Accepted Manuscript Title: WHEN IS SURGERY INDICATED FOR SMALL-CELL LUNG CANCER? Author: Giulia Veronesi Edoardo Bottoni Giovanna Finocchiaro Marco Alloisio PII: DOI: Reference:
S0169-5002(15)30086-6 http://dx.doi.org/doi:10.1016/j.lungcan.2015.10.019 LUNG 4971
To appear in:
Lung Cancer
Received date: Revised date: Accepted date:
6-8-2015 8-10-2015 12-10-2015
Please cite this article as: Veronesi Giulia, Bottoni Edoardo, Finocchiaro Giovanna, Alloisio Marco.WHEN IS SURGERY INDICATED FOR SMALL-CELL LUNG CANCER?.Lung Cancer http://dx.doi.org/10.1016/j.lungcan.2015.10.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
WHEN IS SURGERY INDICATED FOR SMALL-CELL LUNG CANCER?
Giulia Veronesi 1, Edoardo Bottoni 1, Giovanna Finocchiaro 2 and Marco Alloisio1
1
Division of thoracic and general surgery, Istituto Clinico Humanitas IRCCS, Rozzano, Italy
2
Department of Medical Oncology, Istituto Clinico Humanitas IRCCS, Rozzano, Italy
Corresponding author: Dr. Giulia Veronesi Division of Thoracic Surgery, Humanitas Research Hospital Via Manzoni 56, Rozzano, Italy [email protected] Tel: +39 02 82241
1
Highlights
SCLC prognosis is poor and has hardly changed over the last 30 years
Recent studies indicate that surgery has a role in early SCLC
Lobectomy + nodal dissection is OK for SCLC/mixed histology found intraoperatively
Postoperative chemotherapy is indicated after surgical removal of early SCLC
Surgery may improve local control/survival after chemotherapy in stage I/II SCLC
CT screening identifies SCLC at an earlier stage promising to increase survival
2
Abstract Small-cell lung cancer (SCLC) comprises 13-20% of all lung cancers but is the fifth leading cause of cancer death worldwide. SCLC prognosis remains poor despite improvements in diagnosis and therapy over the last 30 years. Current treatment is systemic chemotherapy, flanked by thoracic irradiation for limited stage disease; however about two-thirds of patients are diagnosed with extensive stage disease when thoracic irradiation is not worthwhile. Randomized trials on surgical resection in patients with limited stage disease conducted in the pre-PET era, when both staging and treatment were inadequate, did not support a role for surgery in disease management. However recent retrospective and population-based studies indicate that outcomes after surgery in patients with very early SCLC are comparable to those in patients with nonSCLC, and that survival is better than in SCLC patients not given surgery. CT screening identifies SCLC at an earlier stage – with better survival – than usual care, and offers the hope that more SCLC patients may become long-term survivors. However cases must be exhaustively staged to identify those likely to benefit from surgery. Finding a specific SCLC marker to facilitate early diagnosis remains a priority.
Keywords: Small cell lung cancer; limited disease; TNM; surgery; radiotherapy; early detection
3
Introduction Lung cancer is the leading cause of cancer-related death in the world, accounting for more deaths than breast, prostate, pancreatic, and colon cancer combined. [1] Over 1.6 million cases of lung cancer were diagnosed worldwide in 2008 [2]. Small-cell lung cancer (SCLC) accounts for 13 to 20% of all lung cancers, and is the fifth leading cause of cancer death when considered independently of non-small-cell lung cancer (NSCLC). [3, 4] SCLC is a malignant epithelial neoplasm usually consisting of small cells with scant cytoplasm, ill-defined cell borders, granular nuclear chromatin, and absent or inconspicuous nucleoli. The cells can be round, oval, or spindle-shaped. Nevertheless it can be difficult to distinguish SCLC from other lung malignancies and, in addition to morphology, immunohistochemistry to detect cytokeratins (epithelial marker) and neuroendocrine markers is often useful to distinguish SCLC from other lung cancers. Notwithstanding improvements in treatment and earlier diagnosis, leading to small survival improvements [5], five-year relative survival for SCLC was only 5-7% in the last decade of the last century (latest available data) [5], making it the most aggressive lung cancer subtype. The aggressive, rapidly fatal natural history of SCLC may be due to the large number of mutations present, usually including TP53 mutations [6, 7] in turn probably related to the fact that around 98% of SCLC patients have a history of heavy smoking. [3] Both smoking intensity (cigarettes/day) and number of years of smoking increase the risk of developing SCLC. [4] Approximately two-thirds of SCLC patients have clinical evidence of metastasis at diagnosis; most of the remaining third have clinical evidence of extensive involvement of hilar, mediastinal, and sometimes supraclavicular lymph nodes. Typical local symptoms are cough, shortness of breath, and chest pain. Weight loss and weakness suggest metastatic disease. About 80% of patients die within 1-2 years of diagnosis. [5] Without treatment, patients with 4
limited disease typically die within 3-6 months and those with extensive disease die within 1-2 months. [5]. As yet no specific molecular markers to facilitate early diagnosis of SCLC have been identified. [8] However evidence suggests that CT can identify SCLC at an earlier stage than usual with favorable impact on survival. [9]
Staging The first SCLC staging system was introduced by the Veterans Administration Lung Cancer Study Group (VALSG) in 1973 for use in clinical trials [10]. It divided patients into those with ‘limited stage’ (LS) disease, confined to the hemithorax, and those with ‘extensive stage’ disease (ES) at sites beyond those included in LS. In 1989 [11] the International Association for the Study of Lung Cancer (IASLC) recommended that the VALSG staging system be modified to include all non-metastatic patients in the LS group. This meant in practice that cases with involvement of controlateral mediastinic and supraclavicular lymph nodes were to be considered LS, provided these nodes could be included in a single irradiation field. The VALSG system was developed at a time when the utility of surgery was being questioned, and it is likely that the absence (or non use) of a more detailed staging system made it very difficult to select patients who might benefit from surgery. On the other hand so few SCLC patients were eligible for surgery that more precise staging was not considered necessary. Patients with LS were usually given chemotherapy and thoracic radiation, whereas those with ES only received chemotherapy. More recent TNM staging systems [12, 13] were not considered applicable to SCLC, since surgical confirmation was seldom available. However, Karrier et al. in 1989 [14] and Shepherd et al. [15] in 1991 showed that the TNM system was useful for predicting SCLC outcomes. In their analyses, survival for operable stage I disease ranged from 51% to 59%, while the timing of surgery (before or after chemotherapy) 5
made little difference. Stage II and III patients had survival comparable to that of stage III NSCLC, with surgery recommended only to responders. Pathologic TNM stage predicted survival, while clinical stage did not. For stage I operable patients, those with clinical T1 had significantly better survival than those with clinical T2, and all other T categories. Furthermore patients with clinical N0 or N1 disease had significantly better survival than those with N2 or N3 tumors. [16] Another problem with the simple LS categorization is that it does not indicate whether or not lymph nodes are involved, or whether or not there is controlateral nodal involvement; it is therefore useless for planning radiotherapy even in non-surgical cases. [17] The IASLC analyzed 12,620 SCLC cases when revising TNM staging system [16]. Only 349 (2.8%) patients underwent surgery, with five-year survival of 56% for stage I, 38-40% for stage II, and 0-12% for stage III. It was concluded that the TNM staging should be applied to SCLC, and was particularly useful for resectable SCLC. [16]
Chemoradiotherapy for limited SCLC SCLC was found highly sensitive to various chemotherapeutic agents in the 1960s. The cyclophosphamide, doxorubicin, vincristine combination (CAV) came to be widely used in the 1970s as it was effective and had good tolerability. [18] However the benefit to patients was short-lived, and more effective treatments were required. Chemotherapy was soon combined with thoracic radiotherapy. A 1984 study [19] reported on CAV in combination with thoracic radiotherapy and prophylactic cranial irradiation in 153 LS and 167 ES cases. In the LS group, 52% had complete response and median survival was 49 weeks. Later, cisplatin plus etoposide was compared with cyclophosphamide, epirubicin and vincristine (CEV) in a phase III trial [20] on 436 LS and ES patients. Cisplatin and etoposide proved 6
superior to CEV in terms of survival (14.5 vs. 9.7 months, p=0.001) and toxicity profile, and subsequently became the most frequently used chemotherapy regimen for SCLC. That radiotherapy is superior to surgery in LS SCLC was first shown in the 1970s. For example, in the British Medical Research Council (MRC) study on 144 patients randomized to surgery vs. radical radiotherapy, median overall survival was longer in the radiotherapy group (9.9 months vs. 6.5 months, p=0.04). [21] However the early trials were carried out using staging procedures now known to be inadequate, while the chemotherapy and radiotherapy regimens available today may be more effective than those available in the 1970s and 1980s. Two meta-analyses published in 1992 [22, 23] consolidated radiotherapy in combination with chemotherapy as the cornerstone of treatment for SCLC patients with LS. The Pignon et al. study [22] reviewed data on 2140 patients from 13 randomized trials, excluding those with ES. They found that addition of radiotherapy resulted in a 14% reduction in mortality and better overall survival at three years (5.4%) compared to chemotherapy alone. The meta-analysis of Warde et al. [23] assessed individual patient data from 11 randomized trials and found that addition of radiation to chemotherapy improved two-year survival by 5.4%. The timing of thoracic irradiation in relation to chemotherapy was controversial for some time. Trials and systematic reviews addressed the issue [24-28] and it became evident in the mid 2000s that radiotherapy was best administered during first or second cycle of platinum-based chemotherapy. The 2007 systematic review of Pijls-Johannesma et al. [29] assessed seven randomized trials and found significantly better two- and five-year survival when radiotherapy was started within 30 days of the start of chemotherapy. It has been suggested that cancer cell repopulation is induced by chemotherapy resulting in resistance to subsequent irradiation; this is avoided if irradiation is concurrent. [30] Radiation dose and fractionation have been investigated by several studies. [31-35] A recent 7
meta-analysis of NSCLC and SCLC trials [34] indicated that accelerated or hyperfractionated radiotherapy is associated with better overall survival at a cost of greater esophageal toxicity. However for SCLC patients, the advantage was not significant (hazard ratio, HR, for death compared to conventional schedule 0.87; 95% CI, 0.74-1.02; P = 0.08) and absolute survival benefits were 1.7% at three years and 5.1% at five years. Two large ongoing randomized phase III trials [36, 37] are investigating dose fractionation. One [36] is comparing three thoracic radiotherapy regimens in LS-SCLC patients receiving standard chemotherapy. The other, the CONVERT trial [37], is comparing once-daily with twice-daily radiotherapy in good performance status LS patients. Over 50% of SCLC patients develop brain metastases. Since chemotherapy agents do not pass the blood-brain barrier they unable to prevent or treat brain metastases and prophylactic cranial irradiation (PCI) was proposed as a means of reducing the incidence of brain metastasis and improving overall survival in LS patients who achieve complete response after induction chemoradiotherapy. PCI became standard from 1999 when Auperin et al. [38] published a metaanalysis of data from seven prospective trials on individual LS patients who achieved complete remission after chemoradiation. Patients were randomized to PCI or follow-up; those who received PCI had a significant reduction in risk of death (RR 0.84, 95%CI 0.73-0.97, p=0.01) compared to controls, which translated into 5.4% more survival at three years, and a significant reduction in incidence of brain metastasis. A 2001 meta-analysis [39] of data from 1547 patients enrolled in 12 trials, found concordant results among all trials. For the five trials that enrolled patients with complete response to chemotherapy, overall mortality was significantly reduced (HR: 0.82; 95 % CI 0.71-0.96) in the PCI compared to no PCI arm. For all studies, the incidence of brain metastasis was lower in the PCI arm (HR 0.48, CI 0.39-0.60). A phase III randomized trial published in 2009 [39] investigated whether PCI dose escalation (36 8
Gy in 10 daily 2 Gy fractions, or 36 Gy in 16 twice-daily 1.5 Gy fractions) reduced the risk of brain metastasis compared to 25 Gy in 10 daily fractions. The study found no significant differences in incidence of brain metastasis, but higher rates of cancer-related death in the experimental arms. Based on these data, 25 Gy at 2.5 Gy once a day is considered the standard dose for PCI in LS patients who achieve complete remission. As regards long-term cognitive impairment after PCI, data are discordant. [40, 41]
Newer chemotherapeutic agents While for NSCLC there have been significant improvements in diagnosis, treatment and survival in recent years [42], little has changed in the management of SCLC since the platinum-etoposide doublet was introduced nearly forty years ago. In fact, although numerous new cytotoxic agents and combinations have been investigated, especially in ES SCLC, most have not proven effective [43]. It is also the case that disease biomarkers and molecular subtypes (that can be targeted by specific agents) have not yet been identified, mainly because insufficient quantities of tumor tissue for molecular research have been collected: most SCLCs are diagnosed by small biopsy. Nevertheless, there have been some recent advances. Comprehensive genome analyses [44, 6, 7] of SCLC specimens and cell lines confirm that SCLCs have high mutation rates, and that mutations due to mechanisms induced by tobacco smoke carcinogens predominate; several common genomic alterations have been identified, with potential for targeting by new therapeutic targets. [45, 6, 7] Recent data also suggest that immunotherapies may be promising. Thus, MK-3475 (pembrolizumab), an antibody that targets the programmed death-1 (PD1) protein to unblock apoptosis and is being used to treat of melanoma, is also to be tested in a phase I study 9
(NCT02402920) on LS SCLC patients. Ipilimumab – another monoclonal antibody successfully used to treat melanoma and which blocks a receptor that downregulates the immune system, has shown promise as a first-line treatment in combination with chemotherapy in ES SCLC patients. [45, 46] Ongoing early phase studies are also evaluating nivolumab (anti-PD-1) with or without ipilimumab. [47]
Role of surgery Up to the early 1970s, surgery was standard treatment for operable SCLC. [48, 49] After 1973 the standard of care gradually switched to thoracic radiotherapy as local treatment, with chemotherapy as systemic treatment. This change was ushered in by the ten-year findings of the MRC trial, which, as noted previously, reported better survival with radical radiotherapy than with surgery. [21] The Lung Cancer Study Group trial, published in 1994, was also important in consolidating radiotherapy: it compared radiotherapy with radiotherapy plus surgery for the local treatment of SCLC after chemotherapy, and found that surgery did not improve median or longterm survival. [50] Nevertheless, these studies had limitations. In the MRC study, only 48% of the surgical arm actually received radical resection, 34% had exploratory thoracotomy, and 18% had no surgery at all, probably in relation to inadequate preoperative staging. In the Lung Cancer Study Group trial only 54 of the 70 thoracotomy cases received complete resection. Furthermore small peripheral nodules were specifically excluded and patients had central disease. [50] Further evidence came from the 1985 retrospective analysis of Osterlind et al. [51] Thirty-three electively operated patients and 46 non-operated patients who received radiotherapy were considered resectable. There were no 10-year survivors in the surgical group and three in the radiotherapy group, however the difference was not significant. The authors concluded that surgery for resectable SCLC did provide better overall results than chemotherapy and 10
radiotherapy alone. Nevertheless as staging systems and procedures have improved, allowing better selection of operable cases, surgery as part of the multimodal treatment of stage I and II SCLC has been associated with encouraging outcomes in retrospective and non-randomized prospective studies [52-61]. Five-year survival for cases receiving surgery followed by adjuvant systemic treatment was 26-76% for stage I, 14-50% for stage II, and 0-40% for stage III disease [52-56,62-79]. Fiveyear survival for cases receiving neoadjuvant treatment and then surgery was 44-80% for stage I, 12-100% for stage II, and 0-20% for stage III disease [55-59, 80-86]. Overall perioperative morbidity and mortality appear unaffected by the order of treatment. However induction chemotherapy often results in better general condition before surgery. As early as 1983, the experience of Meyer et al. [54] on 10 patients who underwent surgical resection followed by intensive combination chemotherapy had suggested that surgery might be a valid option. The results of the 1989 Toronto Lung Oncology Group prospective study on adjuvant surgery after chemotherapy for LS SCLC were more solid. [87] Adjuvant surgery was associated with significantly better survival in patients with stage I but not stage II-III disease. The authors emphasized the importance of extensive preoperative staging, including mediastinoscopy, to select patients for surgery. In 2015 Takenaka et al. [88] published their experience: 88 LD SCLC patients who received surgical resection were compared with 189 LD SCLC patients who received conventional nonsurgical treatments. Five-year survival overall was 58% stage I, 29% stage II, and 18% stage III. Survival in the surgery and non-surgery groups was, respectively, 62% vs. 25% stage I (p
S0169-5002(15)30086-6 http://dx.doi.org/doi:10.1016/j.lungcan.2015.10.019 LUNG 4971
To appear in:
Lung Cancer
Received date: Revised date: Accepted date:
6-8-2015 8-10-2015 12-10-2015
Please cite this article as: Veronesi Giulia, Bottoni Edoardo, Finocchiaro Giovanna, Alloisio Marco.WHEN IS SURGERY INDICATED FOR SMALL-CELL LUNG CANCER?.Lung Cancer http://dx.doi.org/10.1016/j.lungcan.2015.10.019 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
WHEN IS SURGERY INDICATED FOR SMALL-CELL LUNG CANCER?
Giulia Veronesi 1, Edoardo Bottoni 1, Giovanna Finocchiaro 2 and Marco Alloisio1
1
Division of thoracic and general surgery, Istituto Clinico Humanitas IRCCS, Rozzano, Italy
2
Department of Medical Oncology, Istituto Clinico Humanitas IRCCS, Rozzano, Italy
Corresponding author: Dr. Giulia Veronesi Division of Thoracic Surgery, Humanitas Research Hospital Via Manzoni 56, Rozzano, Italy [email protected] Tel: +39 02 82241
1
Highlights
SCLC prognosis is poor and has hardly changed over the last 30 years
Recent studies indicate that surgery has a role in early SCLC
Lobectomy + nodal dissection is OK for SCLC/mixed histology found intraoperatively
Postoperative chemotherapy is indicated after surgical removal of early SCLC
Surgery may improve local control/survival after chemotherapy in stage I/II SCLC
CT screening identifies SCLC at an earlier stage promising to increase survival
2
Abstract Small-cell lung cancer (SCLC) comprises 13-20% of all lung cancers but is the fifth leading cause of cancer death worldwide. SCLC prognosis remains poor despite improvements in diagnosis and therapy over the last 30 years. Current treatment is systemic chemotherapy, flanked by thoracic irradiation for limited stage disease; however about two-thirds of patients are diagnosed with extensive stage disease when thoracic irradiation is not worthwhile. Randomized trials on surgical resection in patients with limited stage disease conducted in the pre-PET era, when both staging and treatment were inadequate, did not support a role for surgery in disease management. However recent retrospective and population-based studies indicate that outcomes after surgery in patients with very early SCLC are comparable to those in patients with nonSCLC, and that survival is better than in SCLC patients not given surgery. CT screening identifies SCLC at an earlier stage – with better survival – than usual care, and offers the hope that more SCLC patients may become long-term survivors. However cases must be exhaustively staged to identify those likely to benefit from surgery. Finding a specific SCLC marker to facilitate early diagnosis remains a priority.
Keywords: Small cell lung cancer; limited disease; TNM; surgery; radiotherapy; early detection
3
Introduction Lung cancer is the leading cause of cancer-related death in the world, accounting for more deaths than breast, prostate, pancreatic, and colon cancer combined. [1] Over 1.6 million cases of lung cancer were diagnosed worldwide in 2008 [2]. Small-cell lung cancer (SCLC) accounts for 13 to 20% of all lung cancers, and is the fifth leading cause of cancer death when considered independently of non-small-cell lung cancer (NSCLC). [3, 4] SCLC is a malignant epithelial neoplasm usually consisting of small cells with scant cytoplasm, ill-defined cell borders, granular nuclear chromatin, and absent or inconspicuous nucleoli. The cells can be round, oval, or spindle-shaped. Nevertheless it can be difficult to distinguish SCLC from other lung malignancies and, in addition to morphology, immunohistochemistry to detect cytokeratins (epithelial marker) and neuroendocrine markers is often useful to distinguish SCLC from other lung cancers. Notwithstanding improvements in treatment and earlier diagnosis, leading to small survival improvements [5], five-year relative survival for SCLC was only 5-7% in the last decade of the last century (latest available data) [5], making it the most aggressive lung cancer subtype. The aggressive, rapidly fatal natural history of SCLC may be due to the large number of mutations present, usually including TP53 mutations [6, 7] in turn probably related to the fact that around 98% of SCLC patients have a history of heavy smoking. [3] Both smoking intensity (cigarettes/day) and number of years of smoking increase the risk of developing SCLC. [4] Approximately two-thirds of SCLC patients have clinical evidence of metastasis at diagnosis; most of the remaining third have clinical evidence of extensive involvement of hilar, mediastinal, and sometimes supraclavicular lymph nodes. Typical local symptoms are cough, shortness of breath, and chest pain. Weight loss and weakness suggest metastatic disease. About 80% of patients die within 1-2 years of diagnosis. [5] Without treatment, patients with 4
limited disease typically die within 3-6 months and those with extensive disease die within 1-2 months. [5]. As yet no specific molecular markers to facilitate early diagnosis of SCLC have been identified. [8] However evidence suggests that CT can identify SCLC at an earlier stage than usual with favorable impact on survival. [9]
Staging The first SCLC staging system was introduced by the Veterans Administration Lung Cancer Study Group (VALSG) in 1973 for use in clinical trials [10]. It divided patients into those with ‘limited stage’ (LS) disease, confined to the hemithorax, and those with ‘extensive stage’ disease (ES) at sites beyond those included in LS. In 1989 [11] the International Association for the Study of Lung Cancer (IASLC) recommended that the VALSG staging system be modified to include all non-metastatic patients in the LS group. This meant in practice that cases with involvement of controlateral mediastinic and supraclavicular lymph nodes were to be considered LS, provided these nodes could be included in a single irradiation field. The VALSG system was developed at a time when the utility of surgery was being questioned, and it is likely that the absence (or non use) of a more detailed staging system made it very difficult to select patients who might benefit from surgery. On the other hand so few SCLC patients were eligible for surgery that more precise staging was not considered necessary. Patients with LS were usually given chemotherapy and thoracic radiation, whereas those with ES only received chemotherapy. More recent TNM staging systems [12, 13] were not considered applicable to SCLC, since surgical confirmation was seldom available. However, Karrier et al. in 1989 [14] and Shepherd et al. [15] in 1991 showed that the TNM system was useful for predicting SCLC outcomes. In their analyses, survival for operable stage I disease ranged from 51% to 59%, while the timing of surgery (before or after chemotherapy) 5
made little difference. Stage II and III patients had survival comparable to that of stage III NSCLC, with surgery recommended only to responders. Pathologic TNM stage predicted survival, while clinical stage did not. For stage I operable patients, those with clinical T1 had significantly better survival than those with clinical T2, and all other T categories. Furthermore patients with clinical N0 or N1 disease had significantly better survival than those with N2 or N3 tumors. [16] Another problem with the simple LS categorization is that it does not indicate whether or not lymph nodes are involved, or whether or not there is controlateral nodal involvement; it is therefore useless for planning radiotherapy even in non-surgical cases. [17] The IASLC analyzed 12,620 SCLC cases when revising TNM staging system [16]. Only 349 (2.8%) patients underwent surgery, with five-year survival of 56% for stage I, 38-40% for stage II, and 0-12% for stage III. It was concluded that the TNM staging should be applied to SCLC, and was particularly useful for resectable SCLC. [16]
Chemoradiotherapy for limited SCLC SCLC was found highly sensitive to various chemotherapeutic agents in the 1960s. The cyclophosphamide, doxorubicin, vincristine combination (CAV) came to be widely used in the 1970s as it was effective and had good tolerability. [18] However the benefit to patients was short-lived, and more effective treatments were required. Chemotherapy was soon combined with thoracic radiotherapy. A 1984 study [19] reported on CAV in combination with thoracic radiotherapy and prophylactic cranial irradiation in 153 LS and 167 ES cases. In the LS group, 52% had complete response and median survival was 49 weeks. Later, cisplatin plus etoposide was compared with cyclophosphamide, epirubicin and vincristine (CEV) in a phase III trial [20] on 436 LS and ES patients. Cisplatin and etoposide proved 6
superior to CEV in terms of survival (14.5 vs. 9.7 months, p=0.001) and toxicity profile, and subsequently became the most frequently used chemotherapy regimen for SCLC. That radiotherapy is superior to surgery in LS SCLC was first shown in the 1970s. For example, in the British Medical Research Council (MRC) study on 144 patients randomized to surgery vs. radical radiotherapy, median overall survival was longer in the radiotherapy group (9.9 months vs. 6.5 months, p=0.04). [21] However the early trials were carried out using staging procedures now known to be inadequate, while the chemotherapy and radiotherapy regimens available today may be more effective than those available in the 1970s and 1980s. Two meta-analyses published in 1992 [22, 23] consolidated radiotherapy in combination with chemotherapy as the cornerstone of treatment for SCLC patients with LS. The Pignon et al. study [22] reviewed data on 2140 patients from 13 randomized trials, excluding those with ES. They found that addition of radiotherapy resulted in a 14% reduction in mortality and better overall survival at three years (5.4%) compared to chemotherapy alone. The meta-analysis of Warde et al. [23] assessed individual patient data from 11 randomized trials and found that addition of radiation to chemotherapy improved two-year survival by 5.4%. The timing of thoracic irradiation in relation to chemotherapy was controversial for some time. Trials and systematic reviews addressed the issue [24-28] and it became evident in the mid 2000s that radiotherapy was best administered during first or second cycle of platinum-based chemotherapy. The 2007 systematic review of Pijls-Johannesma et al. [29] assessed seven randomized trials and found significantly better two- and five-year survival when radiotherapy was started within 30 days of the start of chemotherapy. It has been suggested that cancer cell repopulation is induced by chemotherapy resulting in resistance to subsequent irradiation; this is avoided if irradiation is concurrent. [30] Radiation dose and fractionation have been investigated by several studies. [31-35] A recent 7
meta-analysis of NSCLC and SCLC trials [34] indicated that accelerated or hyperfractionated radiotherapy is associated with better overall survival at a cost of greater esophageal toxicity. However for SCLC patients, the advantage was not significant (hazard ratio, HR, for death compared to conventional schedule 0.87; 95% CI, 0.74-1.02; P = 0.08) and absolute survival benefits were 1.7% at three years and 5.1% at five years. Two large ongoing randomized phase III trials [36, 37] are investigating dose fractionation. One [36] is comparing three thoracic radiotherapy regimens in LS-SCLC patients receiving standard chemotherapy. The other, the CONVERT trial [37], is comparing once-daily with twice-daily radiotherapy in good performance status LS patients. Over 50% of SCLC patients develop brain metastases. Since chemotherapy agents do not pass the blood-brain barrier they unable to prevent or treat brain metastases and prophylactic cranial irradiation (PCI) was proposed as a means of reducing the incidence of brain metastasis and improving overall survival in LS patients who achieve complete response after induction chemoradiotherapy. PCI became standard from 1999 when Auperin et al. [38] published a metaanalysis of data from seven prospective trials on individual LS patients who achieved complete remission after chemoradiation. Patients were randomized to PCI or follow-up; those who received PCI had a significant reduction in risk of death (RR 0.84, 95%CI 0.73-0.97, p=0.01) compared to controls, which translated into 5.4% more survival at three years, and a significant reduction in incidence of brain metastasis. A 2001 meta-analysis [39] of data from 1547 patients enrolled in 12 trials, found concordant results among all trials. For the five trials that enrolled patients with complete response to chemotherapy, overall mortality was significantly reduced (HR: 0.82; 95 % CI 0.71-0.96) in the PCI compared to no PCI arm. For all studies, the incidence of brain metastasis was lower in the PCI arm (HR 0.48, CI 0.39-0.60). A phase III randomized trial published in 2009 [39] investigated whether PCI dose escalation (36 8
Gy in 10 daily 2 Gy fractions, or 36 Gy in 16 twice-daily 1.5 Gy fractions) reduced the risk of brain metastasis compared to 25 Gy in 10 daily fractions. The study found no significant differences in incidence of brain metastasis, but higher rates of cancer-related death in the experimental arms. Based on these data, 25 Gy at 2.5 Gy once a day is considered the standard dose for PCI in LS patients who achieve complete remission. As regards long-term cognitive impairment after PCI, data are discordant. [40, 41]
Newer chemotherapeutic agents While for NSCLC there have been significant improvements in diagnosis, treatment and survival in recent years [42], little has changed in the management of SCLC since the platinum-etoposide doublet was introduced nearly forty years ago. In fact, although numerous new cytotoxic agents and combinations have been investigated, especially in ES SCLC, most have not proven effective [43]. It is also the case that disease biomarkers and molecular subtypes (that can be targeted by specific agents) have not yet been identified, mainly because insufficient quantities of tumor tissue for molecular research have been collected: most SCLCs are diagnosed by small biopsy. Nevertheless, there have been some recent advances. Comprehensive genome analyses [44, 6, 7] of SCLC specimens and cell lines confirm that SCLCs have high mutation rates, and that mutations due to mechanisms induced by tobacco smoke carcinogens predominate; several common genomic alterations have been identified, with potential for targeting by new therapeutic targets. [45, 6, 7] Recent data also suggest that immunotherapies may be promising. Thus, MK-3475 (pembrolizumab), an antibody that targets the programmed death-1 (PD1) protein to unblock apoptosis and is being used to treat of melanoma, is also to be tested in a phase I study 9
(NCT02402920) on LS SCLC patients. Ipilimumab – another monoclonal antibody successfully used to treat melanoma and which blocks a receptor that downregulates the immune system, has shown promise as a first-line treatment in combination with chemotherapy in ES SCLC patients. [45, 46] Ongoing early phase studies are also evaluating nivolumab (anti-PD-1) with or without ipilimumab. [47]
Role of surgery Up to the early 1970s, surgery was standard treatment for operable SCLC. [48, 49] After 1973 the standard of care gradually switched to thoracic radiotherapy as local treatment, with chemotherapy as systemic treatment. This change was ushered in by the ten-year findings of the MRC trial, which, as noted previously, reported better survival with radical radiotherapy than with surgery. [21] The Lung Cancer Study Group trial, published in 1994, was also important in consolidating radiotherapy: it compared radiotherapy with radiotherapy plus surgery for the local treatment of SCLC after chemotherapy, and found that surgery did not improve median or longterm survival. [50] Nevertheless, these studies had limitations. In the MRC study, only 48% of the surgical arm actually received radical resection, 34% had exploratory thoracotomy, and 18% had no surgery at all, probably in relation to inadequate preoperative staging. In the Lung Cancer Study Group trial only 54 of the 70 thoracotomy cases received complete resection. Furthermore small peripheral nodules were specifically excluded and patients had central disease. [50] Further evidence came from the 1985 retrospective analysis of Osterlind et al. [51] Thirty-three electively operated patients and 46 non-operated patients who received radiotherapy were considered resectable. There were no 10-year survivors in the surgical group and three in the radiotherapy group, however the difference was not significant. The authors concluded that surgery for resectable SCLC did provide better overall results than chemotherapy and 10
radiotherapy alone. Nevertheless as staging systems and procedures have improved, allowing better selection of operable cases, surgery as part of the multimodal treatment of stage I and II SCLC has been associated with encouraging outcomes in retrospective and non-randomized prospective studies [52-61]. Five-year survival for cases receiving surgery followed by adjuvant systemic treatment was 26-76% for stage I, 14-50% for stage II, and 0-40% for stage III disease [52-56,62-79]. Fiveyear survival for cases receiving neoadjuvant treatment and then surgery was 44-80% for stage I, 12-100% for stage II, and 0-20% for stage III disease [55-59, 80-86]. Overall perioperative morbidity and mortality appear unaffected by the order of treatment. However induction chemotherapy often results in better general condition before surgery. As early as 1983, the experience of Meyer et al. [54] on 10 patients who underwent surgical resection followed by intensive combination chemotherapy had suggested that surgery might be a valid option. The results of the 1989 Toronto Lung Oncology Group prospective study on adjuvant surgery after chemotherapy for LS SCLC were more solid. [87] Adjuvant surgery was associated with significantly better survival in patients with stage I but not stage II-III disease. The authors emphasized the importance of extensive preoperative staging, including mediastinoscopy, to select patients for surgery. In 2015 Takenaka et al. [88] published their experience: 88 LD SCLC patients who received surgical resection were compared with 189 LD SCLC patients who received conventional nonsurgical treatments. Five-year survival overall was 58% stage I, 29% stage II, and 18% stage III. Survival in the surgery and non-surgery groups was, respectively, 62% vs. 25% stage I (p
