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Observation-Only Management of Early Stage, Medically Inoperable Lung Cancer^*

Poor Outcome

^* From the Department of Radiation Oncology, Indiana University, Indianapolis, IN.

Correspondence to: Ronald C. McGarry, MD, PhD, Department of Radiation Oncology, Indiana University, 535 Barnhill Dr, RT 041, Indianapolis, IN 46202

	Abstract

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Study objectives: To assess the treatments received and outcomes of patients with early stage non-small cell lung carcinoma (NSCLC).

Design: A retrospective study of patients identified from the institutional tumor registry between 1994 and 1999.

Setting: The Richard L. Roudebush VA Medical Center, Indianapolis, IN.

Patients: All patients with stage I and II NSCLC as identified above.

Interventions: None.

Measurements and results: Of 128 patients identified, 49 patients received no cancer treatment, 36 patients received radiation therapy only, and 43 patients were treated with primary surgery. Median ± SD survival time following surgery was 46.2 ± 3.15 months; for no treatment, 14.2 ± 2.37 months (p = 3.2 x 10^-6); and radiotherapy alone, 19.9 ± 5.6 months (p = 0.0005). Of those who received no specific cancer treatment, 14 patients refused treatment and the remainder were not treated for a variety of medical reasons. Cause of death was cancer in 53% of untreated patients and 43% for those receiving radiotherapy. Radiotherapy was administered for postobstructive atelectasis, hemoptysis, increasing tumor size, pain, pleural effusion, and medical inoperability. Radiation dosages had no apparent standard. No significant differences in survival were found for patients receiving radiotherapy with either curative or palliative intent (20.3 months vs 16.0 months, respectively; p = 0.229).

Conclusions : Within the limitations of this retrospective study, it appears that untreated early stage lung cancer has a poor outcome, with > 50% of patients dying of lung cancer. Surgery remains the treatment of choice, but lung cancer screening programs will result in increasing numbers of medically inoperable patients with no clear policies for their management.

Key Words: medically inoperable • non-small cell lung cancer • observation • radiotherapy • surgery

Lung cancer remains the most frequent cause of cancer death in both men and women in North America. It was estimated that there were 164,100 new lung cancer cases in the United States in the year 2000, with an estimated 156,900 deaths due to this highly lethal malignancy. This accounts for approximately 14% of all cancers diagnosed but 28% of all cancer deaths.¹ This suggests that the risk of developing a bronchogenic carcinoma is approximately 1 in 12 for male subjects and 1 in 18 for female subjects (birth to death, based on cases diagnosed during from 1994 to 1996).¹ Of the 419 new cases of cancer diagnosed at the Richard L. Roudebush VA Medical Center in 1998, lung cancer was the most common, comprising 131 cases, which reflects the overall aging of the US Department of Veterans Affairs population and apparent high rates of tobacco abuse. Of these, 112 cases were non-small cell lung carcinoma (NSCLC). Approximately 25% of these patients presented with stage I or II disease. Optimally, the definitive management of these cases of early stage lung carcinoma is considered to be surgical, with a 60 to 80% 5-year survival time.^{2 3} In contrast, the management of those patients with early stage bronchogenic carcinoma deemed medically inoperable is less clear. Involved-field radiotherapy is generally considered the treatment of choice for those patients who cannot undergo surgery,⁴ but no randomized trials have examined the benefit of radiotherapy to patients compared with observation. With the advent of nationwide programs screening high-risk patients for lung carcinoma, it will be important to understand the natural history of the disease to develop a rational approach to the treatment of medically inoperable lung cancer. We review the results of the management of stage I and II lung cancers within the Richard L. Roudebush VA Medical Center between 1994 and 1999.

	Results

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Patient Population
All patients with a diagnosis of stage I and IIa NSCLC (T1–2N0–1M0) as defined by the American Joint Committee on Cancer (1997) were retrieved from the institutional tumor registry at the Richard L. Roudebush VA Medical Center. All cases had been reviewed following diagnosis by the institutional multidisciplinary tumor conference where staging and disposition were discussed. Included in the analysis were those patients with squamous cell, adenocarcinoma, and non-small cell carcinoma not otherwise specified. The time period covered included from 1994 to 1999 and was stratified by those patients receiving no therapy, radiation therapy only, or surgery only. One hundred twenty-eight patients were identified for analysis. Of these, 49 patients (45 node negative and 4 T1 node positive) were found to have received no treatment, 36 patients (32 node negative and 4 T1 node positive) received radiation therapy only, and 43 patients (all node negative) were treated with primary surgery. Probability of survival from time of diagnosis was calculated by Kaplan-Meier method (Fig 1 ), and a log-rank test was used to provide pairwise treatment comparisons.

View larger version (13K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Probability of survival from time of diagnosis for patients with stage I or II NSCLC by treatment modality (solid line = no treatment; dotted line = treated with radiotherapy; broken line = surgery only).

Stage I and II Patients With Surgical Resection
Forty-three patients received curative resection, all with lobectomy. Mean age of these patients was 66 years (mean FEV₁, 2.09 ± 0.66 L). Average size of tumors resected was 3.04 cm. Median survival time was 46.2 ± 3.15 months, which was highly significant compared with either untreated patients (p = 3.2 x 10^-6) or those receiving radiotherapy (p = 0.0005).

	Discussion

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Surgery is the preferred form of treatment for early stage NSCLC, with many reviews showing a 60 to 80% 5-year survival rate.^{2 3} The data reported here confirm this optimistic outlook. In contrast, the outcome of the subset of patients reviewed here who did not undergo surgical management of their cancers was dismal. Of the 128 stage I and II patients seen at the Richard L. Roudebush VA Medical Center between 1994 and 1999, 85 patients (66%) were declared inoperable, most commonly for medical reasons. Due to the lack of prospective trials to assess the benefit of definitive radiotherapy to patients with early stage lung carcinoma, no firm treatment policies for these patients are in place. As seen in the patients managed with radiotherapy only, many different radiation regimens were used. The characteristics of the patients and their reason for referral for radiotherapy is predominantly that of palliative intent as the patient’s disease progressed and they began to experience symptoms (eg, atelectasis, hemoptysis). Radiotherapy seems to have been reserved for symptomatic therapy rather than with curative intent. We attempted to stratify patients based on treatment intent, comparing those who received radiotherapy with curative intent with those who received palliative courses of treatment only. While the median survival time of those patients treated with curative intent was approximately 5 months longer than the patients undergoing palliative radiotherapy, statistical significance was not achieved, likely due to the small numbers involved. The cause of death in the patients receiving no therapy was lung cancer in 53% of patients. In this retrospective review, only the International Classification of Disease, Ninth Revision cause of death is available, listing lung cancer vs other causes of death, eg, cardiac, stroke, etc. Given that some of the patients had no cause of death reported in the registry, the estimates of cancer as cause of death may be conservative. It is clear that many patients with initial diagnoses with stage I or II lung cancer will die of their cancer despite the presence of many comorbidities.

Local radiotherapy to a limited volume of tissue is considered the standard therapy for patients with stage I or II NSCLC who do not receive surgery due to refusal or medical comorbidity; however, no randomized trials to compare the outcome of radiotherapy to observation only have been done. Thus, the natural history of untreated NSCLC is not clear. Vrdoljak et al⁵ reviewed 130 patients with newly diagnosed lung cancer between from 1980 to 1987 and found that essentially all patients died within 36 months of diagnosis. Due to the rarity of untreated early stages, no T1N0 patients and only one T2N0 patient were included in the analysis. This study confirms the dismal outcome for untreated lung cancer.

Flehinger and Melamed⁶ reviewed a multi-institutional screening trial done at Memorial Sloan Kettering, Johns Hopkins, and the Mayo Clinic, in which each clinic screened 10,000 high-risk patients, randomizing each to either chest radiography every 12 months vs chest radiography and sputum cytology every 12 months with sputum cytology every 4 months. Within this study, a series of 45 patients had stage I lung cancers diagnosed and received no therapy. The medically inoperable/refusal rate in these three institutions varied between 5% and 21%. Most patients in this group died of lung cancer, and only two patients survived for 5 years. The authors concluded that if it were true that these small, early stage lung cancers would remain dormant for many years without treatment, then a substantially higher percentage of this subgroup of patients would have survived for 5 years compared to the poor outcome observed.

The present study does not answer the question of the benefit of local radiotherapy in the treatment of early stage, medically inoperable NSCLC. The lack of a consistent policy for the management of these patients has resulted in many of them being observed for significant periods of time with radiotherapy reserved for symptomatic or palliative therapy. Radiotherapy delivered to these patients also was found to be offered in a nonconsistent manner. Nonetheless, significant numbers of those patients not receiving therapy died of their cancer. The approach to management of these patients is not clear, but the trend to screening of patients for early stage NSCLC will result in the identification of increasing numbers of patient for whom therapy decisions other than surgery must be made. The malignant nature of lung cancer has made prospective clinical trials with a best supportive care arm for these early stage lung cancers not feasible. Thus, the benefit of conventional local radiotherapy for these patients and the natural history of early stage lung cancer become relevant.

	Footnotes

 
Abbreviation: NSCLC = non-small cell lung carcinoma

Received for publication April 17, 2001. Accepted for publication September 13, 2001.

	References

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1. Cancer facts and figures 2000. 2000,28-31 American Cancer Society Atlanta, GA.
2. Flehinger, BJ, Kimmel, M, Melamed, MR (1992) The effect of surgical treatment on survival from early lung cancer: implications for screening. Chest 101,1013-1018[Abstract/Free Full Text]
3. Gail, MH, Eagan, RT, Feld, R, et al (1984) Prognostic factors in patients with resected stage I NSCLC: a report from the lung cancer study group. Cancer 54,1802-1813[CrossRef][ISI][Medline]
4. Cheung, PCF, MacKillop, WJ, Dixon, P, et al (2000) Involved field radiotherapy alone for early stage non-small-cell lung cancer. Int J Radiol Oncol Biol Phys 48,703-710[CrossRef][ISI][Medline]
5. Vrdoljak, E, Mise, K, Sapunar, D, et al (1994) Survival analysis of untreated patients with non-small-cell lung cancer. Chest 106,1797-1800[Abstract/Free Full Text]
6. Flehinger, BJ, Melamed, MR (1994) Current status of screening for lung cancer. Chest Surg Clin N Am 4,1-15[Medline]

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (33) Citing Articles via Google Scholar Google Scholar Articles by McGarry, R. C. Articles by Timmerman, R. Search for Related Content PubMed PubMed Citation Articles by McGarry, R. C. Articles by Timmerman, R.