Results of Lung Cancer Surgery for Octogenarians

Abstract

Purpose: Growing number of elderly lung cancer patients reflecting a lengthening life span has become a serious problem. Purpose of this study was to elucidate the short and long-term outcome of the surgery for octogenarians, and to evaluate the role of lung cancer surgery for this high age group.

Methods: The patients with lung cancer aged 80 years or more who underwent the surgery at our institute from January 1998 through December 2012 were retrospectively analyzed by chart review, and the operative mortality, morbidity and the long-term survival were assessed.

Results: Out of a total of 1107 patients with primary lung cancer who received surgery during the study period, 94 were octogenarians (8.5%). Sixty-nine patients (73.4%) had preoperative co-morbidity including hypertension in 50 (53.2%), coincidence of other malignancy in 35 (37.2%), anti-coagulant therapy in 29 (30.9%). Twenty-six patients (27.7%) had major or minor postoperative morbidity, and one (1.1%) died due to bronchopleural fistula. Overall-5-year survival rate was 57.5%. Univariative and multivariative analysis using Cox proportional hazard model revealed that male gender and non-adenocarcinoma histology were significant risk factors for poor prognosis.

Conclusion: Gender and histology should be taken into account in preoperative evaluation of indication for lung cancer in octogenarians.

Introduction

Lung cancer has become the leading cause of death in many countries including Japan.¹⁾ Reflecting the rapid aging society in Japan, lung cancer patients in elderly are remarkably increasing. Management of lung cancer in elderly patients, especially in octogenarians, has become challenging problem. Current guidelines for lung cancer surgery suggest that advanced age alone is not a contraindication to surgery under the condition of careful patient selection and attentive postoperative care.²⁾ But the precise information of postoperative morbidity/mortality and the outcome is still limited.³⁾ We retrospectively reviewed the results of lung cancer surgery for octogenarians in our institute, and evaluated the possible risk factors.

Materials and Methods

The patients with lung cancer aged 80 years or more who underwent the surgery at our institute from January 1998 through December 2012 were retrospectively analyzed by chart review, and the operative mortality, morbidity and the long-term survival was assessed. Before the study, the Research Review Board at our institution examined and approved our research protocol in accordance with the Declaration of Helsinki. All the patients provided written informed consent for the review of their medical charts before the surgery. Preoperative information, including past medical history, physical examination, blood test, electrocardiography, pulmonary function test, were collected. In case with cardiac co-morbidity, the data of echocardiogram and cardiac catheterization were recorded. The preoperative examination for staging included computed tomography (CT) scan of the chest and upper abdomen, CT or magnetic resonance imaging of the brain, and bone scintigraphy or F-18 fluorodeoxyglucose-positron emission tomography (FDG-PET). The tumor stage was determined according to the seventh edition of the Tumor, Lymph Nodes, Metastasis (TNM) staging system of the International Union Against Cancer, and the histologic tumor type was determined according to the third edition of the World Health Organization classification.^4,5) Operative indication for lung cancer patient aged over 80 was determined based on performance status (PS): 0 to 1, clinical stage: I to III expected to be completely resectable, and mental status: not senile. As for operative procedure, video-assisted thoracic surgery (VATS) was first choice, but if not favorable for VATS procedure, open thoracotomy was selected.

The operative mortality/morbidity and the overall survival (OS) were assessed. Follow-up information was obtained from the medical records or by telephone interviews. The OS was calculated from the date of surgery to the time of death. The interval between the follow-ups was every 3 months for the first two years and every 4 months for up to 5 years. A full examination and a chest X-ray were performed at each visit, and a CT scan was performed annually. Other investigations were determined by clinical necessity.

Statistical analysis was performed using JMP 10.0 pro (SAS institute Inc., Cary, North Carolina, USA). Survival was calculated by the Kaplan-Meier method, and differences in survival were assessed by Log-rank test. Univariative and multivariative analysis were calculated by Cox proportional hazard model. A p value <0.05 was considered statistically significant.

Results

Out of a total of 1107 patients with primary lung cancer who received surgery in our institute from January 1998 through December 2012, 94 consecutive octogenarian patients were identified (8.5%). Followed up period was 1 month to 118 months, mean 34.4, median 25.5 months. Especially in recent 3 years, octogenarian patients have grown to account for 12.2% (44/362 patients). Preoperative characteristics of patients are shown in Table 1. No patients were received preoperative chemotherapy or radiotherapy. Four patients had a history of primary lung cancer before 80-year-old and those histologies were adenocarcinomas in three and squamous cell carcinoma in one. One patient had a history of double primary lung cancers those were proven pathologically to be adenocarcinomas stage IA and IB, respectively. As for pulmonary function test, vital capacity (VC) was relatively maintained in this cohort, but 85.1% (80/94) patients showed obstructive disorder with mean value of (forced expiratory volume in 1 s)/(forced vital capacity) to be 0.613. The rate of preoperative co-morbidity was 73.4% (69/94 patients), including high rate of hypertension (50/94, 53.2%), co-incidence of other malignancy (35/94, 37.2%) and intake of anticoagulant drug (29/94 30.9%). Perioperative characteristics of patients, including surgical approach, procedure selected, extent of lymph node dissection, operation time, blood loss during the operation, histologic type, pathological staging, and postoperative hospital stay, are described in Table 1. Lobectomy was performed in 73.2% patients (67/94) and radical hilar/mediastinal lymph node dissection was done in 40.4% (38/94). The results of postoperative morbidity and mortality were listed in Table 2. Overall rate of postoperative complications was 27.7% (26/94), with the highest ratio of pneumonia (13/94, 13.8%). There was no 30-day mortality, but one patient died due to bronchopleural fistula, which required open window thoracostomy for drainage 61 days after the first operation, 79 days after right lower lobectomy and hilar/mediastinal lymph node dissection.

Table 1.

Preoperative and perioperative characteristics of patients

Gender
Male	63 (67%)
Female	31 (33%)
Age (years)	80–90 (mean 81)
CEA level (ng/ml)
>5	45 (48.4%)
≦5	48 (51.6%)
Pulmonary function
VC (L)	2.73 ± 0.62 (1.49–4.19)
VC (predicted)	102.7 ± 17.4 (67.4–162.6)
FEV1 (L)	1.76 ± 0.47 (0.9–3.48)
FEV1/FVC	0.613 ± 0.096 (0.38–0.88)
Smoking history
Never	26 (27.7%)
Ever and current	64 (68.1%)
Unknown	3 (3.2%)
Brinkman index	Mean (range)
	804.5 (0–3600)
Co-morbidity
Hypertension	50 (53.2%)
Complication of other malignancy	35 (37.2%)
Anticoaglant therapy	29 (30.9%)
Ishemic heart disease	13 (13.8%)
Arrhythmia	4 (4.3%)
Thoracic aortic disease	4 (4.3%)
Total patients	69 (73.4%)
Surgical approach
VATS	61 (64.9%)
Open thoracotomy	33 (35.1%)
Surgical procedure
Lobectomy	67 (73.2%)
Segmentectomy	3 (3.2%)
Wedged resection	23 (24.5%)
Thoracoscopic examination	1 (1.1%)
Lymph node dissection
ND2	38 (40.4%)
ND1	29 (30.9%)
sampling	6 (6.4%)
ND0	21 (22.3%)
Operation time (min)
Lobectomy	207 (65–530)
Segmentectomy/Wedge resection	116.8 (40–240)
Total	181.5 (40–530)
Operative blood loss (ml)
Lobectomy	197 (0–975)
Segmentectomy/Wedge resection	37.3 (0–290)
Total	153.4 (0–975)
Histologic type
Adenocarcinoma	65 (68.2%)
Squamous cell carcinoma	24 (25.3%)
Adenosquamous cell carcinoma	3 (3.2%)
Large cell carcinoma	1 (1.1%)
LCNEC	1 (1.1%)
Small cell carcinoma	1 (1.1%)
Staging	Clinical	Pathological
IA	58 (61.7%)	33 (34.7%)
IB	28 (29.8%)	34 (35.8%)
IIA	5 (5.3%)	5 (5.3%)
IIB	2 (2.1%)	8 (8.5%)
IIIA	2 (2.1%)	12 (12.8%)
IIIB	0 (0%)	0 (0%)
IV	0 (0%)	3 (3.2%)
Postoperative stay (day)	Mean (range)	Median
1998–2008	20.8 (5–105)	14
2009–2012	13.1 (4–70)	8	p = 0.04
Total	16 (4–105)	10

CEA: carcinoembryonic antigen; VC: vital capacity; FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; VATS: video-assisted thoracic surgery; ND2: radical mediastinal and hilar lymph node dissection; ND1: hilar lymph node dissection; ND0: no lymph node dissection; LCNEC: large cell neuroendocrine carcinoma

Table 2.

Postoperative co-morbidity, mortality and summary of cause of death

Co-morbidity
Pneumonia		13
	Percutaneous tracheal catheter	6
	Mechanical Ventilator	2
Delirium		5
Empyema		4
Prolonged air leak (>7 days)		3
Arrhythmia		3
Postoperative bleeding		2
Gastrointestinal bleeding		2
Postoperative hypoxia		2
Bronchopleural fistula		1
Chylothrax		1
Cerebral infarction		1
Total		26/94 (27.7%)
30-day mortality		0/94 (0%)
Cause of death
Lung cancer-related death	13
Died of nonmalignant diseases	12
Other cancer-related death	1
Surgical mortality	1
Unknown	2
Total	29
Details of died of nonmalignant disease
Pneumonia	5
Cerebral infarction	2
Heart failure	2
Acute subdural hematoma	1
Trauma	1
Rupture of Thoracic Aortic Aneurysm	1

BPF: bronchopleural fistula

Out of 13 patients (nine lobectomy, four wedge resection) with pneumonia, percutaneous tracheal catheter placement for suction was done in six patients, and mechanical ventilation was applied for two patients. In nine lobectomies, seven patients underwent right or left lower lobectomy. No patient died of postoperative pneumonia, but induction of home oxygen therapy on discharge was required in two patients because of hypoxia. Two patients with impaired PS (one complicated with brain infarction, and another complicated with postoperative pneumonia) were transferred to rehabilitation hospital.

Postoperative adjuvant chemotherapy was performed in three patients. A patient whose pleural lavage cytology was positive was treated with Pemetrexed, and kept alive at 26 months after the operation. The other two patients with pleural dissemination received chemotherapy using Gefitinib from October in 2009 and Tegafur/gimeracil/oteracil potassium, respectively, and kept alive at 45 months and at 13 months after the surgery, respectively.

Twenty patients (21.3%) experienced recurrence. The most frequent recurrent sites were lung (seven patients) and hilar/mediastinal lymph node (seven patients). Among 67 patients who had received lobectomy and radical hilar/mediastinal lymph node dissection, four patients (6.0%) had recurrent hilar/mediastinal lymph node. Among 27 patients who received partial resection or segmentectomy without radical lymph node dissection, three patients (11.1%) had recurrent lymph node. Other recurrent sites were bone in four patients, pleura in three, brain in three and abdominal organs in three. Treatment for the metastatic lesion was performed in 10 patients and the best supportive care was selected in the other 10 patients. Seven patients received radiotherapy for metastatic lymph nodes and/or brain metastases. One patient with bone and lymph node metastasis was treated with Gefitinib as first line from February in 2008, one patient received chemotherapy including platinum-based regimen and one patient enrolled in immunotherapy trial. No patients treated with antitumor agents and radiotherapy had severe side effects.

Twenty-nine patients died of various causes, as listed in Table 2. Half of the deaths were nonmalignant diseases in which pneumonia was a leading cause of death. The 5-year overall survival and disease-specific survival (DSS) were 57.5% (95% CI [confidence interval]: 42.0%–71.8%), 79.5% (95% CI: 64.0%–89.4%), respectively. The 5-year overall survival with and without postoperative mortality/morbidity were 37.2% (95% CI: 14.2%–68.0%) and 66.3% (95% CI: 48.1%–80.7%) respectively. There was a significant difference by Log-rank test (p = 0.0324). Survival curves according to histology and pathological stage were shown in Fig. 1 and Fig. 2. Log-rank tests revealed that, non-adenocarcinoma pathology, p-stage II–III, and postoperative morbidity and mortality were associated with poor OS. The results of univariative and multivariative analysis using Cox proportional hazards model are shown in Table 3. Male gender and non-adenocarcinoma histology were identified as significant risk factors for poor OS by univariative and multivariative analysis.

Fig. 1.

Kaplan-Meier survival curves based on lung cancer histology. Squamous cell carcinoma and Others were significantly poorer prognosis compared with adenocarcinoma. Each 5-year survival rate was 74.5% (95% CI: 54.0%–87.9%) in adenocarcinoma, 34.7% (95% CI: 14.3%–62.9%) in squamous cell carcinoma and 0% in Others. Adeno ca: adenocarcinoma; Sq ca: squamous cell carcinoma; Others: adenosquamous cell carcinoma, large cell carcinoma, large cell neuroendocrine carcinoma, and small cell carcinoma; CI: confidence interval.

Fig. 2.

Kaplan-Meier survival curves based on p stage. P stage II–IV was poorer prognosis compared with p stage I. Five-year survival rate was 69.0% (95% CI: 51.3%–82.4%) in p stage I and 18.3% (95% CI: 2.8%–63.5%) in p stage II–IV. CI: confidence interval.

Table 3.

Cox proportional hazards univariative and multivariative analysis

	Uunivariative analysis		Multivariative analysis
	HR (95% CI)	p value	HR (95% CI)	p value
Gender (M/F)	6.99 (2.09–43.35)	0.005	5.15 (1.42–33.03)	0.0094
Age	1.09 (0.85–1.35)	0.46
CEA level	1.03 (0.97–1.08)	0.301
Procedure (Open/VATS)	2.47 (1.14–5.32)	0.023	2.00 (0.79–5.00)	0.093
p-stage (II–IV/I)	2.48 (1.06–5.51)	0.036	2.21 (0.81–5.96)	0.12
Preoperative co-morbidity	1.24 (0.55–3.16)	0.612
Postoperativemorbidity	2.34 (1.02–5.23)	0.0045	1.60 (0.68–3.69)	0.28
Histology(Others/Ad)	4.10 (1.96–9.00)	0.0002	2.53 (1.19–5.66)	0.016

HR: hazard ratio; CI: confidence interval; CEA: carcinoembryonic antigen; Open: open Thoracotomy; VATS: video-assisted thoracic surgery; Ad: adenocarcinoma; Others: adenosquamous cell carcinoma, large cell carcinoma, large cell neuroendocrine carcinoma, small cell carcinoma

Discussion

The patient number with lung cancer continues to increase and lung cancer has become leading cause of death in many countries. The life expectancy for octogenarians in Japan in 2011 was reported to be 8.48 years for men and 11.43 years for women, and those has been becoming longer by years.⁶⁾ Lung cancers in octogenarians are also increasing. According to annual report by The Japanese Association for Thoracic Surgery, lung cancer patients aged over 80 accounted for 8.7% (2273/26092 patients) in 2007 and 11.5% (3890/33878 patients) in 2011.^7,8) Our aim was to clarify the perioperative characteristics of lung cancer in octogenarians, and to reveal the results of postoperative morbidity, mortality, and the outcome. The analysis would help selecting optimal operative strategy for lung cancer in octogenarians.

Finlayson, et al. reported that the age over 80 increased the postoperative mortality in 2007.⁹⁾ But current reports and guidelines suggested that high age was not regarded as a contraindication for curative operation.^10–12) Saha, et al. and Okami, et al. reported that preoperative co-morbidity, not age, was thought to be risk factor for postoperative morbidities.^13,14) Concerning preoperative co-morbidities, Brock, et al. suggested that reduced forced expiratory volume in 1s (<1.5L) was risk factor for poor long-term survival.¹⁵⁾ Considering these reports, preoperative careful estimation of tolerability for curative surgery, as well as clinical staging, is considered to be essential for determination of operative indication for octogenarians.

Some authors reported that clinical stage I may be acceptable for curative operation for octogenarians.^10,14) The background reason of their conclusion was mainly dependent on good survival compared with more advanced stage. In our institute, clinical stage II to III was included in the indication for surgery if macroscopic R0 resection was expected to be achieved, because elderlies, especially octogenarians, might not tolerate the toxicity of chemotherapy. As anticipated, cases with advanced diseases showed poorer prognosis than earlier diseases in our series.

Operative procedure was also important discussing issue. A lot of recent reports suggested that VATS procedure was thought to be acceptable and reasonable approach for elderly patients.^13,16,17) According to previous reports, VATS was less invasive, led lower postoperative morbidity, showed shorter hospital stay than open surgery, and could achieve acceptable survival with maintaining good quality of life. In our institute VATS procedure was done in 64.9% cases and was increasing in these several years.

The mode of lymph node dissection in octogenarians with lung cancer is another important issue. Radical lymphadenectomy was thought to be invasive and might force an excessive burden to elderly patients. According to some reports, radical mediastinal lymph node dissection in octogenarians resulted in increase of postoperative pulmonary complication, shorter survival, and increase of non-cancer related death.^14,18,19) More short and long-term results of pulmonary resection in octogenarians would need to be estimated.

Postoperative morbidity was observed in 26 patients (27.7%) in this study and complications tended to be more severe than younger generation possibly due to physical weakness and preoperative co-morbidity in octogenarians. Postoperative cautious observation and management after lung resection has been stressed to be very important process especially in octogenarians.¹¹⁾ In our series, 13 patients (13.8%) had complicated with postoperative pneumonia. Aggressive rehabilitation, physical therapy and insertion of percutaneous tracheal catheter when necessary were performed and those might help preventing the stuck sputum in the respiratory tract and might be one of the reason why no octogenarian patients died of postoperative pneumonia in this series, although home oxygen therapy was started in two patients.

There were 20 recurrent patients after lung resection. Most recurrent sites were lung and hilar/mediastinal lymph node. Regional lymph node recurrence rate was 6% (4/67 patients) in lobectomy and 11.1% (3/27 patients) in limited surgery, which was acceptable result. Chemotherapy and radiotherapy were performed in only half of the recurrent patients, because of excessively advanced tumor and poor general condition. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), Gefitinib was used for the recurrent case with mutation positive because the side effect was mild compared with cytotoxic chemotherapy and effective response was expected. EGFR-TKI is thought to be useful anti-cancer drug with little burden especially in elderly patient. However it was not clear whether survival time was extended or not because EGFR-TKI was used for only two cases in our cohort. Yasuda, et al. investigated postoperative recurrence in octogenarians and reported good long-term survival in intensive treatment group compared with supportive care group.²⁰⁾ The role of chemotherapy and radiotherapy in the treatment of lung cancer in octogenarians should be elucidated in the future.

Five-year OS was 57.5% in this study which was almost the same survival rate compared to previous reviews.^21,22) In recent reports, 5-year OS rate was getting better from 30% to 65.9%, partly because of proper patient selection, improvement of surgical skill, and aggressive postoperative management and rehabilitation.^11,15,16,23) Fanucchi, et al. and Osaki T, et al. showed that there was no significant dependence on stage of disease or histologic type in survival rate.^24,25) In this study, multivariative analysis revealed that overall survival had significant relation with histological difference (others/adenocarcinoma, p = 0.016) but not with pathological stage (p = 0.12). Different from younger generation, half of the octogenarians with lung cancer died of non-cancer related disease, which might explain why pathological stage had little impact on OS. Okami, et al. also reported that non-cancer related death was 30.1% of total death after lung cancer surgery in octogenarians, which would be helpful information for considering the strategy for lung cancer treatment in octogenarians.¹⁴⁾ This retrospective single-arm study had obvious limitation and biases of patient selection. Information from larger cohort should be expected.

Conclusion

The mortality/morbidity rate and the outcome of lung cancer surgery for selected octogenarians were acceptable in this study. Gender and histology should be taken into account in preoperative evaluation of indication for lung cancer in octogenarians.

Disclosure Statement

None declared.