The benefit of chemotherapy in elderly patients with small cell lung cancer

Abstract

Elderly patients with small cell lung cancer derive a statistically significant benefit from the administration of combination chemotherapy. Numerous clinical trials have demonstrated high response rates and impressive median survivals with carboplatin and etoposide, cisplatin and etoposide, and other regimens. All elderly patients with small cell lung cancer should be evaluated by a medical oncologist to determine whether they are candidates for chemotherapy.

Keywords::

• chemotherapy
• clinical trials
• elderly
• lung cancer
• radiation
• small cell lung cancer
• survival

In 2013, the American Cancer Society estimates that there will be 228,190 cases of lung cancer diagnosed in the USA and 159,480 deaths [1]. Small cell lung cancer (SCLC) accounts for approximately 13.6% of all lung cancer cases [2]. According to the Surveillance, Epidemiology and End Results database, among all patients diagnosed with lung cancer in the USA, 68.2% are aged 65 and older and 36.8% are aged 75 and older at the time of diagnosis. The median age at diagnosis is 70, and the median age at death is 72. The 5-year overall survival is 16.6% [1]. While elderly patients make up the majority of patients diagnosed with lung cancer, they have consistently been underrepresented in randomized clinical trials focusing on combination chemotherapy [3].

Two very distinctive characteristics that helped establish SCLC as a unique entity were established almost half a century ago. The first is that SCLC is the most aggressive subtype of lung cancer. In a 1960s trial conducted by the Medical Research Council of Great Britain prior to the introduction of systemic chemotherapy in SCLC, median survival among patients with limited and extensive disease was approximately 12 weeks and 5 weeks, respectively [4].

The second distinctive characteristic is that SCLC is far more responsive to systemic chemotherapy than other lung cancer subtypes. Indeed, the first report of an improvement in survival in SCLC with the use of chemotherapy was in 1969 [5]. The Veterans Administration Lung Cancer Study Group trial showed that three cycles of cyclophosphamide could more than double median survival when compared to supportive care in extensive SCLC. The results of this seminal study and other trials rapidly established combination chemotherapy as the mainstay of therapy for both limited and extensive SCLC by the early 1970s.

Staging & treatment

SCLC has been staged as either limited stage or extensive stage, as established by the Veterans Administration Lung Cancer Study Group in the 1960s [5,6]. Limited stage disease can be encompassed in a single radiation port. Extensive stage disease is defined as disease beyond a single radiation port or the presence of metastatic disease [7]. For patients with limited stage disease, concurrent chemoradiation with four to six cycles of platinum-based chemotherapy is the standard of care [8]. For patients with extensive stage disease, chemotherapy alone can be given with radiation reserved for palliation of the primary tumor or metastases [9]. Whole-brain radiation is used for treatment of brain metastases [9], and prophylactic cranial irradiation should be strongly considered in patients who have achieved a partial or complete response to therapy [10,11]. Surgical resection is generally reserved for patients with T1N0 or T2N0 disease followed by chemotherapy [9].

Retrospective studies

Rossi et al. reviewed nine retrospective studies involving elderly patients with SCLC who received chemotherapy [12]. Elderly was defined as being 70 years or older in eight out of the nine studies. All of the studies included limited stage disease patients and four studies included extensive stage disease patients. Chemotherapy regimens consisted of cisplatin and etoposide; cyclophosphamide, doxorubicin and vincristine (CAV) or other chemotherapy regimens. Eight out of the nine trials included radiation. There was no statistically significant difference in 2-year, 3-year or 5-year survival in elderly patients versus younger patients in seven out of the nine trials [12]. Five retrospective studies of chemoradiation in the elderly mostly involving the CAV regimen or cisplatin and etoposide demonstrated overall response rates of 50–82%. In three of the studies, the overall survival was comparable or superior in patients over the age of 70 compared to those younger than 70 [8].

Prospective studies

Eleven Phase II trials of chemotherapy involving mostly carboplatin and etoposide in elderly patients with both limited stage and extensive stage disease reported response rates of 57.8–93% and median survivals of 7.9–15.1 months [12]. A Phase II trial of carboplatin and irinotecan in patients aged 70–86 with limited or extensive stage SCLC demonstrated a response rate of 83.3% (95% CI: 65.3–94.4%), a median overall survival of 26 months for limited stage patients and a median overall survival of 11 months for extensive stage patients [13].

Toxicity

Elderly patients may be less tolerant of chemotherapy because of comorbidities and hematologic toxicity. A retrospective analysis of the Intergroup Trial 0096 compared patients older and younger than 70 years who received concurrent chemoradiation with cisplatin and etoposide for limited stage SCLC [14]. Patients who were 70 years and older had a 5-year overall survival rate of 16 versus 22% for those younger than 70 years (p = 0.05). The response rate of the older and younger patients was comparable (80 vs 88%; p = 0.11); but severe hematologic toxicity, defined as grades 4–5, was greater in older patients (84 vs 61%; p < 0.01) [14]. A Phase III trial of carboplatin and etoposide versus cisplatin and etoposide in extensive stage SCLC patients with a median age of 74 demonstrated a response rate of 73% for both regimens and an overall survival of 10.6 and 9.9 months, respectively. The risk of grade 3–4 neutropenia was 95 versus 90% and thrombocytopenia 56 versus 16% [15].

A retrospective review of the Alberta Cancer Registry evaluated patients aged 75 years and older with SCLC diagnosed between 2004 and 2008 [16]. In this study, 171 patients were included in the analysis and 117 (68%) received combination chemotherapy. Among those beginning chemotherapy, 52% completed all cycles, 66% had no dose reductions and 31% completed all cycles at the planned dose. The chemotherapy regimens included cisplatin and etoposide, carboplatin and etoposide, oral etoposide and CAV. Using Cox-proportional hazards regression, the hazard ratio of death for patients who did not complete all cycles of chemotherapy was 2.72 (95% CI: 1.52–4.87; p = 0.0007) compared to those who completed chemotherapy with no dose reductions. The hazard ratio for those who completed all cycles but with a dose reduction was 1.02 (95% CI: 0.57–1.82; p = 0.94) compared to those who completed full-dose chemotherapy. Accordingly, the authors recommended reducing doses and continuing chemotherapy rather than discontinuing chemotherapy entirely among those unable to tolerate full-dose therapy [16].

Quantifying the benefit of chemotherapy

All of the above studies compared various chemotherapy regimens and chemoradiation regimens. The true question is this, ‘How much longer will my elderly patient with SCLC live if I give chemotherapy compared to best supportive care?’ A retrospective cohort study of 10,428 patients aged 65 years and older selected from the Surveillance, Epidemiology, and End Results-Medicare database was designed to answer this question by evaluating the independent effect of chemotherapy on survival in patients with SCLC in the community [17]. In this study, 67.1% of patients received chemotherapy, 39.1% received radiation, 3.4% had surgery and 21.8% received no treatment. The median overall survival was 10 months for limited stage disease and 5 months for extensive stage disease.

Patients who received no treatment lived only 2 months. Using Cox-proportional hazards regression, the authors demonstrated a hazard ratio of 0.37 (95% CI: 0.36–0.39; p < 0.001) for cisplatin and etoposide or carboplatin and etoposide compared to no chemotherapy. For all chemotherapy regimens combined, the hazard ratio was 0.40 (p < 0.001). To determine the improvement in median survival in months, two techniques were used: a propensity score method and multivariate quantile regression. Using propensity scores, the improvement in survival was 6.9 months for patients receiving chemotherapy compared to those not receiving chemotherapy. Quantile regression provided a similar improvement in survival of 6.5 months. The effect was seen even among patients aged 85 and older [17].

Conclusion

All available evidence supports the conclusion that systemic chemotherapy significantly improves survival in elderly patients with both limited and extensive stage SCLC. Nonetheless, recent data demonstrate that a substantial minority of such patients never receive chemotherapy; indeed, many are never referred to a medical oncologist.

Given that survival for SCLC without treatment is only approximately 2 months on average, and that potentially, elderly patients who are given chemotherapy can live 15 months or even longer, virtually all elderly patients with SCLC should be referred for evaluation by a medical oncologist. Moreover, unless the medical status of the patient is dominated by clinically significant medical comorbidities, the vast majority of elderly patients should undergo combination chemotherapy. Recent evidence indicates that combination chemotherapy is associated with a greater-than-6-month improvement in median survival. Such a survival advantage is seen even among SCLC patients over the age of 80 years [17].

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.