Cho, B. C. John MD*; Feld, Ron MD†; Leighl, Natasha MD†; Opitz, Isabelle MD‡; Anraku, Masaki MD‡; Tsao, Ming-Sound MD§; Hwang, David M. MD§; Hope, Andrew MD*; de Perrot, Marc MD‡
Industrialized countries are currently at the peak of an epidemic of malignant pleural mesothelioma (MPM).1 The incidence is expected to plateau by 2020 because asbestos has been banned for more than 30 years in most of these countries.2–4 However, the consumption of asbestos continues to increase in many areas of the world where its usage has not been regulated and could lead to a new surge of MPM in the near future.1
The overall prognosis of MPM is grim and treatment outcomes are disappointing. The median survival is 4 to 12 months without treatment and the 2-year overall survival is 0% to 12%.5–7 Various therapeutic approaches, from best supportive care to multimodal therapy, have been studied. The most aggressive therapy includes an extrapleural pneumonectomy (EPP) where the affected lung, pleural lining, diaphragm, pericardium, and areas of suspected involvement such as chest wall and lymph nodes are resected en bloc. The optimal treatment options for patients with resectable MPM remain controversial, but investigators at the most recent meeting from the International Mesothelioma Interest Group agreed that complete macroscopic surgical resection plays a vital role in the multimodality therapy of MPM, as is the case for other solid malignancies.8–10
In our experience, neoadjuvant chemotherapy followed by EPP and adjuvant hemithoracic intensity-modulated radiation therapy (IMRT) achieved a cumulative 3-year survival of 53% with a median survival of 59 months in patients with ypN0 disease who completed all three modalities.11 We and others observed that hemithoracic radiation was particularly successful to achieve local control after EPP.12–14 Unfortunately, the success of hemithoracic radiation is limited by distant failures, the most common sites being the abdominal peritoneal cavity and contralateral lung.11,13
A possible mechanism for this pattern of distant failure is inadvertent tumor spillage at time of EPP. If true, this suggests a possible theoretical advantage with neoadjuvant treatment designed to control the proliferative ability of clonogens spilt intraoperatively by means of tumoricidal and/or tumorostatic effects to prevent distant seeding. We, therefore, developed a new protocol with a short accelerated course of high-dose hypofractionated hemithoracic radiation followed by EPP in the hopes to improve radiation delivery and survival. We report the results of a seamless phase I/II study testing the safety and feasibility of Surgery for Mesothelioma After Radiation Therapy (SMART).
We conducted a two-step combined phase I/II prospective single cohort clinical feasibility study on surgically resectable MPM (Fig. 1). Eligible patients were at least 18 years of age, Eastern Cooperative Oncology Group performance status of 0 to 2, with good pulmonary function tests (defined as forced expiratory volume in 1 second >40% predicted or diffusing capacity of the lungs for carbon monoxide >45% predicted), a new histological diagnosis of MPM previously untreated, clinical stage T1-3N0M0, suitable for combined modality therapy, and able to give informed consent. Clinical stage was determined by computed tomography (CT) scan of the chest and abdomen, positron emission tomography (PET)-CT scan, and brain magnetic resonance imaging or CT. Preoperative nodal sampling with endobronchial ultrasound (EBUS) or mediastinoscopy was not routinely performed. The protocol was approved by our institutional review board. Written informed consent was obtained from each patient.
The clinical target volume is defined as the ipsilateral hemithorax, from the thoracic inlet down to the diaphragmatic insertion, including biopsy and drainage tract sites. The gross tumor volume is defined as any tumor seen on imaging (such as CT and PET). The dose prescription to the clinical target volume is 25 Gy in five daily fractions during approximately 1 week with a concomitant boost of 5 Gy to the gross tumor volume and tract sites. Typically, a multibeam IMRT technique is used. The complete details of IMRT will be published separately.
All patients underwent EPP within 1 week of completing the neoadjuvant IMRT. Surgery was completed according to a standard technique as previously described.11,15 EPP specimens were reviewed and reported by at least one subspecialty thoracic pathologist (M-ST or DMH). Histological diagnosis and staging were on the basis of the World Health Organization classification system and tumor, node, metastasis (TNM) staging system.16,17 Cases demonstrating mediastinal lymph node involvement (i.e., ypN2) were offered adjuvant chemotherapy, usually cisplatin and an antifolate, either raltitrexed or pemetrexed (as per the discretion of the medical oncologists), within 24 weeks after EPP.
After completing therapy, patients were followed every 4 weeks until 3 months; every 6 weeks until 6 months; every 2 months until 12 months; every 3 months until 2 years; and then every 6 months for 5 years. At each follow-up, a complete history, physical examination, and Eastern Cooperative Oncology Group performance status were recorded in addition to morbidity and mortality status. Routine tests included complete blood count, liver profile, creatinine, and chest radiograph. CT scan of the thorax and abdomen were done at 3, 6, 12, 18, and 24 months and then yearly afterward. Additional tests were done at the discretion of the oncologist. Recurrences were diagnosed clinically, usually by serial imaging and proven pathologically when feasible.
The study aim is to evaluate the feasibility of SMART. The primary end point is that the proportion of patients treated with grade 5 (G5) treatment–related mortality should not exceed 8%. The secondary aims are (1) to evaluate acute and late morbidity related to treatment; (2) to evaluate local recurrence, distant recurrence, disease-free survival, and overall survival rates; and (3) to identify factors and parameters associated with increased risk of treatment morbidity. Treatment-related toxicity was defined by the CTCAE v3.18
The initial pilot phase I study had a planned accrual of 12 patients. The risk of perioperative surgical mortality and morbidity (defined by 30-day or in-hospital grade 3–5 complications according to CTCAE v3) associated with EPP was anticipated to be 8% and 35%, respectively, on the basis of our previous experience.19 We assumed Bayesian posterior probability stopping rules with a sample size of 12, a priori probability of 0.08 for mortality (G5), and 0.35 for serious morbidity (G3+) with a confidence level of 0.95 that the (study) posterior probability was worse than the a priori probability.
On-going marginal posterior probability analysis with these assumptions gave the following stopping boundaries: if there were ≤1 treatment-related deaths (or ≤3 serious morbidity) in the first quartet of patients, then accrue second quartet; if there were ≤2 treatment-related deaths (or ≤5 serious morbidity) in total after the second quartet, then accrue third quartet (total of 12 patients). If there were ≤3 treatment-related deaths (or ≤7 serious morbidity) in the first 12 patients, we expanded to a phase 2 study and accrued an additional 13 patients (total of 25 patients) using the same protocol.
The analysis of the feasibility study was primarily descriptive. The proportion of patients treated without a major protocol violation as well as acute and long-term morbidity and mortality was collected. The cumulative rate of local and distant tumor recurrence was determined using the Kaplan–Meier method. The identification of factors associated with increased risk of treatment morbidity was determined by using the Student’s t test for continuous variables and either χ2 test or Fisher’s exact test for categorical variables. Variables tested were age, sex, side of tumor, histology, and stage of disease. Survival curves were compared using the log-rank test. Threshold for statistical significance was 0.05.
The accrual goal of 25 patients was completed between November 2008 and October 2012. Patient information is presented in Table 1. A total of 138 patients were seen during the same time frame and 82% were not eligible for the study because of advanced disease (n = 70), presence of comorbidities (n = 28), or patients’ refusal (n = 15). All 25 patients completed their intended IMRT and EPP. IMRT was well tolerated with no grade 3 to 5 toxicities (G3+). The most common grade 1 and 2 symptoms related to the IMRT were fatigue, nausea, and esophagitis. EPP was performed 6 ± 2 days after completion of IMRT. All but one patient had resection of the diaphragm and pericardium along with the parietal pleura and lung. In two patients, a chest wall resection of three ribs was required to achieve complete macroscopic resection.
Thirteen patients (52%) developed G3+ surgical complications (Table 2). The main G3+ complication was atrial fibrillation, occurring in five patients. No patients died within 30 days of surgery or during the postoperative hospital stay. One patient (4%) died from treatment-related complication (empyema) during follow-up at 88 days. Despite the preoperative radiation, no patient developed bronchopleural fistula immediately after surgery or during follow-up. The median length of stay after EPP was 12 days (range, 5–51 days). Age was the only factor potentially associated with increased risk of G3+ complications (66 ± 7 versus 60 ± 8 years in patients without G3+ complications; p = 0.06).
All but one patient were stage III (n = 11) or IV (n = 13) on final pathologic findings. One patient with biphasic histologic subtype had stage IB disease. Five of 13 patients (38%) with ypN2 disease underwent three to six cycles (median, 4 cycles) of adjuvant chemotherapy.
After a median follow-up of 23 months (range, 6–51 months), the cumulative overall survival reached 58% at 3 years (Fig. 2) The 3-year survival was significantly better for epithelial compared with biphasic histologic subtypes (Fig. 3). At 3 years, the cumulative survival reached 84% and disease-free survival 65% in patients with epithelial histologic subtype (Fig. 4). All patients with epithelial, ypT3 or ypT4, N2-negative disease were alive at last follow-up and only one (ypT4N0) developed recurrence.
Overall, 11 patients developed recurrence (7 biphasic and 4 epithelial subtypes). Recurrences were in the ipsilateral chest only (n = 2, 18%), ipsilateral chest and distant sites (n = 3, 27%), and distant sites only (n = 6, 55%). Distant sites of recurrences were located in the retro-peritoneal lymph nodes (n = 3), peritoneal cavity (n = 3), liver (n = 1), contralateral lung parenchyma (n = 4), and contralateral pleura (n = 1).
This study demonstrates for the first time that EPP after a short accelerated course of high-dose hemithoracic radiation is feasible. The radiation was extremely well tolerated with no grade 3+ toxicity and all patients proceeded to EPP within the predefined time frame with no perioperative mortality. Grade 3+ toxicity developed in 13 patients (52%) after surgery and included predominantly atrial fibrillation. We observed remarkably good outcomes in patients with epithelial histologic subtypes with a 3-year survival of 84% after a median follow-up of 23 months. At the last follow-up, only one of nine patients with epithelial N2-negative disease had developed recurrence despite the fact that all tumors were pathologic staged ypT3 and ypT4. Although longer follow-up and larger number of patients are required to make definitive conclusions on the long-term impact of this treatment protocol, these initial results are extremely encouraging for patients with epithelial MPM.
Nonepithelial histology was the most significant negative prognostic factors, confirming the findings of others.20,21 In this trial, most patients with biphasic tumor recurred within 18 months, suggesting that nonepithelial histology are likely not as radio-sensitive as epithelial subtypes to high-dose hypofractionated radiation. Hence, patients with biphasic disease should potentially be treated with a different approach than accelerated high-dose hemithoracic radiation and EPP.
Although the presence and the number and distribution of nodes are important predictors for survival, we elected not to perform systematic mediastinoscopy and/or EBUS in this initial phase I/II study.22 Mediastinoscopy and EBUS have a poor negative predictive value to rule out N2 disease and we thus decided not to exclude patients with potentially low-bulk N2 disease from this protocol as long as the CT and PET scan were negative for N2 disease.12,23 Furthermore, the impact of neoadjuvant IMRT on low-burden N2 disease was unknown and important to assess.
Despite the large number of right-sided EPP, which has been reported to be a risk factor for perioperative mortality,19,24 we observed only one treatment-related death after discharge from hospital in a patient with biphasic left-sided disease in this series of patients. Overall, our morbidity rate was similar to other surgical series with a 52% rate of grade 3 or 4 complications.24–26 Noteworthy, three patients developed venous thromboembolic event after discharged from hospital, and our protocol was therefore modified during the study to maintain patients on venous thromboembolic prophylaxis after discharged from hospital for at least a month.
The SMART protocol has several advantages related to the accelerated course of treatment. However, all patients must proceed to EPP after IMRT to avoid potential radiation-induced pulmonary toxicity. The protocol therefore requires a high degree of coordination and cooperation between radiation oncology and thoracic surgery. This may hamper its implementation in centers where multidisciplinary interest is lacking.
The therapeutic indication for SMART differs from standard induction protocols of radiation and chemoradiation because the short time course of radiation does not allow meaningful cytoreductive down staging. SMART aims to induce a tumorostatic and tumoricidal effect to prevent or delay the successful implantation of clonogens to distant sites at time of EPP and thereafter. In addition, increasing evidence suggest that the mechanisms of action of high-dose hypofractionated radiation differ from standard radiation in that the response is partly because of a specific activation of the immune system against the tumor rather than only a direct cytotoxic effect from the ionizing radiation.27,28 Hence, our protocol of high-dose radiation and surgery could provide a net benefit on the immune system by activating the immune system against the tumor and then removing the immunosuppressive environment generated by the tumor. The impact on the immune system of high-dose hypofractionated radiation therapy will potentially open the door for new combination therapies in the near future between immunotherapy and radiation to optimize their synergism on the immune system.28,29 This combined strategy will potentially be particularly valuable for patients with MPM.
Our study has several limitations related to the fact that this is a nonrandomized, single cohort phase I/II study. Hence, patient selection is a potential confounding factor. We note, however, that 18% of our patients were included into this trial during the 4-year period, which is similar to previously reported surgical series where typically 17% to 19% of patients screened in clinic are eligible for EPP.8,20 In addition, only one of 25 patients was found to have stage IB on final pathologic findings, suggesting that our population of patients had relatively advanced disease.
Normally, we would proceed to a phase 3 randomized trial but, as the Mesothelioma and Radical Surgery (MARS) trial showed, mounting such a study will likely be challenging and perhaps impossible.8 Most patients are reluctant to be randomized in a study with widely disparate treatment options. Although equipoise among the clinicians exist, patients often have strong treatment biases and may refuse randomization out right. MPM are rare tumors and these cases are technically challenging with a steep learning curve. Such cases are usually best handled by a dedicated radiation oncologist and thoracic surgeon to maintain volume of practice and retain technical expertise.
In conclusion, for the first time we have demonstrated that SMART is feasible in resectable MPM patients. Although larger number of patients and longer follow-up are required, this innovative protocol may potentially improve survival in selected epithelial MPM patients.
The authors thank Lea Dungao and Pat Merante for their assistance. This work has been supported by the Princess Margaret Hospital Foundation Mesothelioma Research Fund.
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Mesothelioma; Neoadjuvant therapy; Hemithoracic radiotherapy; High-dose radiation; Accelerated radiation; Extrapleural pneumonectomy; Multimodality therapy
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