Current Research on Consolidation Therapy and Follow-up Health Care in Advanced Non-small Cell Lung Cancer Patients

Treatment of non-operable dry Stage-IIIB NSCLC

Research during a period from 1980 to 1990 showed that associated radio-chemotherapy had a marked curative effect on Stage-III patients^[1], with the median survival up to about 18 months^[2]. Therefore, based on the Manual of the American Society of Clinical Oncology (ASCO), associated radio-chemotherapy was highly recommended for non-operable Stage-III NSCLC patients with a favorable PS scoring.

In the 1990s, important research demonstrated that synchronal radio-chemotherapy had an advantage over sequential (i.e. step by step) radio-chemotherapy. In the clinical trials, a study was conducted comparing MVP chemotherapy plus concurrent radiotherapy versus MVP with post-chemotherapeutic radiotherapy^[3]. Survival time of the group with concurrent radio-chemotherapy significantly increased, with the median survivals of 16.5 and 13.3 months, and the 5-year survival rates of 16% and 9%, respectively. In another clinical trial, i.e. the RTOG9410 trial, concurrent radiotherapy and sequential radio-chemotherapy with the NP regimen were compared^[4]. Survival time of the concurrent radio-chemotherapy group was superior to that of the sequential therapy group, with the median survival times of 17.0 and 14.6 months. Four-year survival rates were 21% and 12% respectively in the two groups.

However what kind of therapeutic regimen, and how many courses of treatment should be used for the consolidation therapy, following concurrent radio-chemotherapy, still remains undetermined.

Kaplan et al.^[5] continued the chemotherapeutic regimen of paclitaxel with carboplatin (TC) for 4 courses, after appraising the TC regimen with concurrent radiotherapy. The first step of the research included the TC regimen (Taxol 50 mg/m², carboplatin AUC 2), and concurrently a daily 2-Gy radiotherapy. The duration of the concurrent treatment lasted for 6.5 weeks. Then the second step followed, i.e. a 4-course TC consolidation chemotherapy (Taxol 175 mg/m², d1,22; carboplatin AUC 6, d1,22), with a median survival of 13.9 months, and a 1-year survival rate of 65.1%.

In the Test S9019, Stage-IIIB NSCLC patients were treated with a 2-course EP chemotherapy (cisplatin 50 mg/m 2/d, d1,8; VP16 50 mg/m2/d, d1~d5), and concurrently with a 61-Gy radiotherapy^[6]. Then 2 more courses of EP chemotherapy were administered. The median survival of the patients was 15 months, and the 5-year survival rate was 15%.

These inspiring data revealed that after concurrent radio-chemotherapy, the subsequent consolidation chemotherapy might be an important treatment method for non-operable Stage-III patients. In concurrent radio-chemotherapy, it is necessary to reduce the dose of the new chemotherapeutics such as TC^[7,8], however, a tentative full dose of EP regimen can be used.

A follow-up assessment of the effect of consolidation therapy was performed in 83 patients in the succedent Test S9504^[9,10], which maintained the same inclusion criteria and treatment method employed in the Test S9019. After receiving a 2-course EP chemotherapeutic regimen combined with concurrent radiotherapy, the patients were treated with a Taxotere consolidation therapy. A 75 mg/m² of Taxotere was administered in the first course, then 100 mg/m² in the next 2 courses, once every three weeks.

The effective rate of the test S9504 was 67% with concurrent radio-chemotherapy, the median survival was 26 months, and 5-year survival rate was 29%. The survival data of this test had an overt advantage over the test S9019 using EP for consolidation therapy. The shortcomings of the S9504 test showed that brain metastasis occurred in nearly half of the patients. Considering the other findings of this period^[11,12], Taxotere with 75 mg/m² was regarded as an optimal dosage, which was adopted in the following clinical trial with NSCLC patients.

Sakai et al.^[13] continued their consolidation chemotherapy test using the DC regimen, following appraisement of the regime for concurrent radiotherapy. The patients received the DC chemotherapeutic regime (Taxotere with 30 mg/m², carboplatin AUC 3, once every 2 weeks, totaling 4 courses of chemotherapy), and at the same time they underwent radiotherapy (2 Gy per day, with a total dose of 60 Gy). Then 2 courses of chemotherapy with the original dose were conducted. The effective rate was 91% and median survival 27 months. The 1-year and 2-year survival rates were respectively 76% and 61%. These experimental results were even superior to the test S9504, however, the sample size was too small.

Therefore the results from clinical research regarding non-operable Stage-III NSCLC patients, the succedent 2 or 3 courses of Taxotere (75 mg/m²) consolidation therapy may gain extended survival time, after the EP chemotherapy with concurrent radiotherapy.

Concerning the patients with non-operable Stage-III NSCLC, who receive concurrent radio-chemotherapy and a subsequent Taxotere consolidation therapy, there has not been a final conclusion as to whether or not the succedent therapy should be changed into an extended biological-targeted therapy.

Test S0023 was used to evaluate the therapeutic efficacy of oral Iressa and placebo after the test S9504^[14]. Following 3 cycles of Taxotere consolidation therapy, the patients were randomly divided into the groups receiving oral Iressa or an oral placebo. The median survival of the group with the placebo was 29 months, and that of the group with Iressa 19 was months. The test S0023 validated the result from the test S9504, however, the survival time of the group receiving Iressa was shortened. This result probably occurred because the selected patients were not those who benefited from Iressa treatment.

Treatment of moist Stage-IIIB and IV NSCLC

The Eastern Cooperative Oncology Group 1594 research showed that the effects on survival time using 4 different platinic chemotherapeutic regimens (TP, TC, GP and DP) for NSCLC patients were similar, showing no statistical difference in improvement of the results^[15].

The present conclusion is that the number of optimal courses of first-line therapy is 3 or 4. Extending the course number not only fails to improve the response rate, but may result in a cumulation of toxic effects. The purpose for shortening the course of first-line therapy is to maintain the physical stamina of the patients and to allow rebuilding of the immune system, so as to have an opportunity to employ second-line therapy as the progression of disease (PD) occurs. About 30 to 40% of the patients have the opportunity of receiving second-line therapy, after the first-line therapy^[16]. Taxotere has been proven to suit the second-line therapy for NSCLC patients having received platinic chemotherapy^[11,12,17].

At the 2006 ASCO meeting a question was raised, i.e. as to whether second-line therapy should be conducted immediately after completion of first-line therapy with a focus at SD or if second-line therapy should be performed following PD. A study^[18] indicated that the effective rate was 42% when Taxotere second-line therapy was conducted immediately after completion of the first-line therapy with a focus at SD, and the clinical beneficiary rate of this group (CR+PR+SD) was 88.2%, while the effective rate was only 6.1% in the group receiving Taxotere second-line therapy until PD, with a clinical beneficiary rate of 60.6%. The results showed that the effective rate of the latter group with a delayed treatment was significantly lower compared to the former with active therapy.

Schuette et al.^[19] compared the curative effect of second-line therapy of advanced NSCLC using a regimen of 3-week Taxotere chemotherapy (Taxotere 75 mg/m², d1, once 3 weeks) with a weekly regimen (Taxotere 35 mg/m², d1, 8, 15). The median survival with the 3-week regimen was 6.3 months, and that of the latter regimen 9.2 months, with an effective rate of 12.6% vs 10.5% for the two regimens. Moreover the toxic reaction of the weekly regimen was clearly lower compared to the 3-week regimen. So it was suggested by Schuette et al.^[19] that the weekly regimen of Taxotere 35 mg/m2 might be more suitable for second-line chemotherapy, probably because of a less toxic reaction and a more acceptable tolerance by the patients.

All these studies indicated that second-line therapy should immediately be conducted if the patient has a focus of SD following a first-line therapy. The survival status of the patients receiving a low-dose weekly Taxotere (35 mg/m²) regimen of maintenance chemotherapy was the same as the survivals of those receiving the standard dosage chemotherapy, however, the low-dose regimen caused less toxic reactions and was easily accepted by the patients. Therefore a subsequent 2 to 4-course of Taxotere (35 mg/m²) consolidation therapy might be suitable for the patients with SD after the first-line chemotherapy.

Place of biological-targeted therapy in advanced NSCLC

Iressa has been validated to have a satisfactory efficacy for suitable patients, i.e. Orientals, women, non-smokers and those with adenocarcinoma. This relates to the probability that these patients have a higher epidermal growth factor receptor in their genes. IDEAL studied second-line Iressa therapy for advanced NSCLC patients, and found that the average effective rate of Iressa therapy was 18%. The effective rate of Iressa treatment was 27% in Japanese patients, with a median survival of 11.8 months, while the effective rate was only 11% in Europeans, showing a median survival of 6.5 months. There was a great disparity between the two groups.

The conclusion from another study indicated that there was a failure of first-line therapy, with a PS score of over 3, in 31 reports from Asian countries during a period from 2003 to 2005. It was found that in advanced NSCLC patients with secondary brain metastasis receiving a daily regimen of oral Iressa (250 mg)^[20], the effective rate was over 25% and the disease control rate was over 50%. Among these cases, the PD time was over 3 months and the median survival over 6 months in most trials. All the data suggested that Iressa has superior features for treating suitable subjects.

Although the above cited authors have mentioned that the test S0023 had shown there was no advantage for Iressa utilization, after consolidation therapy, it is worth noting that all patients enrolled in the test S0023 were randomized, without designedly selecting the possible patients that would benefit with Iressa therapy.

A SIGN study showed that in research on advanced NSCLC patients with a failure of first-line therapy, either receiving a randomized daily regimen of oral Iressa (250 mg) or a 3-week regimen of Taxotere (75 mg/m²), the remission rates were respectively 13.2% and 13.7%, with median survival of 7.5 and 7.1 months in the two groups. Adverse reactions were less in the group receiving oral Iressa compared to the other group, but without predominance in survival time.

It has been demonstrated by the above trials that the curative effect of Iressa treatment for selected patients requiring second-line therapy, after first-line therapy, is positive. However it is unsettled as to whether it is suitable to conduct targeted therapy on non-targeted patients enrolled without a randomized selection in clinical work.

Summary

At present a 2 or 3-course of standard dosage Taxotere consolidation therapy may extend survival time for non-operable dry Stage-IIIB NSCLC patients after concurrent radio-chemotherapy, as well as for moist Stage-IIIB and IV patients who fail to receive concurrent radiochemotherapy. The immediate performance of second-line Taxotere maintenance therapy with low dose, after the first-line therapy, and biological-targeted therapy of the patients with suitable symptoms are both in accord with EBM. In conclusion, individualized treatment is the only choice for advanced NSCLC patients. According to EBM, the longest survival time can be obtained only by selecting the most favored treatment method.