Eur J Cardiothorac Surg 2003;24:1002-1007
© 2003 Elsevier Science NL
Long term results of surgery versus continuous hyperfractionated accelerated radiotherapy (CHART) in patients aged >70 years with stage 1 non-small cell lung cancer
Sudip Ghosh*,
Vijay Sujendran,
Christos Alexiou,
Lynda Beggs,
David Beggs
Department of Cardiothoracic Surgery, Nottingham City Hospital NHS Trust, Hucknall Road, Nottingham NG5 1PB, England, UK
Received 11 June 2003;
received in revised form 19 July 2003;
accepted 23 July 2003.
* Corresponding author. Fax: +44-116-2709664
e-mail: sudip.ghosh{at}talk21.com
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Abstract
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Background: Patients with T1N0 non-small cell lung cancer (NSCLC) are preferably treated by anatomic lobectomy. However, not all such patients are suitable for lobectomy due to their age or co-morbidity. Our aim was to determine the results obtained following lobectomy, wedge resection (WR) or continuous hyperfractionated accelerated radiotherapy (CHART) in patients aged >70 years. Patients: Two hundred and fifteen consecutive patients aged >70 years, with pathologic stage 1 NSCLC in our unit between 1991 and 2001 were studied. Of these patients, 149 had a lobectomy, 47 had a WR and 19 had CHART. Follow-up was 100% complete. Results: Analysis demonstrated the WR and CHART patients to have reduced pulmonary function (FEV1 59% and 52%, respectively, of predicted vs. 76%, P<0.001) when compared to the lobectomy group but there were no differences among the groups with regard to mean age and histologic tumour type. There were no operative mortality among patients after WR; however, a 2.7% 30-day operative mortality among patients undergoing lobectomy (P=0.29). Kaplan–Meier survival curves at 1 and 5 years for patients undergoing WR, lobectomy and CHART was 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). Conclusion: Loco-regional recurrence and survival after WR and lobectomy in elderly patients with stage I NSCLC are comparable. Although the numbers are small, these data suggest that CHART is a reasonable treatment option for those who are not suitable candidates for surgery.
Key Words: Non-small cell lung cancer • Surgery • Radiotherapy • Continuous hyperfractionated accelerated radiotherapy
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1. Introduction
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Lung cancer continues to be the leading cause of cancer death in the United Kingdom. The incidence of non-small cell lung cancer (NSCLC) continues to increase, with this increase being most noticeable in the elderly [1]. As life expectancy increases, currently 81 years for males and 84 years for females, respectively, in the UK [2], we will be seeing more cases of lung cancer among the elderly. Despite the continuing efforts of both clinicians and researchers, the overall prognosis of NSCLC remains poor.
Anatomic lobectomy with mediastinal nodal staging is presently the standard of care for patients with stage I and stage II NSCLC. However, many patients with localised disease do not proceed to surgery because they either refuse surgery or are judged to be poor candidates, often because of age and associated medical conditions, such as poor cardiac or respiratory function. Even in those elderly lung cancer patients judged to be fit for surgery, surgical resection is a procedure that has a number of potential problems associated with it including the possibility of peri-operative mortality and significant pulmonary disability.
Continuous hyperfractionated accelerated radiotherapy (CHART) with curative intent may offer a viable alternative to surgery in those patients who are either medically unfit or deemed too old for surgery. Most patients treated with CHART can be managed as outpatients with generally, only slight treatment related morbidity.
The following report describes our retrospective review of patients aged >70 years with T1 N0 M0 NSCLC at Nottingham City Thoracic Centre. Our aim was to determine the long term results obtained following lobectomy, wedge resection (WR) or CHART in this cohort of patients
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2. Patients and methods
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Between January 1991 and May 2001, 947 patients with squamous cell carcinoma, adenocarcinoma or large cell carcinoma (NSCLC) underwent resections at our institution. Among 379 of these patients who were pathologically classified as having T1 N0 M0 carcinoma, 196 patients were aged >70 years. twenty-nine further patients were deemed medically inoperable and underwent CHART; 19 of these patients were aged >70 years; 47 patients (24%) underwent wedge resections and 149 patients (76%) had a standard lobectomy procedure (lobectomy plus hilar/mediastinal lymph node dissection). The wedge resection group were considered unsuitable candidates for lobectomy because of poor pulmonary reserve or combined co-morbidity such as ischaemic heart disease. The CHART patients were medically inoperable because of severe pre-existing co-morbidity, mostly cardiopulmonary. The demographic data on these patients are noted in Table 1.
Preoperative evaluation was by means of physical examination, haematological and biochemical investigations, chest X-ray, electrocardiogram, computerised tomography (CT) of the chest and abdomen and bronchoscopy. Additional investigations such as liver ultrasound, bone scan, head CT, etc., were performed if required on the basis of clinical findings and/or laboratory parameters (e.g. abnormal liver enzymes or serum calcium, skeletal symptoms, hepatomegaly, splenomegaly, lymphadenopathy, abnormal neurological examination, etc.).
Cervical mediastinoscopy and anterior parasternal mediastinotomy were important diagnostic and staging procedures in patients having mediastinal lymph nodes greater than 1 cm on the CT scan. Cervical medianstinoscopies were carried out in 57 of the 149 WR patients and 14 of the 47 WR patients. In all these patients, mediastinal (N2) nodes were negative for malignancy. None of the CHART cohort underwent mediastinoscopies and their staging was based on CT scan findings only. To accomplish open pulmonary resections, all patients had general anaesthesia with the use of double lumen endotracheal tube. A standard postero-lateral thoracotomy approach was employed in all patients. Hilar and mediastinal lymph node staging was routinely performed during the surgical management of all patients undergoing resection to ensure that inadvertent inclusion of higher stage cancers did not adulterate this analysis. Radical mediastinal lymph node dissection was not performed.
Postoperative care was similar between lobectomy and wedge resection groups. Patients undergoing lung resections were routinely extubated early after reversal of anaesthetic and admitted to a higher dependency unit immediately after anaesthetic recovery. A thoracic epidural was used in all patients undergoing open thoracotomies for the early post-operative analgesic requirements. All untoward post-operative events and the total period of post-operative hospitalisation were recorded. Complications considered as significant in this analysis included respiratory failure necessitating ventilatory support, empyema, wound infection, air leak greater than 7 days, myocardial infarction/failure, cardiac arrhythmias and post-operative sepsis.
Patients receiving CHART were CT-planned and received up to 54 Gy in 36 fractions over 12 days on an outpatient basis. Criteria for entry into CHART treatment was FEV1>0.8 l and could travel daily. All 19 patients had performance status >1 at the time of diagnosis. All patients were staged at a multi-disciplinary meeting in the presence of a radiologist, surgeon and oncologist.
After discharge from hospital, all patients have been followed up by the operating surgeon/clinical oncologist in their respective clinics with physical examination and a standard chest roentgenograms at 3–6-month intervals for the first 2 years after the procedure and at yearly intervals thereafter. Computed tomography was only selectively used as a follow-up screening study when the screening roentgenographic studies suggested a new abnormality. Patient follow-up was complete with regard to survival and documentation of recurrence in all patients to within months of this analysis. The median length of documented follow-up for wedge resection was 64 months; for lobectomy 75 months and for CHART, 47 months.
Local recurrence was defined as any recurrence of the primary cancer in the hemithorax after wedge resection or hilar/mediastinal adenopathy in the drainage basin from the lobe in question. With specific regard to patients undergoing lobectomy, local recurrence was defined as new disease in the ipsilateral lung parenchyma, bronchial stump, or the hilar or mediastinal lymph nodes. Local and systemic was defined as the association of local disease and new roentgenographic, nuclear scintigraphic or biopsy evidence of metastatic disease outside the ipsilateral hemithorax. Systemic disease alone was defined as the presence of metastatic disease without recurrence within the ipsilateral hemithorax.
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3. Statistical analysis
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All statistical analysis was performed using Arcus Biostat Program on International Business Machine (IBM, USA) compatible PC computers. Statistical significance for difference among the three treatment groups (i.e. WR, lobectomy and CHART) for each continuous variable was evaluated by means of a one-way analysis of variance (ANOVA). Significant differences in survival times among the three treatment groups were calculated from Kaplan–Meier curves with the use of log rank test; P<0.05 was considered statistically significant.
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4. Results
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There was no difference noted between the mean ages in the cohort of patients investigated. Analyses of the surgical specimens and CT-guided biopsies demonstrated that there was no difference in the distribution of histologic types of non-small-cell lung cancers between the three groups. The mean diameter of the lesions resected by lobectomy was slightly larger (1.95 cm, range 1.2–2.2) than that of lesions managed by wedge resection (1.85 cm, range 1.1–2.05); however, these differences did not reach statistical significance.
The primary oncologic end-points focussed on this study were the relative risks for local recurrence and long-term survival after either WR, lobectomy or CHART for peripheral T1 N0 NSCLC. The differences in operative mortality and length of hospital stay between the WR and lobectomy groups were also of interest. These results are shown in Table 2. Operative mortality favoured the wedge resections but failed to reach statistical significance. Interestingly, local recurrence did not approach significance in favour of the surgical groups when compared to CHART and within the surgical arms both lobectomy and WR fared equally well. However, it must be borne in mind the former result is probably attributed to the small numbers in the CHART group. There was no difference in the local/systemic recurrence rate between all the groups.
Local recurrence was identified at a median time interval of 14 months among patients having WR, 19 months among those having lobectomy and 10 months among those receiving CHART. Only two of the nine patients in whom local recurrence occurred after WR were considered to be candidates for re-resection. The remaining patients were not considered for re-resection because of the severity of cardiopulmonary insufficiency, the presence of an associated malignant pleural effusion, or significant ipsilateral mediastinal adenopathy. Completion lobectomies were performed in both these patients. Completion pnemonectomy was accomplished in three of 17 patients having limited hilar recurrences after lobectomy.
We also evaluated the occurrence of significant post-operative complications as defined earlier in the Patients and methods section of this article. Post-operative complications occurred in 14% of patients having WR in contrast to 31% of patients undergoing lobectomy (P<0.001).
Fig. 1
shows the overall survival in all groups in this cohort of patients. The median survival for lobectomies, WR and CHART are 70.4 (CI=51.3–89.4), 62.3 (CI=54.1–76.2) and 49.2 (CI=40.3–71.2) months, respectively. The Kaplan–Meier survival proportions for all causes excluding operative mortality appeared nearly identical at 1 year with 97.5±2% for lobectomies, 97.9±1% for WR and 80±9% for CHART. At 3 years, the overall survival was 83.9±6 %, 86.4±3% and 68.4±13% for lobectomies, WR and CHART, respectively (P=NS). The overall survival proportions over the entire 5-year period did not differ significantly between the lobectomy (68.1±7%) and WR (73.6±5%) groups (log rank test, P=0.24). The CHART patients, however, exhibited a trend towards poorer survival at 5 years (39.7±13%) [log rank test, P=0.0484] but it must be borne in mind with small number of patients in this cohort, it would not be advisable to place much emphasis on this.
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Fig. 1. Kaplan–Meier survival for stage T1 N0 following lobectomy (Lob-), wedge resection (WR) and continuous hyperaccelerated fractionated radiotherapy (CHART).
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5. Discussion
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The average age of patients with lung cancer is increasing and there are now large numbers of elderly, symptomatic patients with this common disease [1]. Moreover, the need for treatment is also increasing as the number of elderly people maintaining an active, independent lifestyle increases. In the UK, where the population age structure follows a similar pattern to that the found throughout the developed world, the projected life expectancy at age 75 years is between 6 and 8 years for males and close to 10 years for females [2]. Despite this documented increase in elderly lung cancer patients, there is limited evidence available on how the outcome of treatment of this group differs from that younger patients. Previous reports have confirmed that age alone appears to be a major factor in influencing treatment choices with elderly patients being less likely to be offered active, potentially curative treatment [3–5].
In the case of technically operable early stage NSCLC, surgical resection remains the standard treatment modality. Previous series have shown that surgery for NSCLC in the elderly should not be denied on the basis of age alone with postoperative outcome being mainly related to concomitant cardiopulmonary disease. Excellent survival rates can be achieved with surgical therapy alone and number of authors have previously reported that surgical treatment can significantly improve survival in the elderly. Harvey et al. [6] reported 5-year survival rates in stage 1 tumours of 65% in 81 patients aged >70 years. More recently, Hanagiri reported 5-year survival after surgery of 42.6% in patients aged >80 years [7]. As well, Ciricao et al. reported a 53% 54-month actuarial survival in surgically treated patients aged 70 years or older [8]. Our 5-year survival in this age group is no different with a 5-year survival rate of 68%.
Lobectomy combined with regional lymph node dissection has now become accepted as the standard treatment for early lung cancer. Since Jensik and associates [9] reported the outcome after segmental resection for lung cancer, the procedure has become the accepted surgical option for patients with compromised pulmonary reserve. Recent retrospective analyses by Warren and Faber [10] suggested that lobectomy offered no survival advantage over segmentectomy for patients with small tumours (<3 cm) but patients undergoing segmentectomy were reported to have a nearly fivefold increased risk of developing local/regional recurrence. We have demonstrated that neither overall survival or the rate of loco-regional recurrence is any higher in either the lobectomy or wedge resection groups. Our review differs from Warren's study and the earlier Lung Cancer Study Group [11] in two important aspects. First, the mean age in both these studies was almost a decade younger than in our series and second, the cardiopulmonary reserve in the limited resection groups were significantly lower than in the lobectomy patients and therefore a lower anticipated 5-year survival, which is clearly not the case in our review.
However, it should be mentioned that the outcome figures reported for surgery alone are representative of only a small subset of patients with stage 1 disease. Surgical patients are generally meticulously staged and only those deemed to be technically operable and of good performance status will actually proceed to operation. Moreover, the findings at the time of the operation may preclude curative surgery in a small but significant proportion of cases. Surgery in the elderly patients is further complicated by the presence of pre-existing medical conditions, such as cardiovascular disease or poor pulmonary function due to previous cigarette smoking. This has the potential to result in high peri-operative morbidity and mortality. As seen in our study, reported operation mortality rate in the lobectomy group was close to 3% compared to none in the WR group, although this did not reach statistical significance. In other contemporary series, the reported operation mortality rates for elderly patients range from 4.9 to as high as 12.8% [6,12].
In view of the limitations noted above, it becomes apparent that a proportion of elderly early stage NSCLC will require a viable alternative to surgery because they are either unwilling or medically inoperable. There are limited data to indicate that a significant number of elderly, medically inoperable patients with stage 1 NSCLC can be cured by radiation therapy alone [13]. Although a large variation of pre-treatment and treatment characteristics was noted in the available studies, a median survival time of >30 months and a 5-year survival rate of up to 30% had been achieved. Accumulated experience seems to suggest that doses of at least 65 Gy with standard fractionation, or its equivalent when altered fractionation is used, are necessary for control of NSCLC. Smaller tumours seem to have a favourable prognosis, and the issue of elective nodal radiotherapy continues to be controversial. Analyses of patterns of failure have clearly identified local failure as the predominant pattern. Although a number of potential pre-treatment patient- and tumour-related prognostic factors have been examined, none has been shown to clearly influence survival. Toxicity was usually low, but very high doses (e.g. 80 Gy) given with a conventional approach may carry a risk of an excessive rate of side effects. In the past two decades, a number of series reported encouraging 5-year survival rates for patients treated with radical therapy alone [14–16]. In a recent subset analysis of 169 patients with stage I–II NSCLC initially enrolled in CHART study [17] showed a benefit of 13% at 2 years (37% vs. 24%) and 6% at 4 years (18% vs. 12%) at 4 years for CHART (54 Gy) over conventionally fractionated radical radiotherapy. Our results indicate that survival at 1 year with CHART is comparable to surgery but not at 5 years (68% vs. 39%, P<0.05) although our numbers are small.
The question of whether surgery is more effective than radiotherapy alone in the elderly or poor performance status patients requires a randomised trial. It is recognised that in view of excellent outcome of surgical resection in early stage disease, even in elderly patients of good performance status, it is unlikely that such a randomised trial would generate much interest. However, while surgery (lobectomy) continues to be the treatment of choice in resectable tumours, the view held by some that surgery holds the only hope of cure in lung cancer is becoming unjustifiable. Therapeutic bronchoscopic techniques such as brachytherapy, stents, and photodynamic therapy (PDT) are effective tools in the treatment of early lung cancer in selected patients. Palliation of malignant tracheobronchial obstruction by stents, brachytherapy, PDT, or a combination thereof results in relief of dyspnoea, haemoptysis, and post-obstructive pneumonia. Importantly, it avoids intubation in patients with respiratory distress and facilitates the weaning of patients from mechanical ventilation. In the exciting field of lung cancer screening and treatment of early lung cancer, PDT, brachytherapy, electrocautery, and laser therapy may represent treatment alternatives to surgical resection, especially in a select group of patients with high surgical risk or favourable endobronchial lesions. Clinicians await the results of future studies, which will (1) better define the impact of each treatment modality on patient care in terms of cost, survival, and improvement in quality of life; and (2) determine the optimal combination therapy relative to bronchoscopic and conventional treatment for effective palliation and cure of lung cancer. There now exists abundant data within the literature to suggest against a pessimistic approach in those patients with unresectable tumours. In particular, our own study suggests that elderly patients can have their disease potentially cured by limited surgery or CHART without major complications. These results also re-introduce the concept that limited surgery in elderly patients provide as good chance of cure as the traditional lobectomy.
In conclusion, this study shows that loco-regional recurrence and survival after wedge resection and lobectomy in elderly patients with stage T1N0 NSCLC are comparable. Although the numbers are small, these data suggest that CHART is a reasonable treatment option for those who are not suitable candidates for surgery.
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References
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Abstract
1. Introduction
