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K. Rosenzweig

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    PC 03 - Pro vs Con: Prophylactic Cranial Irradiation (PCI) Post Chemotherapy Response / Pro vs Con: Is There a Role for Radiation in Oligometastatic Disease? (ID 49)

    • Event: WCLC 2015
    • Type: Pro Con
    • Track: Treatment of Advanced Diseases - NSCLC
    • Presentations: 4
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      PC03.01 - Prophylactic Cranial Irradiation (PCI) Post Chemotherapy Response - Pro (ID 2034)

      14:20 - 14:40  |  Author(s): B. Slotman

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Background Brain metastases are an important clinical problem in patients with small cell lung cancer (SCLC), with 20% of patients having them at diagnosis and about 80% at autopsy. In patients with LS-SCLC, prophylactic cranial irradiation (PCI) significantly reduces the risk of brain metastases, and it improves survival [1]. A meta-analysis showed a survival benefit of almost 6% at 3 years with PCI (21 vs 15%). A subsequent international multi-center study comparing higher and lower dose PCI found no improvement in outcomes with higher doses [2]. Consequently, a dose of 25 Gy in 10 fractions remains the standard dose for PCI. Since the risk of brain metastases is even higher in patients with ES-SCLC, PCI has also been investigated in these patients.A randomized EORTC study showed that PCI both reduced the risk of brain metastases and improved overall survival [3]. Survival at 1 year was 27% for the patients who received PCI compared to 13% for the controls. Interestingly, patients who received PCI were more likely to receive 2[nd] or 3[rd] line chemotherapy with subsequent disease progression (68 vs45%), presumably because they remained fitter without brain metastases. PCI was well tolerated in the effect on quality of life was small and transient [4]. The beneficial effect of of PCI was underscored in the recent CREST trial, where the risk of brain metastases was less than 5% [5]. Controversies surrounding the use of PCI Firstly, PCI can have a negative effect on cognition [6], with important risk factors being advanced age, pre-existing cerebrovascular problems, diabetes and the use of anti-epileptics. It should however be appreciated that brain metastases by themselves also have an important negative effect on cognition and quality of life. Moreover, SCLC patients may have impaired cognitive functioning in comparison with healthy controls, independent of the use of chemotherapy or radiotherapy. Another point to consider is that metastases in SCLC, often are multiple with limited options for high dose (stereotactic) radiotherapy, in contrast to NSCLC. Use of radiotherapy techniques that reduce doses to the hippocampus [7], as well as the use of Alzheimer drugs drugs such as memantine and donezepil [8] may further mitigate the effect of PCI. The effectiveness and safety of these approaches remains to be be evaluated in prospective clinical trials. Second, it has been questioned whether PCI will continue to show a beneficial effect if a brain MRI is repeated after completion of chemotherapy, in order to eliminate some subclinical metastases. This is discussion intensified after the presentation of a Japanese study in 2014 [9]. In the study, MRI brain was not only performed after chemotherapy, but also at regular intervals during the follow-up. Any brain metastases detected were treated with radiotherapy or radiosurgery. The study was designed as a superiority study for PCI, with overall survival as primary endpoint, but closed early due to futility. The likelihood of finding a survival benefit of PCI was less than 0,1%, but the discussion was fueled by the incorrect and misleading title using the word ‘detrimental’. Due to slow accrual, the Japanese study enrolled 160 patients entered from 40 centers in 4 years, thereby suggesting that patient selection may have played a roll. The publication of this analysis is awaited with interest. In order to address this topic from another angle, we have re-analyzed the effect of PCI on brain metastases and survival in a previous EORTC PCI study, after excluding patients who either died or developed brain metastases in the first 8 weeks after randomization, as such patients may have had asymptomatic brain metastases, visible if an MRI would have been performed. Even after exclusion of these patients, the EORTC PCI trial found a significant effect on brain metastases (HR 0.40; p<0.001) and overall survival (HR0.74; p=0.035) [unpublished data]. Conclusion In conclusion, PCI should remain standard of care in SCLC patients who have responded to chemotherapy. The pros and cons of PCI should be individually weighted and discussed with the patient. Some promising new techniques undergoing evaluation now may reduce the side-effects of PCI. References 1. Aupérin A, Arriagada R, Pignon JP, et al.. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group. N Engl J Med. 1999 Aug 12;341(7):476-84. 2. Le Péchoux C, Dunant A, Senan S, et al. Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial. Lancet Oncol. 2009 May;10(5):467-74. 3. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007 Aug 16;357(7):664-72. 4. Slotman BJ, Mauer ME, Bottomley A, et al. Prophylactic cranial irradiation in extensive disease small-cell lung cancer: short-term health-related quality of life and patient reported symptoms: results of an international Phase III randomized controlled trial by the EORTC Radiation Oncology and Lung Cancer Groups. J Clin Oncol. 2009 Jan 1;27(1):78-84. 5. Slotman BJ, van Tinteren H, Praag JO, et al. Use of thoracic radiotherapy for extensive stage small-cell lung cancer: a phase 3 randomised controlled trial. Lancet. 2015 Jan 3;385(9962):36-42. 6. Gondi V, Paulus R, Bruner DW, et al. Decline in tested and self-reported cognitive functioning after prophylactic cranial irradiation for lung cancer: pooled secondary analysis of Radiation Therapy Oncology Group randomized trials 0212 and 0214. Int J Radiat Oncol Biol Phys. 2013 Jul 15;86(4):656-64. 7. Kundapur V, Ellchuk T, Ahmed S, Gondi V. Risk of hippocampal metastases in small cell lung cancer patients at presentation and after cranial irradiation: a safety profile study for hippocampal sparing during prophylactic or therapeutic cranial irradiation. Int J Radiat Oncol Biol Phys. 2015 Mar 15;91(4):781-6 8. Day J, Zienius K, Gehring K, et al. Interventions for preventing and ameliorating cognitive deficits in adults treated with cranial irradiation. Cochrane Database Syst Rev. 2014 Dec 18;12:CD011335. 9. Seto T, Takahashi T, Yamanaka T, et al. Prophylactic cranial irradiation (PCI) has a detrimental effect on the overall survival (OS) of patients (pts) with extensive disease small cell lung cancer (ED-SCLC): Results of a Japanese randomized phase III trial. J Clin Oncol 32 (Suppl) Jun 11, 2014, abstract 7503

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      PC03.02 - Prophylactic Cranial Irradiation (PCI) Post Chemotherapy Response - Con (ID 2035)

      14:40 - 15:00  |  Author(s): N. Yamamoto

      • Abstract
      • Presentation

      Abstract not provided

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      PC03.03 - Is There a Role for Radiation in Oligometastatic Disease? - Pro (ID 2036)

      15:00 - 15:20  |  Author(s): C. Le Pechoux

      • Abstract
      • Presentation

      Abstract:
      Fewer than 20% of all lung cancers are small cell lung carcinomas (SCLCs). As SCLC is an aggressive tumor because of its high and early risk of dissemination, most patients (60-70%) have metastatic disease at diagnosis. Given the high propensity of SCLC for early metastatic dissemination, chemotherapy has been and still is the cornerstone of treatment based on etoposide and platinum, but SCLC is also very sensitive to radiotherapy. Median survival for patients with non-metastatic disease for whom the standard treatment is combined chemotherapy and thoracic radiotherapy, as well as prophylactic cranial irradiation (PCI), is currently 15–20 months, with 20–40% surviving to 2 years, and 25% surviving at 5 years in the best series. For metastatic patients, median survival is 8–13 months and 2 year survival is around 5%. Recent advances in SCLC management derive mostly from a better integration of chemotherapy and radiotherapy. So patients with a limited number of metastases in number and location may have an intermediate outcome; and local treatment of both the primary tumor as well as oligometastatic disease could be discussed. Such an approach is supported by the fact that many patients in early studies that established the role of thoracic radiation therapy in limited disease would now be considered as having metastatic disease. The percentage of such metastatic patients seems to have increased partly because of stage migration with the more frequent use of PET scan and brain MRI. Thus there is a category of patients with oligometastatic disease for whom local treatment may be envisaged. The oligometastatic status was first described by Hellman and Weichselbaum as an intermediate clinical state between locoregionally confined and widespread cancer in 1995. There has been strong interest lately in this subgroup of non-small cell lung cancer oligometastatic patients, with the development of stereotactic ablative radiotherapy. Until recently, there were few data supporting the role of radiation therapy in metastatic small cell lung cancer, except PCI. As there are few therapeutic options in second line, local treatment approaches have been evaluated in extensive disease. Prophylactic cranial irradiation is now part of the standard treatment in responders and more recently a phase III trial has shown that consolidation thoracic radiotherapy could improve outcome. The 2-year survival rate was 13% in the investigational arm versus 3% in the control arm where patients had 4-6 cycles of chemotherapy and PCI [Auperin, 1999; Slotman 2007; Slotman, 2015]. A randomized phase II trial (RTOG 0937) went further in the local approach of metastatic disease after systemic chemotherapy and really addressed the issue of oligometastatic disease [Gore, RTOG 0937]. It compared PCI to PCI and consolidative radiation therapy not only to the primary intrathoracic disease but also to residual extracranial metastatic lesions (1-4 extracranial metastases who achieve a CR/PR following chemotherapy). The trial has included 96 patients and has closed recently after a planned protocol interim analysis. Results are eagerly awaited. Even if there are studies supporting the role of radiotherapy in metastatic SCLC, new strategies are needed for this category of patients. There are promising preclinical data showing a strong synergy between radiotherapy and immune treatments. Such approaches are starting to be explored in SCLC in prospective studies.

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      PC03.04 - Is There a Role for Radiation in Oligometastatic Disease? - Con (ID 2037)

      15:20 - 15:40  |  Author(s): W.J. Curran

      • Abstract
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      Abstract not provided

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Author of

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    MINI 33 - Radiotherapy and Complications (ID 164)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      MINI33.14 - Discussant for MINI33.11, MINI33.12, MINI33.13 (ID 3477)

      19:45 - 19:55  |  Author(s): K. Rosenzweig

      • Abstract
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      Abstract not provided

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    MINI 38 - Biology and Prognosis (ID 167)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI38.14 - Surgery and Not Radiation Improves Survival in Malignant Pleural Mesothelioma (ID 3168)

      19:45 - 19:50  |  Author(s): K. Rosenzweig

      • Abstract
      • Presentation

      Background:
      Surgery has a controversial role in the treatment of malignant pleural mesothelioma (MPM) as no trial has demonstrated independent survival benefit of surgery. Likewise, there is lack of consensus regarding the role of radiation in MPM. We evaluated whether cancer-directed surgery and/or radiation independently influenced MPM survival in a large population-based dataset.

      Methods:
      The Surveillance, Epidemiology, and End Results database was explored from 1973 to 2009 to identify all cases of pathologically-proven MPM. Age, sex, race, diagnosis year, stage, cancer-directed surgery, radiation, and vital status were analyzed (chemotherapy data not available). The association between prognostic factors and survival was estimated using a Cox proportional hazards model.

      Results:
      There were 14,228 patients with pathologic diagnosis of MPM. On multivariable analysis, female gender, younger age, localized stage, and cancer-directed surgery were independently associated with longer survival (Table). Survival was longer for patients who underwent surgery or surgery and radiation but not for those who underwent radiation only (Figure).

      Table. Association between Patient and Disease Characteristics and Survival
      Variable Category Adjusted HR (95% CI) *
      Sex Male 1 (Ref)
      Female 0.78 ( 0.75-0.82)
      Race White 1 (ref)
      Black 1.07 (0.98-1.16)
      Other 0.99 (0.89-1.09)
      Age (years) continuous 1.24 (1.22-1.26)
      Stage Localized 1 (ref)
      Regional 1.30 (1.21-1.40)
      Distant 1.34 (1.26-1.42)
      Diagnosis year 1973-1989 1 (ref)
      1990-1994 0.91 (0.85-0.97)
      1995-1999 0.86 (0.81-0.92)
      2000-2004 0.86 (0.81-0.91)
      2005-2009 0.80 (0.75-0.84)
      Therapy No radiation or surgery 1 (ref)
      Radiation only 1.17 (1.10-1.25)
      Surgery only 0.65 (0.62-0.68)
      Radiation and surgery 0.69 (0.63-0.75)
      Figure 1



      Conclusion:
      In this study of 14,228 patients over 36 years, cancer-directed surgery was associated with better survival in MPM, independent of other forms of therapy, including radiation. These data support the role of surgery-based therapy as the cornerstone for treatment in this challenging disease.

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    P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P1.08-022 - Intraoperative Brachytherapy for Thoracic Malignancies Resected with Close or Positive Margins (ID 2795)

      09:30 - 09:30  |  Author(s): K. Rosenzweig

      • Abstract
      • Slides

      Background:
      Local recurrence is a significant problem after surgical resection of thoracic tumors, particularly when close or positive margins are anticipated. As intraoperative radiotherapy (IORT) can deliver radiation directly to the threatened margin, we used this technique in an attempt to reduce local recurrence, particularly for patients who had already received external beam radiation. We updated our experience with thoracic IORT to assess disease control and toxicity outcomes.

      Methods:
      We performed a retrospective review of patients undergoing permanent I-125 mesh placement or temporary Ir-192 afterloading therapy during surgical resection of primary or metastatic thoracic tumors between 2001 and 2013. In general, for I-125 brachytherapy, iodine seeds were sutured into a mesh at 1cm intervals to form a planar implant delivering 85-250Gy to the MPD, which was then sutured onto the at-risk site. For Ir-192 brachytherapy, a HAM applicator was apposed to the at-risk site, then connected to the afterloader to deliver 7.5-16Gy to a depth of 0.5cm from the applicator surface. Kaplan-Meier method was used to estimate local control and overall survival, and logrank test was used to assess the impact of various clinical or treatment factors on local control.

      Results:
      Fifty-nine procedures (41 permanent, 18 temporary) were performed on fifty-eight patients (median 56 years old, range 19-77). Most common tumor histologies were NSCLC (n=23), sarcoma (n=18), thymic carcinoma (n=10), and mesothelioma (n=3). Treated sites were chest wall/paraspinal (n=31), lung (n=16), and mediastinum (n=12). Thirty-four procedures were performed on patients who had previously received external beam RT (EBRT) to the area (median 53.1 Gy). Final margins were microscopically negative in 25 cases (42.4%) and positive or not assessed in the remainder. The median size of the treated area was 27cm[2] (range: 4-152cm[2]). Median followup was 28.5 months. Actuarial local control at 1 and 2 years was 68.1% and 63.4% respectively. Median survival was 46.2 months. Overall survival at 1 and 2 years was 80.2% and 70.4% respectively. No perioperative deaths occurred. There was no significant difference in local control according to margin status, brachytherapy technique, use of adjuvant EBRT, or metastatic vs. primary tumor. Two patients (3.4%) experienced grade 3+ toxicities possibly related to IORT: one patient who also received preoperative EBRT developed pneumonitis; a second patient with prior EBRT for lymphoma died from complications of SVC syndrome likely induced by radiation fibrosis. An additional 8 patients had grade 3+ postsurgical complications (such as empyema, chylothorax, and pulmonary emboli) unlikely related to IORT. Four patients had grade 2 nerve injury also unlikely related to IORT.

      Conclusion:
      Intraoperative brachytherapy is associated with good local control after resection of thoracic tumors felt to be at very high risk for recurrence due to close or positive margins. There is a very low incidence of severe toxicity attributable to brachytherapy. Intraoperative brachytherapy should be considered in situations where the oncologic completeness of thoracic tumor resection is in doubt.

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    P2.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 213)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Treatment of Locoregional Disease – NSCLC
    • Presentations: 1
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      P2.03-032 - Prognostic Impact of EGFR and KRAS Mutations in Patients with Lung Adenocarcinoma Treated with Definitive Radiation Therapy (ID 2422)

      09:30 - 09:30  |  Author(s): K. Rosenzweig

      • Abstract
      • Slides

      Background:
      An association of EGFR and KRAS mutations with radiation sensitivity has been postulated in preclinical studies. Recent clinical studies reported longer local control and survival in patients (pts) harboring EGFR mutations treated with definitive radiotherapy (RT). Here, we sought to evaluate the prognostic impact of EGFR and KRAS mutations in 223 adenocarcinoma pts treated with definitive RT at our institution.

      Methods:
      Between 2004 and 2013, 466 inoperable pts with non-squamous lung cancer were treated with definitive RT ± chemotherapy. Mutational testing was performed in 223 pts. 44% were male, 56% female. 65% were former, 13% never, and 22% current smokers. Clinical stage was II in 5%, IIIA in 37% and IIIB in 58%. Median size of tumor was 3.8 cm (range 0.5-12.2 cm). 60% received concurrent, 31% sequential chemo-RT and 9% RT alone. The median RT dose was 63Gy (range 50-80Gy). OS was estimated by the Kaplan-Meier method. Cumulative incidence functions were used to estimate local failure (LF) and distal failure (DF), using death without failure as a competing risk. Association of factors with OS was analyzed by Cox regression and association with LF and DF by competing risk regression.

      Results:
      EGFR status was wild-type in 205 pts (92%) and mutated in 18 (8%). The most common EGFR mutations were exon 19 deletion (8 pts), followed by exon 21 L858R (7 pts), and exon 20 insertion (3 pts). KRAS status was wild- type in 142 pts (64%), mutated in 63 (28%), and not performed in 18 (8%). The most common mutations were G12C (13%), followed by G12V (5%) and G12A and G12D (3% each). With a median follow-up among survivors of 32.7 months (range 0.6-114), the median OS was 38 months for pts with EGFR mutation versus 26 months for pts without (p=0.96); 21 months for patients with KRAS mutation versus 31 months for pts without (p=0.24). 2-year LF was 37% and 46% for pts with and without EGFR mutation, and 48% and 46% for pts with and without KRAS mutation, respectively. 2-year DF was 80% and 64% for pts with and without EGFR mutation, and 62% and 64% for pts with and without KRAS mutation, respectively. On univariate analysis, factors significantly associated with improved OS included KPS ≥ 80 (p=0.01), increasing RT dose (p=0.04) and use of concurrent chemotherapy compared to RT alone (p=0.001). Factors associated with higher risk of LF included stage IIIB (p=0.04) and sequential rather than concurrent chemotherapy (p=0.05). Factors associated with a higher risk of DM included stage IIIB (p=0.03) and lower RT dose (p=0.003). Association of EGFR and KRAS mutations did not reach statistical significance on univariate analysis, thus we did not further investigate their effects by multivariable analysis.

      Conclusion:
      Despite analyzing the largest patient population to date, we did not identify a significant prognostic impact by EGFR or KRAS mutational status. The lack of an observed association could be related to the low rate of EGFR mutations identified. RT dose and use of concurrent chemotherapy were significantly associated with overall survival.

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    PC 01 - Pro vs Con: Surgery vs. SBRT in Operable NSCLC / Pro vs Con: SBRT for Non-Biopsied Lung Nodules (ID 47)

    • Event: WCLC 2015
    • Type: Pro Con
    • Track: Treatment of Localized Disease - NSCLC
    • Presentations: 1
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      PC01.03 - SBRT for Non-Biopsied Lung Nodules - Pro (ID 2028)

      15:00 - 15:20  |  Author(s): K. Rosenzweig

      • Abstract
      • Presentation
      • Slides

      Abstract:
      Stereotactic body radiation therapy (SBRT), also known as stereotactic ablative radiotherapy (SABR), has been rapidly adapted as a standard treatment for inoperable early stage non-small cell lung cancer (NSCLC).[1] Due to the potential risks of biopsy and the ability to evaluate and characterize pulmonary nodules on CT and [18]FDG-PET, centers have had differing standards of whether to treat patients without a pathologic diagnosis. In other diseases, there are well established protocols for treating without a pathologic diagnosis. For example, ten years ago, a diagnostic algorithm was developed and subsequently validated for the diagnosis of hepatocellular carcinoma based on imaging.[ 2] If a screened patient has a liver lesion is greater than 2 cm, shows arterial hypervascularity and venous washout, it is considered diagnostic. Two of the main techniques for establishing pathologic diagnosis for lung tumors are bronchoscopy and transthoracic needle biopsy (TTNB). Since solitary pulmonary nodules are frequently in the periphery, TTNB is the more frequently used method of diagnosis. Pneumothorax is a common complication of TTNB with rates varying in the literature from 9 – 54% with an average of around 20%.[3] Approximately 5% of patients undergoing TTNB require chest tube placement. In surgical series, the observed rate of surgical resection of non-malignant nodules ranges from 9 to 40%. Even programs with prospective CT-screening cohorts and nodule management protocols such as the International Early Lung Cancer Action Program report benign disease in 11% of resected patients.[ 4] Centers that have a relatively high proportion of treated patients with only a clinical diagnosis typically use criteria such as a new or growing lesion that is avid on [18]FDG-PET. Additionally, the probability of malignancy of a specific pulmonary nodule can be estimated based on statistical work of Swensen, et al. and Herder, et al. [5,6 ]The are numerous on-line calculators that incorporate these equations for evaluation of an individual patient. The VU University Medical Center in Amsterdam analyzed their results in patients who underwent SABR on whether they had a pathologic diagnosis.[ 7] In their prospective database of 591 patients, 35% had a pathologic diagnosis (biopsy proven) and 65% were diagnosed clinically. In a comparison of the two groups, the patients with a pathologic diagnosis had significantly larger tumor diameters and higher predicted FEV1 values. There was no significant difference seen in overall survival, local control regional or distant recurrences. In a retrospective analysis of 94 lesions (86 patients) treated with SBRT at the Cleveland Clinic, 35% of patients did not have tissue diagnosis.[ 8] They reported no difference in overall survival between these patients and those with pathologic confirmation. A prospective Phase II trial of SBRT from the Nordic Cancer Union was reported by Baumann, et al.[ 9] Nineteen (33%) of the 57 patients on the trial did not have pathologic confirmation of malignancy and only 14 of those 19 had [18]FDG-PET to help establish the diagnosis. Similar to the VU experience, patients with a pathologic diagnosis tended to have larger tumors. They reported no difference in progression-free, overall or cancer-specific survival between the subgroup with pathological confirmation and the whole patient group. The toxicity of lung SBRT is well established. In the VU experience reported above, they report Grade 3 or worse radiation pneumonitis in 3% of patients. Other complications include rib fracture and chest wall pain. As expected, there is no difference in toxicity between patients with or without pathologic diagnosis. There clearly is a role for SBRT in patients with radiographic-only confirmation of early stage NSCLC. In the centers where treatment of these patients is common practice, there is no evidence of differences in outcomes, nor excess toxicity. But the appropriate threshold for treatment of non-biopsied lung nodules is still unknown. Radiation oncologists need further input from our colleagues in diagnostic radiology, thoracic surgery and pulmonary medicine to develop specific guidelines on patients where biopsy could, and perhaps should, be avoided. This is especially true in countries where the potential of medical liability is relatively high since it is inevitable that some patients who actually do not have cancer will be treated with aggressive radiation therapy. References 1. Palma D, Senan S. Stereotactic radiation therapy: changing treatment paradigms for stage I nonsmall cell lung cancer. Curr Opin Oncol 2011;23:133–9. 2. AASLD Guidelines; Hepatology 2011;53:1020-2 3.Boskovic, et al. Pneumothorax after transthoracic needle biopsy of lung lesions under CT guidance. J Thor Dis 2014; 6: S99-107 4. Flores R, Bauer T, Aye R, et al. Balancing curability and unnecessary surgery in the context of computed tomography screening for lung cancer. J Thorac Cardiovasc Surg. 2014;147(5):1619-1626 5. Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch of Int Med 1997;157:849–55 6. Herder GJ, van Tinteren H, Golding RP, et al. Clinical prediction model to characterize pulmonary nodules: validation and added value of 18Ffluorodeoxyglucose positron emission tomography. Chest 2005;128:2490–6. 7. Verstgen, N., et al., Outcomes of stereotactic ablative radiotherapy following a clinical diagnosis of stage I NSCLC: Comparison with a contemporaneous cohort with pathologically proven disease. Radiotherapy and Oncology 101 (2011) 250–254 8. Stephans KL, Djemil T, Reddy CA, et al. A comparison of two stereotactic body radiation fractionation schedules for medically inoperable stage I non-small cell lung cancer: the Cleveland Clinic experience. J Thorac Oncol 2009;4:976–82. 9. Baumann P, Nyman J, Hoyer M, et al. Outcome in a prospective phase II trial of medically inoperable stage I non-small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol 2009;27:3290–6.

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