Initial Partial Response And Stable Disease Indicate Similar Progression-free Survival For Chemotherapeutical Patients With Advanced Non-small Cell Lung Cancer

ObjectiveThe change of tumour size is regarded as an objective indicator in assessing the efficiency of any anticancer therapy. Currently, the Response Evaluation Criteria in Solid Tumours (RECIST) based on morphologic evaluation, is widely used in evaluating the response to anticancer treatment. Using RECIST measurement criteria, patients in clinical treatments are stratified into one of four groups; i.e. complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) on the basis of change in lesion size.The purpose of stratification of patients into response categories is to acquire optimal treatment schemes. CR and PR indicate apparent decrease in tumour size. PD means a significant increase in tumour size or with the appearance of new lesions SD is a relatively more complex category, and ranges from a minor decrease to a minor increase. It is generally accepted that a decrease in tumour size suggests effectiveness of the current therapy and an increase in tumour size indicates ineffectiveness. But when it comes to replacement of the current medical decision, only PD patients accept an alternative therapy in clinical practice. The maintenance of SD patients on their original treatment schemes is accepted as the norm in routine practice, although RECIST does not provide any reliable suggestion for clinicians to follow. The definition of response categories in RECIST is an arbitrary convention that is not based on any clinical data, for it has been adapted from the earlier WHO criteria on the assumption that the tumour is spherical model. SD, with its complex components, has long been viewed as a controversial category with an equivocal result and its clinical significance is unclear.Chemotherapy is still the dominant treatment for advanced non-small cell lung cancer (NSCLC). However, the reality is that only a few patients with advanced NSCLC experience tumor decrease after standard first-line platinum-based chemotherapy and many more patients experience SD. So, it is very important to choose a suitable treatment regimen for advanced NSCLC patients who get SD in their initial assessment after the first two courses of first-line platinum-based chemotherapy. However, whether the different level of SD undergoes different PFS, whether all SD patients benefit from the original treatments is of great importance in current clinical practice. PFS is believed to be a rapid and accurate indicator for assessing the effectiveness of first-line treatment and predicting survival benefits. It can be used as a scale for retaining/replacing first-line treatments.The objectives of this study were:(1) to clarify the clinical significance of SD by comparing the PFS of PR and SD patients after the first two courses of chemotherapy; and (2) to explore the relationship between the change of tumour size, which ranges from minor decrease to minor increase, and their PFS among the achieved SD patients with advanced NSCLC according to RECIST standard in their initial assessment after the first two cycles of first-line platinum-based chemotherapy, to provide some guidance for clinical practice at a relatively early time.Materials and Methods1. Patient SelectionMale and female patients in the age range 18-80 years were eligible for the research if they met the following criteria; histologically or cytologically confirmed with non-small cell lung cancer (NSCLC) that is unresectable, recurrent or metastatic; no previous adjuvant chemotherapy or recurrent metastatic NSCLC patients who have not received adjuvant chemotherapy for at least 6 months before the trial; at least one measurable tumour lesion not located in the locus that has received radiotherapy according to RECIST. Liver metastatic lesions that had received interventional therapy were not regarded as measurable lesions and hollow viscous lesions were not regarded as target lesions.. The other requisites were: anticipated time of survival of at least three months; a desirable life exponent, i.e.0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) performance status; adequate renal, hepatic, cardiac and hematologic function.Patients were not enrolled in the study if they had only immeasurable lesions, such as malignant pleural effusion, ill-defined pulmonary densities and osseous metastasis, or if their only measurable lesion had received radiotherapy during the research; or they had brain metastases or meningeal metastases.2. TreatmentsAll patients with advanced NSCLC were assigned to a combination of platinum-based chemotherapy, i.e. NP, GP, TP or DP treatment schemes according to their own conditions. Each patient received 4-6 courses of chemotherapy, and each course lasted 3 weeks. An assessment was made after every 2 courses of chemotherapy. Patients with PD were excluded from this group and received a different treatment regimen.3. Dosage Adjustment SchemeAdverse events were graded according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) toxicity scale. If hematologic toxicityⅢor greater occurred, the dosage for the next cycle was decreased to 75-85% of the original dosage or the next course of treatment was postponed by 1 or 2 weeks. If hematologic toxicityⅢor greater remained, or a fever from combined severe infection and granulocytopenia IV occurred, the planned treatment was terminated. If non-hematologic toxicity (except trichomadesis)Ⅲor greater occurs, the dosage for the next course was adjusted to 75-85% of the original dosage. If cardiotoxicityⅡ-Ⅳ occurred, treatment was discontinued.Throughout chemotherapy, adjuvant medicine such as antanacathartic, colony-stimulating factor and diphosphonate were given to reduce adverse events when necessary.4. Image Data Collection and StudyEach patient had a base-line check within one month before their first-line chemotherapeutic treatment started. To ensure the credibility of the study, images of measurable lesions were obtained by the qualified radiologists through Spiro-CT or MRI scans. Subsequent images were obtained by the same radiologist after the first 2 courses of chemotherapy for each patient. To minimize variation between operators, all measurements of the images were done at the same anatomic level and orientation by an independent qualified radiologist. In contrast with the base-line images, any change in the size of target lesions was calculated according to RECIST. Patients with an increase of 20% or more in lesion size or those with new lesions were regarded as having PD and were excluded from the study. Patients with a change of lesion size ranging from an increase of< 20% to a decrease of< 30% and with no new lesion were stratified as having SD. Patients with a 30% or greater decrease in the target lesion were regarded as achieving PR. Patients with disappearance of the lesion were stratified as achieving CR. For those with SD, the percentage of change in tumour size has been recorded for further study.5. Follow-up VisitA follow-up visit was given to each patient who achieved CR, PR and SD. The assessment process was repeated every 2 courses until the end of the chemotherapy, or the aggravation of the disease, and after that, every 2 months until the progression of the disease or death occurred. This kind of service could be provided to meet a patient's need at any time. The percentage of change in size of target tumours and the PFS were the main contents for a follow-up visit.6. Statistical Analysis SPSS13.0 software was used for all statistical analysis. The correlation between the change in size of target lesions before and after the first two courses of chemotherapy and their PFS was calculated. According to the RECIST standard, the sum of the longest dimension of all the target lesions was calculated for each patient to provide the baseline before treatment. The same measurements and calculation were done after the first two courses of chemotherapy to obtain the initial assessment sum. The change ratio of target lesions was calculated as: (Assessment sum-Baseline sum)/Baseline sum PFS was calculated from the date of first treatment to disease progression or death. The Kaplan-Meier curve was used to describe PFS, and a log-rank test was used to compare the PFS of each category defined according to the percentage reduction in tumour size i.e.≥30%[PR],≥25%,≥20%,≥15%,≥10%,≥5%, and> 0%.Theχ2 test was used for qualitative data analysis, and the Kruskal-Wallis test or variance analysis was used to analyse the quantitative data. P<0.05 was set as the level of statistical significance.Results1. Distribution of Response Categories and Patient CharacteristicsAltogether,188 patients were enrolled in the trial but 9 withdrew after completing their first cycle of chemotherapy. The remaining 179 patients with inoperative NSCLC had the initial assessment after the first two courses of first-line platinum-based chemotherapy:37 achieved PR and 117 were regarded as SD and these 154 patients (PR+SD) were eligible for the final analysis. The remaining 25 had PD and no CR according to RECIST. The characteristics of the patients included in this analysis:the median age of the patients when enrolled into the study was 57 years (range 26-77 years), with 38%>60 years. A total of 92 males (60%) were eligible for the analysis. The vast majority of patients (63%) had stage IV disease,64 patients (42%) reported a weight loss of≥5%, and the majority of patients had an ECOG performance status of 0 or 1. 2. Distribution of Change in Tumour Size of Initial SD PatientsThere was a decrease of tumour size of 25-30% for 17,20-25% for 18,15-20% for 16,10-15% for 12 and 5-10% for 8 and 0-5% for 29. The increase of tumour size in the other patients was<20%.3. Comparison of PFS of Patients with Initial PR and SDCareful examination found no statistically significant difference of patient characteristics between the two groups, i.e. baseline characteristics were well balanced between PR and SD. The median PFS was 249 days (95% confidence interval,187-310 days) for the 37 patients with PR and 220 days (95% confidence interval,191-248 days) for the 117 patients with SD. The log-rank test found no significant difference (P= 0.991) of PFS between the PR and SD subgroups.4. Relationship between Change in Target Lesion Size and PFS among Initial SD PatientsThe median PFS of patients with≥25%,>20%,≥15%,≥10%,≥5%or≥0% decrease in tumour size was 289 days,270 days,242 days,225 days,221 days or 221 days, respectively. The P value associated with the log-rank test comparing the PFS of responding patients with that of non-responding patients using different definitions of response. No significantly better cut-off point, i.e. optimal percentage of decrease in tumour size, was found in predicting the PFS of the patients with SD.In addition, among SD patients, those with an initial decrease of 30-20% in tumour size were not significantly distinguishable (P>0.05) from those with an initial increase.5. Multivariate analysis included factors such as sex, age, weight loss, ECOG performance status, and stage of disease, which might have a potential effect on prognosis of NSCLC patients. ECOG 1 and weight loss of≥5% was relatively worse for predicting PFS(P<0.05). Cox regression analysis showed that other prognostic factors like age, sex, stage of disease, the percentage of change in target lesion size of patients with SD derived from the initial assessment after the first two courses of chemotherapy are not associated with PFS (P>0.05)Conclusions1. Initial PR and SD enjoy similar PFS for patients with advanced NSCLC.2. Within the initial SD subgroup, different percentages of tumour shrinkage or increase undergo similar PFS.3. RECIST remains a reliable norm in assessing the effectiveness of chemotherapy for patients with advanced NSCLC before functional assessment has been integrated into the criteria.