Advanced Non–Small-Cell Lung Cancer in the Elderly

Systemic chemotherapy provides improvement in both survival and quality of life for patients with advanced non–small-cell lung cancer (NSCLC). Elderly patients have more comorbidities and tend to tolerate more poorly aggressive chemotherapy and radiation therapy than younger individuals. Our purpose in this article is to summarize recent studies of single-agent chemotherapy and combination regimens with cytotoxic or targeted therapies in the management of elderly patients with advanced NSCLC. We have reviewed the available evidence in the literature to gauge the results of therapy for elderly patients with lung cancer. We found that single-agent chemotherapy remains the standard of care for nonselected elderly patients. Retrospective analyses suggest that the efficacy of platinum-based combination chemotherapy is similar in fit older and younger patients, with increased but acceptable toxicity for elderly patients. Therefore, the outcomes in the fit elderly mirror results observed in younger patients, although toxicity is generally greater.     

Bronchialkarzinom

The treatment of elderly patients with bronchial carcinomas is clinically challenging, because in addition to the tumor histology and staging, the results that can be achieved with treatment can also depend to a decisive extent on comorbidities and on the organ reserve, which may well be limited. With due consideration for absolute and relative contraindications, when modern surgical and radiation techniques are applied even elderly patients and those with multiple pathologies can now benefit from a tumor-specific therapy. However, there is often some uncertainty about whether the use of chemotherapy is justified—and, if it is thought to be, about what intensity of therapy can be used. A geriatric assessment can offer a basic indication of what level of therapy an individual patient will be able to tolerate. Retrospective studies and meta-analyses have shown that in the case of platinum-containing combination therapy the response, survival and toxicity rates in elderly patients with non-small cell lung cancer (NSCLC) and unrestricted treatment tolerance are comparable to those in younger patients. Data recorded in phase II/III studies have yielded contradictory results relating to the question of whether a combination therapy is superior to a monotherapy in elderly patients whose ability to tolerate therapy is limited. The most important treatment modality in elderly patients with small cell lung cancer (SCLC), even when they are very old, however, is polychemotherapy. Initial results suggest that in elderly patients who have a limited capacity for tolerating therapy or whose general condition is poor a monotherapy with carboplatin is comparable to a combination therapy in effectivity but has a lower rate of toxicity.     

Treatment of small cell lung cancer in the elderly

Small cell lung cancer (SCLC) accounts for approximately 20% of lung carcinomas. Chemotherapy is the cornerstone of treatment for SCLC. In limited disease, the median survival time is about 12-16 months, with a 4%-5% long-term survival rate; in extensive disease the median survival time is 7-11 months. More than 50% of lung cancer patients are diagnosed when they are over the age of 65, and about 30% are over 70. Elderly patients tolerate chemotherapy poorly compared with their younger counterparts, because of age-related progressive reductions in organ function and comorbidities. The standard therapy for limited disease is combined chemoradiotherapy, followed by prophylactic brain irradiation for patients achieving complete responses. In the elderly, the addition of radiotherapy to chemotherapy must be carefully evaluated, considering the slight survival benefit and potential for substantial toxicity incurred with this treatment. The best approach is to design clinical trials that specifically include geriatric assessment to develop active and well-tolerated chemotherapy regimens for elderly SCLC patients. Survival improvement for SCLC patients requires a better understanding of tumor biology and the subsequent development of novel therapeutic strategies. Several targeted agents have been introduced into clinical trials in SCLC, but a minority of these new agents offers a promise of improved outcomes, and negative results are reported more commonly than positive ones. This review focuses on the main issues in the treatment of elderly SCLC patients.     

Potential role of molecularly targeted therapy in the management of advanced nonsmall cell lung carcinoma in the elderly

BACKGROUND: More than 50% of all lung carcinoma cases are diagnosed in patients age > 65 years, and approximately 30% are diagnosed in patients age > 70 years. Elderly patients do not tolerate chemotherapy as well as their younger counterparts do, primarily because of the increased prevalence of comorbid conditions and organ failure. Thus, at present, the majority of elderly patients with malignant disease do not receive aggressive chemotherapy. For such elderly patients, alternatives to conventional chemotherapy, such as novel molecularly targeted therapy regimens, are of interest. METHODS: The current review summarizes contemporary approaches to and recent advances in the treatment of elderly patients with nonsmall cell lung carcinoma (NSCLC) and offers perspectives on the future of molecularly targeted therapy in this population. Inhibitors of epidermal growth factor receptor, vascular endothelial growth factor, and cyclooxygenase-2 are discussed in the current report, with such inhibitors being, in our opinion, among the best candidates for clinical development in the setting of interest. RESULTS: Novel biologic agents with putative activity against advanced NSCLC are at various stages of clinical development. Some of these agents have yielded benefits in terms of disease-related symptom reduction, quality of life, and survival. For elderly patients, the potential advantages of such agents include improved tolerability compared with conventional chemotherapy. This feature also makes these novel agents attractive alternatives for younger patients who cannot tolerate or are reluctant to receive conventional chemotherapy. CONCLUSIONS: Current studies are investigating the safety and efficacy of these novel biologic agents administered alone, in combination with other noncytotoxic agents, and in combination with conventional chemotherapy. These studies will help elucidate the role of targeted therapy in the management of elderly patients with advanced NSCLC.     

Targeted therapies in the treatment of advanced non-small cell lung cancer elderly patients

More than 50% of lung cancer cases are diagnosed in patients over the age of 65 years, and about 30% are diagnosed in patients over the age of 70 years. Elderly patients do not tolerate chemotherapy as well as their younger counterparts, mainly because of the higher prevalence of comorbid conditions and organ failure in the elderly. Alternatives to conventional chemotherapy, such as new molecular targeted therapies, are of interest. This review summarizes current approaches and recent advances in the treatment of elderly patients with non-small cell lung cancer and gives a perspective on the future of molecular targeted therapies in this population. Epidermal growth factor receptor inhibitors and vascular endothelial growth factor inhibitors are discussed here, being, in our opinion, among the best candidates for clinical development in this setting. Their potential advantages in elderly patients include better tolerability than conventional chemotherapy.     

Targeted therapy in advanced non-small cell lung cancer (NSCLC): Where do we stand?

Cytotoxic chemotherapy has helped improve the outcomes in patients with advanced non-small cell lung cancer (NSCLC), but we seem to have reached a plateau with respect to the benefit obtained. Also, a large subset of elderly patients and those with a poor performance status cannot tolerate these drugs at recommended doses. There is a growing need to incorporate newer drugs with different mechanisms of action and better safety profile. The epidermal growth factor receptor family (EGFR) and vascular endothelial growth factor (VEGF) have been identified as potential targets and agents acting specifically against these targets have been developed with the hope of improving outcomes. Although recent data with the small molecule EGFR tyrosine kinase inhibitors have been disappointing, there have been instances of dramatic responses thereby raising questions about the ideal patient to whom these drugs should be administered. Cetuximab, the anti-EGFR antibody has shown promising results. Bevacizumab, the anti-VEGF antibody was the first drug to demonstrate a survival benefit in first line treatment when added to chemotherapy. This review will briefly discuss the important trials using these targeted agents in advanced NSCLC.     

Recent topics in chemotherapy for elderly patients with lung cancer

With the prolongation of life expectancy in Japan, lung cancer is increasing not only in the elderly but also in poor-risk patients who can not undergo standard chemotherapy. Because survival benefits from chemotherapy are clearly expected in patients with small-cell lung cancer (SCLC), standard chemotherapy should be established for the elderly as well as for poor-risk patients with SCLC. We recently reported that the combination of AUC-based carboplatin and a standard dose of intravenous etoposide was an active and relatively nontoxic regimen for elderly patients with SCLC (J Clin Oncol 17: 3540-3545, 1999). Had chemotherapy with concurrent chest irradiation been used for patients with limited disease (LD), better survival might have been achieved in this study. However, Pignon et al. reported that combined chemoradiotherapy in elderly patients with LD-SCLC is a possible poor prognostic factor in their meta-analysis. A recent randomized controlled clinical trial has shown that vinorelbine monotherapy contributed to longer survival in elderly patients with advanced non-small-cell lung cancer (NSCLC), compared to best supportive care. Several retrospective studies have shown that cisplatin can be safely and effectively administered to elderly patients who are eligible for protocol treatment. However, there have been no randomized trials indicating that cisplatin-based combination chemotherapy improves survival in elderly patients with advanced NSCLC, compared to single-agent chemotherapy. Similarly, the role of combined chemoradiotherapy remains controversial in elderly patients with locally advanced NSCLC. Thus, standard therapies proven to be beneficial to non-elderly patients with lung cancer have not always been proven to be beneficial to elderly patients. In order to solve these difficult problems, phase III studies are warranted in elderly or poor-risk patients with lung cancer. Moreover, new agents with relatively low toxicities recently approved in Japan should be applied in clinical trials for the elderly or poor-risk patients with lung cancer.     

Sequential, alternating, and maintenance/consolidation chemotherapy in advanced non-small cell lung cancer: a review of the literature

A platinum-based doublet with a third-generation agent (paclitaxel, vinorelbine, gemcitabine, docetaxel) represents the standard first-line treatment for advanced non-small cell lung cancer patients with good performance status (PS). Traditional chemotherapy provides response rates of 20%-40% and a median survival of 8-10 months. In an attempt to improve its outcome, alternative schedules have been proposed, namely sequential, alternating, and maintenance/consolidation therapy. Sequential chemotherapy with a platinum-based doublet followed by a single agent is feasible in patients with good PS; preliminary results from randomized phase III trials with combination chemotherapy as a comparator are promising, suggesting similar efficacy and a better toxicity profile for the sequential arm. The use of sequential single agents is an option for elderly and frail patients unsuitable for a platinum-based combination. Based on trials published so far, it is unlikely that an alternating chemotherapy strategy will be proven superior to standard chemotherapy in patients with good PS. However, sufficient evidence exists that it could be appropriate in the elderly or in unfit individuals. Consolidation/maintenance chemotherapy may provide additional benefit for patients achieving disease control after standard first-line chemotherapy. Better results are seen when maintenance consists of an agent that has proven active in the induction phase. Further evaluation of this strategy, as well as of consolidation/maintenance therapy with targeted agents, is warranted. In conclusion, these approaches may improve the outcome in selected patients with advanced non-small cell lung cancer, but further results from randomized trials are needed. In the meantime, sequential, alternating, and maintenance/consolidation therapy should still be considered investigational.     

Current status of treatment for elderly patients with gastric cancer

In Japan, elderly gastric cancer(GC)patients have been rapidly increasing, and in 2020 when the babyboomers' GC incidence reaches its peak, the number of deaths due to GC will reach seventy thousand per year. Few clinical trials have been done for surgery and chemotherapy for GC so far, and little information is available on the risk benefit for elderly patients. Reports from single institutes described comparable efficacy and safety, while a large national database indicates age as an independent risk factor. Similarly, little study and information are available on chemotherapy for elderly with GC. In future, standardization of comprehensive geriatric assessment(CGA)and preoperative risk assessment in clinical trials with risk-stratified protocol treatment, and a large surgical database with similar standard risk assessment are warranted.     

Role of gemcitabine in cancer therapy

Gemcitabine, a pyrimidine nucleoside antimetabolite, is one of the most promising new cytotoxic agents. The drug has shown activity in a variety of solid tumors, and has been approved for the treatment of non-small cell lung cancer, pancreatic, bladder, and breast cancer. Recent data showed that gemcitabine is also active against ovarian cancer. Gemcitabine has a good toxicity profile, with myelosuppression being the most common side effect, while non-hematological events are relatively uncommon. The low toxicity profile makes the drug a valid option for unfit and elderly patients. Due to the synergistic activity with other chemotherapeutic compounds, mainly cisplatinum, several trials have been conducted to evaluate the efficacy and tolerability of gemcitabine in combination with other cytotoxic agents. Current clinical trials are evaluating the role of gemcitabine in combination with new targeted therapies.     

Chemotherapy in elderly patients with advanced lung cancer. Part II: Treatment of non-small cell lung cancer (NSCLC)

Increasing interest in the treatment of elderly patients or patients with poor performance status (PS) with non-small cell lung cancer (NSCLC) has led to a number of subgroup analyses of clinical trials, and even more importantly, the conduction of trials specifically designed for this cohort. These studies allow some important conclusions. Data from retrospective studies and meta-analyses indicate that the use of platinum-based two-drug combinations in selected, fit elderly patients may produce response rates, survival, and toxicity comparable to those in younger patients. This excludes a per se inferior effectiveness of chemotherapy in the population of elderly patients with NSCLC. A number of more recently introduced agents with a favourable toxicity profile have significantly increased treatment options. Single- agent therapy with vinorelbine, when compared to best supportive care, has been shown to give a statistically significant survival benefit and improve quality of life. Conflicting data from phase II/III trials in elderly patients with NSCLC exist regarding a potential benefit of combination chemotherapy over single-agent treatment in the total cohort of elderly patients, including those with comorbidities or declining functional reserve. A review of the most important trials, assessing treatment options in elderly patients with lung cancer, either prospectively or retrospectively, is provided, and still unresolved issues are addressed.     

Chemotherapy in elderly patients with colorectal cancer

Significant advancements in chemotherapy for metastatic colorectal cancer (mCRC) have been achieved over the past decade, and the median overall survival duration is now close to 24 months with appropriate treatment. The most widely recommended chemotherapy regimens are based on the use of irinotecan or oxaliplatin in combination with 5-fluorouracil and leucovorin; some data suggest further benefit with the addition of the targeted agents bevacizumab or cetuximab. Colorectal cancer primarily affects the elderly; however, much of the defining clinical research in this field has excluded subjects of advanced age or with a poor performance status, making it difficult for clinicians to interpret current treatment paradigms for their older patients. Most clinical trials that have included elderly patients document similar survival rates and toxicity profiles to those seen in younger patients. Moreover, survey data suggest that >70% of elderly patients with cancer are willing to undergo strong, palliative chemotherapy. While these findings suggest that age itself should not determine candidacy for chemotherapy, it is important to note the great heterogeneity of the elderly population with regard to overall health, independence, and performance status. The use of a comprehensive geriatric assessment is recommended to evaluate chemotherapy appropriateness. The management of frail elderly patients and those with a short life expectancy should be focused on palliation, while fit elderly patients can receive aggressive therapy in a similar fashion to younger patients.     

Artesunate in the treatment of metastatic uveal melanoma--first experiences

Artesunate (ART) is a derivative of artemisinin, the active principle of the Chinese herb Artemisia annua L. Artesunate is approved for the treatment of multidrug-resistant malaria and has an excellent safety profile. It has been shown that Artesunate, apart from its anti-malarial activity, has cytotoxic effects on a number of human cancer cell lines, including leukemia, colon cancer and melanoma. We report on the first long-term treatment of two cancer patients with ART in combination with standard chemotherapy. These patients with metastatic uveal melanoma were treated on a compassionate-use basis, after standard chemotherapy alone was ineffective in stopping tumor growth. The therapy-regimen was well tolerated with no additional side effects other than those caused by standard chemotherapy alone. One patient experienced a temporary response after the addition of ART to Fotemustine while the disease was progressing under therapy with Fotemustine alone. The second patient first experienced a stabilization of the disease after the addition of ART to Dacarbazine, followed by objective regressions of splenic and lung metastases. This patient is still alive 47 months after first diagnosis of stage IV uveal melanoma, a situation with a median survival of 2-5 months. Despite the small number of treated patients, ART might be a promising adjuvant drug for the treatment of melanoma and possibly other tumors in combination with standard chemotherapy. Its good tolerability and lack of serious side effects will facilitate prospective randomized trials in the near future.     

Chemotherapy in elderly patients with advanced lung cancer. Part I: General aspects and treatment of small cell lung cancer (SCLC)

There is much uncertainty whether chemotherapy is beneficial for elderly patients with advanced lung cancer. Whereas age alone is not an adverse prognostic factor, decline of physiological function and comorbidity can result in higher rates of treatment-related toxicity, in particular myelosuppression. The higher incidence of comorbid conditions, frequently sharing the risk profile of the malignancy, can translate into worse survival. Therefore, a geriatric assessment of the patient's overall situation should guide decision-making. Mainstay of treatment of small cell lung cancer (SCLC), also in the elderly, is combination therapy. Several retrospective analyses reveal that in elderly patients often lower drug doses are delivered. However, the treatment outcome of these patients does not appear to be worse compared to younger patients. For functionally independent elderly patients, combination chemotherapy with carboplatin and etoposide, supported by optimized supportive care, possibly including hematopoietic growth factors (G-CSF) to minimize toxicity, should be considered. Special attention to renal function should be given and individualized drug dosing, adapted to the glomerular filtration rate, is mandatory. For patients with some functional dependence or showing a certain degree of comorbidity, preliminary data indicate that single-agent therapy with carboplatin can confer the same benefit as combination chemotherapy, but with reduced toxicity. Single agent oral etoposide, however, seems to be inferior to combination treatment and should not be given routinely in the treatment of this cohort. Further evaluation of these topics is needed, and can be achieved by trials specifically designed for elderly patients or patients with reduced performance status.     

Significance of the comprehensive geriatric assessment in the administration of chemotherapy to older adults with cancer: Recommendations by the Japanese Geriatric Oncology Guideline Committee

IntroductionThe number of older patients with cancer is expected to continue to increase owing to the aging population. Recently, the usefulness of geriatric assessment (GA) conducted by multiple staff members from different medical backgrounds has been reported; however, a consensus on the effectiveness of GA has not yet been achieved.Materials and MethodsWe, as the Japanese Geriatric Oncology Guideline Committee for elderly patients with cancer, conducted a literature search of randomized controlled trials published before August 2021 that used GA or comprehensive GA (CGA) as an intervention for patients with cancer undergoing chemotherapy. As the key outcomes for answering the clinical question, we focused on survival benefit, adverse events, and quality of life (QOL). After a systematic review of these studies, the expert panel member developed recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system.ResultsFor older patients with cancer, GA or CGA is suggested during or before chemotherapy (weakly recommended). Chemotherapy-induced adverse events were significantly reduced by GA/CGA interventions without any adverse effects on survival. Health-related QOL tended to improve with the GA/CGA interventions.DiscussionAlthough, in our opinion, GA/CGA does require time and resources, it poses no harm patients. Therefore, we suggest expanding the human resources and educating skills of medical providers for clinical implementation of GA/CGA.     

The Role of Targeted Agents in the Treatment of Elderly Patients with Non-Small Cell Lung Cancer (NSCLC)

The introduction of targeted biological agents represents the most promising approach to improve the disease control and outcome for patients with non-small cell lung cancer. The epidermal growth factor and the vascular endothelial growth factor signaling pathways have been successfully targeted using both orally administered small molecule tyrosine kinase inhibitors and monoclonal antibodies, with associated improvement in overall survival. Although the trials that established the efficacy of these agents allowed the enrollment of patients older than 70 years, the elderly patients constituted the minority. Given the stringent enrolment criteria in terms of organ function and performance status for most clinical trials, the elderly patients on clinical trials are not entirely representative of the overall elderly patient population. Therefore, the applicability of these data to the overall patient population deserves critical appraisal in the absence of trials dedicated specifically to the elderly. Preplanned and unplanned subset analysis of registration trial data is becoming increasingly common as a substitute measure to provide valuable information to guide the use of targeted agents in the elderly. Using this approach, it has been demonstrated that elderly patients are able to tolerate targeted biological therapies but suffer increased rate of toxicities. However, they derive benefit from such agents when they are carefully selected and have their drug doses adjusted appropriately to minimize potential toxicities. This article reviews the use of targeted agents for the treatment of NSCLC in elderly patients.     

Does chemotherapy have a role as palliative therapy for unfit or elderly patients with non-small-cell lung cancer?

Elderly patients and younger "unfit" patients with poor Eastern Cooperative Oncology Group (ECOG) performance status (PS) (> or = 2) suffering from advanced non-small-cell lung cancer (NSCLC) are two different populations--both of which require palliative treatments. Elderly patients frequently experience progressive decline of organ function and multiple comorbidities, which need to be considered when choosing therapy. ECOG 1594 showed that advanced NSCLC patients with an ECOG PS of 2 did not tolerate platinum-based chemotherapy (cisplatin/paclitaxel, carboplatin/paclitaxel, cisplatin/docetaxel, carboplatin/paclitaxel). These data confirm that treatments designed specifically for this patient subset are needed. Single-agent chemotherapy seems to be a reasonable approach, and non-platinum-based combination chemotherapy should also be investigated. The oncology community has become increasingly aware of the magnitude of the problem of cancer in the elderly. More than 30% of lung cancers arise in patients > or = 70 years old. Elderly patients tolerate chemotherapy poorly, according to the few published papers, and are not considered eligible for aggressive cisplatin-based chemotherapy in clinical practice. A phase III randomized trial (ELVIS [Elderly Lung Cancer Vinorelbine Italian Study]) demonstrated survival and quality-of-life benefits with single-agent vinorelbine versus best supportive care. Among the newer drugs, gemcitabine has demonstrated activity and low toxicity in phase II studies. With this background, we performed a randomized, multicenter phase III trial (MILES [Multicenter Italian Lung Cancer in the Elderly Study]) in 707 advanced NSCLC elderly patients. The MILES study compared single-agent chemotherapy with vinorelbine or gemcitabine versus polychemotherapy with gemcitabine plus vinorelbine. Results showed no benefit in response rate, time to progression, survival, and quality of life for the combination. Single-agent chemotherapy remains the standard treatment approach for elderly NSCLC patients with advanced disease.     

Meeting the chemotherapy needs of elderly and poor performance status patients with NSCLC

Increasing interest in designing chemotherapy suitable for use in the elderly and in poor performance status (PS) patients has led to clinical trials in advanced non-small cell lung cancer (NSCLC) which have demonstrated a number of important points. First, the randomized Elderly Lung Cancer Vinorelbine Study Group (ELVIS) trial makes clear that elderly patients treated with vinorelbine plus best supportive care (BSC) have significantly improved survival and quality of life when compared with patients treated with BSC alone. Secondly, the Multicenter Italian Lung Cancer in the Elderly Study (MILES) trial demonstrates that the combination of gemcitabine plus vinorelbine in this patient population does not further improve survival or quality of life as compared to single chemotherapy with vinorelbine or gemcitabine. Weekly docetaxel has considerable potential among patients judged likely to tolerate poorly cisplatin-based chemotherapy. In a trial among 39 previously untreated elderly, poor PS or medically compromised patients, weekly 36 mg/m(2) docetaxel produced a 19% response rate and 28% 1-year survival. These data compare favorably with results achieved with other single agents. Weekly, docetaxel is better tolerated than the q 3-week schedule, and myelosuppression is not severe. Weekly docetaxel is also active as second-line therapy. The combination of gemcitabine and docetaxel, both administered weekly, is well tolerated by elderly and/or poor PS patients, is active (median survival 7 months, 1-year survival 29%) and merits further study.     

Novel combinations with docetaxel in the treatment of non-small-cell lung cancer

The treatment of advanced-stage lung cancer continues to be challenging. Cytotoxic chemotherapy doublets have modestly improved survival and have emphasized more quality of life issues. Many novel targeted agents are in clinical development and could have potential to treat patients with lung cancer whose tumors are refractory to standard cytotoxic regimens. Targeting the epidermal growth factor receptor as well as the vascular endothelial growth factor pathways appears promising. Combining these targeted agents with chemotherapy might help improve overall efficacy. Docetaxel is an active chemotherapeutic agent that has been studied in combination with multiple biologic agents. With continued study, optimizing these combinations for specific patient populations will be the key to improving overall efficacy.     

Radiothérapie des cancers bronchiques non à petites cellules des sujets âgés

People over the age of 65 are often excluded from participation in oncological clinical trials. However, more than half of patients diagnosed with non-small-cell lung cancer are older than 65 years. Any therapeutic strategy must be discussed in multidisciplinary meetings after adapted geriatric assessment. Patients who benefit from the comprehensive geriatric assessment (CGA) of Balducci and Extermann are those whose G8 screening tool score is less than or equal to 14. Age itself does not contraindicate a curative therapeutic approach. Stereotactic radiotherapy is an alternative to surgery for early stages in elderly patients who are medically inoperable or who refuse surgery, because it significantly increases overall survival. Mostly sequential (rarely concomitant) chemoradiotherapy can be proposed to elderly patients with locally advanced stages in good general state of health. For the others, an exclusive palliative radiotherapy, a single or dual agent of chemotherapy, a targeted drug or best supportive care only may be discussed.