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R. Komaki



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    MO17 - Radiotherapy I: Stereotactic Ablative Body Radiotherapy (ID 106)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      MO17.11 - Stereotactic ablative radiotherapy (SABR) for centrally located early-stage or isolated parenchymal recurrences of non-small cell lung cancer (NSCLC): How to fly in a "no fly zone" (ID 1961)

      17:15 - 17:20  |  Author(s): R. Komaki

      • Abstract
      • Presentation
      • Slides

      Background
      SABR has become a standard treatment option for medically inoperable, peripherally located early-stage NSCLC. However, using SABR for centrally located lesions remains challenging because of the potential for severe side effects. Here we sought to validate our previous experience with SABR (50 Gy in 4 fractions) for central lesions, including the dose-volume constraints, and explore a new regimen of 70 Gy in 10 fractions for cases in which dose-volume constraints cannot be met with the previous regimen.

      Methods
      We used 4D-based, volumetric image-guided SABR to treat 101 patients with biopsy-proven and PET/CT-staged centrally located (within 2 cm of bronchial tree, trachea, major vessels, esophagus, heart, pericardium, brachial plexus or vertebral body) T1-2N0M0 tumors (n=82) or isolated lung-parenchyma recurrent lesions (n=19). The treatment period spanned February 2005 through May 2011; follow-up visits (every 3 months for 2 years and every 6 months for the next 3 years) included chest CT or PET/CT. Endpoints were toxicity (CTCAE v3.0), survival, local control, regional control, and distant metastasis.

      Results
      At a median follow-up time of 30.3 months for all patients (40.5 months for those alive), median overall survival time was 56.5 months and 5-year overall survival rate was 49.0%. Three-year actuarial local, regional, and distant control rates were 96.5%, 87.2% and 77.3%. The most common toxicities were chest-wall pain (18% grade 1 and 13% grade 2) and radiation pneumonitis (10.9% grade 2 and 1.9% grade 3). No patient experienced grade 4 toxicity and one patient with tumor invading bronchial tree who received 70 Gy in 10 fractions died from hemoptysis 13 months after SABR. The distance between tumor and chest was associated with chest wall pain (≤1 cm 45% vs >1 cm 17%, p=0.002). Univariate and multivariate analyses showed that for the 82 patients receiving 50 Gy in 4 fractions, mean total lung dose (MLD) >5 Gy or ipsilateral lung V~20~ (iV~20~) >16% were independent predictors of radiation pneumonitis; 3 of 9 patients in that group with D~max~ to brachial plexus >35 Gy experienced brachial neuropathy versus none of the 73 patients with brachial D~max~ ≤ 35 Gy (p=0.001).

      Conclusion
      SABR for centrally located lesions produces clinical outcomes similar to those for peripheral lesions when normal tissue constraints are respected. For 50 Gy in 4 fractions, we recommend MLD ≤5 Gy, lung iV~20~ ≤16%; bronchial tree D~max~ ≤ 38 Gy, V~35~ ≤1 cm[3]; major vessel D~max~≤ 56 Gy, V~40~≤1 cm[3]; esophageal D~max~ ≤35 Gy, V~30~≤1 cm[3 ]; brachial plexus D~max~ ≤35 Gy, V~30~≤0.2 cm[3] and spinal cord D~max~ <25 Gy. Giving 70 Gy in 10 fractions is another option for challenging cases but can produce severe toxicity if significant amounts of critical structures are exposed to ≥70 Gy. Proper selection of cases (based on tumor location and normal tissue constraints) and SABR regimens and volumetric image-guided delivery are all crucial to avoid overdosing critical structures. Typically, a minimum 5-10 mm distance between critical structures and gross tumor is required to meet dose-volume constraints.

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    P1.05 - Poster Session 1 - Preclinical Models of Therapeutics/Imaging (ID 156)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.05-005 - VEGF signaling inhibition by cediranib enhances the antitumor and anti-metastatic effects of radiation therapy more substantially than chemotherapy in orthotopic lung cancer models (ID 1443)

      09:30 - 09:30  |  Author(s): R. Komaki

      • Abstract

      Background
      The outcome for lung cancer patients remains poor and new therapeutic approaches are urgently needed. Cediranib is an orally available inhibitor of all 3 VEGFR tyrosine kinases. We evaluated the therapeutic efficacy and radiosensitizing effects of cediranib and paclitaxel, alone or in combination, in orthotopic models of human lung adenocarcinoma that mimic clinical patterns of malignant progression.

      Methods
      PC14PE6 or NCI-H441 human lung adenocarcinoma cells (1 x 10[6]) were injected into the left lungs of nude mice. Mice were randomized (8/group) to treatment with vehicle control, cediranib (3 mg/kg/day po), paclitaxel (200 µg/week ip), radiation to the left lung and mediastinum (20 Gy in 5 fractions over 2 weeks), or radiation with cediranib and/or paclitaxel. When controls became moribund, all mice were sacrificed and assessed for lung tumor burden and mediastinal nodal metastasis. Lung tumors and adjacent tissues were analyzed immunohistochemically.

      Results
      All treatments were well tolerated without significant differences in body weight between groups. In both models, cediranib or radiation therapy alone inhibited tumor growth and lymph node metastasis with efficacy superior to paclitaxel. Cediranib markedly enhanced the antitumor and antimetastatic effects of radiation with 99.3% and 92.1% reductions in primary lung tumor volume in the PC14PE6 and NCI-H441 models, respectively, while paclitaxel only modestly improved the effects of radiation therapy. Trimodality therapy resulted in a near-complete suppression of tumor growth and metastasis, with 99.8% and 98.3% reductions in tumor volume compared to control in the PC14PE6 and NCI-H441 models, respectively, without evidence of lymph node metastasis. Immunohistochemical analyses of lung tumors revealed that cediranib inhibited angiogenesis and tumor cell proliferation and increased tumor and endothelial cell apoptosis. The antiangiogenic and apoptotic effects of cediranib were substantially enhanced when combined with radiation and paclitaxel. Cediranib alone or in combination with radiation and/or paclitaxel increased VEGFR2 expression, but VEGF expression was not significantly impacted by treatment. VEGFR2/3 activation was blocked by cediranib alone or in combination therapy.

      PC14PE6 NCI-H441
      Treatment Left Lung Weight (mg) Left Lung Tumor Volume (mm[3]) Mediastinal Lymph Node Metastasis Left Lung Weight (mg) Left Lung Tumor Volume (mm[3]) Mediastinal Lymph Node Metastasis
      Vehicle 710 (490-1210) 753 (254-1089) 7/8 935 (800-1230) 1146 (860-1601) 8/8
      Paclitaxel 200ug/week 545 (150-860) 506 (37-817) 6/8 785 (485-820) 820 (576-1208) 7/8
      Radiation 20Gy/5fractions 220** (50-360) 154* (34-270) 4/8 485** (330-820) 501* (333-879) 6/8
      Cediranib 3mg/kg/day 215* (70-540) 137* (13-316) 4/8 395** (230-570) 414** (261-698) 5/8
      Radiation +Paclitaxel 185** (60-260) 87** (21-268) 2/8 360** (260-650) 327** (236-651) 5/8
      Cediranib + Paclitaxel 125** (60-260) 41** (0-150) 1/8[†] 225** (160-630) 241** (79-651) 4/8[†]
      Radiation + Cediranib 50* (40-60) 0** (0-28) 0/8[†] 120** (70-190) 88** (1-182) 2/8[†]
      Radiation + Cediranib + Paclitaxel 40** (40-60) 0** (0-1) 0/8[†] 100** (60-120) 9** (1-64) 0/8[†]
      Data are presented as medians and ranges or as incidence. [†]p<0.05 versus vehicle (lymph nodes), *p<0.01, **p<0.001 versus vehicle (others)

      Conclusion
      Trimodality therapy with cediranib, paclitaxel, and radiation resulted in the near complete suppression of lung tumor growth and metastasis with markedly enhanced antiangiogenic and apoptotic effects. The radiosensitizing effects of cediranib upon lung tumors and their vasculature was superior to those of paclitaxel with markedly enhanced apoptosis. The combination of cediranib with radiotherapy or chemoradiotherapy is a potentially promising therapy for cancer and our data provides a strong basis for the design of clinical trials in lung adenocarcinoma patients.

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    P3.08 - Poster Session 3 - Radiotherapy (ID 199)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Radiation Oncology + Radiotherapy
    • Presentations: 1
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      P3.08-011 - Stereotactic Ablative Radiotherapy: A Potentially Curable Approach to Multiple Primary Lung Cancer (ID 1454)

      09:30 - 09:30  |  Author(s): R. Komaki

      • Abstract

      Background
      Lung parenchymal recurrent or multiple lobe cancer is typically considered to have metastatic disease and treated with palliative approach such as chemotherapy. However, some of these patients may have multiple primary lung cancer (MPLC) that could be potential curable. Surgical resection has been the standard treatment for early-stage multiple primary lung cancer (MPLC). However, a significant proportion of patients with MPLC cannot undergo surgery. We explored here the role of stereotactic ablative radiotherapy (SABR) for patients with MPLC.

      Methods
      We reviewed MPLC cases treated with SABR (50 Gy in 4 fractions) for the second tumor. Four-dimensional CT–based planning/volumetric image-guided treatment was used for all patients. Patients underwent chest CT scanning every 3 months for 2 years after the SABR and then every 6 months for another 3 years. PET scans were recommended at 3–12 months after SABR. Toxic effects were scored according to the National Cancer Institute Common Terminology Criteria for Adverse Effects version 4.

      Results
      For the 101 patients treated with SABR, at a median follow-up interval of 36 months and median overall survival of 46 months, 2-year and 4-year in-field local control rates were 97.4% and 95.7%. 2- and 4-year rates of overall survival (OS) were 73.2% and 47.5% and progression-free survival (PFS) were 67.0% and 58.0%. Patients with metachronous tumors had higher OS and PFS than did patients with synchronous tumors (2-year OS 80.6% metachronous vs. 61.5% synchronous; 4-year OS 52.7% vs. 39.7%; p=0.047; 2-year PFS 84.7% vs. 49.4%; 4-year PFS 75.6% vs. 30.4%; p=0.0001). For patients whose tumors were both of the same histology (meaning that the second lesion could have been a satellite, a metastasis, or a recurrent lesion), the 2-year and 4-year OS rates were 76.4% and 51.2%, which were no different from the OS rates for patients with tumors of different pathology (2-year OS: 66.7% and 4-year OS: 40.5%; p=0.406). The 2- and 4-year OS of patients in whom both tumors were classified as stage I were 76.1% and 55.2%, which was better than the OS rates for the patients whose index tumors were of higher stage (2-year OS 66.7%, 4-year OS 26.6%; p=0.049). For patients whose index tumor was treated with surgery or SABR, the incidence of grade ≥3 radiation pneumonitis was 3% (2/71), but this increased to 17% (5/30) for patients whose index tumor was treated with conventional radiotherapy. Other grade ≥3 toxicities included grade 3 chest wall pain (3/101, 3%) and grade 3 skin toxicity (1/101, 1%).

      Conclusion
      1. SABR achieves an excellent long-term tumor control and promising PFS and OS in early-stage MPLC. 2. Toxicity could happen but within the scope of SABR in stage I disease. 3. Caution should be taken integrating SABR with prior conventional radiotherapy for stage II/III disease. SABR could be an effective alternative to surgery for curative treatment of early-stage MPLC tumors.