**8. Adjuvant chemotherapy**

The use of adjuvant chemotherapy in the elderly is increasingly popular (Wang et al., 2008). In a SEER database, 25.8% of patients aged between 66 and 69 years received adjuvant treatment compared to 19.8% for those aged 70 to 74, 13.7% for those of 75 to 79 and only 9% for patients older than 80 years old. In the LACE meta-analysis of 4,584 patients with adjuvant chemotherapy, the hazard ratio for mortality was 0.89 and favored chemotherapy, with a 5-year absolute survival benefit of 5.4%. The authors concluded that the benefit of chemotherapy is similar between the elderly and their younger counterpart (Pignon et al., 2006). Another meta-analysis of the impact of adjuvant chemotherapy done by the Non-Small Cell Lung Cancer Collaborative Group and regrouping 52 trials with 9,387 patients between 1963 and 1992 has showed the same absolute benefice on survival of 5% at 5 years. The odds ratio for survival is similar between the different groups of age (Cochrane review, 2000).

Pepe et al. at ASCO meeting in 2006 presented an age-specific evaluation of BR10 study, a phase III trial with patients with stage Ib and II NSCLC and comparing four cycles of cisplatin and vinorelbine with observation. 155 patients of the 482 enrolled in this study were aged 65 years and older. Baseline characteristics were similar between age cohorts except for the histology with more elderly patients with squamous cell cancer. In general, elderly received a lower mean dose intensity of chemotherapy. Overall survival was in favor of the younger patients, but chemotherapy led still to a benefit effect compared with standard observation in elderly. There were few patients aged over 75 and without regard to treatment, survival was still poor at 26% at 5 years (Pepe et al., 2007).

Other studies have been conducted on adjuvant chemotherapy, but the elderly subgroup was either absent, very little or without subgroup analysis as in the IALT study (Arriagada et al., 2004), Anita study (Douillard et al., 2006), Italian study Alpi (Scagliotti et al., 2003), Big Lung Trial (Waller et al., 2004) and CALGB (Strauss et al., 2004, 2006).

Because studies on this subject are retrospective, it is still difficult to conclude on the exact role of surgery in elderly patients with lung cancer. However, surgery should be considered for patients in good condition. Lobectomy is preferable to the limited resections if patients are medically fit (Alberts et al., 2007). Pneumonectomy is associated with greater morbidity and mortality and should only be performed in a highly selected group of patients. With

A review of 297 articles was done by Chambers (2010) to consider the impact of lung resection on morbidity, mortality and postoperative quality of life for patients aged over 70 years. They found twelve articles to answer this question. The collective analysis of these 12 articles showed a five-year survival following surgery for early stages in those under age 70 between 69 and 77%, for those over 70 years, the five-year survival ranges from 59 to 78%. The 30-day mortality rate was 5.7% in patients younger than 70 years against 1.3 to 3.3% in those over 70 years, length of hospital stay after thoracoscopy was respectively 4.6 and 4.9 to 5.2 days. The post-operative lung functions were also equivalent between the two groups. FEV1 decreased 13% compared to 18% in patients older than 70 years (p=0.34) comparing the functional vital capacity decrease were equivalent between both groups (9% vs 14%). Lung function was also compared among young and elderly patients after lobectomy for early stage NSCLC. Changes in FEV1 and functional vital capacity were not significant although postoperative complications occurred in 32% of younger patients and 48% in the

The use of adjuvant chemotherapy in the elderly is increasingly popular (Wang et al., 2008). In a SEER database, 25.8% of patients aged between 66 and 69 years received adjuvant treatment compared to 19.8% for those aged 70 to 74, 13.7% for those of 75 to 79 and only 9% for patients older than 80 years old. In the LACE meta-analysis of 4,584 patients with adjuvant chemotherapy, the hazard ratio for mortality was 0.89 and favored chemotherapy, with a 5-year absolute survival benefit of 5.4%. The authors concluded that the benefit of chemotherapy is similar between the elderly and their younger counterpart (Pignon et al., 2006). Another meta-analysis of the impact of adjuvant chemotherapy done by the Non-Small Cell Lung Cancer Collaborative Group and regrouping 52 trials with 9,387 patients between 1963 and 1992 has showed the same absolute benefice on survival of 5% at 5 years. The odds ratio for survival is similar between the different groups of age (Cochrane review,

Pepe et al. at ASCO meeting in 2006 presented an age-specific evaluation of BR10 study, a phase III trial with patients with stage Ib and II NSCLC and comparing four cycles of cisplatin and vinorelbine with observation. 155 patients of the 482 enrolled in this study were aged 65 years and older. Baseline characteristics were similar between age cohorts except for the histology with more elderly patients with squamous cell cancer. In general, elderly received a lower mean dose intensity of chemotherapy. Overall survival was in favor of the younger patients, but chemotherapy led still to a benefit effect compared with standard observation in elderly. There were few patients aged over 75 and without regard to

Other studies have been conducted on adjuvant chemotherapy, but the elderly subgroup was either absent, very little or without subgroup analysis as in the IALT study (Arriagada et al., 2004), Anita study (Douillard et al., 2006), Italian study Alpi (Scagliotti et al., 2003), Big

Because studies on this subject are retrospective, it is still difficult to conclude on the exact role of surgery in elderly patients with lung cancer. However, surgery should be considered for patients in good condition. Lobectomy is preferable to the limited resections if patients are medically fit (Alberts et al., 2007). Pneumonectomy is associated with greater morbidity and mortality and should only be performed in a highly selected group of patients. With

treatment, survival was still poor at 26% at 5 years (Pepe et al., 2007).

Lung Trial (Waller et al., 2004) and CALGB (Strauss et al., 2004, 2006).

elderly (Sullivan et al., 2005).

2000).

**8. Adjuvant chemotherapy** 

few conclusive results available from studies of adjuvant chemotherapy in elderly, it is difficult to conclude that it should be a standard treatment for older people. However, we can possibly extrapolate from studies done with younger patients and use it in selected patients aged less than 75 years of age.

#### **9. Radiotherapy**

It was demonstrated that nearly 25% of patients with disease stage I or II did not have surgery, most often because of significant comorbidities, patient preferences or poor lung functions (Bach et al., 1999; Spiro et al., 2002). For elderly who are not candidates for surgery, radiation therapy is possible. Unfortunately, it usually gives poor results with a 5 year survival estimated at between 6 to 14% (Razet al., 2007; Wisnivesky et al., 2005). In this section, the curative as well as palliative indication for radiation will be discussed.

Radiation therapy has been shown to improve outcomes compared to best supportive care alone (Raz et al., 2007). A subgroup analysis, in the study of Morita, assessed the impact of age in relation with survival in irradiated patients. One hundred and forty-nine patients older than 80 years with stage I lung cancer were included in this analysis. The survival was lower in older patients compared with younger. The 3- and 5-years actuarial survival was 15.4% and 7.7% in octogenarians versus respectively 38.2% and 25.2% in younger (p=0.035) (Morita et al., 1997). Similar results were found by Sibley (Sibley et al., 1998). However, a retrospective study from 6 studies of EORTC with 1,208 patients has shown no difference in overall survival between patients older or younger of 70 years (Pignon et al., 1998). Other retrospective studies compared treatment outcomes in younger and older patients. The North Central Cancer Treatment Group studied the impact of age (≥ 70 years versus younger) with two different schedules of radiation, either daily or twice per day, combined with concurrent chemotherapy. The 2-year survival rates were 39% in younger and 36% in the elderly and at 5-year, it was 18% versus 13% in patients ≥ 70 years (p=0.4). Toxicity of grade 4 or more were significantly higher in older patients (81%) than in younger ones (62%). The conclusion of this study was that toxicity is higher in elderly, but the survival is similar. Thus for fit patients this treatment can be proposed (Schild et al., 2003).

In the treatment of locally advanced NCSLC, the standard of care is radiation with chemotherapy based on cisplatin. Two major trials demonstrated a survival advantage for the use of induction chemotherapy prior to radiation therapy (Dillman et al., 1990; Sause et al., 2000). After the publication of these results, studies have been done to test the combined treatment. These studies shown that combined chemoradiotherapy is more effective compared to radiation alone (Dillman et al., 1990; Furuse et al., 1999). Elderly were in general excluded from these studies and few trials have been done about the role of combined chemoradiation in this particular population. A phase II study in 40 elderly patients with unresectable stage III or medically inoperable stage I and II lung cancer treated with concurrent carboplatin and radiation was done. For stage IIIA/IIIB patients, the median survival time was 15.1 months and 1-and 2-year actuarial survival rates were 52.6% and 20.5%, respectively. For stage I/II patients, 1- and 3-year actuarial survival rates were 90.9% and 69.3%, respectively (Atagi et al., 2000).

A phase III trial was performed by Atagi in 2005 with patients older than 70 years with stage III NSCLC. Patients were randomly assigned to either radiation therapy (dose of 60 Gy) with concurrent carboplatin or radiation therapy alone. 4 patient's death may have resulted

Lung Cancer in Elderly 235

with 2D planning. They found a better survival in patients treated with a more complex

In 2008, Yu conducted a multicenter prospective study in older patients with Intensity Modulated Radiotherapy (IMRT), an inverse planning technique. 80 patients had stage I and II disease and were medically inoperable or refused surgery. Patients received 66 Gy to involved field including primary tumor and clinical enlarged nodes. Objective response rate was 88.6%, with 1-, 2- and 5-year overall survival rates of 65.8%, 55.7% and 25.3% respectively and local progression-free survival was 84.8%. Toxicity was minimal. This study confirms that involved field radiation is a reasonable treatment for elderly patients.

Stereotactic body irradiation (SBRT) is a technique that utilizes precisely targeted radiation to tumor while minimizing radiation to adjacent normal tissue. This is accomplished by using multiple beams (typically 10 to 12) or large angle arc rotations. This technique is promising in the elderly. SBRT accurately delivers highly hypofractionated doses of radiation. High biologically effective radiation doses are generally of advantage with regard to tumor cell kill and local tumor control. SBRT is in general well tolerated and local control

In Zimmermann study, 68 patients were treated with a mean dose of 37.5 Gy in 3-5 fractions. The mean age was 76 years. Actuarial local tumor control at 1, 2 and 3 years was 96%, 88% and 88%. Disease-specific survival was 96%, 82% and 73% at 1, 2, and 3 year follow-up. 2 patients died by local tumor progression and a total of 8 patients died from their lung cancer disease. 55% of patients had mild acute and subacute toxicities (Zimmerman 2006). In Indiana University study, patients received in a phase I trial 66 Gy in 3 fractions for T2 tumors. The maximum tolerated dose was not reached for T1 tumors at 60 Gy in 3 fractions (McGarry et al., 2005; Timmerman et al., 2003). A RTOG multicenter study treated 59 patients with T1-T2N0 tumor with 54 Gy in 3 fractions. Three-year local control of the tumor was 98%. The three-year disease-free and overall survivals were 48% and 56% respectively

In general, the results for stereotactic radiotherapy appear better than those of standard radiotherapy. Local control at 3 years vary from 86-95% (Baumann et al., 2006, 2009; Onishi et al., 2007; Xia et al., 2006; Zimmermann et al., 2006) for patients treated with SBRT while for external radiotherapy, local recurrences are more than 50% (Rowell et al., 2001 & Qiao et

Moreover a Palma analysis on 875 elderly patients shown that SBRT introduction was associated with an improvement of 16% in the use of radiation, and a decline in the number

The main goal of palliative radiation is to decrease the pulmonary symptoms of the patients. The number of treatment may vary according to the general functional status of the patients. According to a review of 13 randomized trials, no significant difference was observed for specific symptom control end points, but there is an improvement in survival favoured with high dose radiotherapy. For good functional status patients, it is recommended to use a palliative dose of radiation with a biological effective dose (BED) of at least 35 Gy10 (Fairchild et al., 2008). Another review of 12 randomized controlled studies recommends a

planning (Park et al., 2010).

**9.2 Stereotactic radiation** 

(Timmerman, 2010).

**9.3 Palliative radiation** 

is similar than for patients treated with surgery.

al., 2003) with 5-years survival around 10 to 30%.

of untreated elderly patients (Palma et al., 2010).

from poor compliance in the design of the radiation fields. This trial was closed early with only 46 randomised patients.

A retrospective study of Langer (2002b) examined 104 patients older than 70 years with good performance status and minor weight loss receiving either sequential chemotherapy followed by daily radiotherapy, concomitant chemotherapy with daily radiotherapy or concomitant chemotherapy with twice daily radiation in phase III RTOG protocol 94-10. Concurrent treatment was proved to be favourable in the elderly, but toxicities were increased in this group. Median survival was 22.4 months for concurrent therapy with daily radiation, 16.4 months for concurrent chemotherapy with twice daily radiation treatment and 10.8 months for sequential treatment (p=0.069).

Patients over 70 years of prospective studies performed by CALGB were retrospectively analyzed by Rocha Lima (2002). In CALGB 9130, patients were randomised between vinblastine and cisplatin followed by radiation alone at dose of 60 Gy or neoadjuvant vinblastine and cisplatin followed by concurrent radiation with carboplatin. 22% of the patients enrolled in this study had between 70-79 years and no patients had more than 80 years of age. Age was not found to be a factor in survival or response rate, but elderly had more neutropenia and renal toxicity of grade 3 or more.

Hayakawa (2001) showed an alteration of performance index in only 5% of patients between 75-79 years and 8% in those more than 80 years when they are treated with radiation alone of 60 Gy. Another study presenting results about toxicity in 51 patients older than 65 years shows no augmentation of the toxicity in these patients in function with age, but survival was significantly correlated with performance status and importance of comorbidities (Fiorica et al., 2010).

Retrospective case series of older patients treated with curative radiation alone have demonstrated a median survival of up to 37 months for stage I-II and 8 months pour stage III (Bonfili et al., 2009; Lonardi et al., 2000; San José et al., 2006 & Tombolini et al., 2000).

It is recommended to provide elderly patients with advanced lung cancer disease in good general condition radiotherapy combined with chemotherapy. Concomitant treatment gives better results, but it is also more toxic to patients. For those that concomitant treatment is not possible, chemotherapy may be given before sequential radiotherapy. If the general condition of the patient or his comorbidities do not allow use of chemotherapy, he should receive radiation therapy alone either for curative or palliative purpose.

#### **9.1 Radiotherapy planning**

#### **9.1.1 Treatment volume**

There would be an increase of interruption of radiation treatment with the increased volume of the radiation field in patients over 80 years (Zachariah et al., 1997). For patients over 90 years, Ikeda (1999) showed that radiotherapy is better tolerated if treatment is limited to the macroscopic volume. In Pergolizzi (2002), 40 patients with stage IIIA, aged older than 75 years, were treated with involved field with median dose of 60 Gy. The overall survival was 18% at 3-years and 12% at 5 years.

#### **9.1.2 Radiation technique**

Technique of radiation could also influence the response to treatment in elderly population. Thus, Park's study evaluate whether complex radiotherapy planning with 3D techniques was associated with improvement outcomes in elderly compared with intermediate analysis

from poor compliance in the design of the radiation fields. This trial was closed early with

A retrospective study of Langer (2002b) examined 104 patients older than 70 years with good performance status and minor weight loss receiving either sequential chemotherapy followed by daily radiotherapy, concomitant chemotherapy with daily radiotherapy or concomitant chemotherapy with twice daily radiation in phase III RTOG protocol 94-10. Concurrent treatment was proved to be favourable in the elderly, but toxicities were increased in this group. Median survival was 22.4 months for concurrent therapy with daily radiation, 16.4 months for concurrent chemotherapy with twice daily radiation treatment

Patients over 70 years of prospective studies performed by CALGB were retrospectively analyzed by Rocha Lima (2002). In CALGB 9130, patients were randomised between vinblastine and cisplatin followed by radiation alone at dose of 60 Gy or neoadjuvant vinblastine and cisplatin followed by concurrent radiation with carboplatin. 22% of the patients enrolled in this study had between 70-79 years and no patients had more than 80 years of age. Age was not found to be a factor in survival or response rate, but elderly had

Hayakawa (2001) showed an alteration of performance index in only 5% of patients between 75-79 years and 8% in those more than 80 years when they are treated with radiation alone of 60 Gy. Another study presenting results about toxicity in 51 patients older than 65 years shows no augmentation of the toxicity in these patients in function with age, but survival was significantly correlated with performance status and importance of comorbidities

Retrospective case series of older patients treated with curative radiation alone have demonstrated a median survival of up to 37 months for stage I-II and 8 months pour stage III (Bonfili et al., 2009; Lonardi et al., 2000; San José et al., 2006 & Tombolini et al., 2000). It is recommended to provide elderly patients with advanced lung cancer disease in good general condition radiotherapy combined with chemotherapy. Concomitant treatment gives better results, but it is also more toxic to patients. For those that concomitant treatment is not possible, chemotherapy may be given before sequential radiotherapy. If the general condition of the patient or his comorbidities do not allow use of chemotherapy, he should

There would be an increase of interruption of radiation treatment with the increased volume of the radiation field in patients over 80 years (Zachariah et al., 1997). For patients over 90 years, Ikeda (1999) showed that radiotherapy is better tolerated if treatment is limited to the macroscopic volume. In Pergolizzi (2002), 40 patients with stage IIIA, aged older than 75 years, were treated with involved field with median dose of 60 Gy. The overall survival was

Technique of radiation could also influence the response to treatment in elderly population. Thus, Park's study evaluate whether complex radiotherapy planning with 3D techniques was associated with improvement outcomes in elderly compared with intermediate analysis

receive radiation therapy alone either for curative or palliative purpose.

only 46 randomised patients.

(Fiorica et al., 2010).

**9.1 Radiotherapy planning 9.1.1 Treatment volume** 

18% at 3-years and 12% at 5 years.

**9.1.2 Radiation technique** 

and 10.8 months for sequential treatment (p=0.069).

more neutropenia and renal toxicity of grade 3 or more.

with 2D planning. They found a better survival in patients treated with a more complex planning (Park et al., 2010).

In 2008, Yu conducted a multicenter prospective study in older patients with Intensity Modulated Radiotherapy (IMRT), an inverse planning technique. 80 patients had stage I and II disease and were medically inoperable or refused surgery. Patients received 66 Gy to involved field including primary tumor and clinical enlarged nodes. Objective response rate was 88.6%, with 1-, 2- and 5-year overall survival rates of 65.8%, 55.7% and 25.3% respectively and local progression-free survival was 84.8%. Toxicity was minimal. This study confirms that involved field radiation is a reasonable treatment for elderly patients.

#### **9.2 Stereotactic radiation**

Stereotactic body irradiation (SBRT) is a technique that utilizes precisely targeted radiation to tumor while minimizing radiation to adjacent normal tissue. This is accomplished by using multiple beams (typically 10 to 12) or large angle arc rotations. This technique is promising in the elderly. SBRT accurately delivers highly hypofractionated doses of radiation. High biologically effective radiation doses are generally of advantage with regard to tumor cell kill and local tumor control. SBRT is in general well tolerated and local control is similar than for patients treated with surgery.

In Zimmermann study, 68 patients were treated with a mean dose of 37.5 Gy in 3-5 fractions. The mean age was 76 years. Actuarial local tumor control at 1, 2 and 3 years was 96%, 88% and 88%. Disease-specific survival was 96%, 82% and 73% at 1, 2, and 3 year follow-up. 2 patients died by local tumor progression and a total of 8 patients died from their lung cancer disease. 55% of patients had mild acute and subacute toxicities (Zimmerman 2006). In Indiana University study, patients received in a phase I trial 66 Gy in 3 fractions for T2 tumors. The maximum tolerated dose was not reached for T1 tumors at 60 Gy in 3 fractions (McGarry et al., 2005; Timmerman et al., 2003). A RTOG multicenter study treated 59 patients with T1-T2N0 tumor with 54 Gy in 3 fractions. Three-year local control of the tumor was 98%. The three-year disease-free and overall survivals were 48% and 56% respectively (Timmerman, 2010).

In general, the results for stereotactic radiotherapy appear better than those of standard radiotherapy. Local control at 3 years vary from 86-95% (Baumann et al., 2006, 2009; Onishi et al., 2007; Xia et al., 2006; Zimmermann et al., 2006) for patients treated with SBRT while for external radiotherapy, local recurrences are more than 50% (Rowell et al., 2001 & Qiao et al., 2003) with 5-years survival around 10 to 30%.

Moreover a Palma analysis on 875 elderly patients shown that SBRT introduction was associated with an improvement of 16% in the use of radiation, and a decline in the number of untreated elderly patients (Palma et al., 2010).

#### **9.3 Palliative radiation**

The main goal of palliative radiation is to decrease the pulmonary symptoms of the patients. The number of treatment may vary according to the general functional status of the patients. According to a review of 13 randomized trials, no significant difference was observed for specific symptom control end points, but there is an improvement in survival favoured with high dose radiotherapy. For good functional status patients, it is recommended to use a palliative dose of radiation with a biological effective dose (BED) of at least 35 Gy10 (Fairchild et al., 2008). Another review of 12 randomized controlled studies recommends a

Lung Cancer in Elderly 237

years included in this trial was 27% or 155 patients. In that study, there was no formal subgroup analysis based on age, but the general data revealed no obvious difference between age groups (Lilenbaum et al., 2005). Further studies with subgroup analysis showed similar results (Belani et al., 2005; Earle et al., 2001; Hensinget al., 2003; Iberti et al., 1995; Langer et al., 2003; Rocha Lima et al., 2002). We can then conclude that the survival

As previously discussed, age by itself should not be a factor to decide if a patient will received or not chemotherapy treatment. That decision should be taken considering the global functional status of the patients and his comorbidities, particularly cardiovascular and pulmonary ones. Aging is associated with several physiologic changes in organ function. Those changes could alter drug pharmacokinetics and they could have an impact on cytotoxic chemotherapy toxicity and tolerability (Wildiers et al., 2003). Thus, it is always mandatory to know the serum creatinine, but also the creatinine clearance to assess renal function, particularly for chemotherapy agents whose main route of elimination is by the kidney, as platinum derivatives and methotrexate. It is also important to evaluate the bone marrow reserve as this reserve may diminish with increasing age, and the risk of

This question was evaluated in elderly patients with advanced/metastatic NSCLC in the Italian phase III trial, Elderly Lung Cancer Vinorelbine Italian Group Study (ELVIS) (Ardizzoni et al., 2005). Patients over 70 years of age were randomly assigned to either receive vinorelbine (30 mg/m2 on days 1 and 8) or to receive best supportive care (BSC). Even if the accrual of this study was poor, with only 161 evaluable patients, it demonstrated that there was a significant advantage of survival in the vinorelbine arm (p=0.03). The median survival was 21 weeks for BSC versus 28 weeks for vinorelbine. Survival rates were 41% at 6 months for control arm compared to 55% in the vinorelbine arm. At 12 months, survival was respectively 14% for BSC and 32% with vinorelbine. This study also shown that patients receiving chemotherapy had a significant benefit in disease-related quality-of-life (QoL) measures (decreased pain p=0.02, decreased dyspnea p=0.05). Toxicity was acceptable. Only 5 of 71 older patients discontinued treatment secondary to severe toxic events (3 patients had constipation grade 3, 1 patient had constipation grade 4 and 1 patient had grade 2 heart toxicity). Even if 4 patients had a grade 4 leukopenia, treatment had not

Others chemotherapy were tested to find the best one in elderly patients. A phase III trial of West Japan Thoracic Oncology Group Trial (WJTOG 9904) randomized 182 patients older than 70 years between two agents: docetaxel (60 mg/m2 on day 1) or vinorelbine (25 mg/m2 on days 1 and 8). Patients received 4 cycles every 21 days. Median survival was not significantly different between two arms with docetaxel group being 14.3 months compared to 9.9 months with vinorelbine (p=0.138). However, others outcomes were significantly in favour of docetaxel. Thus, the progression-free survival was 5.5 months versus 3.1 months (p<0.001) and the response rate was 22.7% compared to 9.9% (p=0.019). Even if no

benefit is similar in elderly as in younger patients.

**10.1 Importance of patient evaluation for chemotherapy treatment** 

neutropenia increases with age (Langer et al., 2002; Rocha Lima et al., 2002).

**10.2 Single-agent chemotherapy versus best supportive care** 

been interrupted.

**10.3 Type of single-agent chemotherapy** 

short course (one or two fraction) of hypofractioned radiotherapy for the majority of the patients. Selected patients with good performance status should be considered for higher dose regimens as this could increase their survival (Toy et al., 2003).

#### **9.3.1 Brachytherapy as palliation**

Another way to treat lung cancer disease is using palliative brachytherapy. This treatment is effective to treat endobronchial disease. This often causes cough, hemoptysis and dyspnea. Stout compared external beam radiation therapy (EBRT) with endobronchial brachytherapy. He showed that EBRT offers a better palliation. Furthermore, there was slightly improved in survival (Stout et al., 2000). However, some patients cannot be treated with external beam radiation and brachytherapy could be offered to them. This approach seems to be more effective than other types of treatment, such as cryotherapy, cauterization or phototherapy, which only superficially destruct cancer cell (Hetzel et al., 1985; Sutedja et al., 1994; Walsh et al., 1990). High-dose rate brachytherapy is cost-effective and convenient owing to its short irradiation time and the fact that it can be provided on an outpatient basis. Endobronchial brachytherapy treats tumors up to 1-cm deep with 100% of prescribed dose and a decreasing dose can reach up to 2-cm deep.

A retrospective study with inoperable endobronchial lung cancer or metastasis had shown a significant improvement of symptoms and a good survival. 85% of patients had an improvement of the dyspnea during or shortly after the end of the treatment. Hemoptysis was stopped in all 23 patients of the study and 77% of them had an improvement of their cough. Patients had received 4 weekly fractions of 5 Gy each time. The complication rate during treatment was low (Dagnault et al., 2010).

Thus, for palliation, hypofractionated external beam radiation therapy and brachytherapy are alternatives to proper treatment for the relief of symptoms.

#### **10. Chemotherapy**

The treatment of advanced lung cancer requires chemotherapy. The standard combination is based on a combination of platinum and either vinorelbine, gemcitabine, paclitaxel or docetaxel. Few studies have yet been made to assess the best chemotherapy agents in elderly people. Many of the available data are from analysis of subgroups. The American College of Chest Physician guidelines recommends chemotherapy for stage IV NSCLC for selected patients older than 70 years. They caution that the benefits of chemotherapy in patients over 80 years of age are unknown and recommend instead a case by case assessment (Socinski et al., 2007).

The first important question is to determine if older people tolerates chemotherapy as well as younger patients and if the outcome of the treatments is the same. Some studies have been done in this direction. Nguyen (1999) compared cisplatin and gemcitabine to cisplatin alone and showed that tolerance to treatment and outcome of patients were identical for patients aged more or less than 70 years. In a subset analysis of an Eastern Cooperative Oncology Group study (ECOG 5592) patients received cisplatin and etoposide or paclitaxel. A total of 574 patients were included in this trial, which 15% were 70 or older. The response rate, the time to progression and the survival rate did not differ across groups but there was higher hematological and neuropsychiatric toxicities in the elders. There was no difference in the quality of life (Langer et al., 2002a). In the CALGB 7730 trial, 561 patients received paclitaxel compared to paclitaxel and carboplatin. The total of patients aged more than 70

short course (one or two fraction) of hypofractioned radiotherapy for the majority of the patients. Selected patients with good performance status should be considered for higher

Another way to treat lung cancer disease is using palliative brachytherapy. This treatment is effective to treat endobronchial disease. This often causes cough, hemoptysis and dyspnea. Stout compared external beam radiation therapy (EBRT) with endobronchial brachytherapy. He showed that EBRT offers a better palliation. Furthermore, there was slightly improved in survival (Stout et al., 2000). However, some patients cannot be treated with external beam radiation and brachytherapy could be offered to them. This approach seems to be more effective than other types of treatment, such as cryotherapy, cauterization or phototherapy, which only superficially destruct cancer cell (Hetzel et al., 1985; Sutedja et al., 1994; Walsh et al., 1990). High-dose rate brachytherapy is cost-effective and convenient owing to its short irradiation time and the fact that it can be provided on an outpatient basis. Endobronchial brachytherapy treats tumors up to 1-cm deep with 100% of prescribed dose and a decreasing

A retrospective study with inoperable endobronchial lung cancer or metastasis had shown a significant improvement of symptoms and a good survival. 85% of patients had an improvement of the dyspnea during or shortly after the end of the treatment. Hemoptysis was stopped in all 23 patients of the study and 77% of them had an improvement of their cough. Patients had received 4 weekly fractions of 5 Gy each time. The complication rate

Thus, for palliation, hypofractionated external beam radiation therapy and brachytherapy

The treatment of advanced lung cancer requires chemotherapy. The standard combination is based on a combination of platinum and either vinorelbine, gemcitabine, paclitaxel or docetaxel. Few studies have yet been made to assess the best chemotherapy agents in elderly people. Many of the available data are from analysis of subgroups. The American College of Chest Physician guidelines recommends chemotherapy for stage IV NSCLC for selected patients older than 70 years. They caution that the benefits of chemotherapy in patients over 80 years of age are unknown and recommend instead a case by case

The first important question is to determine if older people tolerates chemotherapy as well as younger patients and if the outcome of the treatments is the same. Some studies have been done in this direction. Nguyen (1999) compared cisplatin and gemcitabine to cisplatin alone and showed that tolerance to treatment and outcome of patients were identical for patients aged more or less than 70 years. In a subset analysis of an Eastern Cooperative Oncology Group study (ECOG 5592) patients received cisplatin and etoposide or paclitaxel. A total of 574 patients were included in this trial, which 15% were 70 or older. The response rate, the time to progression and the survival rate did not differ across groups but there was higher hematological and neuropsychiatric toxicities in the elders. There was no difference in the quality of life (Langer et al., 2002a). In the CALGB 7730 trial, 561 patients received paclitaxel compared to paclitaxel and carboplatin. The total of patients aged more than 70

dose regimens as this could increase their survival (Toy et al., 2003).

**9.3.1 Brachytherapy as palliation** 

dose can reach up to 2-cm deep.

**10. Chemotherapy** 

assessment (Socinski et al., 2007).

during treatment was low (Dagnault et al., 2010).

are alternatives to proper treatment for the relief of symptoms.

years included in this trial was 27% or 155 patients. In that study, there was no formal subgroup analysis based on age, but the general data revealed no obvious difference between age groups (Lilenbaum et al., 2005). Further studies with subgroup analysis showed similar results (Belani et al., 2005; Earle et al., 2001; Hensinget al., 2003; Iberti et al., 1995; Langer et al., 2003; Rocha Lima et al., 2002). We can then conclude that the survival benefit is similar in elderly as in younger patients.

#### **10.1 Importance of patient evaluation for chemotherapy treatment**

As previously discussed, age by itself should not be a factor to decide if a patient will received or not chemotherapy treatment. That decision should be taken considering the global functional status of the patients and his comorbidities, particularly cardiovascular and pulmonary ones. Aging is associated with several physiologic changes in organ function. Those changes could alter drug pharmacokinetics and they could have an impact on cytotoxic chemotherapy toxicity and tolerability (Wildiers et al., 2003). Thus, it is always mandatory to know the serum creatinine, but also the creatinine clearance to assess renal function, particularly for chemotherapy agents whose main route of elimination is by the kidney, as platinum derivatives and methotrexate. It is also important to evaluate the bone marrow reserve as this reserve may diminish with increasing age, and the risk of neutropenia increases with age (Langer et al., 2002; Rocha Lima et al., 2002).

#### **10.2 Single-agent chemotherapy versus best supportive care**

This question was evaluated in elderly patients with advanced/metastatic NSCLC in the Italian phase III trial, Elderly Lung Cancer Vinorelbine Italian Group Study (ELVIS) (Ardizzoni et al., 2005). Patients over 70 years of age were randomly assigned to either receive vinorelbine (30 mg/m2 on days 1 and 8) or to receive best supportive care (BSC). Even if the accrual of this study was poor, with only 161 evaluable patients, it demonstrated that there was a significant advantage of survival in the vinorelbine arm (p=0.03). The median survival was 21 weeks for BSC versus 28 weeks for vinorelbine. Survival rates were 41% at 6 months for control arm compared to 55% in the vinorelbine arm. At 12 months, survival was respectively 14% for BSC and 32% with vinorelbine. This study also shown that patients receiving chemotherapy had a significant benefit in disease-related quality-of-life (QoL) measures (decreased pain p=0.02, decreased dyspnea p=0.05). Toxicity was acceptable. Only 5 of 71 older patients discontinued treatment secondary to severe toxic events (3 patients had constipation grade 3, 1 patient had constipation grade 4 and 1 patient had grade 2 heart toxicity). Even if 4 patients had a grade 4 leukopenia, treatment had not been interrupted.

#### **10.3 Type of single-agent chemotherapy**

Others chemotherapy were tested to find the best one in elderly patients. A phase III trial of West Japan Thoracic Oncology Group Trial (WJTOG 9904) randomized 182 patients older than 70 years between two agents: docetaxel (60 mg/m2 on day 1) or vinorelbine (25 mg/m2 on days 1 and 8). Patients received 4 cycles every 21 days. Median survival was not significantly different between two arms with docetaxel group being 14.3 months compared to 9.9 months with vinorelbine (p=0.138). However, others outcomes were significantly in favour of docetaxel. Thus, the progression-free survival was 5.5 months versus 3.1 months (p<0.001) and the response rate was 22.7% compared to 9.9% (p=0.019). Even if no

Lung Cancer in Elderly 239

Toxicity for the combination arm resulted in grade 3-4 neutropenia and thrombocytopenia in 38% and 13% respectively, and it was more prevalent than in the vinorelbine arm (Frasci

The Cancer and Leukemia Group B reported results of a phase III trial (CALGB-9730) that compared a combination of carboplatin and paclitaxel with paclitaxel in monotherapy. In this study, in which 155 patients had over 70 years, the response rate was 36% versus 21% respectively. The median survival was better in patients treated with the combination compared with monotherapy (8.0 vs 5.8 months respectively- non significant) (Lilenbaum et

Docetaxel and cisplatin doublet was compared with docetaxel in monotherapy in a phase III trial for elderly patient with NSCLC (Ansari et al., 2007). The planned sample size was 115 patients per arm, but the study was closed when the planned interim analysis showed that

However, results remain conflicting about the impact of a combination of chemotherapy. Multicenter Italian Lung cancer in the elderly Study (MILES) is another randomized study that involves patients aged 70 years or older. 698 patients were randomly assigned to gemcitabine alone (1,200 mg/m2 days 1 and 8, every 3 weeks), vinorelbine alone (30 mg/m2 on days 1 and 8, every 3 weeks) or gemcitabine (1,000 mg/m2) plus vinorelbine (25 mg/m2) both administrated on days 1 and 8 every 3 weeks (Gridelli et al., 2003). In this study, there was no difference between each single-agent and the combination arm for progression-free survival and overall survival. The estimated 1-year survival was 38% and 28% for patients respectively with vinorelbine and gemcitabine alone. In the combination arm, the overall survival was 30%. Median survival was 36 weeks for vinorelbine, 28 weeks for gemcitabine alone and 30 weeks for the combination. Toxicities were more frequent in the patients receiving combination chemotherapy. Thus, the combination of vinorelbine and gemcitabine was not shown to be more effective than single agent vinorelbine or gemcitabine in elderly

A study analysed the baseline assessment of functional status, comorbidity and quality of life in elderly patients randomised in MILES trial. The presence of comorbidity was assessed with a checklist of 33 items, items 29 and 30 of the European Organisation for research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 were used for the quality of life and the Charlson scale was used to summarize cormorbidity. Better values of activities of instrumental activities of daily living (IADL) (p=0.04) and of baseline quality of life (p=0.0003) were significantly associated with better prognosis. Two others factors, either activities of daily living (ADL) and the Charlson scale score had no prognostic value

An analysis from SEER data on patients with NSCLC over 65 years old evaluated the role of chemotherapy. Of over 21,000 patients evaluated, only 25.8% received first-line chemotherapy. After adjusting for comorbidities, age and performance status, patients with chemotherapy had an increased adjusted 1-year survival rate of 27% when compared to those without chemotherapy (11%) and a reduction of the adjusted risk of death, with a hazard ratio of 0.558. In this study, the use of combination of platinum agents was associated with an increase

A meta-analysis involving 2,867 patients of randomized controlled trial had shown superior results for efficacy and tolerability of docetaxel compared with vinorelbine or vindesine (Douillard et al., 2007; Laporte et al., 2007). The overall survival was 11% greater in patients

survival at 30.1% compared with single-agent at 19.4% (Davidoff et al., 2010).

the doublet may be beneficial for patient aged 70 to 74 years.

patients with NSCLC (Gridelli et al., 2003).

(Maione et al., 2005).

et al., 2000).

al., 2005).

significant differences in global QoL were observed between the two groups, it is interesting to notice that patients in the docetaxel group had a significant greater improvement in overall symptom score than those in vinorelbine group. One disadvantage of docetaxel is that it induces significantly severe neutropenia more frequently. To conclude, docetaxel in monotherapy can be considered as an option of treatment in older patients (Kudoh et al., 2006). A phase 2 study performed in older patients compared gemcitabine and docetaxel and these agents had comparable efficacy and tolerability profiles (Leong et al., 2007).

In 2010, a phase II trial was published on the role of single-agent vinorelbine in patient older than 70 years with poor performance status (ECOG 2 or more). Forty-three patients received oral vinorelbine at the dose of 60 mg/m2 on days 1 to 8 every 3 weeks. Overall response rate was 18.6%, median time to progression was 4.0 months and median overall survival was 8.0 months. This treatment was safe, without grade 3 or 4 toxicity, exception of a single nonfebrile grade 3 neutropenia. Therefore, vinorelbine is safe for elderly patient, even in those with poor performance status (Camerini et al., 2010). Previously, another study with docetaxel in monotherapy, comparing weekly to 3-weekly administration, had also conclude that this treatment is effective and well tolerated in older patients, even with poor performance status (Lilenbaum et al., 2007).

An international expert panel ruled in favour of the use of single-agent chemotherapy in the elderly cancer patient. A third-generation agent is recommended for patients with any performance status and a platinum-based chemotherapy is recommended for those with performance status 0 or 1 and no contre-indications for comorbidities (Gridelli et al., 2005).

#### **10.4 Combination versus single-agent chemotherapy**

When studies revealed that single-agent chemotherapy improved survival, the search for more effective treatment continued and studies with combinations of chemotherapy have been done. Few randomized trials compared a combination of chemotherapy to a single agent. A French Intergroup study randomly assigned 451 patients of 70-89 years with performance status 0-2 that previously had untreated stage III or IV disease. Patients received a combination of carboplatin (AUC 6 on day 1) plus paclitaxel (90 mg/m2, days 1, 8 and 15) every 4 weeks for a total of four cycles or a single agent (gemcitabine or vinorelbine, as predetermined by each institution). Gemcitabine (1,150 mg/m2) or vinorelbine (30 mg/m2) were given on days 1 and 8 for 5 cycles, every 3 weeks. At ASCO meeting in 2010, preliminary results were presented. For the first 313 patients, overall survival was significantly better in the combination arm with 10.4 months versus 6.2 months for single agent chemotherapy. Progression-free survival was significantly improved with combination chemotherapy (6.3 versus 3.2 months) and this difference was significant. The combined treatment was well tolerable even if neutropenia grade 3 and 4 were more frequent with the combination chemotherapy (Quoix et al., 2010).

A phase III study done by The South Italian Cooperative Oncology Group (SICOG) randomized patients between vinorelbine (30 mg/m2 days 1 and 8 every 3 weeks), versus vinorelbine/gemcitabine (vinorelbine 30 mg/m2 and gemcitabine 1,200 mg/m2, days 1 and 8 every 3 weeks). In this study an interim analysis of survival with the first 60 patients was done. This analysis showed a significant survival advantage for the combination arm, with median survival of 29 weeks versus 18 weeks for the single arm. Following these results, the study was closed prematurely. The estimated 6-months and 1-year survival were 56% and 30% for the combination group and 32% and 13% in the single-agent arm (p<0.01). Patients receiving monotherapy treatment had more symptoms and deterioration of quality of life.

significant differences in global QoL were observed between the two groups, it is interesting to notice that patients in the docetaxel group had a significant greater improvement in overall symptom score than those in vinorelbine group. One disadvantage of docetaxel is that it induces significantly severe neutropenia more frequently. To conclude, docetaxel in monotherapy can be considered as an option of treatment in older patients (Kudoh et al., 2006). A phase 2 study performed in older patients compared gemcitabine and docetaxel and these agents had comparable efficacy and tolerability profiles (Leong et al., 2007). In 2010, a phase II trial was published on the role of single-agent vinorelbine in patient older than 70 years with poor performance status (ECOG 2 or more). Forty-three patients received oral vinorelbine at the dose of 60 mg/m2 on days 1 to 8 every 3 weeks. Overall response rate was 18.6%, median time to progression was 4.0 months and median overall survival was 8.0 months. This treatment was safe, without grade 3 or 4 toxicity, exception of a single nonfebrile grade 3 neutropenia. Therefore, vinorelbine is safe for elderly patient, even in those with poor performance status (Camerini et al., 2010). Previously, another study with docetaxel in monotherapy, comparing weekly to 3-weekly administration, had also conclude that this treatment is effective and well tolerated in older patients, even with poor

An international expert panel ruled in favour of the use of single-agent chemotherapy in the elderly cancer patient. A third-generation agent is recommended for patients with any performance status and a platinum-based chemotherapy is recommended for those with performance status 0 or 1 and no contre-indications for comorbidities (Gridelli et al., 2005).

When studies revealed that single-agent chemotherapy improved survival, the search for more effective treatment continued and studies with combinations of chemotherapy have been done. Few randomized trials compared a combination of chemotherapy to a single agent. A French Intergroup study randomly assigned 451 patients of 70-89 years with performance status 0-2 that previously had untreated stage III or IV disease. Patients received a combination of carboplatin (AUC 6 on day 1) plus paclitaxel (90 mg/m2, days 1, 8 and 15) every 4 weeks for a total of four cycles or a single agent (gemcitabine or vinorelbine, as predetermined by each institution). Gemcitabine (1,150 mg/m2) or vinorelbine (30 mg/m2) were given on days 1 and 8 for 5 cycles, every 3 weeks. At ASCO meeting in 2010, preliminary results were presented. For the first 313 patients, overall survival was significantly better in the combination arm with 10.4 months versus 6.2 months for single agent chemotherapy. Progression-free survival was significantly improved with combination chemotherapy (6.3 versus 3.2 months) and this difference was significant. The combined treatment was well tolerable even if neutropenia grade 3 and 4 were more

A phase III study done by The South Italian Cooperative Oncology Group (SICOG) randomized patients between vinorelbine (30 mg/m2 days 1 and 8 every 3 weeks), versus vinorelbine/gemcitabine (vinorelbine 30 mg/m2 and gemcitabine 1,200 mg/m2, days 1 and 8 every 3 weeks). In this study an interim analysis of survival with the first 60 patients was done. This analysis showed a significant survival advantage for the combination arm, with median survival of 29 weeks versus 18 weeks for the single arm. Following these results, the study was closed prematurely. The estimated 6-months and 1-year survival were 56% and 30% for the combination group and 32% and 13% in the single-agent arm (p<0.01). Patients receiving monotherapy treatment had more symptoms and deterioration of quality of life.

performance status (Lilenbaum et al., 2007).

**10.4 Combination versus single-agent chemotherapy** 

frequent with the combination chemotherapy (Quoix et al., 2010).

Toxicity for the combination arm resulted in grade 3-4 neutropenia and thrombocytopenia in 38% and 13% respectively, and it was more prevalent than in the vinorelbine arm (Frasci et al., 2000).

The Cancer and Leukemia Group B reported results of a phase III trial (CALGB-9730) that compared a combination of carboplatin and paclitaxel with paclitaxel in monotherapy. In this study, in which 155 patients had over 70 years, the response rate was 36% versus 21% respectively. The median survival was better in patients treated with the combination compared with monotherapy (8.0 vs 5.8 months respectively- non significant) (Lilenbaum et al., 2005).

Docetaxel and cisplatin doublet was compared with docetaxel in monotherapy in a phase III trial for elderly patient with NSCLC (Ansari et al., 2007). The planned sample size was 115 patients per arm, but the study was closed when the planned interim analysis showed that the doublet may be beneficial for patient aged 70 to 74 years.

However, results remain conflicting about the impact of a combination of chemotherapy. Multicenter Italian Lung cancer in the elderly Study (MILES) is another randomized study that involves patients aged 70 years or older. 698 patients were randomly assigned to gemcitabine alone (1,200 mg/m2 days 1 and 8, every 3 weeks), vinorelbine alone (30 mg/m2 on days 1 and 8, every 3 weeks) or gemcitabine (1,000 mg/m2) plus vinorelbine (25 mg/m2) both administrated on days 1 and 8 every 3 weeks (Gridelli et al., 2003). In this study, there was no difference between each single-agent and the combination arm for progression-free survival and overall survival. The estimated 1-year survival was 38% and 28% for patients respectively with vinorelbine and gemcitabine alone. In the combination arm, the overall survival was 30%. Median survival was 36 weeks for vinorelbine, 28 weeks for gemcitabine alone and 30 weeks for the combination. Toxicities were more frequent in the patients receiving combination chemotherapy. Thus, the combination of vinorelbine and gemcitabine was not shown to be more effective than single agent vinorelbine or gemcitabine in elderly patients with NSCLC (Gridelli et al., 2003).

A study analysed the baseline assessment of functional status, comorbidity and quality of life in elderly patients randomised in MILES trial. The presence of comorbidity was assessed with a checklist of 33 items, items 29 and 30 of the European Organisation for research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 were used for the quality of life and the Charlson scale was used to summarize cormorbidity. Better values of activities of instrumental activities of daily living (IADL) (p=0.04) and of baseline quality of life (p=0.0003) were significantly associated with better prognosis. Two others factors, either activities of daily living (ADL) and the Charlson scale score had no prognostic value (Maione et al., 2005).

An analysis from SEER data on patients with NSCLC over 65 years old evaluated the role of chemotherapy. Of over 21,000 patients evaluated, only 25.8% received first-line chemotherapy. After adjusting for comorbidities, age and performance status, patients with chemotherapy had an increased adjusted 1-year survival rate of 27% when compared to those without chemotherapy (11%) and a reduction of the adjusted risk of death, with a hazard ratio of 0.558. In this study, the use of combination of platinum agents was associated with an increase survival at 30.1% compared with single-agent at 19.4% (Davidoff et al., 2010).

A meta-analysis involving 2,867 patients of randomized controlled trial had shown superior results for efficacy and tolerability of docetaxel compared with vinorelbine or vindesine (Douillard et al., 2007; Laporte et al., 2007). The overall survival was 11% greater in patients

Lung Cancer in Elderly 241

Regarding the use of bevacizumab, few subsets analyses were done. In ECOG 4599, patients over 70 years were randomized to carboplatin and paclitaxel, with or without the addition of bevacizumab. The overall incidence of severe or fatal (grade 3 to 5) toxicity was significantly higher (87% versus 61%) in those receiving bevacizumab and treatment-related deaths were more frequent (6.3% versus 2.6%). This trial revealed a trend toward improvement in disease response (29% versus 17 %) and progression-free survival (5.9

Lung cancer is already a significant problem in our population. It is one of the major causes for cancer mortality in the younger population, even more in the elderly. The aging population will continue to grow and the proportion of elderly with lung cancer will increase in coming decades. Oncologist will have to develop their abilities to better evaluate them and to give them the appropriate treatment for their condition. Actually, no specific assessment tool is proved to be better than other, but we demonstrated the importance of a

Many treatment options are available and proved to be effective in the elderly. It can vary from standard treatment, as for younger patient, to more adapted treatment, in regard to the

For patients with early stage disease, surgery remains the treatment of choice with or without adjuvant chemotherapy. When it is not possible, radiation therapy is an excellent alternative, well tolerated with limited side effects. In case of advanced disease, radiation combined or not to chemotherapy is the option, according to the general functional status of the patient. Palliative treatment, either radiation or chemotherapy can also be offered to the

A good evaluation of the patient and realistic goal for treatment remain essential in this population, but treatment decisions based solely on chronological age is no longer

Alberts, W. M. et al. (2007). Diagnosis and management of lung cancer : ACCP evidence-

Ansari, R. H. et al. (2007). Elderly subgroup analysis of a randomized phase 3 trial of

Ardizzoni, A. et al. (2005). Platinum-etoposide chemotherapy in elderly patients with non-

based clinical practice guidelines (2nd edition). *Chest*, Vol. 132. No.3 suppl,

gemcitabine (G) in combination with carboplatin (Cb) or paclitaxel (P) compared to paclitaxel plus carboplatin in advanced (stage IIIB, IV) non-small-cell lung cancer. *Proceeding of American Society of Clinical Oncology*, ISSN 0732 183X, Chicago, IL, June

small lung cancer: results of a randomized multicenter phase II study assessing attenuated-dose or full-dose with lenograstim prophylaxis- a Forza Operativa Nazionale Italiana Carcinoma Polmonare and Gruppo Studio Tumori Polmonari Veneto (FONICAP-GSTPV) study. *Journal of Clinical Oncology*, Vol.23, No.3,

versus 4.9 months), without benefit in overall survival (Ramalingam et al., 2008).

form of CGA and all his components in the evaluation of these persons.

general functional status of the person and his comorbidities.

elderly patient, according to their symptoms and wishes.

(September), pp. 1S-19S, ISSN 0012-3692.

(January 2005). pp. 569-75, ISSN 0732-183X.

**11. Conclusion** 

acceptable at this time.

2007.

**12. References** 

with doxetaxel compared with vinca alkaloid-based regimen (HR 0.89). This benefit was observed when docetaxel was used with or without a platinum agent as part of the regimen. In this meta-analysis, the benefit of docetaxel was at least as much important in older patients than in younger (Laporte et al., 2007).

In conclusion, for fit elderly patients, combination chemotherapy with a platinum-based regimen can improve survival without much toxicity. For patients without a good performance status a single-agent may be proposed.

#### **10.5 Second-line therapy**

No definitive studies have been conducted in the second-line setting in older patients with NSCLC. A phase II study has shown utility of docetaxel as second-line therapy. Tibaldi's trial demonstrated an objective response rate of 21% (Tibaldi et al., 2006). A subset analysis of a phase III trial compared docetaxel with pemetrexed, in 86 patients older than 70 years. This study demonstrated an objective response rate of 6% and a median overall survival of 9.5 months in the pemetrexed group and 7.7 months in docetaxel (not statistically significant) (Weiss et al., 2006).

#### **10.6 EGFR-thyrosin kinase inhibitors**

Over the last years, many biologic and targeted therapies have been approved. Molecules which target epidermal growth factor receptor (EGFR) include erlotinib and gefitinib. Some monoclonal antibodies are also now approved for the use in lung cancer like cetuximab which targets EGFR and bevacizumab which targets the vascular endothelial growth factor (VEGF).

Thanks to their oral administration and their toxicity profile, the EGFR may be alternative treatments in chemotherapy-naïve elderly. In a phase II trial, chemotherapy-naïve patients older than 75 years with advanced NSCLC received gefitinib in monotherapy. The primary objective of this study was the objective response rate. 49 patients were eligible. The response rate was 25% with median survival of 10 months and 1-year survival of 50%. Skin disorders were the most frequent adverse side effects, in 76% of patients (Ebi et al., 2008).

A phase II trial, INVITE, compared gefitinib versus vinorelbine in chemotherapy-naïve elderly patients with advanced non-small-cell lung cancer. 97 patients were randomly assigned to gefitinib and received 250 mg/d orally and 99 patients received vinorelbine (30 mg/m2 infusion on days 1 and 8 of a 21–day cycle). The primary endpoint was progressionfree survival and the hazard ratio was 1.19 (gefitinib versus vinorelbine). Overall survival was 2.7 months for gefitinib versus 2.9 months for vinorelbine and hazard ratio was 0.98. Disease control rates were 43.3% for gefitinib and 53.5% for vinorelbine. The quality of life (QoL) was also analysed in this study. There was no statistical difference between gefitinib and vinorelbine for pulmonary symptom improvement (PSI) and QoL. The improvement of overall QoL and PSI were 24.3% and 36.6% for gefitinib and 10.9% and 31.0% for vinorelbine respectively. 54 patients had EGFR FISH-positive and the hazard ratio were 3.13 for PFS and 2.88 for OS (Crinò et al., 2008).

A phase III trial, TOPICAL, compared erlotinib versus placebo in chemotherapy-naïve patients with poor performance status who were not candidate for first line chemotherapy. Overall survival was not significantly different between both groups (Lee et al., 2010).

For elderly patients whose tumor contains an EGFR mutation, it is recommend to treat with an EGFR TK inhibitor, as erlotinib or gefitinib, rather than chemotherapy.

with doxetaxel compared with vinca alkaloid-based regimen (HR 0.89). This benefit was observed when docetaxel was used with or without a platinum agent as part of the regimen. In this meta-analysis, the benefit of docetaxel was at least as much important in older

In conclusion, for fit elderly patients, combination chemotherapy with a platinum-based regimen can improve survival without much toxicity. For patients without a good

No definitive studies have been conducted in the second-line setting in older patients with NSCLC. A phase II study has shown utility of docetaxel as second-line therapy. Tibaldi's trial demonstrated an objective response rate of 21% (Tibaldi et al., 2006). A subset analysis of a phase III trial compared docetaxel with pemetrexed, in 86 patients older than 70 years. This study demonstrated an objective response rate of 6% and a median overall survival of 9.5 months in the pemetrexed group and 7.7 months in docetaxel (not statistically

Over the last years, many biologic and targeted therapies have been approved. Molecules which target epidermal growth factor receptor (EGFR) include erlotinib and gefitinib. Some monoclonal antibodies are also now approved for the use in lung cancer like cetuximab which targets EGFR and bevacizumab which targets the vascular endothelial growth factor

Thanks to their oral administration and their toxicity profile, the EGFR may be alternative treatments in chemotherapy-naïve elderly. In a phase II trial, chemotherapy-naïve patients older than 75 years with advanced NSCLC received gefitinib in monotherapy. The primary objective of this study was the objective response rate. 49 patients were eligible. The response rate was 25% with median survival of 10 months and 1-year survival of 50%. Skin disorders were the most frequent adverse side effects, in 76% of patients (Ebi et al., 2008). A phase II trial, INVITE, compared gefitinib versus vinorelbine in chemotherapy-naïve elderly patients with advanced non-small-cell lung cancer. 97 patients were randomly assigned to gefitinib and received 250 mg/d orally and 99 patients received vinorelbine (30 mg/m2 infusion on days 1 and 8 of a 21–day cycle). The primary endpoint was progressionfree survival and the hazard ratio was 1.19 (gefitinib versus vinorelbine). Overall survival was 2.7 months for gefitinib versus 2.9 months for vinorelbine and hazard ratio was 0.98. Disease control rates were 43.3% for gefitinib and 53.5% for vinorelbine. The quality of life (QoL) was also analysed in this study. There was no statistical difference between gefitinib and vinorelbine for pulmonary symptom improvement (PSI) and QoL. The improvement of overall QoL and PSI were 24.3% and 36.6% for gefitinib and 10.9% and 31.0% for vinorelbine respectively. 54 patients had EGFR FISH-positive and the hazard ratio were 3.13 for PFS and

A phase III trial, TOPICAL, compared erlotinib versus placebo in chemotherapy-naïve patients with poor performance status who were not candidate for first line chemotherapy. Overall survival was not significantly different between both groups (Lee et al., 2010). For elderly patients whose tumor contains an EGFR mutation, it is recommend to treat with

an EGFR TK inhibitor, as erlotinib or gefitinib, rather than chemotherapy.

patients than in younger (Laporte et al., 2007).

**10.5 Second-line therapy** 

significant) (Weiss et al., 2006).

2.88 for OS (Crinò et al., 2008).

(VEGF).

**10.6 EGFR-thyrosin kinase inhibitors** 

performance status a single-agent may be proposed.

Regarding the use of bevacizumab, few subsets analyses were done. In ECOG 4599, patients over 70 years were randomized to carboplatin and paclitaxel, with or without the addition of bevacizumab. The overall incidence of severe or fatal (grade 3 to 5) toxicity was significantly higher (87% versus 61%) in those receiving bevacizumab and treatment-related deaths were more frequent (6.3% versus 2.6%). This trial revealed a trend toward improvement in disease response (29% versus 17 %) and progression-free survival (5.9 versus 4.9 months), without benefit in overall survival (Ramalingam et al., 2008).
