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Radiotherapy for non-small cell lung cancer in patients aged 75 and over: safety, effectiveness and possible impact on survival
Lung Cancer 28 (2000) 43 – 50 www.elsevier.nl/locate/lungcan
Radiotherapy for non-small cell lung cancer in patients aged 75 and over: safety, effectiveness and possible impact on survival Federico Lonardi a,*, Manuela Coeli a, Giovanni Pavanato a, Francesca Adami b, Gloria Gioga b, Franco Campostrini a a
Unita` di Radioterapia Oncologica, Azienda ULSS 21, Via Gianella 1, 37045 Legnago (VR), Italy b Unita` di Oncologia Medica, Azienda ULSS 21, 37045 Legnago (VR), Italy
Received 19 August 1999; received in revised form 11 November 1999; accepted 15 November 1999
Abstract For patients with advanced, inoperable non-small cell lung cancer (NSCLC), increasing age seems to be the primary reason of receiving no treatment. The elderly aged 75 years and over are more likely to be given only supportive care (irrespective of symptoms) or no therapy at all. We 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. Based on WHO criteria, of 47 assessable patients, 21 had partial remission, 17 stable disease, and nine had progressive disease. Most symptoms were successfully palliated. Toxicity was negligible and mainly consisted of WHO grade I-II esophagitis. Despite the overall median survival being short (5 months), 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. These results confirm that radiation therapy may be safely delivered to very aged patients with advanced NSCLC at not merely palliative doses, both to achieve better local control and to give likely survival benefits. Adequate pretreatment evaluation should be always performed to exclude any comorbidity unfit to chest radiation and to individualize treatment to the single patient requirements. Because a large amount of literature data now concurs with the feasibility and safety of high-dose radiotherapy in the elderly, specifically designed, age-oriented trials are needed to settle definitively the issue of survival advantage from curative radiotherapy in these patients. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Elderly; Non-small cell lung cancer; Radiotherapy; Survival
1. Introduction * Corresponding author. Tel.: +39-0442-632-275/632-403; fax: + 39-0442-632-403/632-364. E-mail address: [email protected] (F. Lonardi)
Elderly patients constitute the majority of patients treated with radiation therapy in a cancer
0169-5002/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 9 9 ) 0 0 1 1 7 - 8
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F. Lonardi et al. / Lung Cancer 28 (2000) 43–50
center. Half of all lung cancers occur in persons aged 65 years and older [1]. The incidence of lung cancer in the general population has been found to be 49–69/100 000, whereas it rises up to 751/ 100 000 in men aged 75 and over [2,3]. One of the most frequent tumors in the elderly, non-small cell lung cancer (NSCLC), constitutes 75 – 80% of all lung cancers [4,5]. Since the cure rate is merely 13% at 5 years [6], it accounts for substantial deaths and costs, and is a major health concern in western countries. Most of these cancers are locoregionally advanced and comorbidity often exists at clinical presentation in older patients; hence, curative treatment is unlikely to be performed and local control becomes the main therapeutic purpose in most cases. However, increasing age seems to be the most important determinant of receiving treatment or not: it was found in a recent review that patients with advanced disease aged 75 years and over were more likely to have no treatment (or radiotherapy on demand) than younger patients under 75 years, thus creating a sort of threshold point for treatment or not [7]. Despite chemo-radiation schedules having been shown to impact on response and survival compared to radiation alone in selected patient populations [8,9], chemotherapy and combined chemo-radiotherapy regimens have no definite role in the treatment of aged patients with NSCLC. However, promising results with benefits on quality of life and survival have been recently reported by various groups [10 – 12]. Table 1 Patient details Total number Male/female ratio Median age (range) Median ECOG performance status
48 44/4 77 (75–85) 2 (1–3)
Histology Squamous Adenocarcinoma Large cells Others/unspecified
31/48 03/48 03/48 11/48
Stage IIIA IIIB N3
22 (46%) 26 (54%) 08
Radiotherapy is widely used to treat lung cancer in the elderly, both with curative and palliative intent. When given alone, it has been shown to be beneficial in older patients with resectable disease as an alternative to surgery [13–15]. The information on the effectiveness and tolerance of radiation therapy in the elderly has been limited so far, because older patients have been routinely excluded from clinical trials [16] because of their apparent lack of compliance. Hence, data on the treatment of NSCLC in older patients are not completely satisfactory, although reports on aged are rapidly increasing [17–21]. Since there is fear of toxicity and side effects in full dose treatment in older patients, radiation has been usually given at ‘middle-of-the-road’ doses, irrespective of patient status. Yet, some reports have demonstrated the feasibility and effectiveness of radiotherapy at full doses in selected aged patients with lung cancer without causing serious complications [18,21,22], allowing benefits similar to those achieved in younger patients [23] and showing there is no apparent age limit to deliver curative radiation treatment in NSCLC [24]. Therefore, the question ‘Can we deliver higher doses of radiation to aged NSCLC cancer patients without worsening tolerance and quality of life?’ should now be turned to: ‘How can we justify giving very aged patients radiation doses higher than those fit for symptom palliation?’ We tried to answer such a question by evaluating the outcome of a group of aged patients treated with ‘non- palliative’ radiation therapy for advanced, symptomatic NSCLC.
2. Materials and methods The medical records of 48 consecutive, untreated patients aged 75 years and over, who received external beam radiation therapy for NSCLC in our center from January 1989 to January 1997 were retrospectively reviewed (Table 1). Before receiving treatment, each patient underwent a complete physical examination and a detailed medical history highlighting any comorbidity relevant to radiation therapy, full chemistry and age-adjusted staging of the disease.
F. Lonardi et al. / Lung Cancer 28 (2000) 43–50 Table 2 Radiation therapy parameters Sources
Cobalt-60 (17 patients treated) 10 MV photons LinAc (30 patients treated)
Technique
Opposed parallel/multiple blocked fields
Median dose planned (range) Median dose given (range) Fraction size Median field size (range) Equivalent square field size (range)
50 Gy (30–60) 50 Gy (0–60) 1.8–2.5 Gy per daily fraction 10×13 cm (8×10–22×20) unblocked 10×10 cm (8.5×8.5–15×15) customized
All patients were deemed not to have impending life-threatening disease at presentation and life expectancy reasonably longer than 3 months. Since the policy of our center was not to treat older (\ 75 years) patients with advanced NSCLC unless symptomatic, all patients considered in this review entered treatment immediately because of symptom relevance. Performance status (PS) was scored according to ECOG scale. The median age was 77 years (range 75 – 85), the male/female ratio 44/4, and the median PS 2 [1 – 3]. All patients had histologically (93%) or cytologically (7%) proven non-small cell lung cancer unfit for surgery because of disease extension and/or comorbidity. The prominent histology was squamous (65%). Symptoms consisted of cough (87%), dyspnea (79%), chest pain (54%) and haemoptysis (48%). Relevant, but not severe comorbidity was present in 63% of patients, and mostly consisted of obstructive pulmonary disease (62%), peptic ulcer (23%), hypertension (15%), coronary artery disease (37%), congestive heart failure (17%), diabetes mellitus (8%). On the whole, 33% of patients had more than one chronic medical problem besides NSCLC. Concurrent morbidity notwithstanding, PS was more favorable than expected, as it did not overcome 2 in most patients (66%). According to the stage grouping of the 1997 TNM Staging System, 22 patients (46%) have been staged IIIA, and 26 IIIB (54%). Eight have
45
been classified as nodal stage N3 owing to ipsilateral supraclavicular involvement. Either a Cobalt-60 unit or a linear accelerator (10 MV photons) was used to treat 17 and 30 patients, respectively (Table 2). The target volume always included the primary tumor as well as regional involved nodes. Two centimeters laterally, superiorly and inferiorly were allowed around the visible disease. Custom blocks were used in most fields (87%) to minimize the normal tissue involvement. Carefully designed blocks with lesser clear margins (1–1.5 cm) surrounding tumor were used in patients suffering from obstructive pulmonary disease in order to spare as much normal lung tissue as possible. Unblocked field size ranged between 8× 10 to 22×20 cm. In most cases, the anterior–posterior field technique was used to deliver up to 40 Gy; then oblique and/or multiple fields were used to complete irradiation up to 60 Gy. This technique allowed normal lung to be spared as much as possible and spinal cord to be given no more than 48 Gy. Physicians involved recommended that the dose to be delivered should be at least the biologic equivalent of 45 Gy, with daily fractions not exceeding 2.5 Gy, in order ‘to achieve as much local control as possible without affecting tolerance, and palliate symptoms’ (as reported in the clinical charts of most patients). There was no statement whether treatment had to be considered curative or palliative from the beginning. Standard fractionation was used (1.8–2 Gy per daily fraction) in all but four patients, who received 30–35 Gy/12–14 fractions (2.5 Gy per fraction). The median dose administered was 50 Gy (range 0–60) matching the median prescribed dose of 50 Gy (30–60). Twenty-five patients had doses of 50 Gy and higher (median 50.4 Gy, range 50–60). Forty-one patients completed the therapeutic program as planned. Four patients refused to continue treatment because of discomfort related to repeated accesses. Doses delivered were respectively 39.6, 43.2, 46.8, and 48 Gy. Two patients stopped irradiation owing to intercurrent illness at the doses of 39.6 and 48 Gy. Most treatments (73%) were carried out and completed in an outpatient setting. Eight patients required hospital admission during treatment for supportive care. Five pa-
F. Lonardi et al. / Lung Cancer 28 (2000) 43–50
46 Table 3 Response and overall survival Response
Complete Partial Stable Progressive
Overall survival
0 21 (44%) 17 (35%) 09 (21%)
Months
%
6 12 24
48 23 10
tients were hospitalized to have radiotherapy because they were unable to sustain repeated accesses. One patient died of a bronchial hemorrhage before starting treatment. Unspecific supportive care (bronchodilatating drugs, steroids, and analgesics) was given on demand during treatment.
3. Results Response, survival and toxicity were studied in 47 patients out of 48 (Table 3). According to WHO criteria, responses were classified as complete (CR), partial (PR), stable (SD) and progressive (PD). Symptom relief was evaluated on the basis of patients’ self-evaluation by means of a visual analog scale: a decrease of 50% or more of cough, dyspnea, pain and hemoptysis was considered effective palliation. To correctly assess response to treatment and therapy-related complications, patients were examined by two Table 4 Dose-related survival Dose level
B50 Gy
]50 Gy
Patients Median survival
22 4 months
25 8 months
Sur6i6al at: 6 months 12 months 13 months 18 months 24 months
35% 9% 4%* 4% 4%
52% 28% 28%* 20% 20%
physicians only both on treatment and follow-up. Since we tried to give patients as little discomfort as possible during follow-up, they were evaluated at the completion of therapy and every 3–4 months thereafter by means of chest X-rays, chest CT when required, and routine chemistry. We observed no complete remission, PR in 21 patients (44%), SD in 17 patients (35%) and PD in 9 patients (21%). PR in 25 patients given at least 50 Gy accounted for 60%, compared to 22% of the group who had lower doses (median 35 Gy, range 0–48). Overall survival was 48% at 6 months, 23% at 12 months and 10% at 24 months. Median survival was 5 months (range 1–29). When dose-related survival was analyzed (Table 4), a better outcome emerged in patients treated with doses higher than, or equal to, 50 Gy. Median survival was 8 months in the higher dose group as compared to 4 months in the lower dose group. Overall survival was 52% versus 35% at 6 months, 28% versus 9% at 12 months and 20% versus 4% at 24 months. As for symptoms, radiation therapy was mostly successful in palliating chest pain (88% effective), hemoptysis (100%), and cough (82%). Dyspnea did not benefit from radiotherapy to the same degree (67% effective), however the coexistence of obstructive respiratory illness in many patients prevented us from evaluating correctly. On the whole, 39 out of 47 patients (83%) experienced effective symptom palliation. It is noteworthy that one patient had quasi-complete remission of chest pain despite mediastinal progressive disease. Toxicity was evaluated according to the WHO scale (Table 5). Early toxicity mostly Table 5 Toxicity WHO grade
1
2
3
4
Esophagitis Nausea/Vomiting Dermatitis Leucopenia
12 (26%) 7 8 (17%)a 3
15 (32%) 1 17 (36%)b –
– – – –
– – – –
Fatigue Weight loss 55%
31 (67%) 11 (23%)
a
* P =0.03.
b
Five patients on 60-Co, three patients on LinAc. Fourteen patients on 60-Co, three patients on LinAc.
F. Lonardi et al. / Lung Cancer 28 (2000) 43–50
consisted of fatigue (67%), grade I-II esophagitis (58%) and nausea (17%). Dermatitis not exceeding GII occurred in 53% of patients, more intensively in the supraclavicular fossa of patients treated by means of Cobalt-60 gamma rays. There was no routinely given symptomatic therapy for these toxic effects. Weight loss 55% occurred in 11 patients (23%) during treatment. Blood counts were performed weekly only in patients who had larger radiation fields (15× 15 cm or over), otherwise on demand. G-I leucopenia was observed in three patients. We were not able to detect any significant late toxicity in longer survivors. There was no toxicity-related delay or interruption of treatment. All forms of toxicity and side effects cleared within 4–5 weeks after the completion of therapy.
4. Discussion At mid-century, world life expectancy at birth was less than 47 years. Better nutrition and medical care have lengthened lives in many countries, so that by the years 2045 – 2050 people are expected to live 79 years in Canada, 78 in Spain and Australia, 77 in the USA and Germany [25]. According to the United Nations Population Division 1996 Database, the number of people over 65 years is likely to double by the year 2020. As a consequence, oncologists have become increasingly aware — and they will become more so in the future — of the many problems with the treatment of aged cancer patients [26], including the psychological aspects [27], as shown by the high proportion of patients treated worldwide, the number of conferences, and the considerable amount of data emerging in literature about this topic. However, many questions are still in debate, as far as optimum treatment selection, normal tissue tolerance, and potential benefits from treatment are concerned. The optimal management of NSCLC in older patients is one of the more discussed, since widespread prejudice exists in treating elderly patients with advanced disease. The tendency to equate older age with poor compliance to aggressive strategies of treatment forces the elderly to be excluded from most treatment
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options or to be under-treated. Potential undertreatment of NSCLC may result from some belief that these tumors are less aggressive in the elderly than in younger people, and that the normal tissue tolerance is decreased in older age. Both these factors may cause inappropriate radiation dose reductions, excessive narrowing of radiation fields, not-to-treat choices, and palliative therapeutic approaches in patients who, conversely, could benefit from radical treatments. According to recent data, people living of 70–75 years are expected to live 10–15 more years [28], so that less than appropriate therapies may adversely affect life span and the quality of residual life. A lot of literature reports have undoubtedly shown that the elderly can tolerate high doses of radiation therapy as safely as younger patients, achieving similar benefits both in terms of response and, possibly, survival. In their recent review, Pignon et al. [29] reported results from 1208 patients aged 50–70 years, treated with radiation for lung and esophageal cancer, accrued in six EORTC trials: no age-related impact on acute and late toxicity emerged, reinforcing the assertion that older patients are not to be excluded from curative approaches with radiation on the basis of simple age considerations. Similar conclusions have been addressed for the surgery option [30]. ASCO recently published the Clinical Practice Guidelines for the treatment of advanced NSCLC [31]. Though the problem of older patients was not highlighted, the expert panel outlined that ‘radiation therapy should be included as part of the standard treatment for selected patients with unresectable stage III NSCLC, whose performance status and pulmonary function are adequate’ and that ‘definitive-dose thoracic radiotherapy should be no less than 60 Gy’. Conversely, the 21 May 1998 NIA/NCI/ACR Collaborative Workshop focused specifically on ‘Radiation Therapy and Cancer in Older Persons’ [32] to ‘recommend strategies to advance the current knowledge base and propose research opportunities for radiation therapy in older patients’. With luck, all these efforts will stimulate research in those areas where information for the treatment of these patients is still limited.
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F. Lonardi et al. / Lung Cancer 28 (2000) 43–50
As a whole, radical radiotherapy is still regarded by many radiation oncologists as the standard treatment for locally advanced NSCLC, despite survival benefits being poor and significant advantages having come from the combination of cisplatin-based chemotherapy with radiotherapy [31,33]. However, while it seems no longer reasonable to administer younger patients with a treatment that can cure so few, elderly patients are a different matter. Comorbidity of the aged often makes therapeutic decisions difficult and the right balance between expected benefits of treatment and potential toxicity hard to reach. Since the risk of serious complications from radiation therapy has been demonstrated to be small, even in patients older than 70 years [34], this treatment option may overcome many of the age-related drawbacks which prevent more aggressive and toxic therapies from being administered to these frail patients. To date, uncertainties about the actual role and potential benefits from radiation therapy in the elderly with NSCLC should no longer exist, though the large variety of doses and schedules used both in limited and advanced stages does not help to define standard approaches [35,36]. In treating this group of patients we chose to deliver no less than 45 Gy in order to overcome the equation elderly= palliation. Dose levels beyond 45 Gy in a palliative setting have shown no evident impact on survival [37]. In our review, patients given doses of 50 Gy and higher seemed to experience some survival advantages in comparison with those who received lesser doses. At 13 months, differences in survival reached a statistically significant value (28 vs. 4%, P = 0.03), but a definitive conclusion cannot be drawn because of the limited accrual. Nevertheless, our findings substantially match the conclusions of the review by Damstrup et al. [38], i.e. that doses of at least 55 Gy should be delivered in NSCLC patients for a better outcome, and they demonstrate that these recommendations may apply to aged and very aged patients too. Our patients were administered with a median dose of 50 Gy, which cannot be considered a curative dose and is far from ASCO’s indications of 60 Gy. However, neither can 50 Gy be considered a merely palliative dose, nor has it been given with substantial
toxicity to our patients; this indicates that curative doses in the range of 60 Gy are a reliable target in aged NSCLC patients not impaired by any se6ere concomitant illness. Since our patients had been checked to detect any relevant comorbidity unfit for high-dose chest radiation (huge lung necrotic masses, severe chronic bronchitis, severe diffuse emphysema, etc.), the compliance to therapy was surprisingly good in most cases, and tolerance was not adversely affected by any supposed age-related limiting factor. This experience confirms that age per se should not be considered a determinant for excluding older patients from radical radiotherapy. However, careful evaluation of any concurrent illness is mandatory prior to treatment decisions. Similar conclusions have been addressed by other studies, like the nationwide survey of the Geriatric Radiation Oncology Group (GROG) in Italy [39], giving the basis for the much awaited design of specifically age-oriented trials to achieve definitive data. Granted that the limited number of patients does not allow for any definitive conclusion from our review, yet the results prove the feasibility of higher doses of radiation in elderly patients, and suggest possible advantages in terms of survival in the absence of any significant toxicity and worsening of quality of life. All in all, the results of this review and the emerging data in literature convinced us to change the treatment policy and administer elderly NSCLC patients with ‘curative’ doses of radiation (higher than 50 Gy) in the range of 55–60 Gy, irrespective of symptoms at presentation. In our opinion, a comprehensive pretreatment evaluation is necessary to detect both adverse prognostic factors and concurrent illness which may affect the cost/benefit ratio and contra-indicate curative irradiation.
5. Conclusions This study supports the hypothesis that doses higher than 50 Gy may impact on survival of aged advanced NSCLC patients. However, the small sample size and the possibility that these observations may be affected with bias, indicate that such
F. Lonardi et al. / Lung Cancer 28 (2000) 43–50
a relationship has to be further investigated in a prospective setting. As matters stand, the notions that aged patients tolerate radiation therapy worse than younger people and that potentially curative doses of radiation are precluded to older NSCLC patients have been debunked. We may conclude that: 1. Higher and curative doses of radiation are likely to be fully delivered to aged and very aged NSCLC patients, unless medically precluded, in order to achieve a better control rate and possibly gain survival advantages. 2. Careful evaluation is required to exclude any comorbidity unfit for high-dose chest-radiation therapy, and to deliver the best treatment tailored to every single patient requirement. 3. Specifically age-oriented clinical trials should be carried out to investigate whether survival advantages can be actually gained with higher doses of radiation.
[9]
[10]
[11]
[12]
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[15]
Acknowledgements [16]
We are grateful to Dr Giovanni Pavanato for his contribution. Dr Pavanato is now at the Divisione di Radioterapia, Ospedale Civile, ASL 18, 45100 Rovigo, Italy.
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Radiotherapy for non-small cell lung cancer in patients aged 75 and over: safety, effectiveness and possible impact on survival Federico Lonardi a,*, Manuela Coeli a, Giovanni Pavanato a, Francesca Adami b, Gloria Gioga b, Franco Campostrini a a
Unita` di Radioterapia Oncologica, Azienda ULSS 21, Via Gianella 1, 37045 Legnago (VR), Italy b Unita` di Oncologia Medica, Azienda ULSS 21, 37045 Legnago (VR), Italy
Received 19 August 1999; received in revised form 11 November 1999; accepted 15 November 1999
Abstract For patients with advanced, inoperable non-small cell lung cancer (NSCLC), increasing age seems to be the primary reason of receiving no treatment. The elderly aged 75 years and over are more likely to be given only supportive care (irrespective of symptoms) or no therapy at all. We 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. Based on WHO criteria, of 47 assessable patients, 21 had partial remission, 17 stable disease, and nine had progressive disease. Most symptoms were successfully palliated. Toxicity was negligible and mainly consisted of WHO grade I-II esophagitis. Despite the overall median survival being short (5 months), 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. These results confirm that radiation therapy may be safely delivered to very aged patients with advanced NSCLC at not merely palliative doses, both to achieve better local control and to give likely survival benefits. Adequate pretreatment evaluation should be always performed to exclude any comorbidity unfit to chest radiation and to individualize treatment to the single patient requirements. Because a large amount of literature data now concurs with the feasibility and safety of high-dose radiotherapy in the elderly, specifically designed, age-oriented trials are needed to settle definitively the issue of survival advantage from curative radiotherapy in these patients. © 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Elderly; Non-small cell lung cancer; Radiotherapy; Survival
1. Introduction * Corresponding author. Tel.: +39-0442-632-275/632-403; fax: + 39-0442-632-403/632-364. E-mail address: [email protected] (F. Lonardi)
Elderly patients constitute the majority of patients treated with radiation therapy in a cancer
0169-5002/00/$ - see front matter © 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 9 - 5 0 0 2 ( 9 9 ) 0 0 1 1 7 - 8
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F. Lonardi et al. / Lung Cancer 28 (2000) 43–50
center. Half of all lung cancers occur in persons aged 65 years and older [1]. The incidence of lung cancer in the general population has been found to be 49–69/100 000, whereas it rises up to 751/ 100 000 in men aged 75 and over [2,3]. One of the most frequent tumors in the elderly, non-small cell lung cancer (NSCLC), constitutes 75 – 80% of all lung cancers [4,5]. Since the cure rate is merely 13% at 5 years [6], it accounts for substantial deaths and costs, and is a major health concern in western countries. Most of these cancers are locoregionally advanced and comorbidity often exists at clinical presentation in older patients; hence, curative treatment is unlikely to be performed and local control becomes the main therapeutic purpose in most cases. However, increasing age seems to be the most important determinant of receiving treatment or not: it was found in a recent review that patients with advanced disease aged 75 years and over were more likely to have no treatment (or radiotherapy on demand) than younger patients under 75 years, thus creating a sort of threshold point for treatment or not [7]. Despite chemo-radiation schedules having been shown to impact on response and survival compared to radiation alone in selected patient populations [8,9], chemotherapy and combined chemo-radiotherapy regimens have no definite role in the treatment of aged patients with NSCLC. However, promising results with benefits on quality of life and survival have been recently reported by various groups [10 – 12]. Table 1 Patient details Total number Male/female ratio Median age (range) Median ECOG performance status
48 44/4 77 (75–85) 2 (1–3)
Histology Squamous Adenocarcinoma Large cells Others/unspecified
31/48 03/48 03/48 11/48
Stage IIIA IIIB N3
22 (46%) 26 (54%) 08
Radiotherapy is widely used to treat lung cancer in the elderly, both with curative and palliative intent. When given alone, it has been shown to be beneficial in older patients with resectable disease as an alternative to surgery [13–15]. The information on the effectiveness and tolerance of radiation therapy in the elderly has been limited so far, because older patients have been routinely excluded from clinical trials [16] because of their apparent lack of compliance. Hence, data on the treatment of NSCLC in older patients are not completely satisfactory, although reports on aged are rapidly increasing [17–21]. Since there is fear of toxicity and side effects in full dose treatment in older patients, radiation has been usually given at ‘middle-of-the-road’ doses, irrespective of patient status. Yet, some reports have demonstrated the feasibility and effectiveness of radiotherapy at full doses in selected aged patients with lung cancer without causing serious complications [18,21,22], allowing benefits similar to those achieved in younger patients [23] and showing there is no apparent age limit to deliver curative radiation treatment in NSCLC [24]. Therefore, the question ‘Can we deliver higher doses of radiation to aged NSCLC cancer patients without worsening tolerance and quality of life?’ should now be turned to: ‘How can we justify giving very aged patients radiation doses higher than those fit for symptom palliation?’ We tried to answer such a question by evaluating the outcome of a group of aged patients treated with ‘non- palliative’ radiation therapy for advanced, symptomatic NSCLC.
2. Materials and methods The medical records of 48 consecutive, untreated patients aged 75 years and over, who received external beam radiation therapy for NSCLC in our center from January 1989 to January 1997 were retrospectively reviewed (Table 1). Before receiving treatment, each patient underwent a complete physical examination and a detailed medical history highlighting any comorbidity relevant to radiation therapy, full chemistry and age-adjusted staging of the disease.
F. Lonardi et al. / Lung Cancer 28 (2000) 43–50 Table 2 Radiation therapy parameters Sources
Cobalt-60 (17 patients treated) 10 MV photons LinAc (30 patients treated)
Technique
Opposed parallel/multiple blocked fields
Median dose planned (range) Median dose given (range) Fraction size Median field size (range) Equivalent square field size (range)
50 Gy (30–60) 50 Gy (0–60) 1.8–2.5 Gy per daily fraction 10×13 cm (8×10–22×20) unblocked 10×10 cm (8.5×8.5–15×15) customized
All patients were deemed not to have impending life-threatening disease at presentation and life expectancy reasonably longer than 3 months. Since the policy of our center was not to treat older (\ 75 years) patients with advanced NSCLC unless symptomatic, all patients considered in this review entered treatment immediately because of symptom relevance. Performance status (PS) was scored according to ECOG scale. The median age was 77 years (range 75 – 85), the male/female ratio 44/4, and the median PS 2 [1 – 3]. All patients had histologically (93%) or cytologically (7%) proven non-small cell lung cancer unfit for surgery because of disease extension and/or comorbidity. The prominent histology was squamous (65%). Symptoms consisted of cough (87%), dyspnea (79%), chest pain (54%) and haemoptysis (48%). Relevant, but not severe comorbidity was present in 63% of patients, and mostly consisted of obstructive pulmonary disease (62%), peptic ulcer (23%), hypertension (15%), coronary artery disease (37%), congestive heart failure (17%), diabetes mellitus (8%). On the whole, 33% of patients had more than one chronic medical problem besides NSCLC. Concurrent morbidity notwithstanding, PS was more favorable than expected, as it did not overcome 2 in most patients (66%). According to the stage grouping of the 1997 TNM Staging System, 22 patients (46%) have been staged IIIA, and 26 IIIB (54%). Eight have
45
been classified as nodal stage N3 owing to ipsilateral supraclavicular involvement. Either a Cobalt-60 unit or a linear accelerator (10 MV photons) was used to treat 17 and 30 patients, respectively (Table 2). The target volume always included the primary tumor as well as regional involved nodes. Two centimeters laterally, superiorly and inferiorly were allowed around the visible disease. Custom blocks were used in most fields (87%) to minimize the normal tissue involvement. Carefully designed blocks with lesser clear margins (1–1.5 cm) surrounding tumor were used in patients suffering from obstructive pulmonary disease in order to spare as much normal lung tissue as possible. Unblocked field size ranged between 8× 10 to 22×20 cm. In most cases, the anterior–posterior field technique was used to deliver up to 40 Gy; then oblique and/or multiple fields were used to complete irradiation up to 60 Gy. This technique allowed normal lung to be spared as much as possible and spinal cord to be given no more than 48 Gy. Physicians involved recommended that the dose to be delivered should be at least the biologic equivalent of 45 Gy, with daily fractions not exceeding 2.5 Gy, in order ‘to achieve as much local control as possible without affecting tolerance, and palliate symptoms’ (as reported in the clinical charts of most patients). There was no statement whether treatment had to be considered curative or palliative from the beginning. Standard fractionation was used (1.8–2 Gy per daily fraction) in all but four patients, who received 30–35 Gy/12–14 fractions (2.5 Gy per fraction). The median dose administered was 50 Gy (range 0–60) matching the median prescribed dose of 50 Gy (30–60). Twenty-five patients had doses of 50 Gy and higher (median 50.4 Gy, range 50–60). Forty-one patients completed the therapeutic program as planned. Four patients refused to continue treatment because of discomfort related to repeated accesses. Doses delivered were respectively 39.6, 43.2, 46.8, and 48 Gy. Two patients stopped irradiation owing to intercurrent illness at the doses of 39.6 and 48 Gy. Most treatments (73%) were carried out and completed in an outpatient setting. Eight patients required hospital admission during treatment for supportive care. Five pa-
F. Lonardi et al. / Lung Cancer 28 (2000) 43–50
46 Table 3 Response and overall survival Response
Complete Partial Stable Progressive
Overall survival
0 21 (44%) 17 (35%) 09 (21%)
Months
%
6 12 24
48 23 10
tients were hospitalized to have radiotherapy because they were unable to sustain repeated accesses. One patient died of a bronchial hemorrhage before starting treatment. Unspecific supportive care (bronchodilatating drugs, steroids, and analgesics) was given on demand during treatment.
3. Results Response, survival and toxicity were studied in 47 patients out of 48 (Table 3). According to WHO criteria, responses were classified as complete (CR), partial (PR), stable (SD) and progressive (PD). Symptom relief was evaluated on the basis of patients’ self-evaluation by means of a visual analog scale: a decrease of 50% or more of cough, dyspnea, pain and hemoptysis was considered effective palliation. To correctly assess response to treatment and therapy-related complications, patients were examined by two Table 4 Dose-related survival Dose level
B50 Gy
]50 Gy
Patients Median survival
22 4 months
25 8 months
Sur6i6al at: 6 months 12 months 13 months 18 months 24 months
35% 9% 4%* 4% 4%
52% 28% 28%* 20% 20%
physicians only both on treatment and follow-up. Since we tried to give patients as little discomfort as possible during follow-up, they were evaluated at the completion of therapy and every 3–4 months thereafter by means of chest X-rays, chest CT when required, and routine chemistry. We observed no complete remission, PR in 21 patients (44%), SD in 17 patients (35%) and PD in 9 patients (21%). PR in 25 patients given at least 50 Gy accounted for 60%, compared to 22% of the group who had lower doses (median 35 Gy, range 0–48). Overall survival was 48% at 6 months, 23% at 12 months and 10% at 24 months. Median survival was 5 months (range 1–29). When dose-related survival was analyzed (Table 4), a better outcome emerged in patients treated with doses higher than, or equal to, 50 Gy. Median survival was 8 months in the higher dose group as compared to 4 months in the lower dose group. Overall survival was 52% versus 35% at 6 months, 28% versus 9% at 12 months and 20% versus 4% at 24 months. As for symptoms, radiation therapy was mostly successful in palliating chest pain (88% effective), hemoptysis (100%), and cough (82%). Dyspnea did not benefit from radiotherapy to the same degree (67% effective), however the coexistence of obstructive respiratory illness in many patients prevented us from evaluating correctly. On the whole, 39 out of 47 patients (83%) experienced effective symptom palliation. It is noteworthy that one patient had quasi-complete remission of chest pain despite mediastinal progressive disease. Toxicity was evaluated according to the WHO scale (Table 5). Early toxicity mostly Table 5 Toxicity WHO grade
1
2
3
4
Esophagitis Nausea/Vomiting Dermatitis Leucopenia
12 (26%) 7 8 (17%)a 3
15 (32%) 1 17 (36%)b –
– – – –
– – – –
Fatigue Weight loss 55%
31 (67%) 11 (23%)
a
* P =0.03.
b
Five patients on 60-Co, three patients on LinAc. Fourteen patients on 60-Co, three patients on LinAc.
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consisted of fatigue (67%), grade I-II esophagitis (58%) and nausea (17%). Dermatitis not exceeding GII occurred in 53% of patients, more intensively in the supraclavicular fossa of patients treated by means of Cobalt-60 gamma rays. There was no routinely given symptomatic therapy for these toxic effects. Weight loss 55% occurred in 11 patients (23%) during treatment. Blood counts were performed weekly only in patients who had larger radiation fields (15× 15 cm or over), otherwise on demand. G-I leucopenia was observed in three patients. We were not able to detect any significant late toxicity in longer survivors. There was no toxicity-related delay or interruption of treatment. All forms of toxicity and side effects cleared within 4–5 weeks after the completion of therapy.
4. Discussion At mid-century, world life expectancy at birth was less than 47 years. Better nutrition and medical care have lengthened lives in many countries, so that by the years 2045 – 2050 people are expected to live 79 years in Canada, 78 in Spain and Australia, 77 in the USA and Germany [25]. According to the United Nations Population Division 1996 Database, the number of people over 65 years is likely to double by the year 2020. As a consequence, oncologists have become increasingly aware — and they will become more so in the future — of the many problems with the treatment of aged cancer patients [26], including the psychological aspects [27], as shown by the high proportion of patients treated worldwide, the number of conferences, and the considerable amount of data emerging in literature about this topic. However, many questions are still in debate, as far as optimum treatment selection, normal tissue tolerance, and potential benefits from treatment are concerned. The optimal management of NSCLC in older patients is one of the more discussed, since widespread prejudice exists in treating elderly patients with advanced disease. The tendency to equate older age with poor compliance to aggressive strategies of treatment forces the elderly to be excluded from most treatment
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options or to be under-treated. Potential undertreatment of NSCLC may result from some belief that these tumors are less aggressive in the elderly than in younger people, and that the normal tissue tolerance is decreased in older age. Both these factors may cause inappropriate radiation dose reductions, excessive narrowing of radiation fields, not-to-treat choices, and palliative therapeutic approaches in patients who, conversely, could benefit from radical treatments. According to recent data, people living of 70–75 years are expected to live 10–15 more years [28], so that less than appropriate therapies may adversely affect life span and the quality of residual life. A lot of literature reports have undoubtedly shown that the elderly can tolerate high doses of radiation therapy as safely as younger patients, achieving similar benefits both in terms of response and, possibly, survival. In their recent review, Pignon et al. [29] reported results from 1208 patients aged 50–70 years, treated with radiation for lung and esophageal cancer, accrued in six EORTC trials: no age-related impact on acute and late toxicity emerged, reinforcing the assertion that older patients are not to be excluded from curative approaches with radiation on the basis of simple age considerations. Similar conclusions have been addressed for the surgery option [30]. ASCO recently published the Clinical Practice Guidelines for the treatment of advanced NSCLC [31]. Though the problem of older patients was not highlighted, the expert panel outlined that ‘radiation therapy should be included as part of the standard treatment for selected patients with unresectable stage III NSCLC, whose performance status and pulmonary function are adequate’ and that ‘definitive-dose thoracic radiotherapy should be no less than 60 Gy’. Conversely, the 21 May 1998 NIA/NCI/ACR Collaborative Workshop focused specifically on ‘Radiation Therapy and Cancer in Older Persons’ [32] to ‘recommend strategies to advance the current knowledge base and propose research opportunities for radiation therapy in older patients’. With luck, all these efforts will stimulate research in those areas where information for the treatment of these patients is still limited.
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F. Lonardi et al. / Lung Cancer 28 (2000) 43–50
As a whole, radical radiotherapy is still regarded by many radiation oncologists as the standard treatment for locally advanced NSCLC, despite survival benefits being poor and significant advantages having come from the combination of cisplatin-based chemotherapy with radiotherapy [31,33]. However, while it seems no longer reasonable to administer younger patients with a treatment that can cure so few, elderly patients are a different matter. Comorbidity of the aged often makes therapeutic decisions difficult and the right balance between expected benefits of treatment and potential toxicity hard to reach. Since the risk of serious complications from radiation therapy has been demonstrated to be small, even in patients older than 70 years [34], this treatment option may overcome many of the age-related drawbacks which prevent more aggressive and toxic therapies from being administered to these frail patients. To date, uncertainties about the actual role and potential benefits from radiation therapy in the elderly with NSCLC should no longer exist, though the large variety of doses and schedules used both in limited and advanced stages does not help to define standard approaches [35,36]. In treating this group of patients we chose to deliver no less than 45 Gy in order to overcome the equation elderly= palliation. Dose levels beyond 45 Gy in a palliative setting have shown no evident impact on survival [37]. In our review, patients given doses of 50 Gy and higher seemed to experience some survival advantages in comparison with those who received lesser doses. At 13 months, differences in survival reached a statistically significant value (28 vs. 4%, P = 0.03), but a definitive conclusion cannot be drawn because of the limited accrual. Nevertheless, our findings substantially match the conclusions of the review by Damstrup et al. [38], i.e. that doses of at least 55 Gy should be delivered in NSCLC patients for a better outcome, and they demonstrate that these recommendations may apply to aged and very aged patients too. Our patients were administered with a median dose of 50 Gy, which cannot be considered a curative dose and is far from ASCO’s indications of 60 Gy. However, neither can 50 Gy be considered a merely palliative dose, nor has it been given with substantial
toxicity to our patients; this indicates that curative doses in the range of 60 Gy are a reliable target in aged NSCLC patients not impaired by any se6ere concomitant illness. Since our patients had been checked to detect any relevant comorbidity unfit for high-dose chest radiation (huge lung necrotic masses, severe chronic bronchitis, severe diffuse emphysema, etc.), the compliance to therapy was surprisingly good in most cases, and tolerance was not adversely affected by any supposed age-related limiting factor. This experience confirms that age per se should not be considered a determinant for excluding older patients from radical radiotherapy. However, careful evaluation of any concurrent illness is mandatory prior to treatment decisions. Similar conclusions have been addressed by other studies, like the nationwide survey of the Geriatric Radiation Oncology Group (GROG) in Italy [39], giving the basis for the much awaited design of specifically age-oriented trials to achieve definitive data. Granted that the limited number of patients does not allow for any definitive conclusion from our review, yet the results prove the feasibility of higher doses of radiation in elderly patients, and suggest possible advantages in terms of survival in the absence of any significant toxicity and worsening of quality of life. All in all, the results of this review and the emerging data in literature convinced us to change the treatment policy and administer elderly NSCLC patients with ‘curative’ doses of radiation (higher than 50 Gy) in the range of 55–60 Gy, irrespective of symptoms at presentation. In our opinion, a comprehensive pretreatment evaluation is necessary to detect both adverse prognostic factors and concurrent illness which may affect the cost/benefit ratio and contra-indicate curative irradiation.
5. Conclusions This study supports the hypothesis that doses higher than 50 Gy may impact on survival of aged advanced NSCLC patients. However, the small sample size and the possibility that these observations may be affected with bias, indicate that such
F. Lonardi et al. / Lung Cancer 28 (2000) 43–50
a relationship has to be further investigated in a prospective setting. As matters stand, the notions that aged patients tolerate radiation therapy worse than younger people and that potentially curative doses of radiation are precluded to older NSCLC patients have been debunked. We may conclude that: 1. Higher and curative doses of radiation are likely to be fully delivered to aged and very aged NSCLC patients, unless medically precluded, in order to achieve a better control rate and possibly gain survival advantages. 2. Careful evaluation is required to exclude any comorbidity unfit for high-dose chest-radiation therapy, and to deliver the best treatment tailored to every single patient requirement. 3. Specifically age-oriented clinical trials should be carried out to investigate whether survival advantages can be actually gained with higher doses of radiation.
[9]
[10]
[11]
[12]
[13] [14]
[15]
Acknowledgements [16]
We are grateful to Dr Giovanni Pavanato for his contribution. Dr Pavanato is now at the Divisione di Radioterapia, Ospedale Civile, ASL 18, 45100 Rovigo, Italy.
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