I. Introduction

Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. The population of elderly people increases and lung cancer is also the most common cause of cancer deaths aong this population. More than 50% of all patients with NSCLC are older than 65 years and about one-third of all patients are >70 years old at the time of diagnosis (Mountain, 1997).

However, there is no standard chronological age to consider a person as “ elderly”. In most of the historical series this was defined by the age of 65 or older, but it is not an exact definition since health status differs and there is a great heterogeneity of patients in this group according to functional organ capacity. Therefore, biological age should be defined individually and before making a treatment decision a careful evaluation of functional status, coexisting diseases, nutritional status, psychological functioning, and social support should be performed.

II. Surgery in elderly patients with early stage NSCLC

The five-year survival rate for patients with Stage I NSCLC is better than 60% and surgery is the treatment of choice for patients in early stage (I/II) NSCLC. Resection for Stage IIIA patients is acceptable if the affected N1 lymph nodes can be resected, or only micrometastatic disease is present in N2 lymph nodes, or restaging after neoadjuvant therapy shows no residual cancer in N2 lymph nodes. (Mountain, 1997). Although, lung cancer resection in elderly patients is justified and has decreasing morbidity and mortality rates, age is sometimes used as an excuse not to resect lung cancer. In a recent analyze by Dexter et al. it was determined that of the 33% of elderly patients who had stage I or II disease, only 6% underwent surgical resection (Dexter et al, 2004).

O’Connell et al, (2004) recently reviewed elderly patients for cancer-directed surgery for localized adenocarcinoma of the breast, esophagus, stomach, pancreas, colon, rectum, non-small-cell lung carcinoma and sarcoma and found out that rates of cancer-directed surgery (CDS) declined steadily with increasing age for all these tumors beginning at 60 years (O'Connell et al, 2004).

Despite the fact that curative resection should be performed in older patients, the type of the resection is discussed in many studies since the extent of surgery directly influences the overall morbidity and mortality. In most of the studies (Bates, 1970; Whittle et al, 1991; Damhuis and Schutte, 1996; Janssen-Heijnen et al, 2004), pneumonectomy is accompanied by an increase in the morbidity and mortality in elderly patients thus especially right pneumonectomy should be performed only in highly selected patients (Teeter et al, 1987; Au et al, 1994).

Lobectomy or sub-lobar resection is preferred as a curative resection in many studies for older adults. The postoperative complications are lower than the patients who undergo pneumonectomy. Oliaro et al. analyzed patients who were 70 years and older undergoing curative resection. Postoperative complication rates were 78.5% for patients receiving pneumonectomy and 58% for patients undergoing lobectomy or wedge resection. All cases of postoperative death occurred in patients who were treated with pneumonectomy. Prognostic factors were poor performance status (WHO 2 or more), chronic obstructive pulmonary disease, and elevated levels of blood urea nitrogen (Oliaro et al, 1999).

In a different study by Whittle et al. most of the patients were treated with standard lobectomy. The major complication rate was 11%, and per operative death was seen in 3.7% of patients. The survival rates for patients with Stage I disease were 86% at one year, 62% at three years, and 43% at five years. The authors concluded that postoperative mortality rises with increasing age (Whittle et al, 1991).

Lobectomy is now the most frequently performed procedure in the elderly NSCLC patients, though pneumonectomy can be performed in selected cases. However lobectomy, and pneumonectomy can hardly be compared directly some recent studies report similar results for pneumonectomy and lobectomy (Au et al, 1994; Sioris et al, 1999) while most of the studies report higher operative mortalities (17%-30%) with pneumonectomy (Bates, 1970; Kirsh et al, 1976; Harviel et al, 1978; Yellin et al, 1985). Since almost all deaths are caused by cardiopulmonary adverse effects (Harviel et al, 1978; Sherman and Guidot, 1987; Mane et al, 1994), it is necessary to carefully evaluate patients preoperatively and select appropriate surgical procedures (Ishida et al, 1990; Roxburgh et al, 1991). Using modern surgical and imaging techniques and advances in anesthesiology and per operative care can also reduce postoperative mortality and morbidity (Tsuchiya et al, 1981; Ginsberg et al, 1983; Ishida et al, 1990; Thomas et al, 1993; Morandi et al, 1997).

The effect of increasing age on the incidence of major complications or postoperative death is controversial. While some studies (Ginsberg et al, 1983; Sherman and Guidot, 1987; Deneffe et al, 1988; Whittle et al, 1991; Romano and Mark, 1992; Thomas et al, 1993; Cangemi et al, 1996; Damhuis and Schutte, 1996) demonstrated older age as an adverse prognostic factor, there are also studies that found no significant relationship between age and postoperative complications (Ishida et al, 1990; Breyer et al, 1981; Nagasaki et al, 1982; Kadri and Dussek, 1991).

Yamamoto, et al, 2003 analyzed the surgical results of 797 patients with Stage I NSCLC and found out that patients aged 70 and older had similar 5- and 10-year survival rates compared with younger patients (Yamamoto et al, 2003).

In a different study, older age (defined as 65 years or more), anemia, and higher stage were found as prognostic factors for patients who underwent surgical resection for Stages I and II NSCLC. Patients older than 65 had a shorter event-free survival time (34 vs. 55 months, p= 0.002) and overall survival (39 versus 58 months, p= 0.002) compared with younger patients (Jazieh et al, 2000).

Van Rens et al. analyzed 2,361 patients who were treated with curative resection for Stages I, II, and IIIA NSCLC. The overall five-year survival rate for patients younger than 65 was 44% compared with 38% for older patients (p= 0.001); however, the authors noted that survival rates were similar for as long as four years after surgery, and thus the five-year survival rate difference may be secondary to comorbid disease (Van Rens et al, 2000).

Kamiyoshihara et al. analyzed 160 patients with non-small cell lung cancer underwent lobectomy or pneumonectomy with mediastinal lymph node dissection. Of these, 37 (23%) were 70 years of age or older. The outcome of this group was compared with 123 non-elderly patients. Five- and 10-year survivals in the elderly patients were 35.1%, and 24.3%, respectively. In outcome more than 5 years from operation, elderly patients had a significantly poorer prognosis than non-elderly patients by any causes of death, but a similar prognosis by primary death (p=0.04). Deaths from non-tumoral reasons were more in the elderly group than non-elderly patients with no significant difference (p=0.6) (Kamiyoshihara et al, 2000).

Mane et al. reviewed 1433 patients with lung cancer concerning tobacco use, stage of disease, treatment and survival rate of patients treated surgically. A comparison was made between patients aged 65 or less with those over 65. The stage of disease at the time of diagnosis was similar in both groups but the distribution by histological type showed significant differences (p < 0.05) with a higher percentage of squamous carcinoma in the younger group (54% versus 44%). Surgery was performed in 30% of the patients aged 65 years or less but only in 19% of the older cases (p < 0.05). There was no difference in the survival of younger and older patients (Mane et al, 1994).

Froeschle et al. analyzed 70 patients with 70 years of age or older who underwent surgery for lung cancer. Standard lung resections were performed in 42 cases and 17 patients underwent enlarged resections. In the postoperative period, complications occurred in 32 cases (47%). The overall operative mortality rate of 13% was mainly due to concomitant cardiovascular diseases and enlarged lung resections (Froeschle et al, 1996).

Pagni et al. analyzed 1506 patients with NSCLC treated by lung resection for perioperative morbidity and mortality. 385 (25.6%) patients aged 70 years and older were operated. Operations included 293 (77%) lobectomies, 24 pneumonectomies (6%), 16 bilobectomies (4%) and 52 wedge or segmental resections (13%). The pathology was bronchogenic carcinoma in 89% and metastasis or other tumours in 11% of patients. The mortality for all resections in elderly group was 4.2% (16/385) and was 1.6% for the control group. Mortality in the octogenarian group was 2.8%. Female gender correlated with a decreased risk of death, with only two of 16 deaths in females (P < 0.005). Overall morbidity was higher in the study than in control patients (34% vs. 25%), although major morbidity was similar in both groups (13.2% vs. 13%). Abnormal pulmonary-function testing and positive cardiac history did not correlate with increase overall or specific risk. Pneumonectomy carried a higher risk for death, with three of 24 deceased (12.5%; P < 0.05). The authors concluded that, age alone no longer appears to be a risk factor for mortality and pneumonectomy should undertaken cautiously in this age group. Based on this data, functional elderly patients should not be denied curative lung resection based on age alone (Pagni et al, 1998).

Although Romano and Mark, (1992) identified advanced age (>79 years) as the strongest risk factor for death, Harvey et al, (1995) and Higgins and Beebe, (1967) reported that survival after surgery was negatively correlated with increasing age.

In a recent study by Port et al, (2004) 61 elderly patients were evaluated. The surgical techniques were 46 lobectomies, 6 segmentectomies, 5 wedge resections, and 4 pneumonectomies. There was one perioperative death (1.6%) and the overall complication rate was 38% with a major complication rate of 13%. Overall 5-year survival was 82% for stage IA patients. Patients with more advanced disease had a significantly worse survival. The authors agree that appropriately selected elderly patients with early stage disease should be offered anatomic surgical resection for cure and should not be denied an operation on the basis of age alone (Port et al, 2004).

Videothoracoscopic lobectomy can be used in the treatment of stage I and II lung cancer. Roviaro et al, (2004) analyzed 257 patients with stage I lung cancer, 193 patients underwent VATS lobectomy. There was no intraoperative mortality and no recurrence. The survival rates at 3 years and 5 years were 77.7% and 63.64%, respectively. T1N0 patients had a better survival curve at 3 years and 5 years (83.50% and 70.21%, respectively) compared to T2N0 patients (71.13% and 56.12%). Patients < 70 years of age had better 3-year and 5-year survival rates (82.37% and 73.32%, respectively) than those > 70 years of age (57.49% and 37.09%). The results showed that VATS approach match the "best" results reported in literature following conventional surgery and this minimally invasive surgery seems to imply reduced tissue damage and decreased impairment of immunologic function especially in elderly patients (Roviaro et al, 2004).

The results of these studies show that surgery is the main treatment for early stage NSCLC in both young and elderly patients. The risk of postoperative complications can be minimized with the selection of the surgical procedure, careful preoperative evaluation and attentive postoperative care.

III. Radical radiotherapy in early stage NSCLC

Radical radiation therapy is used for curative intent in elderly patients who are not candidates to surgery because of poor performance status, old age or refusal of surgery in early stage NSCLC or who can not tolerate chemoradiotherapy in locally advanced disease, however, the survival rates are lower than those reported after surgery. Gauden et al retrospectively analyzed 347 patients with T1 and T2N0M0 tumours who were treated with radical radiotherapy. The median age was 70 years and the minimum radiation dose was 50 Gray. 5-year survivals were 22% in the patients aged < 70 years and 34% in patients > or=70 years. Median survivals were 22 months and 26 months respectively. 5-year disease free survivals were 18% and 30% with no statistical significance. The 75-79-year group showed better survival than other age groups with the 5-year overall survival for this group being 53%, while the 5-year recurrence free survival was 45%. The toxicity in both groups was minimal. The authors concluded that radical radiation therapy with curative intent may be a viable alternative to surgery in those elderly patients who either refuse surgery or are judged to be unfit for operation (Gauden et al, 2001).

Pignon et al, 1998 analyzed 1208 patients receiving chest irradiation in six EORTC randomized trials. Patients were split into six age ranges from 50 to 70 years and over. Data regarding age and acute toxicity were available for 1208 patients who experienced 640 grade > or =1 toxicities. The difference in distribution over age was not significant for acute nausea, dyspnea, oesophagitis, weakness and WHO performance status alteration. Weight loss was significantly different with regards to age with a trend toward increased weight loss in older age groups (P=0.002). 1082 grade > or =1 late toxicities were recorded in 935 patients. The mean time to complication was 13 months and was similar in all age groups. Forty percent of patients were free of complication at 4 years showing no significant difference between age groups (P=0.57). For grade >2 side-effects, late dyspnea and late weakness, there was also no significant difference, including grade >2 late oesophagitis (P = 0.1). The results of this study showed that age alone is not a sufficient reason to exclude patients in good general condition with thoracic tumor from curative radiotherapy when medically indicated (Pignon et al, 1998).

The proportion of patients who receive radiation decreases with increasing age. Among patients who receive treatment, the likelihood of receiving radiation is higher than any other therapy (p=0.0008)(41). Hillner et al. evaluated 1706 NSCLC patients of whom 1212 were age > or=65 years ("elderly"). Radiation was used more often in elderly patients compared with younger patients with local disease (30.5% vs. 14.0%) but less often in patients with distant disease (76.2% vs. 54.9%). In comparison with elderly patients, younger patients more often were treated with surgery for local disease (80.2% vs. 54.8%) and surgery alone or in combination with radiation for regional disease (51.9% vs. 32.0%) (Hillner et al, 1998).

Different fractionation schedules and new applications of radiotherapy are currently available due to improvements in technology. In a recent study by Ghosh et al, 2003 lobectomy, wedge resection (WR) or continuous hyperfractionated accelerated radiotherapy (CHART) were compared in 215 patients with T1N0 NSCLC aged >70 years. Survivals at 1 and 5 years for patients undergoing WR, lobectomy and CHART were 98% and 74% vs. 97% and 68% vs. 80% and 39%, respectively (P=0.0484). The frequency of local/regional recurrence in the WR group (19.1%) was not significantly higher than in the lobectomy group (18.4%, P=0.38) when compared to the CHART group (27%, P=0.07). The results of this study showed that loco-regional recurrence and survival after WR, and lobectomy in elderly patients with stage I NSCLC were comparable and CHART was a reasonable treatment option for those who are not suitable candidates for surgery (Ghosh et al, 2003).

Lester et al. used CT-planned accelerated hypofractionated radiotherapy in the radical treatment of non-small cell lung cancer. 135 patients with stage I-IIIB NSCLC were treated with CT-planned accelerated hypofractionated radical radiotherapy to a dose of 50-55Gy in 15-20 fractions over 3-4 weeks. The 2-year overall and cause-specific survival for all patients was 44.4% and 47.8% respectively. Overall median survival was 21 months. There were no reports of severe acute or late treatment-related toxicities (Lester et al, 2004).

Stereotactic hypofractionated high-dose irradiation for stage I nonsmall cell lung carcinoma was evaluated by Onishi et al, 2004 245 patients with a median age of 76 years (T1N0M0, n=155; T2N0M0, n=90) were treated with stereotactic hypofractionated high-dose radiotherapy. A total dose of 18-75 gray (Gy) at the isocenter was administered in 1-22 fractions. The median calculated biologic effective dose (BED) was 108 Gy (range, 57-180 Gy). Grade > 2 toxicities were observed in only 6 patients (2.4%). Local progression occurred in 33 patients (14.5%), and the local recurrence rate was 8.1% for BED > or=100 Gy compared with 26.4% for < 100 Gy (P < 0.05). The 3-year overall survival rate of medically operable patients was 88.4% for BED > or=100 Gy compared with 69.4% for < 100 Gy (P < 0.05). The authors concluded that hypofractionated high-dose STI with BED < 150 Gy was feasible and beneficial for curative treatment of patients with Stage I NSCLC (Onishi et al, 2004).

Wulf et al used stereotactic radiotherapy for primary lung cancer and pulmonary metastasis in 61 medically inoperable patients.The patients were treated with stereotactic radiotherapy at 3 x 10 Gy (n=19), 3 x 12-12.5 Gy to the planning target volume enclosing 100%-isodose, with normalization to 150% at the isocenter; n=26) or 1 x 26 Gy to the planning target volume enclosing 80%-isodose (n=26). The actuarial local control rate was 92% for lung cancer patients and 80% for metastasis patients > or =1 year after treatment and was significantly improved by increasing the dose from 3 x 10 Gy to 3 x 12-12.5 Gy or 1 x 26 Gy (p=0.038). The overall survival rate after 1 and 2 years was 52% and 32%, respectively, for lung cancer patients and 85% and 33%, respectively, for patients with metastasis, was impaired because of systemic disease progression. No severe acute or late toxicity was observed, and only 2 patients (3%) developed symptomatic Grade 2 pneumonitis, which was successfully treated with oral steroids (Wulf et al, 2004).

The results show that stereotactic radiotherapy is a very effective treatment option for lung cancers without significant complications in medically impaired patients who are not amenable to surgery.

Respiratory gated radiation therapy is developed for minimizing respiratory-induced anatomic motion and found to be practical during both simulation and treatment. With proper patient selection and training, this system is currently being used in some radiotherapy departments.

Regarding the results of these studies doses ≥ 65 Gy with continuous fractionation are recommended and the target volume should enclose the location of tumor volume with the ipsilateral hilum and the adjacent mediastinum (Dosoretz et al, 1993).

IV. Radiotherapy alone in locally advanced NSCLC

Radical radiotherapy is also a good management for locally advanced NSCLC in the elderly patients who can’t tolerate chemoradiotherapy. Zachariah et al. evaluated elderly patients who were treated with 59.40–66 Gy with standard fractionation. The response rate was 43% and only 24% of patients had progressive disease The authors concluded that aggressive radiotherapy should not be withheld from older patients because of chronological age alone since older patients with good functional status tolerate radiotherapy as well as younger patients and have comparable tumor response and survival rates (Zachariah et al, 1997).

Lonardi et al. evaluated the outcome of 48 patients, aged 75 years and over, treated with radiation therapy for advanced (stage IIIA-B), inoperable, symptomatic NSCLC. A median dose of 50 Gy was delivered to the primary site and mediastinum with standard fractionation. 21 patients had partial remission, 17 stable disease, and nine had progressive disease. Toxicity was negligible and mainly consisted of grade I-II esophagitis. Overall median survival was 5 months but dose-related survival was much better in patients given at least 50 Gy than in those treated with lower doses: 52% versus 35% at 6 months, and 28% versus 4% at 13 months. The results confirmed that radiation therapy could be safely delivered to very aged patients with advanced NSCLC (Lonardi et al, 2000).

In a retrospective trial by Nakano et al. in locally advanced NSCLC patients, median survival was 11.5 months in the younger group and 6.3 months in the elderly group (p=0.0043). A good performance status, age of <75 years, and good response to treatment were found as significant prognostic factors (Nakano et al, 1999).

Tombolini et al. analyzed 41 medically inoperable IIIA and IIIB elderly patients (aged > or=70 years), treated with radiotherapy alone. The 2-year overall survival and disease free survival were respectively 27% and 14.6%. Patients presenting with weight loss > 10% experienced 14% overall survival at 2 years compared to 58% for those without weight loss (p=0.0027). Patients with tumor size less than 4 cm had a overall survival of 64% at 2 years but patients with tumor size > 4 cm had only a 2 year survival of 7% (p=0.0009). They concluded that radiotherapy is a good management for locally advanced NSCLC in elderly patients assuring good quality of life, high rates of relief of symptoms and overall and disease free survival similar to those obtained with chemotherapy and chemotherapy plus radiotherapy (Tombolini et al, 2000).

Rengan et al, 2004 investigated 72 patients with Stage III NSCLC and gross tumor volumes (GTV) of greater than 100 cc which were treated with three-dimensional conformal radiotherapy (3D-CRT) to understand whether high-dose radiation improved local control. Patients were divided into two groups: those treated to less than 64 Gy (37 patients) and those treated to 64 Gy or higher (35 patients). The 1-year and 2-year local failure rates were 27% and 47%, respectively, for Stage III patients treated to 64 Gy or higher, and 61% and 76%, respectively, for those treated to less than 64 Gy (p=0.024). The median survival time for patients treated to 64 Gy or higher was 20 months vs. 15 months for those treated to less than 64 Gy (p=0.068). A 10 Gy increase in dose resulted in a 36.4% decreased risk of local failure. These data suggested that administration of higher doses using 3D-CRT improves local control in Stage III NSCLC patients with large GTVs (Rengan et al, 2004).

Radiation is frequently used for palliation of lung cancer-related symptoms. Radiotherapy can palliate thoracic pain and hemoptysis in 60% to 80% of cases and control other local symptoms in approximately 50% to 70% of cases. The median duration of benefit is 7 to 14 weeks. The main toxicity is self-limiting esophagitis (Higgins and Beebe, 1967).

V. Conclusion

Appropriate treatment for elderly patients with early stage non-small cell lung cancer should be surgical resection for cure and these patients should not be denied for an operation on the basis of age. Patients who have good performance status and no other medical problems should be offered standard resection. Extended resections should be avoided when possible. Radical radiation therapy is used for curative intent in elderly patients who are not candidates to surgery because of poor performance status, old age or refusal of surgery in early stage NSCLC or who can not tolerate chemoradiotherapy in locally advanced disease but the survival rates are lower than those reported after surgery.

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Drs Cuneyt Ulutin and Gorkem Aksu