 369-77.
11 Adjuvant radiotherapy in non-small cell lung cancer with pathological stage I: definitive results of a phase III randomized trial, Radiother Oncol 2002 Jan;62(1):11-19.
12. Fontanini, Microvessel Count Predicts Metastatic Disease and Survival in Non-Small Cell Lung Cancer, J Pathol 1995; 177: 57-63.
13. Lucchi, et. al, Tumor Angiogeneis and Biologic Markers in Resected Stage I NSCLC, Eur J. Cardiothorac Surg, 1997; 12: 535-41.
14. Minami, Prognostic Significance of p53, Ki-67, VEGF and Glut 1 in resected Stage 1 Adenocarcinoma of the Lung, Lung Cancer 38 (2002) 51-57.
15. Ray, Monitoring Stage 1 and II Lung Cancer Patients Post-Thoracotomy Using Low Dose Spiral CT, Lung Cancer 34 (Suppl. 1 S1-S76, S 41).
16. Osaki, Prognostic Impact of Micrometastatic Tumor Cells in the Lymph Nodes and Bone Marrow of Patients With Completely Resected Stage I Non–Small-Cell Lung Cancer Journal of Clinical Oncology, Vol 20, Issue 13 (July), 2002: 2930-2936.
17. Izbicki, Mode of spread in the early phase of phymmphatic metastases in non-small cell lung cancer: significance of nodal miscrometastases. J Thorac Cardiovasc Surg 1996;112:623-630
18. Buccheri, Identifying patients at risk of early postoperative recurrence of lung cancer: a new use of the old CEA test. Ann Thorac Surg. 2003 Mar;75(3):973-80.
19. Soria, Overexpression of Cyclin B1 in Early-Stage Non-Small Cell Lung Cancer and Its Clinical Implication,Cancer Res. 2000 Aug 1;60(15):4000-4.
20. Hassan, Clinical Significance of Cyclin B1 Protein Expression in Squamous Cell Carcinoma of the Tongue, Clinical Cancer Research Vol. 7, 2458-2462, August 2001.
21 Liao, Vascular Endothelial Growth Factor and Other Biological Predictors Related to the Postoperative Survival Rate on Non-Small Cell Lung Cancer, Lung Cancer, Vol. 33 (2-3) (2201) 125-132.
22. The gene was discovered as the translocated locus in a B-cell Leukemia and thereby acquired its name. The gene has also been associated with B-cell lymphoma.
23. The mammalian Bcl-2 protein family comprises at least 24 members encoded by 20 genes.The various members function as sensors of cellular stress and they receive input from various sources including ... the cytoskeleton, the nucleus and the mitochondria The archetypal family member called Bcl-2 and its pro-survival homologues process most of the information collected by these sensors. Bcl-2 was the first member to be discovered when the encoding gene was found to be translocated in human follicular lymphoma. Bcl-2 protects cells from growth factor deprivation or against exposure to cytotoxic drugs, taxol, cisplatin, glucocorticoids or ionising radiation.
24. Lung Cancer Targeted Therapies, Cox-2 Inhibitors, Retinoids and Aerosolized Delivery, www.webtie.org/sots/Meetings/Lung/June192001/lectures/Transcripts/Dmitrovsky/transcript.htmwww.webtie.org/sots/Meetings/Lung/June192001.
25. Driscolle, Lung Cancer Mollecular Pathology and Methods, (Humana Press, 2002), available online at no charge on Google books.
 

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REVIEWS  
 
Quality Books "This book provides an invaluable resource for anyone who has or who is caring others with Mesothelioma or other Lung cancers. Itprovides a wealth of relevant and useful information on various types of lung cancers, medical trials, treatments and medications. This well researched and comprehensive book is quite unique on the subject. This book also contains a detailed discussion on the emotional burden of Lung Cancer upon the patient and their families and ways to manage it."
                    
 Lorraine Kember. Author of "Lean on Me - Cancer through a Carer's Eyes", "The very mention of the word Cancer, strikes fear into all of us.... From personal experience I know that knowledge is the key to providing a better "quality of life" for the cancer patient. Better understanding of the stages of the disease and of methods and medications available to treat the pain and symptoms caused by it, allow for the patient and those who care for them, to make informed decisions regarding their care. In this way, they are able to regain some control over their lives. Rarely does one find all the information they need in one book, however I believe Howard's well researched and comprehensive book "Lung Cancer & Mesothelioma", is quite unique. It provides a wealth of relevant and useful information including; how various types of cancer are formed, medical trials, available treatments and medications, insight and discussion regarding the emotional burden of cancer upon the patient and their families and ways by which to manage grief. I believe this book will provide an invaluable resource for anyone who has or who is caring for someone with cancer.

 

NEWSLETTER

The Lung Cancer Newsletter is a publication devoted to recent developments in lung cancer treatment and diagnosis.  Published at least 5 times per year the newsletter surveys developments in over 100 medical journals, excerpting significant findings and trends in cancer treatment, chemotherapy, cancer etiology, clinical trials, and more.   The newsletter is compiled by Howard Gutman, author of the upcoming book Lung Cancer and Mesothelioma.    

Topics Covered in the July, 2004 Newsletter

1. Abstracts and Presentations at the June, 2004 American Society of Clinical Oncologists (ASCO) Conference
2. Tissue typing to determine which patients are likely to benefit from Iressa.
3.  New drugs and treatments.
4.  Bibliography of available lung cancer publications and coferences.

Cost and Method of Delivery

The newsletter cost $75.00 per year and is emailed to subscribers.  For those with a proven financial need, the newsletter can be supplied at no cost.

Profile

Howard Gutman is the author of the upcoming book, Lung Cancer and Mesothelioma (Exlibris Printing Co. 2004).   He served as a caregiver for a family member with lung cancer, was a member of the board of directors of a leading cancer support, and is an attorney specializing in lung cancer legal issues.

Contact Information

Telephone

 

Howard A. Gutman, 973-257-9400 

FAX

973-257-9128

Postal address

1259 Route 46, Troy Office Center, Parsippany, New Jersey 07054

Email

Howian@aol.com

The foregoing is intended only to provide general information.  The author of the book Lung Cancer and Mesothelioma is not a physician and the information is not intended to be the basis for medical treatment.   Other information may be important to your condition.   For advice and information regarding your medical condition, please see a qualified physician.  No warranty or representation is made as to the accuracy, completeness or applicability of the material set forth herein.