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Click here to read this article as a CME activity
a Division of Medical Oncology, University of Maryland School of Medicine and University of Maryland Greenebaum Cancer Center, Baltimore, Maryland
b Division of Thoracic Surgery, University of Maryland School of Medicine and University of Maryland Greenebaum Cancer Center, Baltimore, Maryland
c Department of Radiation Oncology, University of Maryland School of Medicine and University of Maryland Greenebaum Cancer Center, Baltimore, Maryland
Accepted for publication June 2, 2008.
* Address correspondence to Dr Edelman, University of Maryland Greenebaum Cancer Center, 22 S Greene St, Room N9E08, Baltimore, MD 21201 (Email: medelman{at}umm.edu).
| General thoracic surgery:
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Abstract |
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Methods: Patients with documented stage IIIA/B nonsmall-cell lung cancer, performance status 0 to 2, and adequate organ function were eligible. A phase I portion utilized escalating doses of carboplatin and vinorelbine, commencing with areas under the curve of 1 and 5 mg/m2, respectively, and concurrent 69.6 Gy hyperfractionated radiotherapy. A phase II portion utilized the identical radiotherapy with carboplatin/vinorelbine at the maximum tolerated dose established in phase I. Patients for whom mediastinal nodal clearance was demonstrated underwent resection. All patients were to receive consolidation chemotherapy consisting of carboplatin/vinorelbine for three cycles, followed by docetaxel for three cycles. Prophylactic cranial irradiation was offered to patients after completion of therapy.
Results: Forty-seven patients participated in the study (33 IIIA, 14 IIIB; 15 men, 32 women; median age, 56 years). The maximum tolerated dose for concurrent carboplatin/vinorelbine and hyperfractionated radiotherapy was established at areas under the curve of 1 and 10 mg/m2, respectively. Twenty-eight patients completed trimodality treatment including surgery. Median survival time for the entire study cohort (n = 47) is 29.6 months, and it is 55.8 months for patients with mediastinal clearance who underwent resection (n = 28).
Conclusions: Surgical resection of locally advanced stage IIIA and IIIB nonsmall-cell lung cancer after induction hyperfractionated radiation and concurrent chemotherapy is safe and well tolerated. Whether this approach is superior to less aggressive therapy is uncertain and will require comparative studies.
Nonsmall-cell lung cancer (NSCLC) is the major cause of cancer death in the United States. Approximately 40% of patients present with locally advanced (stage III) disease. Recent trials have demonstrated that the addition of chemotherapy to surgery or radiotherapy, or both, can improve outcomes [1]. Currently, the optimum regimen, timing, doses, and sequence of chemotherapy and radiotherapy are subject to debate.
Two issues must be addressed in any study of stage III NSCLC: local control and systemic control. Local control may be addressed by radiotherapy or surgery whereas systemic control is addressed utilizing chemotherapy. Chemotherapy may also be utilized to enhance the effects of radiotherapy. Concurrent administration of chemotherapy and radiotherapy has been demonstrated to result in superior outcomes in terms of response and survival in a randomized trial, albeit at the expense of greater acute toxicity [2].
For systemic disease, the combination of cisplatin-vinorelbine has been demonstrated to be superior to older platinum-based therapies in two randomized trials and to be equal to carboplatin and paclitaxel [3]. The major difficulty with this regimen is the inconvenience and toxicity of cisplatin administration, which requires extensive prehydration, and has led to the substitution of carboplatin by many investigators [4, 5].
Given the proven efficacy of the platinum-vinorelbine combination in metastatic disease, it is logical to employ this regimen in earlier stage disease. Both agents have demonstrated radiosensitizing effects. Vinorelbine and cisplatin have been combined with standard radiation and demonstrated to be a tolerable regimen. The Cancer and Leukemia Group B (CALGB) evaluated this regimen as part of a randomized phase II trial of different regimens in the management of stage III NSCLC and demonstrated it to be potentially more effective and better tolerated than other regimens (eg, carboplatin and paclitaxel) [6].
The use of altered fractionation techniques, specifically hyperfractionated accelerated radiotherapy (HART), has also improved outcome compared with standard fractionation techniques [7]. It is therefore logical to explore concurrent chemoradiotherapy in which radiotherapy is administered as HART. Several groups have been able to combine regimens containing various agents including cisplatin/etoposide, paclitaxel, carboplatin/paclitaxel, cisplatin/vindesine with HART [8–11].
The role of trimodality therapy in stage III NSCLC is highly controversial. Studies by both the Southwest Oncology Group (SWOG) and the Radiation Therapy Oncology Group (RTOG) have demonstrated the potential of trimodality therapy in the management of stage III disease [12]. In these studies, patients who had residual disease at the time of surgery were completely resected and became long-term survivors. This advantage was particularly notable in patients with T4 disease without nodal involvement. In both of these trials, standard radiation fractionation was employed. We have previously documented the ability to safely resect residual disease after chemoradiotherapy utilizing radiation to 61 Gy [13].
It is clear that despite optimal local control in NSCLC, most patients will fail, and fail systemically. Therefore, the use of optimal systemic therapy is indicated. The type and duration of systemic therapy is controversial. It appears that three cycles of any particular chemotherapy regimen results in maximum benefit. In a randomized trial, three to four cycles of a specific platinum based chemotherapy have been demonstrated to be equivalent to six cycles for treatment of metastatic disease in terms of response and survival [14, 15].
As noted above, the regimen of cisplatin/vinorelbine is at least equal to any currently accepted regimen in NSCLC. Previous studies have demonstrated that the substitution of carboplatin for cisplatin at the schedule employed in this study is well tolerated [16].
The best way to add additional active agents is uncertain. Mathematical modeling, in-vitro data, and clinical evidence support the utilization of planned sequential therapy, namely, the introduction of new agents before the emergence of clinical drug resistance [17]. At the time that this study was formulated, the only class of agents with unequivocal activity in platinum-resistant NSCLC were the taxanes. Docetaxel has demonstrated activity in this setting in two randomized controlled trials [18, 19]. In addition, a report from SWOG demonstrated excellent outcomes for docetaxel consolidation after concurrent chemoradiotherapy [20].
In large multimodality trials as well as in our own institutional experience, a major site of relapse with consequent morbidity and mortality is the brain. A recent report indicates the potential of prophylactic cranial irradiation to decrease central nervous system relapse from 54% to 13% without any evidence of increased neuropsychiatric impairment relative to controls [21]. Therefore, patients who achieved a complete response at the end of therapy (whether from chemoradiotherapy or trimodality) were advised to undergo prophylactic cranial irradiation.
The overall goal of this study was to evaluate the tolerability and efficacy of a treatment approach that would attempt to maximize disease control locally and systemically. The approach utilized incorporated the most aggressive therapeutics available at the time of its design in 1999.
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Material and Methods |
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Induction Therapy Regimen
The study schema is demonstrated in Figure 1. All patients received induction combination chemotherapy consisting of three cycles of vinorelbine (5 to 15 mg/m2) and carboplatin (area under the curve = 1.0) in conjunction with hyperfractionated radiotherapy. The dose escalation schema is indicated in Table 1. Patients were accrued in cohorts of three. Dose-limiting toxicity was defined as grade III or greater nonhematologic toxicity (excluding nausea/vomiting) or sustained grade IV or greater hematologic toxicity (defined as 7 or more days), and any instance of febrile neutropenia or delay in therapy of greater than 2 weeks.
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Radiation therapy began on day 1 in conjunction with the administration of systemic chemotherapy. Hyperfractionated three-dimensional conformal radiation therapy was administered at 1.2 Gy twice a day for 5 days each week. Daily radiotherapy fractions were separated by at least 6 hours. A total of 50.4 Gy (42 fractions) was delivered to the primary tumor and mediastinum. An additional boost dose of 19.2 Gy (16 fractions) was delivered to the primary tumor and any involved lymph node basins. The total radiation dosage was delivered by 58 fractions over the span of 29 treatment days. Radiation portals were defined by three-dimensional CT scan reconstruction and tailored to minimize toxicity to nearby structures such as normal lung tissue, heart, esophagus, and spinal cord.
Surgery After Induction Treatment
Three to 4 weeks after completion of the chemoradiation therapy, patients were reassessed. Those who did not show evidence of local disease progression and systemic metastasis, and demonstrated mediastinal clearance as verified by surgical lymph node restaging, underwent attempted resection. Mediastinal nodes were reassessed either by thoracoscopy, mediastinoscopy, bronchoscopy, or transesophageal ultrasonography, as appropriate. Reassessment could take place either before a planned definitive procedure or at the same time, in which case the surgeon would await the results of lymph node sampling before thoracotomy. A posterior-lateral operative approach was used in all cases. At operation, a lobectomy or pneumonectomy was performed, if possible. Any areas of direct tumor extension were resected en bloc with the involved lung. All visible and surgically accessible bronchopulmonary, hilar, and mediastinal lymph nodes were resected and submitted along with the primary lung tumor specimen for pathology review. Routine coverage of the bronchial stump with an intercostal or serratus muscle flap was employed. The choice of muscle flap was dependent on the patient's anatomy, reach of the muscle flap, and surgeon preference; however, the bulkier serratus muscle flap was preferred for pneumonectomy operations. A pathologic complete response was demonstrated when the surgical specimen contained no histologic evidence of viable cancer.
Consolidation Chemotherapy
After recovery from successful surgical resection, the patient subsequently received adjuvant chemotherapy as described below. Alternatively, if a patient failed to demonstrate mediastinal lymph node clearance as a result of chemoradiation treatment, if progression of disease occurred, or if the patient was determined to be anatomically unresectable, chemotherapy was administered as soon as possible. Treatment consisted of three cycles of vinorelbine (25 mg/m2 days 1 and 8) and carboplatin (area under the curve = 6 mg/mL x min) every 21 days, followed by three additional cycles of docetaxel, 75 mg/m2, every 21 days. After the completion of chemotherapy, patients with successful surgical resections were offered prophylactic cranial irradiation (3,000 cGy in 15 fractions delivered over 3 weeks).
Patient Follow-Up
Patients were evaluated every 3 months during the first 2 years postoperatively and then every 6 months thereafter by history, physical examination, and chest CT scan. Brain magnetic resonance imaging and CT scan were done annually for the first 2 postoperative years or if symptoms indicated.
Statistical Objectives and Analyses
There were two goals for this trial. First, to determine the tolerability of this approach (phase I portion); and second, the efficacy. The objective of the phase II portion of this study was to determine if the 2-year survival exceeded 60%. Prior studies found a 2-year survival of approximately 40% for a similar group of patients treated with chemoradiotherapy and surgery. By entering a total of 41 patients at the phase II dose level, we would be able to determine if we could obtain a 60% 2-year overall survival with an alpha = 0.10 and beta = 0.10.
To increase the power of the study in terms of the phase II endpoint, all patients enrolled in the trial are considered. Survival was determined utilizing Kaplan-Meier analysis. The 95% confidence intervals are calculated, where appropriate. All patients are considered in the analysis of survival. Survival was calculated from the date of study entry until the date of death or last contact. Only patients who underwent resection are considered in analysis of pathologic response. All data were analyzed using Graph-Pad statistical software (Graph Pad, San Diego, California).
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Results |
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Demographics
Forty-seven patients were enrolled. The study population (Table 2) included 15 men (mean age, 58 years; range, 39 to 73) and 32 women (mean age, 58 years; range, 39 to 78). Primary tumor histology included adenocarcinoma (n = 22), squamous cell carcinoma (n = 6), poorly differentiated carcinoma (n = 17), large cell carcinoma (n = 1), and adenosquamous cell carcinoma (n = 1). Pretreatment TNM staging consists of stage IIIA (n = 33) and stage IIIB (n = 14). Stage IIIA patients consisted of T1N2 (n = 6), T2N2 (n = 17), T3N2 (n = 8), and T3N1 (n = 2). Stage IIIB patients consisted of T1N3 (n = 3), T2N3 (n = 3), T3N3 (n = 2), T4N0 (n = 3), T4N1 (n = 1), and T4N2 (n = 2). Histologic confirmation of nodal status was determined by mediastinoscopy (n = 28), transbronchial needle aspiration (TBNA) (n = 12), video-assisted thoracoscopic surgery (VATS) (n = 2), or biopsy at time of bronchoscopy or initial diagnostic procedure (n = 2). Three patients did not undergo mediastinal assessment owing to either unequivocal T4 status (n = 1) or massively enlarged, positron emission tomography–positive disease (n = 2). The median pretherapy forced expiratory volume of air in one second (FEV1) was 2.11 L (range, 1.00 to 3.57 L).
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Phase II
For purposes of analysis of toxicities and survival, all patients enrolled (including those on the phase I portion at doses other than the final phase II selected dose [n = 6]) are included. All patients registered began chemoradiation, but 19 patients were unable to proceed to surgery for the following reasons: 2 early deaths; 15 patients demonstrated persistent mediastinal disease despite successful completion of induction therapy; 1 patient had brain metastasis during chemoradiation therapy; and 1 patient with a T4 tumor remained obviously inoperable by CT scan despite induction therapy. Hyperfractionated radiotherapy was successfully tolerated in 45 patients, with a mean total radiation dose of 68.7 Gy.
Chemoradiation Toxicity
Chemoradiation was generally well tolerated (Table 3). Forty-five of 47 patients (96%) completed the prescribed course of chemoradiotherapy, and 40 of 47 (85%) were considered for surgical resection. Virtually all patients experienced some degree of esophagitis (grade 1 or 2). There were four episodes of grade 3 esophagitis. Radiation pneumonitis occurred in 3 patients. One patient, who had a history of cardiac disease, died of a myocardial infarction during chemoradiation therapy. Another patient with a history of cardiovascular and cerebrovascular disease died of an apparent cerebrovascular accident. Two patients were deemed unfit for surgery owing to cardiac or pulmonary disease, and 3 patients demonstrated progressive disease after chemoradiotherapy.
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Treatment Response and Survival Analysis
At this time, 16 patients remain alive, all of whom were in the group that underwent surgery. Two patients have metastatic disease and are undergoing chemotherapy. One patient had a scalp metastasis and later an intra-abdominal metastasis. These were resected, and the patient received additional chemotherapy. He remains free of disease on no additional therapy for more than 2 years. One patient was treated with stereotactic radiotherapy for a solitary central nervous system metastasis. She has been free of disease for more than 6 years. Thirty-one patients have died. The stages at presentation for these long-term survivors were T3N1 (1), T1N2 (1), T2N2 (7), T3N2 (4), T1N3 (2), and T4N0 (1). Two patients died during chemoradiotherapy. Four other patients died after completion of therapy without evidence of relapse. The remaining patients died of metastatic disease. There were no local recurrences in resected patients. The 2-year survival (Fig 2) was 64% (95% confidence interval: 49% to 77%), exceeding the hypothesis. Overall median survival time for the entire patient population (n = 47) is 29.6 months, and median event-free survival is 16.9 months. Twenty-eight patients who had negative mediastinal reassessment and underwent resection (including the 2 T3N1 patients) after chemoradiation have a median survival time of 55.8 months.
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Comment |
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In this study, 55% of patients were downstaged as a result of chemoradiation therapy and proceeded to surgery with fairly low morbidity and no mortality. A pathologic complete response rate of 28% in the operative group, with significant complications occurring in only 10 of the 29 surgical patients, is comparable with that of others employing a similar treatment strategy [25]. The most common morbidity was postoperative atrial fibrillation (15% patients), and was without additional sequelae. Second most common was prolonged chest tube airleaks (11% patients), which were not associated with any significant bronchopulmonary fistula but were rather likely from divided interlobar parenchyma within an irradiated field. Adult respiratory distress syndrome occurred in only 1 patient (3.8% incidence), who ultimately required prolonged ventilatory support, tracheostomy, and increased hospital stay. This low level of complications results from a standardized approach to patients after chemoradiotherapy. Intraoperatively, care is taken to avoid overly devascularizing the resulting bronchial stump; and to guard against potential bronchopleural fistula, routine use of a viable muscle flap to cover the bronchial stump is employed [26]. Perioperatively, we minimize all intravenous fluid administration to prevent the development of pulmonary edema.
The role of surgical resection in the management of stage III patients after chemoradiotherapy is the subject of intense debate. Intergroup Trial 0139 failed to demonstrate a survival advantage for resection after chemoradiotherapy [27]. However, there was an improvement in progression-free survival. Early mortality in the surgical arm, almost exclusively due to pneumonectomy, clearly led to the negative results. The 26% mortality rate seen in that trial is likely the result of inexperience in surgery after aggressive chemoradiatiotherapy and is well above that expected from major centers.
Emerging from recent studies of aggressive trimodality treatment of locally advanced NSCLC is the importance of mediastinal clearance. This and several prior studies of multimodality therapy in stage III disease support the approach of limiting definitive surgery to patients who have documented mediastinal sterilization after chemoradiotherapy [12, 28, 29]. This approach limits the risk of major thoracic surgery to patients who are most likely to experience long-term benefit. It is clear, however, that occasional patients may benefit from resection. In SWOG 8805, approximately 10% of patients with persistent mediastinal disease at the time of surgery became longterm survivors [12]. Future studies should address methods of identifying such patients, perhaps through evaluation of biological markers.
Sites of failure were available for 29 patients, with 12 patients failing locally, 12 systemically, and 5 both locally and systemically. Distant brain metastasis represented 50% of all recurrences in this series and affected 11% of all surgical patients. We have previously found a similar distant failure pattern and rate among NSCLC Pancoast tumor patients undergoing trimodality treatment [30]. At present, the role for prophylactic cranial irradiation in improving survival unclear. RTOG 0214, a phase III study comparing prophylactic cranial irradiation versus frequent observation after definitive treatment in stage IIIA and IIIB NSCLC, closed without completing accrual. However, more than 200 patients were enrolled, and the study may provide significant data addressing this question.
The chemotherapy regimen chosen for this trial and the use of consolidation therapy with sequential chemotherapy merit discussion. The goal of this study was to demonstrate the feasibility of using an intensive therapy with the intent of increasing cure rate. At the time of its design, the most promising chemotherapy approaches involved the use of sequential chemotherapy and the use of docetaxel consolidation. Recently, the value of consolidation chemotherapy, particularly with docetaxel, has been questioned. Hanna and colleagues [31] demonstrated that docetaxel consolidation did not improve outcome after definitive chemoradiotherapy utilizing full dose cisplatin/etoposide and concurrent radiotherapy. This approach is different from that of the current study, which utilized radiosensitizing doses of chemotherapy followed by full, systemic doses. To date, there has been no comparison of the strategies of concurrent full-dose chemoradiotherapy versus radiosensitizing chemoradiotherapy followed by consolidation. In addition, a trend toward benefit (p = 0.07) for docetaxel therapy after carboplatin/gemcitabine has been seen in advanced disease [32].
The role of radiotherapy is also controversial. There is conflicting evidence regarding the additional benefit of radiation to induction chemotherapy given the increased toxicity and expense [33–35]. RTOG 0412 was a randomized trial that was initiated in an attempt to definitively address this question. This study randomized patients between induction chemotherapy versus chemoradiotherapy followed by surgical resection. Unfortunately, the study failed to accrue and was closed.
It is difficult to directly compare the results of this study to those of others, given both the phase I portion of the trial and the inclusion of patients with N3 as well as T4 disease. The median survival time of this study is superior to that seen on the Intergroup Trial (29.6 versus 23.6 months), a study that was restricted to N2 patients. However, our patient population was clearly highly selected and treated at a single center with considerable experience in multimodality treatment. The general applicability of this or similar strategies remains to be established. Given the persistence of mediastinal adenopathy and the frequency of both local and systemic failure, the development of new, more effective agents capable of addressing both issues is paramount. We have initiated trials utilizing novel agents in this setting.
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