To the surprise and deep disappointment of all involved in the treatment of lung cancer, several large trials did not demonstrate any benefit of tyrosine kinase inhibitors (TKIs) as an addition to chemotherapy [
The biological basis for the negative experience with combined treatment was never given proper attention. Gefitinib and erlotinib met all three standard criteria for inclusion in a combination with chemotherapy: activity as monotherapy, different mechanism of action, and different toxicity. Why, then, did the combination not work? As explained in a recent editorial [
This brief report presents a single-institution experience on intermittent chemotherapy and TKI in a small series of patients with advanced adenocarcinoma of the lung. Our hypothesis was that intermittent treatment would lead to superior time to progression, when compared to experience with chemotherapy alone. If confirmed, such a result would be a solid basis for a randomised clinical trial.
Patients eligible for the trial were chemonaïve with microscopically confirmed adenocarcinoma of the lung, had stage III B (wet) or IV according to UICC-TNM classification (6th edition), had smoking history of less than 10 packs in years, had an ECOG performance status 0 or 1, and had adequate parameters of hematological, liver, and renal function to receive cisplatin-based chemotherapy. In the absence of neurological symptoms, patients with brain metastases were eligible and were treated with brain irradiation only in case of intracranial progression. All patients were fully informed and gave written consent to participate in the trial.
All patients had their diagnosis confirmed by biopsy or cytology. At the time when the trial was initiated, testing for EGFR mutations was not available.
Within three weeks prior to treatment, the precise extent of the disease was determined by chest X-ray and CT scanning of the chest, upper abdomen, and brain. Since 2008, PET-CT scanning has been available and included in the initial diagnostics and in followup.
The treatment started with four cycles of intermittent chemotherapy and erlotinib according to the following schedule: day 1: gemcitabine 1250 mg/m2 in 30-minute infusion, day 2: cisplatin 75 mg/m2, with appropriate hydration and antiemetics, day 4: gemcitabine 1250 mg/m2 in 30-minute infusion, days 5–15: erlotinib 150 mg daily p.o.
Cycle was repeated on day 22.
Patients received 4 to 6 cycles of intermittent treatment. The number of cycles depended on tolerance to cisplatin-based chemotherapy and was determined individually. Immediately after the last cycle, patients continued with erlotinib 150 mg/m2 daily continuously until progression or unacceptable toxicity.
Definition of complete response (CR), partial response (PR), stable disease (SD), and progression followed the RECIST criteria [
The first evaluation of response was done during the third cycle of intermittent therapy, with confirmation of response during the fifth cycle. After 4 cycles, patients were seen every second month. Control radiological examinations were repeated every 2 months for chest X-ray, every 4 months for CT, and at 6 and 12 months for PET-CT (only patients who had this examination during their initial diagnostics).
In October 2010, all biopsy samples were reviewed, and specimens with more than 10% of tumour tissue were analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue sections using QIAAmp DNA FFPE tissue kit (Qiagen, Hilden, Germany) according to the manufacturer's instructions. Quantification of extracted DNA was done on Qubit Fluorometer (Invitrogen, Carlsbad, USA). To detect EGFR gene-activating mutations, we used TheraScreen EGFR29 Mutation Kit (DxS Diagnostics, Qiagen, Manchester, UK). All realtime PCR reactions were performed in a 25
The primary endpoint was time to progression. Secondary endpoints were response rate, toxicity, and overall survival.
After standard chemotherapy for metastatic nonsmall cell carcinoma, the expected TTP is 5 months. The size of this single-arm nonrandomised trial of intermittent therapy was based on the assumption of 9 months as the median time to progression (TTP). To obtain such a result with a confidence interval of 6–12 months, we planned to recruit 40 patients.
The investigators strictly followed recommendations of the Helsinki Declaration (1964, with later amendments) and of the European Council Convention on Protection of Human Rights in Bio-Medicine, as accepted in Oviedo in 1997. The protocol was approved by the Institutional Review Board (Institute of Oncology, Ljubljana) and by the National Committee for Medical Ethics, Ministry of Health, Republic of Slovenia.
Between September 2005 and July 2010, 25 patients were recruited into the trial. One patient was later found to have metastatic carcinoma of the pancreas rather than primary lung cancer and was excluded from all further analyses.
With 12 patients each, male and female patients were equally represented. Median age was 50 years (range: 25 to 73 years). Twelve patients were never-smokers, and most were in good general condition (PS 0-1 for 21 patients). With the exception of a single patient with “wet” stage III B, all other patients had stage IV disease. Bone metastases were the most common site of metastatic disease, followed by pleura/pericardium, contralateral lung metastases, and liver. Two or more sites of metastatic disease were documented in 4 and 12 patients, respectively (Table
Demographics, prognostic factors, and extent of disease.
No. of patients | |
---|---|
Median | 50 |
Range | 25–73 |
Male | 12 |
Female | 12 |
Never-smoker | 12 |
Light smoker (<10 pack years) | 8 |
EGOG PS 0 | 5 |
1 | 16 |
2 | 3 |
III B “wet” | 1 |
IV | 23 |
Bone | 17 |
Pleura and pericardium | 11 |
Distant lung | 11 |
Liver and/or suprarenals | 10 |
Distant lymph nodes and/or soft tissues | 6 |
Brain | 2 |
1 | 8 |
2 | 4 |
3 or more | 12 |
Analysis of the archived bioptic material was completed in October 2010.
Three patients had only cytological diagnosis, and an additional 3 had biopsy samples too small to allow for analysis of EGFR mutations in tumor cells. Of the 18 adequate samples, 8 were positive for EGFR gene-activating mutations.
The actual number of cycles of intermittent therapy was from 1 to 6 cycles (median: 4 cycles). Due to early progression, one patient did not receive erlotinib as maintenance treatment. In October 2010, 7 patients were still on maintenance treatment with erlotinib, and an additional patient stopped treatment with erlotinib after 12 months in PET-CT confirmed complete remission (Figures
A woman, 39, never-smoker, developed adenocarcinoma of the right lower lobe, T4 N2 M1b with metastases in bone and liver. 18F-FDG PET-CT before treatment (a) and after 4 months (b). Complete remission was confirmed also a year later.
The same patient as on Figure
During the initial phase, 3 pts had grade 3 toxicity (2 neutropenia, 1 thrombocytopenia). Side effects of maintenance with erlotinib were skin toxicity (grade 3: 1 pt; grade 2: 11 pts) and diarrhea (grade 2 in 1 pt).
No patient experienced grade 4 or greater toxicity.
All patients are evaluable for response, and no patient has been lost to followup. For the whole group of 24 patients, complete remission (CR) was seen in 5 pts; partial remission (PR) in 9 pts (response rate 58%), minimal response or stable disease (SD) in 8 pts, and progression in 2 pts. A clear and statistically significant (
Response to treatment, time to progression, and survival in relation to EGFR mutations.
EGFR mutations | |||||
Positive | Negative | Unknown | All | ||
Response to treatment | CR | 4 | — | 1 | 5 |
PR | 4 | 2 | 3 | 9 | |
SD | — | 6 | 2 | 8 | |
Progression | — | 2 | — | 2 | |
Time to progression (months) | Median (95% CI) | 21.5 (14.8–27.2) | 5.0 (0.9–9.1) | 5.0 (3.9–4.1) | 13.4 (5.4–20.6) |
Survival (months) | Median (95% CI) | 24.2 | 7.0 (0.1–13.9) | 11.0 | 23.0 (10.9–35.2) |
For the whole group, median time to progression (TTP) was 13.4 months, and median overall survival (OS) was 23 months. Again, patients positive for EGFR gene-activating mutations had-superior experience. Median TTP and OS for this group was 21.5 months and 24.2 months, respectively. For patients without EGFR mutations, TTP was 5 months, and OS was 7 months (Table
Progression-free survival in relation to the status of EGFR gene activating mutations.
Overall survival in relation to the status of EGFR gene activating mutations.
This clinical trial was launched at a time when routine testing for EGFR gene-activating mutations was not yet available. Selection of patients for a combination of chemotherapy and erlotinib was made on the basis of classical histopathology (adenocarcinoma) and smoking status.
Recent developments led to premature closure of our trial. Since testing for EGFR gene mutations is now available, it is clear that patients with activating mutations are those who really benefit from TKIs. In addition, standard first-line treatment for patients with activating EGFR mutations is now monotherapy with a TKI [
In order to get a longer interval for intermittent erlotinib, gemcitabine was given on days 1 and 4 of the cycle. When compared to the standard day 1 and day 8 schedule, this minor modification in timing of cytotoxic drugs did not have any adverse effect on the tolerance to treatment. Clearly, other platin-based schedules which apply chemotherapy on a 3-weekly basis (such as pemetrexed-cisplatin or paclitaxel-carboplatin) can offer an even longer interval for TKIs and might be considered for future trials of intermittent treatment.
Two other groups recently reported promising experience with intermittent chemotherapy and TKIs. In a trial from the USA, two schedules of intermittent treatment were tested [
Despite its small size, our trial can offer valuable experience for further research on optimisation of treatment with combinations of chemotherapy and TKIs. Looking at the whole series of patients, we can conclude that intermittent chemotherapy and erlotinib is a treatment of very low toxicity. It is also clear that the efficacy of treatment is closely related to the presence or absence of EGFR gene-activating mutations.
The most important finding is the excellent response rate with a substantial proportion of complete responses and prolonged TTP and OS for patients positive for EGFR gene-activating mutations. For many years, the maximal expectation of a patient with metastatic nonsmall cell lung cancer was a partial remission of relatively short duration in the range of 5 to 9 months. With intermittent treatment, we now see durable complete remissions in a subpopulation of patients. While the number of patients in our trial is small and any definitive conclusion would be premature, we nevertheless believe that further research of intermittent therapy for patients positive for EGFR gene-activating mutations is warranted. A randomised trial comparing first-line TKI as monotherapy to the intermittent schedule should clarify the real value of this new approach.
The authors declare no conflict of interests.
This paper was supported by Grant J3-6044-0302-04 from the Ministry of Science and Higher Education, Republic of Slovenia. The authors thank the nurses from the Outpatient Department and Day Hospital for their valuable help in conducting the trial and Alan McConnell Duff for language editing.