Casas, Francesc PhD*; Viñolas, Núria MD†; Ferrer, Ferran MD‡; Agustí, Carles MD§; Sanchez, Marcelo MD∥; Maria Gimferrer, Josep MD¶; Lomeña, Francisco MD#; Campayo, Marc PhD†; Jeremic, Branislav MD‡
Radiochemotherapy (RT-CHT) is currently a recommended treatment approach for locally advanced inoperable stage IIIA and stage IIIB non-small cell lung cancer (NSCLC) in patients with good performance status (PS, 0-1).1 A concurrent approach has been shown to be superior to sequential treatment delivery in the meta-analyses in terms of longer survival.2
In 2004, we published our experience3 combining full-dose induction CH (cisplatin plus gemcitabine for two cycles) followed by concurrent administration of accelerated radiotherapy with a concomitant boost (with a total dose of 61.64 Gy administered in 23 fractions), with cisplatin and navelbine for two courses, finally followed by two courses of the same initial chemotherapy (CHT). The median survival was 15.4 months with an actuarial 1-, 2- and 3-year survival of 67, 21 and 15%, respectively. Hematological and esophageal toxicity ≥ grade 3 was not negligible (60% and 30%, respectively). The RT schedule consisted of an accelerated schedule using the concomitant boost technique.4 This was achieved using a “field-in-a-field” technique (simultaneously integrated boost), whereby the larger area was treated to 1.8 Gy followed by a smaller area (boost) being treated with an additional 0.88 Gy with no time delay.
Preliminary reports of a phase I/II study by Uitterhoeve et al.,5 which combined a daily low-dose CHT and a similar accelerated RT schedule, obtained an encouraging overall actuarial 1- and 2-year survival of 53% and 40%, respectively.
With this background, our aim was to make a new phase II trial to assess the safety, activity, survival, and progression-free survival after full-dose induction CH, concurrent RT-CHT based on accelerated RT with weekly paclitaxel (P), and full-dose consolidation CHT as induction therapy. Our hypothesis was that this phase II would reduce toxicity maintaining at least the same effectiveness as our previous experience. The primary objective was to estimate the efficacy and safety of a different RT-CHT scheme.
We present herewith the long-term results of our single-institutional phase II trial that included most of the patients considered as “poor-risk” and, therefore, suitable for this intensive treatment.
PATIENTS AND METHODS
A phase II study on combined RT-CHT in patients with locally advanced NSCLC was undertaken from 2000 to 2003. Patients were staged using the 1997 International Staging System, Tumor Nodes Metastasis Classification. The inclusion criteria were adult patients (18-80 years) and Eastern Cooperative Oncology Group status 0 to 2, minimum pulmonary function of 1 liter with histologic or cytologic proof of NSCLC. Patients with pleural effusions were excluded. Endoscopic esophageal ultrasound was available during the study period. Endoscopic esophageal ultrasound, mediastinoscopy, or direct function of supraclavicular nodes was made to confirm N3 involvement (100%). The tumor and nodes had to be unresectable at the time of diagnosis as evaluated by a multidisciplinary Lung Cancer Committee of experienced radiologists, thoracic surgeons, radiation oncologists, medical oncologist, and pneumologists. Patients had to be in a satisfactory medical condition to undergo CHT and thoracic radiotherapy (Karnosfky Performance Status ≥70%). Active supportive treatment was provided to PS 1 to 2 patients with dietetic and hematopoietic tools including erythropoietin.6 In a previously published trial, a total of 51 patients with lung cancer were enrolled in a prospective phase II protocol in Hospital Clínic between September 1996 and September 2000. After neoadjuvant CHT based on cisplatin, an hemoglobin level of less than 11 g/dl was required (according to Catalonian Erythropoietin Committee law restrictions) to receive erythropoietin (150 IU/KG, 3 times weekly) with oral iron (600 mg/d) for a maximum of 8 weeks to maintain the levels of hemoglobin and the Karnofsky index. After the good results obtained, this protocol was implemented as the habitual clinical practice in our hospital.
Our study was approved by the institutional Ethics Committee, and all patients gave informed consent.
Pretreatment diagnostic aspects included clinical examination, full laboratory/biochemistry and blood tests, computed tomography (CT) scan of the thorax and upper abdomen, and bronchoscopy. Brain imaging or bone scan was not done in the absence of symptoms. PET-CT was not done in this group because it was not allowed for staging in Spain during the study period. We used the Helax TMS 6.1B planning system for three-dimensional (3D) planning. This system corrects for lung density by pencil beam algorithm.
Treatment started with two cycles of induction CHT consisting of P 175 mg/m2, day 1 and carboplatin (C), area under the curve 6, day 1, given at a 3-week interval. Three weeks after the end of the second PC, patients started an RT schedule that consisted of an accelerated schedule using the concomitant boost technique. Patients received 61.64 Gy using 3D conformal RT over a total of 5 weeks (23 treatment days). For the initial larger area, the clinical target volume (CTV) was derived from GTV (primary tumor and lymph nodes of >1 cm at the largest diameter as seen in the planning CT scan) by expanding 0.5 cm in all directions to include microscopic involvement. Finally, we expanded the CTV by 1 cm to create the planning target volume (PTV). Elective nodal irradiation (ENI), defined as prophylactic irradiation of uninvolved mediastinal nodes following CT scan information, was used in this field but only limited to first uninvolved lymphatic level. In the boost field, GTV was equivalent to CTV, and 1 cm was added to create the PTV. In the boost field, only macroscopic disease (primary tumor plus nodal areas) was considered as CTV, and any type of ENI was omitted. The dose was calculated following ICRU recommendations. V20 constraints were not applied in this protocol as their use was initiated in our department in 2003. The total dose and the number of the fractions were chosen after a previous dosimetric study to maintain a safe dose of approximately 45 Gy at the spinal cord level. In the original study of reference of concomitant boost techniques by Graham et al.,4 the total dose and number of fractions were 75.04 Gy and 28, respectively, although the boost area included the primary tumor only instead of the tumor and nodes more than 1 cm that we used.
During the RT course, P was given at a weekly dose of 45 mg/m2. Three weeks after the end of concurrent RT-CHT, patients continued with the same PC with two cycles planned at a 3-week interval.
Patients were evaluated for response after the second cycle of consolidation PC using thoracic and upper abdominal CT according to the RECIST criteria.7 Patients were followed at regular time intervals that included three monthly clinical examination, laboratory and biochemistry analysis, and CT scans of the thorax. Additional tests were performed if clinically indicated. PET-CT was not allowed for follow-up in our country during the period of study. Systematic bronchoscopy or biopsies at the time of regular follow-up visit or at the time of suspected progression was not performed. Toxicity was scored using the WHO criteria8 but was converted into CTCAE v2.0.
Sample size considerations were based on expected hematological toxicity grade 3 or higher. Based on previous experience (Ref. 3), an objective decrease in hematological toxicity of 20% was assumed. Accepting an alpha risk of 0.1 and a beta risk of 0.20 in a one-sided test, approximately 30 patients were needed with a drop-out rate of 0.05. Statistical analysis was done using the SPSS version 14 software package. Statistical analysis was performed by intention to treat. The quantitative characteristics of the patients have been described using median values and interquartile ranges, and qualitative characteristics using proportions. The Fisher's exact test was used to examine the association between different measures. A binomial distribution was assumed to estimate the 95% confidence interval of the relative frequency to be in complete response, partial response, stable disease, or progression. Survival analysis was estimated using the Kaplan-Meier method. The Cox proportional hazard regression model was used to evaluate the effect of explanatory variables on survival time. Factors that were statistically significant in the univariate analysis at a 90% confidence level were added in a stepwise manner to the multivariate model. All p values were based on two-sided testing with a 95% confidence level. All statistical analyses were done by one of the authors (F.F.).
A total of 32 patients were enrolled in this phase II study. No patient was lost to follow-up. The median follow-up for all 32 patients was 17.2 months (range, 3.8-107 months). The median follow-up for the 27 patients who died was 12.7 months (range, 3.8-94.1 months). Patient and tumor characteristics are listed in Table 1. Most of the patients were staged as IIIB, and all but one (3.1%) were smokers. More than 80% of the patients were with PS 1 to 2. Almost 85% of patients were staged T3-4 (nonmalignant pleural or cardiac effusion), and more than 70% patients were N 2-3, representing a “poor-risk” category (Table 1).
All patients received two planned induction CHT cycles of PC and proceeded with concurrent RT-CHT. One patient developed brain hemorrhage after four RT fractions and discontinued the treatment. Another patient stopped the concurrent part due to the development of brain metastasis (after 8 Gy to primary tumor) and was subsequently given palliative brain RT. Both patients were followed up until death and included in the survival analysis. No other patient experienced distant progression until the end of concurrent RT-CHT. Therefore, a total of 30 patients finished concurrent RT-CHT part of the treatment. Weekly P dosing was given six times during the radiation therapy (RT) in 16 patients (50%), five times in six patients (18.8%), four times in five patients (15.6%), thrice in one patient (3.1%), and twice in two patients (6.3%), whereas one patient did not receive weekly P and received only induction CHT. One patient was treated over 7 weeks of RT and, therefore, received a total of 7 weekly doses of P. The protocol required weekly P to begin after 21 days of the second cycle of C-P. RT was begun in the same week as the first P (to be given weekly during the RT course); however, because of various reasons (waiting list, holidays, and machine repair), some patients did not receive the first dose of weekly P concurrently with RT, starting several days later. Depending on the day of the week, the patient began RT, four to six cycles were administered during concurrent RT-CHT. A total of 27 patients (84.4%) received this planned intensity.
Consolidation PC (one cycle) was given to 25 patients, and only seven patients received both planned cycles of CHT due to diminution of PS following the criteria of the medical oncologist (N.V.).
Response to treatment was evaluated at the end of the planned consolidation phase of the treatment. The overall response rate (Table 2) was 72%, whereas both stable disease and progressive disease were observed (12.5% each), not being evaluated in one patient who developed a brain hemorrhage.
The median survival time for all 32 patients was 16.9 months, and the 5- to 10-year survival was 25% and 17.5%, respectively (Figure 1).
The median time for disease progression was 9.5 months with a disease-free survival of 21% at 5 and 8 years (Figure 2).
The median time to local progression was 14.6 months, and the 5- to 10-year local progression-free survival was 35.7% (Figure 3). The median time to distant metastasis was 17.5 months, and the 5- to 10-year distant metastasis-free survival was 41. 4% (Figure 4).
We did not find any breakdown in patient outcome according to T and N status. The surviving patients were staged as T4 N1, T3 N2, T4 N2, T2 N3, and T4 N1 with a survival of 74, 74, 85.66, 92.37, 99.47, and 106.97 months, respectively.
Patterns of failure identified local progression alone in eight patients (25%), distant progression alone in seven patients (22%), whereas both local progression and distant progression were observed in six patients (19%). Of the 11 (34%) nonprogression patients, tumor progression could not be evaluated in only one (3%) patient (with brain hemorrhage). In the remaining 10 (31%) patients, progression was not observed. Causes of death included lung cancer progression in 21 (66%), being cancer-unrelated in five (16%) patients: large bowel perforation (n = 1), brain hemorrhage (n = 1), second or third primary tumor with or without distant metastasis (n = 2), and sudden death at home without previous progression noted on two consecutive follow-up examinations (n = 1). Interestingly, among nonprogression (of lung cancer) patients, three deaths occurred more than 5 years after the beginning of treatment.
To investigate the influence of potential prognostic factors (from Table 1), we performed univariate analysis of these factors. None of the factors investigated influenced survival, and therefore, multivariate analysis was not done.
The acute toxicity pattern (Table 3) revealed grade 3 to grade 4 toxicities in a few patients; grade 3 anemia in one patient (3.1%), leucopenia grades 3 to 4 in two patients (6.2%), and grade 3 thrombocytopenia in one patient (3.1%). Grade 2 esophagitis was found in nine patients (28.1%) and grade 3 in two patients (6.2%) all related to RT-CHT. Only one (3.1%) patient died of treatment-related lung toxicity having a T2N3 tumor and being diagnosed with initial idiopathic pulmonary fibrosis at the same time and had received two cycles of induction PC, followed by 61 Gy and 7 weekly doses of P and only one cycle of consolidation PC. This patient died 4.21 months after having begun induction CHT.
In relationship to delayed toxicities in 10 patients followed up for more than 5 years, we observed that all the patients presented toxicity of pneumonitis and/or grade 1 pulmonary infiltrates with radiographic changes, but five presented grade 2 of dyspnea (on exertion). All these five patients are being followed up by the pneumologist on the Committee. No long-term toxicity, dysfunction, or stenosis were observed at an esophageal level.
To explore novel strategies for RT-CHT in advanced NSNLC stage IIIB and to diminish the toxicity of the combined treatment, we conducted a phase II trial with an induction phase with full doses CP followed by accelerated modified scheduling of RT with a concomitant boost concurrent with weekly P and finally consolidation CHT with PC.
The eligibility criteria included few patients (n = 3) with PS 2, weight loss more than 10% (n = 7), whereas most (90%) were those with stage IIIB. Despite these poor prognostic features, the median survival was 16.9 months, and the 5-year survival and 10-year survival were 25% and 17.5%, respectively. These results are similar to the best results of previous phase III trials of concurrent versus sequential RT-CHT,9–11 those of the phase III induction CHT and RT-CHT,12–14 and those of the consolidation CHT therapy after concurrent RT-CHT.15 The toxicity, albeit significant (one grade 5), was manageable and was diminished compared with that of a previous trial,3 thereby confirming our previous hypothesis.
In the present series, patterns of failure with local progression alone were identified in 25% of the patients with both local and distant progression being observed in 19% of the patients each. These rates show a high local control despite very locally advanced lung tumors (85% staged T3-4 and >70% patients with N 2-3). No relationship was found between outcome and T or N status probably due to the small size of the sample. This good local control could be explained by the RT schedule (accelerated scheduling with concomitant boost) used. As indicated previously, the total dose and the number of the fractions (23 fractions) were chosen after a previous dosimetric study to maintain a safe dose of approximately 46 Gy at a spinal cord level. The main reason for this was that a previous study was begun with two-dimensional tools (in 26 patients) initially using anteroposterior-posteroanterior (AP-PA) fields (large and boost fields consecutively) during 16 fractions maintaining a maximum dose of 43 Gy (42.88 Gy) in the spinal cord, and the last seven fractions were performed with oblique fields by three slices of thoracic CT at the tumor level maintaining a total dose of 46 Gy at the level of the spinal cord. In the last part of the previous study (11 patients), we used 3D planning and avoided AP-PA fields and used only oblique fields while maintaining the total number of fractions. This exact number of fractions (23) was maintained in the present phase II study following our experience with their safety. The local control results could probably be improved using more margins to include all type of uncertainties, and margins of 1 cm to expand CTV to PTV are not sufficient with 3D planning without breathing control. Nonetheless, it should be taken into consideration that our phase II study was conducted before systematic 3D planning in advanced NSCLC.16
This old technique of concomitant boost17 was adapted to substitute a real accelerated hyperfractionated RT treatment because this was not possible in our department due to the existing waiting lists. This technique is currently not common, but at the time this trial was ongoing, two important radiation oncologist groups published very promising results with concomitant boost RT alone18 or in association with CHT.5
The rationale for accelerated fractionation is that experimental and clinical experience suggests that acceleration of the RT course may lead to improved tumor control, likely by allowing less opportunity for tumor repopulation during treatment, and has resulted in improved clinical outcomes in locally advanced NSCLC.19 The continuous hyperfractionated accelerated RT trial with 54 Gy in 36 fractions of 1.5 Gy over 12 consecutive days demonstrated improved survival compared with conventional thoracic RT. The Eastern Cooperative Oncology Group attempted to test continuous hyperfractionated accelerated RT trial, eliminating RT during weekends (HART) in a phase III trial. Nevertheless, the HART trial closed early because of slow accrual. The median survival was 20.3 months for HART compared with 14.9 months with standard RT, but this difference did not reach statistical significance.20 Nevertheless, the results in the HART cohort point to the promise of thoracic RT dose intensity. Finally, in one retrospective trial with 261 patients with NSCLC, Liao et al.21 also found significantly improved locoregional control with accelerated RT.
Despite the high intensity of our protocol, the toxicity observed compares favorably with studies of concurrent RT-CHT given alone or with induction CHT followed by concurrent RT-CHT and consolidation CHT. This is probably based on the radiosensitizing action of weekly P, which improves the local action of RT without increasing the hematological toxicity of CHT as shown in pivotal trials using protacted low-dose CHT (platinum-based in both cases) described by Schaake-Koning et al.22 and Jeremic et al.23 Regarding the low incidence of esophageal toxicity reported in this study, since the beginning of the use of concurrent RT-CHT in 1994, a close relationship has been observed between leucopenia grades 3 to 4 and esophageal toxicity (grades 2-3), as summarized previously.24 In this context, the low incidence of important leucopenia (grades 3-4 was 6.2%) in our trial may have a direct relationship with esophagitis grade 3 (6.2%).
This improvement in local control could also explain the long-term survival by diminishing it as a potential source of distant progression in this very unfavorable prognostic population. It is important to point out that survival was almost the same from 5 to 10 years (∼22% throughout the period) with 3 deaths after 5 years of the first lung cancer treatment for non-NSCLC-related causes (including two second malignancies).
Our phase II trail was also inspired by the first results of phase II trial by Gandara et al.,25 which were, however, not confirmed in a phase III trial. After the Hoosier Oncology Group negative trial consolidation, CH is not currently considered as an evidence-based standard of care. Moreover, based on the studies by Vokes et al.12 and Kim et al.,13 which directly addressed the issue of induction therapy, it is not possible to recommend the use of induction CHT before concurrent RT-CHT in routine clinical practice. A recent and elegant revision about neoadjuvant cisplatin administration at different tumor sites (including NSCLC) showed that induction CHT could activate epidermal growth factor receptor expression that, in itself, may promote radioresistance and accelerated repopulation during RT. In the possible cases that may occur, this overexpression of epidermal growth factor receptor local control can be improved by accelerated fractionation26 as is the case in our protocol.
It currently seems that only two cycles of CHT given during RT provide maximum therapeutic effect in stage III.27 Similarly, concurrent RT-CHT might be integrated in a phase III trial combining accelerated treatment, scheduling RT with weekly CHT. Since no randomized study has yet compared accelerated RT and radiosensitizing low dose versus systemically active high-dose therapy, it remains unknown whether either of these two approaches is superior to another. Thus, the integration of accelerated RT (maybe without ENI) requires further investigation.
Finally, the integration of functional imaging with FDG-PET for RT treatment planning (available in the Spanish Public Health System only since 2005) could aid in selecting patients who are not appropriate candidates for radical thoracic RT, secondarily achieving greater local control and overall survival.
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