Histology-based Combination Induction Chemotherapy for Elderly Patients with Clinical Stage III Non-small Cell Lung Cancer

Patients and Methods

Study population. The eligibility criteria for the study included: histological or cytological diagnosis of NSCLC; unresectable locally advanced clinical stage IIIA or stage IIIB NSCLC according to TNM v7.0 (7); age ≥70 years; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2; adequate haematological, renal and hepatic function; no previous treatment with radiation or chemotherapy. All patients gave their written informed consent to this protocol. Pre-treatment evaluation and baseline clinical staging included: anamnesis; physical examination; computed tomography (CT) scan of brain, chest, abdomen and pelvis; ¹⁸F-fluoro-deoxy-glucose (¹⁸FDG)-positron-emission tomography (PET); laboratory tests for the evaluation of haematological, liver and kidney function; magnetic resonance imaging (MRI) of the brain with gadolinium, when clinically indicated.

For each case, the following criteria were followed for the definition of initial non-resectability: clinical N2 lymph node involvement; surgical indication for pneumonectomy; limiting comorbidities.

Induction chemotherapy. An induction chemotherapy regimen including three cycles delivered every 21 days was administered to all patients. In patients with squamous cell carcinoma, chemotherapy included: gemcitabine (at 1,000 mg/m² i.v. on days 1 and 8) in 250 cc saline solution over 30 minutes; carboplatin [at an area under the curve (AUC) of 5 i.v., on day 1] in 500 cc saline solution over 1 hour. In patients with adenocarcinoma, the following drugs were administered: pemetrexed (at the dose of 500 mg/m² i.v., on day 1) in 150 cc saline solution over 15 min; carboplatin (AUC 5 i.v., on day 1) in 500 cc saline solution over 1 h.

As chemotherapy premedication, the following drugs were used i.v.: 100 mg ranitidine, 8 mg dexamethasone and 8 mg ondansetron 15 min before the chemotherapy of days 1 and 8. Patients treated with pemetrexed received folic acid, vitamin B12, and dexamethasone as recommended in the pemetrexed package insert (8).

On the day 8 of each cycle, a complete blood count and the determination of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were performed. On day 22, complete blood count (CBC) and laboratory tests for the assessment of haematological, hepatic and renal function were requested.

Patients received chemotherapy if the absolute neutrophil count (ANC) was ≥1,500/μl and platelet count was ≥100,000/μl; if ANC or platelet counts were less than these levels, the treatment was held, and a CBC was checked on a weekly basis. In the case of more than two weekly delays, chemotherapy was discontinued. In the case of febrile neutropenia or grade 3 non-haematological toxicity, a dose reduction of both agents (carboplatin AUC 4, pemetrexed or gemcitabine at 75% of the full dose) was carried out; in the case of recurrence of a grade 3 adverse event, chemotherapy was permanently discontinued. Patients who experienced haematological or non-haematological grade 4 adverse events were permanently discontinued from chemotherapy. In the case of grade 3 haematological toxicity, granulocyte-colony stimulating factors and haematopoietic growth factors were used; when clinically indicated transfusions of red blood cells or platelets were administered. If indicated, antibiotics and other supportive care were used.

Assessment of toxicity and response. Toxicity was recorded by clinical evaluation according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0 (9) before each subsequent chemotherapy administration. The assessment of response was performed using CT scan (with ¹⁸FDG-PET only for stage IIIA NSCLC) within 3 weeks after the third cycle.

Locoregional treatment. Patients with stage IIIA disease and responding disease were re-evaluated for possible surgery, based on comorbidities and clinical conditions; in the case of non-resectability, or patient refusal, patients were sent for definitive radiotherapy. Patients with stage IIIB disease, with the responding or stable disease, were intended to be treated with definitive radiotherapy. Patients with disease progression dropped out of the study and were treated with a further line of chemotherapy if clinically indicated. Surgery or radiotherapy was intended to be started within 6 weeks of the response assessment.

Follow-up visits were performed every 3 months for the first 2 years and every 6 months thereafter and included clinical evaluation, a CT scan of the brain, thorax, abdomen and pelvis, and further investigations when clinically indicated.

Design of the study. The study was designed as a single-stage phase II study as described by A'Hern (10), with estimates based on the exact binomial distribution. In fact, designs for single-stage phase II trials commonly calculate the number of patients required using Fleming's single-stage procedure. However, this method is based on a normal approximation to the binomial distribution and is therefore technically incorrect for small trial sizes, as becomes apparent if exact binomial distributions are applied to these designs. Multi-stage designs, rather than single-stage designs, should be used in situations in which early termination is desirable if the treatment is ineffective.

The trial tested the null hypothesis H0: P<p0 against the alternative hypothesis H1: P>p1. For accepting that p1 is to be preferred to p0 (and therefore to accept that a phase III trial should be undertaken), for values of p0 of 0.15 and for values of p1 of 0.40, for one-sided alpha value of 0.05 and for power equal to 0.9, the trial size had to be 27 with a cut-off of eight patients not experiencing an overall response. All analyses were performed on an intention-to-treat basis.

Outcomes. The primary objective of the study was to evaluate the activity and feasibility of a histology-based combination induction chemotherapy for elderly patients with clinical stage III NSCLC. The primary endpoint was overall response rate (ORR), including complete response and partial response according to the Response Evaluation Criteria in Solid Tumours (RECIST) criteria version 1.1 (11), following induction chemotherapy. Secondary endpoints were: toxicity according to the CTCAE v3.0 (9), need for chemotherapy dose reduction or withdrawal, the rate of patients who underwent definitive radiotherapy or surgery following induction chemotherapy, overall survival (OS), and progression-free survival (PFS).

Descriptive statistics were used to summarise the patient demographic and treatment characteristics. The disease responses were reported as relative proportions of the total number of patients. Percentages were approximated to the nearest unit. Statistical significance was investigated by the Fisher exact test with an acceptable significance value of p<0.05. The OS was calculated from the date of diagnosis until death or last date of follow-up. The PFS was calculated from the date of diagnosis until the date of progression, or death from any cause. Patients who had not died or whose disease progressed or who had failed to attend for follow-up at the time of the final analysis were censored at the date of the last contact. The PFS and OS were estimated using the Kaplan–Meier, reported as medians with confidence limits (95% CI) and compared using two-sided log-rank test (12). The 95% CI response rates were estimated according to Simon (13).

In order to study the possible influence of the main baseline characteristics (gender, stage of disease, histology/regimen of chemotherapy, age, PS, comorbidities, and radiotherapy) on the OS and PFS, univariate logistic regression model of Cox was used (14), considering differences statistically significant at p<0.05. Multivariate analysis of factors that were significant at univariate analysis was planned. All analyses were performed according to the intention-to-treat principle with two-sided tests. All statistical analyses were performed using the statistical software Statistica v6.1 (StatSoft Italia Srl, Vigonza, Italy).