Superior sulcus tumors represent a unique subset of nonsmall cell lung malignancies that have been described as early as 1838.1 Over the past several decades, the treatment of superior sulcus tumors has evolved to become multimodal. In a highly cited trial by the Southwest Oncology Group (SWOG), patients with T3-T4N0-N1 superior sulcus tumors were treated with preoperative cisplatin and etoposide and concurrent radiation to 45 grays (Gy), followed by thoracotomy for disease that was stable or responsive to this treatment. Five-year survival rates were promising at 44% for the entire group and >50% for cases in which a complete response was achieved.2, 3 As a result, many have advocated preoperative chemoradiation, even for resectable superior sulcus tumors. However, no studies have established that preoperative chemotherapy, with or without radiation treatment, is superior to surgical resection followed by postoperative treatment in cases that are resectable at diagnosis.
In this context, we initiated a prospective phase 2 study of patients with resectable superior sulcus tumors treated with surgical resection followed by adjuvant chemoradiation. Radiation was delivered in twice-daily fractions to minimize long-term toxicity, which is particularly important as these tumors are often close to the brachial plexus, and to minimize tumor-cell repair and repopulation between fractions.4 We report here the long-term results of this study, focusing on survival outcomes, failure patterns, and treatment complications, with the goal of establishing if this treatment approach is safe and effective for this relatively rare but aggressive disease.
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- MATERIALS AND METHODS
- FUNDING SOURCES
- CONFLICT OF INTEREST DISCLOSURES
The current standard treatment for locally advanced nonsmall cell lung cancer is multimodal and includes surgery (for those who are eligible), chemotherapy, and radiation treatment. Although these modalities are the same as those used for superior sulcus tumors, the general approach to this subgroup of lung tumors has differed from that of primary lung malignancies at other sites, largely because superior sulcus tumors often present with intractable pain or neurologic symptoms resulting from involvement of adjacent nerves or bony structures. Local progression of disease in superior sulcus tumors can also lead to invasion of the spinal canal with subsequent spinal cord compression. As a result, immediate local therapy is often indicated.
Previous retrospective reports of surgical resection as definitive local therapy for superior sulcus tumors demonstrated low rates of gross total resection, high rates of locoregional relapse, and low rates of survival. Rusch et al, reporting on 225 patients who underwent thoracotomy as definitive treatment for T3 or T4 superior sulcus tumors from 1974 to 1998 at Memorial Sloan-Kettering Cancer Center, found that gross total resection could be achieved in 50% to 60% of patients with T3 tumors and 40% of patients with T4 tumors, with an operative mortality rate of 0%. Five-year OS rates ranged from 46% for patients with stage IIB tumors to 0% to 13% for patients with stage IIIA or IIIB tumors.5
As a result of findings such as these, the Southwest Oncology Group began a prospective trial in 1995 examining the role of preoperative chemoradiation (cisplatin and etoposide with 45 Gy radiation) followed by surgical resection for patients with T3-T4N0-N1 superior sulcus tumors. Patients who responded or showed stable disease after this induction therapy were offered definitive surgical resection. With this approach, 83 (75%) of 111 patients completed the entire treatment regimen; R0 was possible for 75 patients (90%) and gross total resection (R0 or R1) in 76 patients (92%). Or, put another way, 68% of initially enrolled patients were able to undergo gross total resection.2 In the most recent update of this trial, the 5-year survival rate was 44% for all patients; 17 patients (15%) experienced local relapse, 19 (17%) experienced brain-only relapse, and 19 (17%) experienced relapse in other distant sites.3 A similar trial conducted by the Japan Clinical Oncology Group (JCOG 9806) involved a regimen of 2 cycles of chemotherapy (mitomycin, vindesine, and cisplatin) with concurrent radiation (45 Gy in 25 fractions delivered in a split-course fashion) followed by surgical resection. In that trial, 75% of patients completed the regimen, and the 5-year DFS and OS rates were 45% and 56%, respectively.6 As a result of these trials, preoperative concurrent chemoradiation followed by surgery (with or without adjuvant chemotherapy) is the treatment currently recommended by the National Comprehensive Cancer Network for patients with marginally resectable or resectable N0 or N1 superior sulcus tumors.7
The approach in the present prospective study was different in that patients received surgical resection first, followed by concurrent chemoradiation (up to 64.8 Gy, given twice daily, with cisplatin and etoposide). If this approach can produce high rates of R0/R1 resections with acceptable morbidity, it has theoretical benefits over induction chemoradiation. First, surgical resection may provide more effective palliation of symptoms as well as spinal decompression in cases involving neurologic compromise. Although we did not measure the efficacy of palliation as an endpoint in the current study, prior studies have demonstrated that, particularly in cases of spinal canal compromise, surgical decompression causes more immediate relief of symptoms. For example, in a randomized trial by Patchell et al comparing decompressive surgical treatment followed by radiation therapy in the setting of metastatic disease, the trial was stopped early because an interim analysis demonstrated that patients who received upfront surgery retained the ability to walk significantly longer than those patients receiving radiation initially.8 Second, the preoperative chemoradiation dose in the SWOG 9416 and JCOG 9806 regimens was relatively low, and thus an R1 or R2 resection may need to be followed by further radiation—which would then be delivered in a split-course fashion, a schedule that is suboptimal in terms of maximizing the probability of local control. This latter concern has been addressed in more recent reports of a more intensive preoperative regimen, with preoperative radiation doses approaching 60 Gy with acceptable toxicity.9, 10
We have previously demonstrated retrospectively that long-term survival can be achieved with superior sulcus tumors using a variety of approaches. The most common approach for resectable tumors was that of surgery followed by radiation, with or without chemotherapy. The 5-year survival rate of patients who underwent a gross total resection in this study and received postoperative radiation was 82%.11 Accordingly, we have now reported the current prospective study and found that proceeding from immediate surgical resection to postoperative chemoradiation produced rates of adherence to treatment, operative mortality, R0 resections, LRC, and OS that were analogous to those found after induction chemoradiation (Table 3). In addition to these similarities, the nature of the operative complications was similar in the 2 approaches, with several complications being common to all studies: postoperative pneumonia, arrhythmias, empyemas, and wound infections. The findings on operative morbidity and mortality are particularly significant because in the current study, patients would be expected to undergo more extensive surgery to treat disease that had not been downsized by chemoradiation. Furthermore, we did not observe any brachial plexopathy after radiation therapy despite >60 Gy being delivered to this region, which we conclude can be attributed at least in part to our use of a hyperfractionated regimen to minimize late radiation effects.
Table 3. Outcome Variables After Preoperative Versus Postoperative Concurrent Chemoradiation for Superior Sulcus Tumors
|Outcome Variables||Preoperative Concurrent Chemoradiation||Postoperative Concurrent Chemoradiation, Current Study|
|SWOG 94-16||JCOG 9806|
|Adherence to treatment regimen||75%a||76%||78%|
|Operative mortality rates||2.4%||3.5%||0%|
|R0/R1 resection rates||92%b||95%||100%|
|Locoregional control rates||85%c||87%d||76%|
|5-year overall survival rates||44%||56%||50%|
Other notable findings were that the rate of brain metastases in our study (15%) was low compared with that of prior reports and that none of the patients who received PCI experienced treatment failure in the brain. PCI has been assessed in several randomized studies, including 3 studies conducted in the 1980s and 1990s demonstrating that PCI could delay and even prevent the development of brain metastases from nonsmall cell lung cancer but did not significantly affect OS.12-14 Preliminary results from a more recent study by the Radiation Therapy Oncology Group assessing the benefit of PCI for 356 patients with stage IIIA or IIIB disease randomized to PCI versus observation indicated that although PCI did not affect the 1-year DFS or OS rates, the relapse rate in the central nervous system was reduced from 18% to 7.7%.15 Thus, based on the lack of a clear survival benefit, PCI is not recommended routinely for patients with locally advanced nonsmall cell lung cancer. However, it has been well established that adenocarcinomas have a higher propensity to metastasize to the brain than do squamous cell carcinomas and that superior sulcus tumors are particularly likely to produce intracranial metastases.16, 17 The results of the current study suggest that an individualized treatment approach to PCI should be used, with highly selective criteria based on the location and histology of the tumor, patient age, and baseline neurocognitive deficits.18
The current study had several limitations. First, the number of patients was smaller than that of previous reports, precluding statistical analyses of predictive factors such as extent of resection and TNM classification. Second, the potential advantages of postoperative chemoradiation for superior sulcus tumors are accompanied by some disadvantages, including the possibility of needing a larger radiation field to cover the entire tumor bed rather than a field limited solely by the initial extent of disease. A second potential disadvantage is an increase in operative complications because of the lack of tumor downsizing away from critical structures; however, no such increase in operative morbidity was found in the current study, and no mortalities were attributed to treatment. Third, this study took place over a protracted period of time, from 1994 to 2007. We acknowledge that during this time period, inherent changes in technique and expertise can occur that can affect tumor control. However, in our study, we found that the locoregional recurrence rate was relatively constant over the duration of enrollment, indicating that the treatment year did not influence local recurrence rates.
Finally, it is important to emphasize that the results of this study, although promising, were undoubtedly dependent on patient selection. Indeed, previous retrospective studies demonstrating low rates of LRC with upfront surgery often included substantial percentages of patients for whom gross total resection could not be achieved. In the current study, all of the patients initially deemed to have resectable disease ultimately underwent R0 or R1 resections, highlighting the importance of surgical experience and a referral to a tertiary medical center when possible. Furthermore, we acknowledge that prior studies, and particularly the SWOG study cited above, demonstrated that the long-term survivors were those patients who had R0 resections, which were not achieved in 22% of the patients in our study. However, the difference in the approaches is that, whereas in the SWOG study the goal was to increase resectability rates and thereby reduce the risk of residual disease postoperatively, in the approach from our institution, microscopic disease is further addressed by adjuvant chemoradiation. We do not present these results as superior to those previously published in prospective trials, but rather present upfront surgery as a viable method to achieve similar rates of local control and OS for this disease. Regardless of the timing of surgery, we advocate that this extensive oncologic resection should be performed by an experienced surgeon with this technique, if necessary at a tertiary academic center.
In summary, we demonstrated that surgical resection followed by adjuvant chemoradiation therapy for superior sulcus tumors is a reasonable alternative to preoperative chemoradiation, with similar survival outcomes and treatment toxicity. We further showed that, with appropriate patient selection and an aggressive chemoradiation regimen, including a radiation fractionation scheme that minimizes late toxicity, 10-year LRC and OS rates were approximately 75% and 50%, respectively, with no treatment-related mortality. Finally, our findings suggest that PCI could be considered for patients with this subset of nonsmall cell lung cancer, as the rate of intracranial failure for all patients (15%) was substantially lower than that of previous reports and was 0% among patients who received PCI. We recognize, however, that the small number of patients limits the strength of this conclusion.