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  • Treatment Failure     - SBRT/RFA salvage     - Chemo Salvage Ongoing Trials
  • BRIEF HISTORY OF  early half of the 20th century, pneumonectomy was considered the only appropriate treatment of primary lung cancer. - Unacceptably high mortality rate associated with pneumonectomy (40%) at the time, lobectomy evolved as the treatment of choice for resectable peripheral cancers. Sublobar, sublobular, conservative, lesser, substandard or limited resections - First reported by Churchill and  Belsey first reported segmentectomy for the treatment of Bronchiectasis in 1939.   - Jensik and colleagues who first described its use for lung cancer resection in 1973. Segmentectomy: implies the removal of an anatomical unit. It requires the identification and dissection of the segmental bronchus and artery, which are sutured and segment and adjacent subsegments plus exploration of mediastinal and hilar lymph nodes, which are examined pathologically as intra-operative frozen sections to confirm pathological node (N)0 status Sleeve segmentectomies: the segmental bronchus is not incised at its origin, but it is removed with part of the lobar bronchus, which is then reconstructed with an end-to-end anastomosis. This is indicated when the tumour is too close to the origin of the segmental bronchus, in order to avoid a lobectomy Wedge/Atypical resection is the removal of part of the lung regardless of its anatomical boundaries.  - Can be part of one segment or a portion of lung parenchyma comprising two or more neighbouring segments. 
  • BRIEF HISTORY OF  early half of the 20th century, pneumonectomy was considered the only appropriate treatment of primary lung cancer. - Unacceptably high mortality rate associated with pneumonectomy (40%) at the time, lobectomy evolved as the treatment of choice for resectable peripheral cancers. Sublobar, sublobular, conservative, lesser, substandard or limited resections - First reported by Churchill and  Belsey first reported segmentectomy for the treatment of Bronchiectasis in 1939.   - Jensik and colleagues who first described its use for lung cancer resection in 1973. Segmentectomy: implies the removal of an anatomical unit. It requires the identification and dissection of the segmental bronchus and artery, which are sutured and segment and adjacent subsegments plus exploration of mediastinal and hilar lymph nodes, which are examined pathologically as intra-operative frozen sections to confirm pathological node (N)0 status Sleeve segmentectomies: the segmental bronchus is not incised at its origin, but it is removed with part of the lobar bronchus, which is then reconstructed with an end-to-end anastomosis. This is indicated when the tumour is too close to the origin of the segmental bronchus, in order to avoid a lobectomy Wedge/Atypical resection is the removal of part of the lung regardless of its anatomical boundaries.  - Can be part of one segment or a portion of lung parenchyma comprising two or more neighbouring segments. 
  • As expected, QOL decreased significantly after surgery in both groups.  The lowest QOL scores were observed immediately after discharge from the hospital, and were followed by a period of slow recovery.  In contrast to other reports, NEITHER group experienced a return to preoperative QOL, even after 24 months.   Comparison of QOL after lobectomy and pneumonectomy for  coughing (top, A),  pain (center, B),  and dyspnoea (bottom, C).  QOL of an age-matched reference group is indicated as a dotted line. *p < 0.05, **p < 0.001 (only available for EORTC QLQ-C30).
  • As expected, QOL decreased significantly after surgery in both groups.  The lowest QOL scores were observed immediately after discharge from the hospital, and were followed by a period of slow recovery.  In contrast to other reports, NEITHER group experienced a return to preoperative QOL, even after 24 months.   Comparison of QOL after lobectomy and pneumonectomy for  coughing (top, A),  pain (center, B),  and dyspnoea (bottom, C).  QOL of an age-matched reference group is indicated as a dotted line. *p < 0.05, **p < 0.001 (only available for EORTC QLQ-C30).
  • **Subsequent studies reported the usefulness of  segmentectomy as a compromise operation in selected, poor-risk patients. Notably, in 1985, Errett et reported a 17-year experience in which 197 patients underwent wedge resection or lobectomy for bronchogenic carcinoma and demonstrated a 2-year survival of 72% versus 74%, as well as a 6-year survival of 69% versus 75%, a difference that was not statistically significant.  Importantly, patients who underwent wedge resection had significantly impaired cardiopulmonary function and were not candidates for lobectomy. Despite these early studies suggesting equivalency in survival between sublobar and lobar resection for lung cancer, the higher technical complexity of performing a  segmentectomy, particularly in dissecting along the intersegmental plane which may increase the potential for a prolonged air leak, was of great concern to many surgeons.  On the other hand, with a limited resection and further preservation of lung volume, perioperative morbidity and mortality can potentially be reduced, and opportunities for additional lung resection in the future could be maintained should the patient develop a recurrence or a second cancer. _____________________ Background Although lobectomy is the procedure of preference for patients with peripheral, clinical Stage I bronchogenic carcinomas, wedge resection of the tumor may be a satisfactory alternative in poor-risk patients.  Methods -1965 & 1982, 197 patients with peripheral bronchogenic carcinomas were operated upon.  - Clinical staging was established by radiography, bronchoscopy, and mediastinoscopy.  - 97 underwent lobectomies & 100 had wedge resections.  - The decision to perform the wedge resection was made preoperatively in the majority of cases based on the assessment of operative risks.  Results - Compared to lobectomy patients, those who had wedge resections were older (70.3 +/- 0.5 versus 64.9 +/- 0.5 years, p less than 0.001) and had a lower 1 second forced expiratory volume (1.56 +/- 0.03 versus 1.94 +/- 0.03 ml, p less than 0.001), a lower arterial oxygen tension (70.5 +/- 1.1 versus 75.6 +/- 1.2 mm Hg, p less than 0.01), and a higher arterial carbon dioxide tension (41.7 +/- 0.6 versus 38.7 +/- 0.3 mm Hg, p less than 0.001).  - Despite their compromised preoperative respiratory functional status, the wedge resection group had a 30 day operative mortality (3% versus 2.1%) and morbidity comparable to those of the lobectomy group.  - Actuarial life-table analysis indicates the cumulative survival rate at 2 years after operation to be virtually identical between wedge and lobectomy groups (72% versus 74%), and even at 6 years the differences in survival rates (69% versus 75%) were not statistically significant.  Conclusion   We conclude, therefore, that by performing wedge resections in selected poor-risk patients, one may reduce the operative mortality and morbidity to an acceptable range without seriously compromising their long-term survival.
  • Background.: It has been reported that limited resection (segment or wedge) is equivalent to lobectomy in the management of early stage (T1–2 N0) non-small cell lung cancer. Methods.: A prospective, multiinstitutional randomized trial was instituted comparing limited resection with lobectomy for patients with peripheral T1 N0 non-small cell lung cancer documented at operation. Analysis included locoregional and distant recurrence rates, 5-year survival rates, perioperative morbidity and mortality, and late pulmonary function assessment. Results:  276 patients randomized 247 patients eligible - no significant differences for all stratification variables, selected prognostic factors, perioperative morbidity, mortality, or late pulmonary function.  - limited resection, there was an observed 75% increase in recurrence rates ( p  = 0.02, one-sided) attributable to an observed tripling of the local recurrence rate ( p  = 0.008 two-sided), an observed 30% increase in overall death rate ( p  = 0.08, one-sided), and an observed 50% increase in death with cancer rate ( p  = 0.09, one-sided) compared to patients undergoing lobectomy ( p  = 0.10, one-sided was the predefined threshold for statistical significance for this equivalency study). Conclusions.: Compared with lobectomy, limited pulmonary resection does not confer improved perioperative morbidity, mortality, or late postoperative pulmonary function. Because of the higher death rate and locoregional recurrence rate associated with limited resection, lobectomy still must be considered the surgical procedure of choice for patients with peripheral T1 N0 non-small celllung cancer.
  • What about QOL w/sublobar  No SS diff in # of postoperative   complications or postoperative  mortality  - lobectomy group -- 6 patients developed Respiratory Failure requiring postoperative ventilation for  >24 hr  -- No patient in the limited resection group required ventilatory assitance. 3 postoperative deaths among  the 276 patients. -- 2  in the |obectomy  -- 1 in the sublobar **SS diff in FEV1 at 6&12 mo -- interestingly NS diff in FVC
  • RFA is a thermal energy delivery system that applies an alternating current supplied by a radiofrequency energy generator, delivered through a needle electrode. The needle electrode is introduced percutaneously under CT guidance into the tumor, and multiple tines are deployed within the tumor This allows for maximal distribution of energy, and the alternating current generates ionic agitation, creating heat that can reach 908C. This leads to coagulative necrosis and tissue destruction in the precise area of the probe.
  • OBJECTIVE. This study retrospectively evaluates complications after lung radiofrequency ablation (RFA). MATERIALS AND METHODS. Complications were assessed for each RFA session in 420 consecutive patients with 1403 lung tumors who underwent 1000 RFA sessions with a cool-tip RFA system. A major complication was defined as a grade 3 or 4 adverse event. Risk factors affecting frequent major complications that occurred with an incidence of 1% or more were detected using multivariate analysis
  • OBJECTIVE.  This study retrospectively evaluates complications after lung radiofrequency ablation (RFA). MATERIALS AND METHODS.  Complications were assessed for each RFA session in 420 consecutive patients with 1403 lung tumors who underwent 1000 RFA sessions with a cool-tip RFA system. A major complication was defined as a grade 3 or 4 adverse event. Risk factors affecting frequent major complications that occurred with an incidence of 1% or more were detected using multivariate analysis. RESULTS.  Four deaths (0.4% [4/1000]) related to RFA procedures occurred. Three patients died of interstitial pneumonia. The other patient died of hemothorax. The major complication rate was 9.8% (98/1000). Frequent major complications were aseptic pleuritis (2.3% [23/1000]), pneumonia (1.8% [18/1000]), lung abscess (1.6% [16/1000]), bleeding requiring blood transfusion (1.6% [16/1000]), pneumothorax requiring pleural sclerosis (1.6% [16/1000]), followed by bronchopleural fistula (0.4% [4/1000]), brachial nerve injury (0.3% [3/1000]), tumor seeding (0.1% [1/1000]), and diaphragm injury (0.1% [1/1000]). Puncture number ( p  < 0.02) and previous systemic chemotherapy ( p  < 0.05) were significant risk factors for aseptic pleuritis. Previous external beam radiotherapy ( p  < 0.001) and age ( p  < 0.02) were significant risk factors for pneumonia, as were emphysema ( p  < 0.02) for lung abscess, and serum platelet count ( p  < 0.002) and tumor size ( p  < 0.02) for bleeding. Emphysema ( p  < 0.02) was a significant risk factor for pneumothorax requiring pleural sclerosis. CONCLUSION.  Lung RFA is a relatively safe procedure, but it can be fatal. Risk factors found in this study will help to stratify high-risk patients.
  • Abstract INTRODUCTION: We set out to investigate a new therapy akin to brain radiosurgery called extracranial stereotactic radioablation (ESR) in a phase I trial. PATIENTS AND METHODS: -cT1 or T2 (tumor size, < or = 7 cm) N0M0 biopsy confirmed NSCLC -All patients had comorbid medical problems that precluded thoracotomy.  -The median age was 75 years, and the median Karnofsky performance status was 80.  -ESR was administered in three separate fractions over 2 weeks.  Three to five patients were treated within each dose cohort starting at 800 cGy per fraction (total, 2,400 cGy) followed by successive dose escalations of 200 cGy per fraction (total increase per cohort, 600 cGy).  Waiting periods occurred between dose cohorts to observe toxicity. Patients with T1 vs T2 tumors underwent separate independent dose escalations.
  • RESULTS: A total of 37 patients were enrolled since February 2000.  1 ptnt experienced G3 pneumonitis 1 patient G3 hypoxia No appreciable decline in cardiopulmonary function as measured by symptoms, physical examination, need for O2 supplementation, PFTs, ABG, or regular chest imaging.  Both T-stage groups ultimately reached and tolerated 2,000 cGy per fraction for three fractions (total, 6,000 cGy).  The MTD for this therapy in either T-stage group has yet to be reached.  Tumors responded to treatment in 87% of patients (complete response, 27%).  After a median follow-up period of 15.2 months, six patients experienced local failure, all of whom had received doses of < 1,800 cGy per fraction. CONCLUSIONS: Very high radiation dose treatments were tolerated in this population of medically inoperable patients with stage I NSCLC using ESR techniques.
  • Introduction:  Hypofractionated stereotactic radiotherapy (HypoFXSRT) has recently been used for the treatment of small lung tumors. We retrospectively analyzed the treatment outcome of HypoFXSRT for stage I non-small cell lung cancer (NSCLC) treated in a Japanese multi-institutional study.   Methods: This is a retrospective study to review 257 patients with stage I NSCLC  median age, 74 years:  164 T1N0M0, 93 T2N0M0 Stereotactic 3D tx using noncoplanar dynamic arcs or multiple static ports.  Tx: total dose of 18 to 75 Gy at the isocenter in one to 22 fractions.  Median calculated biological effective dose (BED) was 111 Gy (range, 57–180 Gy) based on [alpha]/[beta] = 10. Results:  Median follow-up 38 months G2 pulmonary in 14 ptnts 5.4% Local progression in 36 ptnts 14.0% LR rate 8.4% for a BED >100 Gy compared w/42.9% for less than 100 Gy (p < 0.001).  **assumes an early a/b of 10 5 yr OS of medically operable 70.8% if >100Gy BED 30.2% if < 100 Gy (p < 0.05).
  • Purpose Surgical resection is standard therapy in stage I non–small-cell lung cancer (NSCLC); however, many patients are inoperable due to comorbid diseases. Building on a previously reported phase I trial, we carried out a prospective phase II trial using stereotactic body radiation therapy (SBRT) in this population. Patients and Methods Eligible patients included clinically staged T1 or T2 ( 7 cm), N0, M0, biopsy-confirmed NSCLC. All patients had comorbid medical problems that precluded lobectomy. SBRT treatment dose was 60 to 66 Gy total in three fractions during 1 to 2 weeks. Results 100% of 70 patients enrolled completed therapy  - Median follow-up was 17.5 months.  - 3 mo major RR was 60%.  - Kaplan-Meier LC @ 2 years was 95%. - 28 patients have died as a result of cancer (n = 5),  - Treatment (n = 6) - Comorbid illnesses (n = 17) - Median OS was 32.6 mo - 2 yr OS was 54.7%. Purpose Surgical resection is standard therapy in stage I non–small-cell lung cancer (NSCLC); however, many patients are inoperable due to comorbid diseases. Building on a previously reported phase I trial, we carried out a prospective phase II trial using stereotactic body radiation therapy (SBRT) in this population. Patients and Methods Eligible patients included clinically staged T1 or T2 ( 7 cm), N0, M0, biopsy-confirmed NSCLC. All patients had comorbid medical problems that precluded lobectomy. SBRT treatment dose was 60 to 66 Gy total in three fractions during 1 to 2 weeks. Results 100% of 70 patients enrolled completed therapy  - Median follow-up was 17.5 months.  - 3 mo major RR was 60%.  - Kaplan-Meier LC @ 2 years was 95%. - 28 patients have died as a result of cancer (n = 5),  - Treatment (n = 6) - Comorbid illnesses (n = 17) - Median OS was 32.6 mo - 2 yr OS was 54.7%.
  • The study was particularly instructive in terms of local toxicity:  8 patients were deemed by the data safety monitoring board to have grade 3 or 4 adverse events resulting from SBRT;  - the adverse events were primarily respiratory (decline in pulmonary function, PNA,  pleural effusion, apnea) and/or skin reaction;  occurred a median of 7.6 mo after completion of SBRT.  Six patients may potentially have had grade 5 (i.e., fatal) toxicity.  In five patients, these grade 5 adverse events were respiratory:  - one fatal hemoptysis (associated with a  local recurrence)  - four infectious pneumonias;  - Sixth patient died of complications from a  pericardial effusion.  These deaths occurred a median of 10.4 months after SBRT (range 0.6-19.5  mo).  Tumor location was a strong predictor of toxicity, with hilar or pericentral tumors showing an  11-fold increased risk in grade 3-5 adverse events when compared to more peripheral tumors (p=0.004).  2-year freedom from severe adverse events was 54% for these central tumors, as  compared to 83% for the peripheral tumors, defined as outside the “zone of the proximal bronchial tree”, which is a 2 cm radius around the main tracheo-bronchial tree: trachea; left and right main stem bronchi; right upper, middle, and lower lobe bronchus; and left upper, lingular, and lower lobe bronchus.  if solve for r w/vol=10cm^3 4/3*pi*r^3 r= 2.28cm d=4.56 cm
  • Defined as outside the “zone of the proximal bronchial tree”, which is a 2 cm radius around the main tracheo-bronchial tree: trachea; left and right main stem bronchi; right upper, middle, and lower lobe bronchus; and left upper, lingular, and lower lobe bronchus.  strong as tumor location, was the size of gross tumor volume (GTV), with > 10 cc tumors showing greater toxicity than smaller GTVs.
  • Purpose To evaluate the efficacy & adverse effects of image-guided SBRT in centrally/superiorly located NSCLC Materials and Methods -SBRT to 27 patients -13 w/Stage I  -14 w/isolated recurrent NSCLC A central/superior location was defined as being within 2 cm of the bronchial tree, major vessels, esophagus, heart, trachea, pericardium, brachial plexus, or vertebral body, but 1 cm away from the spinal canal.  4D CT planning & daily CBCT  - Prescribed dose of 40 Gy (n = 7) to the PTV - Escalated to 50 Gy (n = 20) in 4 consecutive days. Results -median f/up of 17 mo (range, 6–40 months) -Crude local control @ the tx'd site was 100% using 50 Gy.  - 3/7 patients tx'd w/40Gy had LR - Of those w/Stage I disease  - 7.7% Mediastinal failure - 15.4% Distant metastases Recurrent disease 21.4% Mediastinal failure 35.7% Distant failure  G2 pneumonitis 28.6% with recurrent disease   11.1% developed Grade 2-3 dermatitis and chest wall pain.  1 ptnt w/brachial plexus neuropathy.  No esophagitis was noted in any patient. Conclusions Image-guided SBRT using 50 Gy delivered in four fractions is feasible and resulted in excellent local control.
  • Purpose To evaluate the efficacy & adverse effects of image-guided SBRT in centrally/superiorly located NSCLC Materials and Methods -SBRT to 27 patients -13 w/Stage I  -14 w/isolated recurrent NSCLC A central/superior location was defined as being within 2 cm of the bronchial tree, major vessels, esophagus, heart, trachea, pericardium, brachial plexus, or vertebral body, but 1 cm away from the spinal canal.  4D CT planning & daily CBCT  - Prescribed dose of 40 Gy (n = 7) to the PTV - Escalated to 50 Gy (n = 20) in 4 consecutive days. Results -median f/up of 17 mo (range, 6–40 months) -Crude local control @ the tx'd site was 100% using 50 Gy.  - 3/7 patients tx'd w/40Gy had LR - Of those w/Stage I disease  - 7.7% Mediastinal failure - 15.4% Distant metastases Recurrent disease 21.4% Mediastinal failure 35.7% Distant failure  G2 pneumonitis 28.6% with recurrent disease   11.1% developed Grade 2-3 dermatitis and chest wall pain.  1 ptnt w/brachial plexus neuropathy.  No esophagitis was noted in any patient. Conclusions Image-guided SBRT using 50 Gy delivered in four fractions is feasible and resulted in excellent local control.
  • Context  Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management. Objective:  To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer. Design, Setting, and Patients  Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non–small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment.  EXCLUDED CENTRAL TUMORS (Proximal Zone) The prescription dose was 18 Gy per fraction × 3 fractions (54 Gy total) with entire treatment lasting between 1½ and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009. Main Outcome Measures  The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival.
  • Results   -59 patients accrued -55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors)  -Median f/u 34.4 mo (range, 4.8-49.9 months).  1o tumor failure was based on meeting both criteria: (1) local enlargement defined as at least a 20% increase in the longest diameter of the gross tumor volume per CT scan (2) evidence of tumor viability. Tumor viability could be affirmed by either demonstrating PET imaging with uptake of a similar intensity as the pretreatment staging PET, or by repeat biopsy-confirming carcinoma. Primary tumor failure included marginal failures occurring within 1 cm of the planning target vol- ume (1.5-2.0 cm from the gross tumor volume). Failure beyond the primary tumor but within the involved lobe was collected separately from dissemi- nated failure within uninvolved lobes. 1o tumor failure= marginal failures occurring w/in 1 cm of PTV (1.5-2.0 cm from the GTV Local failure= 1o tumor & involved lobe failure Local control= absence of local failure Regional Failure: 1o, involved lobe, hilum, &/or mediastinum. Disseminated Recurrence: failure beyond the local & regional sites (can include contralteral lobe) - 1 patient had a 1o Failure - Est 3yr LC rate 97.6% (95% CI 84.3%-99.7%) - 3 patients had recurrence w/in the involved lobe - 3 yr 1o tumor & involved lobe (local) control rate was 90.6% (95%CI,76.0%-96.5%) - 2 ptnts w/regional failure  - Local-regional control rate was 87.2% (95% CI, 71.0%-94.7%) - 11 patients exp dissem recurrence - 3yr rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%).  - 3yr DFS 48.3% (95% CI, 34.4%-60.8%) - 3 yr OS 55.8% (95% CI, 41.6%-67.9%) - Median OS 48.1 mo (95% CI, 29.6- not reached). 
  • Results   -59 patients accrued -55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors)  -Median f/u 34.4 mo (range, 4.8-49.9 months).  1o tumor failure= marginal failures occurring w/in 1 cm of PTV (1.5-2.0 cm from the GTV Local failure= 1o tumor & involved lobe failure Local control= absence of local failure Regional Failure: 1o, involved lobe, hilum, &/or mediastinum. Disseminated Recurrence: failure beyond the local & regional sites (can include contralteral lobe) - 1 patient had a 1o Failure - Est 3yr LC rate 97.6% (95% CI 84.3%-99.7%) - 3 patients had recurrence w/in the involved lobe - 3 yr 1o tumor & involved lobe (local) control rate was 90.6% (95%CI,76.0%-96.5%) - 2 ptnts w/regional failure  - Local-regional control rate was 87.2% (95% CI, 71.0%-94.7%) - 11 patients exp dissem recurrence - 3yr rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%).  - 3yr DFS 48.3% (95% CI, 34.4%-60.8%) - 3 yr OS 55.8% (95% CI, 41.6%-67.9%) - Median OS 48.1 mo (95% CI, 29.6- not reached). 
  • Results: Median f/u of 38.7 mo - 1 (2%) G4 pulmonary - 7 (13%) G3 pulmonary/upper respiratory adverse events 2/2 protocol - 2/7 reported PFT decrease - 1/7 reported cough/dyspnea - 1 reported hypoxia - 1 reported pneumonitis - 1 reported cough - 1 patient reported PNX  - 1 G3 dermatitis  - 1 G3 syncope reported as related to protocol treatment.  - No treatment related deaths have been reported. Comparison
  • 48Gy/4fx vs. 34Gy/1   If a/b 10 for early then 48Gy/4fx   BED - Early 105 BED - Late 240 34Gy/1 BED - Early 149Gy BED - Late 419Gy
  • 48Gy/4fx vs. 34Gy/1   If a/b 10 for early then 48Gy/4fx   BED - Early 105 BED - Late 240 34Gy/1 BED - Early 149Gy BED - Late 419Gy
  • Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy technique referred to as stereotactic body radiation therapy SBRT .  The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality.  Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures.  Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy technique referred to as stereotactic body radiation therapy SBRT .  The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality.  Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures. 
  • PET- noninvasive and highly sensitivie and thus excellent at ruling out disease - However, will miss disease about 14% of the time - Negative results from a sensitive test = rule out - Positive result from a specific test = rule in Mediastinscopy- Invasive w/increased sensitivity and sensitivity so useful for both ruling out and ruling in disease - However will still miss 7% of occult disease Even w/most sensitivie means of detecting disease, will miss 7-14% of occult disease resulting in nodal failures - So for every 10 PET scan, you will likely miss 1 presentation of occult disease unless staged operatively and w/imaging. - If we assume that each event are not mutually exclusion then the combined probability of obtaining a: - FN is 1- sensitivity= 7014% - If PET and Med = 1% - If PET and EBUS = 2-4% So for every patient staged at Wake - likely 2-4% chance of missing occult disease as we most commonly complete PET and EBUS (w/limited sampling)
  • PET- noninvasive and highly sensitivie and thus excellent at ruling out disease - However, will miss disease about 14% of the time - Negative results from a sensitive test = rule out - Positive result from a specific test = rule in Mediastinscopy- Invasive w/increased sensitivity and sensitivity so useful for both ruling out and ruling in disease - However will still miss 7% of occult disease Even w/most sensitivie means of detecting disease, will miss 7-14% of occult disease resulting in nodal failures - So for every 10 PET scan, you will likely miss 1 presentation of occult disease unless staged operatively and w/imaging. - If we assume that each event are not mutually exclusion then the combined probability of obtaining a: - FN is 1- sensitivity= 7014% - If PET and Med = 1% - If PET and EBUS = 2-4% So for every patient staged at Wake - likely 2-4% chance of missing occult disease as we most commonly complete PET and EBUS (w/limited sampling)
  • BACKGROUND: To assess for variables predicting pulmonary function test (PFT) changes after SBRT for medically inoperable stage I lung cancer. METHODS: -92 consecutive patients undergoing SBRT for stage I lung cancer between February 2004 and August 2007.  -A total of 102 lesions were treated using prescriptions of 20 Gy x 3 (n = 40), 10 Gy x 5 (n = 56), and 5 Gy x 10 (n = 6).  -Institutional practice was 10 Gy x 5 before March 1, 2006 before changing to 20 Gy x 3 to conform to RTOG 0236 unless otherwise dictated clinically. RESULTS: - Median pretreatment forced expiratory volume at 1 second (FEV1) was 1.21 liter (50% of predicted) and median diffusion capacity to carbon monoxide (DLCO) was 56.5.  **There was no significant overall change in PFT's after SBRT.  **Individual patients experienced both substantial improvements and declines (10% declined at least 14% predicted FEV1% and 19% predicted DLCO).  -The mean change in FEV1 was -0.05 liter (range, -0.98 to +1.29 liter; p = 0.22) representing -1.88% predicted baseline FEV1 (range, -33 to + 43%; p = 0.62).  -DLCO declined 2.59% of predicted (range, -37 to +33%; p = 0.27).  ** Conformality index, V5 and V10 were associated with individual patient changes in FEV1% (p = 0.033, p = 0.0036, p = 0.025, respectively), however, correlations were small and overall treatment dose did not predict for changes (p = 0.95).  -There was no significant difference in FEV1 (p = 0.55) or FEV1% (p = 0.37) changes for central versus peripheral locations.  -No factors predicted for individual changes in DLCO.  -Patients with FEV1% below the median of the study population had significantly longer overall survival (p = 0.0065).  -Although patients dying of cardiac disease died earlier than those dying of other causes, FEV1% below median was not associated with a lower risk of dying of cardiac disease or with lower Charlson comorbidity index. CONCLUSIONS: (1) SBRT was well tolerated and PFT changes were minimal.
  • BACKGROUND: To assess for variables predicting pulmonary function test (PFT) changes after SBRT for medically inoperable stage I lung cancer. METHODS: -92 consecutive patients undergoing SBRT for stage I lung cancer between February 2004 and August 2007.  -A total of 102 lesions were treated using prescriptions of 20 Gy x 3 (n = 40), 10 Gy x 5 (n = 56), and 5 Gy x 10 (n = 6).  -Institutional practice was 10 Gy x 5 before March 1, 2006 before changing to 20 Gy x 3 to conform to RTOG 0236 unless otherwise dictated clinically. RESULTS: - Median pretreatment forced expiratory volume at 1 second (FEV1) was 1.21 liter (50% of predicted) and median diffusion capacity to carbon monoxide (DLCO) was 56.5.  **There was no significant overall change in PFT's after SBRT.  **Individual patients experienced both substantial improvements and declines (10% declined at least 14% predicted FEV1% and 19% predicted DLCO).  -The mean change in FEV1 was -0.05 liter (range, -0.98 to +1.29 liter; p = 0.22) representing -1.88% predicted baseline FEV1 (range, -33 to + 43%; p = 0.62).  -DLCO declined 2.59% of predicted (range, -37 to +33%; p = 0.27).  ** Conformality index, V5 and V10 were associated with individual patient changes in FEV1% (p = 0.033, p = 0.0036, p = 0.025, respectively), however, correlations were small and overall treatment dose did not predict for changes (p = 0.95).  -There was no significant difference in FEV1 (p = 0.55) or FEV1% (p = 0.37) changes for central versus peripheral locations.  -No factors predicted for individual changes in DLCO.  -Patients with FEV1% below the median of the study population had significantly longer overall survival (p = 0.0065).  -Although patients dying of cardiac disease died earlier than those dying of other causes, FEV1% below median was not associated with a lower risk of dying of cardiac disease or with lower Charlson comorbidity index. CONCLUSIONS: (1) SBRT was well tolerated and PFT changes were minimal.
  • PET- noninvasive and highly sensitivie and thus excellent at ruling out disease - However, will miss disease about 14% of the time - Negative results from a sensitive test = rule out - Positive result from a specific test = rule in Mediastinscopy- Invasive w/increased sensitivity and sensitivity so useful for both ruling out and ruling in disease - However will still miss 7% of occult disease Even w/most sensitivie means of detecting disease, will miss 7-14% of occult disease resulting in nodal failures - So for every 10 PET scan, you will likely miss 1 presentation of occult disease unless staged operatively and w/imaging. - If we assume that each event are not mutually exclusion then the combined probability of obtaining a: - FN is 1- sensitivity= 7014% - If PET and Med = 1% - If PET and EBUS = 2-4% So for every patient staged at Wake - likely 2-4% chance of missing occult disease as we most commonly complete PET and EBUS (w/limited sampling)
  • Purpose: Routine assessment was made of tumor metabolic activity as measured by 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) in Stage I non–small-cell lung cancer (NSCLC). This report describes PET correlates prospectively collected after stereotactic body radiotherapy (SBRT) for patients with medically inoperable NSCLC . Methods and Materials: 14 consecutive patients with medically inoperable Stage I NSCLC were enrolled . All patients received SBRT to 60–66 Gy in three fractions. Patients underwent serial planned FDG-PET/computed tomography fusion imaging before SBRT and at 2, 26, and 52 weeks after SBRT. Results:  With median follow-up of 30.2 months , no patients experienced local failure.  One patient developed regional failure, 1 developed distant failure, and 1 developed a second primary. The median tumor maximum standardized uptake value (SUVmax ) before SBRT was 8.70. The median SUVmax values at 2, 26, and 52 weeks after SBRT were 6.04, 2.80, and 3.58, respectively.   Patients with low pre-SBRT SUV were more likely to experience initial 2-week rises in SUV, whereas patients with high pre-SBRT SUV commonly had SUV declines 2 weeks after treatment (p = 0.036).  Six of 13 patients had primary tumor SUVmax >3.5 at 12 months after SBRT but remained without evidence of local disease failure on further follow-up. Conclusions: A substantial proportion of patients may have moderately elevated FDG-PET SUVmax at 12 months without evidence of local failure on further follow-up. Thus, slightly elevated PET SUVmax should not be considered a surrogate for local treatment failure . Our data do not support routine serial FDG-PET/computed tomography for follow-up of patients receiving SBRT for Stage I NSCLC. Fig. 1. Maximum standardized uptake volume (SUVmax) over time. The SUVmax of the 14 study patients at the time of their positron emission tomography/computed tomography (SBRT) scans before and after stereotactic body radiation therapy is graphed. At 12months after SBRT, many patients still had SUVmax values of 3.5 or above, despite a lack of local failure seen on extended follow-up.
  • PURPOSE: The aim of this study was to assess the outcomes of patients treated with stereotactic body radiation therapy (SBRT) in patients with primary, recurrent, or metastatic lung lesions, with a focus on positron emission tomography (PET)/computed tomography (CT)-based management . PATIENTS AND METHODS: Fifty-one patients with primary stage I non-small-cell lung cancer  (NSCLC; n = 26), recurrent lung cancer after definitive treatment (n = 12), or solitary lung metastases (n = 13) were treated with SBRT between 2005 and 2007. Patients were treated with the CyberKnife Robotic Radiosurgery System with Synchrony respiratory tracking. A dose of 60 Gy was delivered in 3 fractions. All patients had CT or PET/CT performed at approximately 3-month intervals after treatment. RESULTS: The median follow-up was 12 months . Local control at median follow-up was 85% in patients with stage I NSCLC, 92% in patients with recurrent lung cancer, and 62% in the patients with solitary lung metastasis. Analysis of the 28 patients with pre- and post-treatment PET/CT scans demonstrated that those with stable disease (n = 4) had a mean standardized uptake value (SUV) decrease of 28%, partial responders (n = 11) had a decrease of 48%, and patients with a complete response (n = 11) had a decrease of 94%. Patients with progressive disease (n = 2) had an SUV decrease of only 0.4%. Only 2 patients (7%) who had reduced fluorodeoxyglucose avidity later progressed locally . No correlations were found between pretreatment SUV and tumor response, disease progression, or survival . Overall 1-year survival rates were 81%, 67%, and 85% among the patients with primary NSCLC, recurrent lung cancer, and solitary lung metastases, respectively. CONCLUSION: Stereotactic body radiation therapy with CyberKnife is an effective treatment for patients with medically inoperable recurrent or metastatic lung cancer. Positron emission tomography/CT is valuable in staging, planning, and evaluating treatment response and might predict long-term outcome.
  • The rate of hilar/mediastinal lymph node involvement found pathologically after surgery, despite a negative staging PET = 13% to 32%  PET-only staged patients treated with SBRT, however, show such failure to be only 4% to 10%, despite careful assessments for recurrence with follow-up imaging.  Why? Grills et al speculate that this may result from low-dose radiation spillage to regional lymph nodes;  - Other speculate there may be an immune “vaccination” effect caused by exposing tumor antigens after ablative radiation.  Target Population -prior trials were slow to accrue either 2/2 difficulty in comparable less invasive surgery or patient desire for choice.
  • Purpose To compare outcomes between lung stereotactic radiotherapy (SBRT) and wedge resection for stage I non–small-cell lung cancer (NSCLC). Patients and Methods One hundred twenty-four patients with T1-2N0 NSCLC underwent wedge resection (n = 69) or image-guided lung SBRT (n = 58) from February 2003 through August 2008. All were ineligible for anatomic lobectomy; of those receiving SBRT, 95% were medically inoperable, with 5% refusing surgery. Mean forced expiratory volume in 1 second and diffusing capacity of lung for carbon monoxide were 1.39 L and 12.0 mL/min/mmHg for wedge versus 1.31 L and 10.14 mL/min/mmHg for SBRT (P = not significant). Mean Charlson comorbidity index and median age were 3 and 74 years for wedge versus 4 and 78 years for SBRT (P < .01, P = .04). SBRT was volumetrically prescribed as 48 (T1) or 60 (T2) Gy in four to five fractions. Results Median potential follow-up is 2.5 years. At 30 months, no significant differences were identified in regional recurrence (RR), locoregional recurrence (LRR), distant metastasis (DM), or freedom from any failure (FFF) between the two groups (P > .16). SBRT reduced the risk of local recurrence (LR), 4% versus 20% for wedge (P = .07). Overall survival (OS) was higher with wedge but cause-specific survival (CSS) was identical. Results excluding synchronous primaries, nonbiopsied tumors, or pathologic T4 disease (wedge satellite lesion) showed reduced LR (5% v 24%, P = .05), RR (0% v 18%, P = .07), and LRR (5% v 29%, P = .03) with SBRT. There were no differences in DM, FFF, or CSS, but OS was higher with wedge. Conclusion Both lung SBRT and wedge resection are reasonable treatment options for stage I NSCLC patients ineligible for anatomic lobectomy. SBRT reduced LR, RR, and LRR. In this nonrandomized population of patients selected for surgery versus SBRT (medically inoperable) at physician discretion, OS was higher in surgical patients. SBRT and surgery, however, had identical CSS.
  • - Over the last decade, many studies have emerged suggesting equivalency between sublobar and lobar resection for the treatment of peripheral, early-stage NSCLC. - Many of these recent contributions emanate from investigators in Japan, where CT screening programs have been in place to detect lung cancer for over 10 years. - Several of these groups have demonstrated comparable outcomes using sublobar resection as primary treatment for lung cancer, even in good-risk patients - It is important to note that, despite the favorable outcomes seen among several Japanese reports, similar results may not necessarily be applicable to Western studies.  ---? higher incidence of more indolent lung cancers such as bronchoalveolar carcinoma, which is more likely to have improved survival at early stages of disease

Early stage lung_cancer- jtl Early stage lung_cancer- jtl Presentation Transcript

  • Early Stage Lung Cancer Wake Forest Baptist Medical Center Radiation Oncology Department John T. Lucas Jr. MD, MSCR PGY2
  • Outline
    • Management
    • Treatment Options
    •     Surgery
    •     Alternative Ablative Modalities
    •     Radiotherapy
    • SBRT
    •     History
    •     Technique
    •     Dose, Fractionation
    •     Dose Constraints 
    •     Side Effects/Complications
    •     Post Treatment Surveillance
    •     Outcomes
    • Ongoing Trials
    •           
  • Surgery
    • - Types of Resection
    • - Operability
    • - Outcomes
    • - QOL
  • Surgery - Types
    • - Types of Resection
    •                      - Pneumonectomy
    •                      - Lobectomy
    •                      - Sublobar: 
    •                          - Segmentectomy
    •                              - Sleeve Segmentectomy
    •                          - Wedge Resection
    •     
    "Sleeve"
  • Surgery - Types
    • Operability
    •     Min absolute FEV1 for:
    •          Pneumonectomy > 2L
    •         Lobectomy > 1.5L
    •         Wedge < 1.5L (variable)
    •      RTOG 0813 def:
    •         FEV1 50%, DLCO 50%
    • Morbidity Predictors:
    •      1. pCO2 <45 mm Hg 
    •      2. pO2 <50 mm Hg 
    •      3. Preop FEV1 <40% of predicted value 
    •      4. Poor exercise tolerance 
    •      5. DLCO <50% of predicted value
    •      6. Postop FEV1 <0.71 or <30% of predicted value
    •      7. Cardiac problems (LV EF<40%, myocardial infarction within 6 mos, arrhythmias) 
    •      8. Obesity 
    •     9. Ongoing smoker pre and post surgery
    •                     
  • Surgery - Morbidity
    •     
    Lobectomy vs. Pneumonectomy Tobias Schulte, Bodo Schniewind, Peter Dohrmann, Thomas Küchler and Roland Kurdow. The Extent of Lung Parenchyma Resection Significantly Impacts Long-Term Quality of Life in Patients With Non-Small Cell Lung Cancer. Chest 2009;135;322-329
  • Surgery - Morbidity
    •     
    Tobias Schulte, Bodo Schniewind, Peter Dohrmann, Thomas Küchler and Roland Kurdow. The Extent of Lung Parenchyma Resection Significantly Impacts Long-Term Quality of Life in Patients With Non-Small Cell Lung Cancer. Chest 2009;135;322-329
  • Surgery - Types - Sublobar Resection
    •     
    Errett LE et al J Thorac Cardiovasc Surg. 1985 Nov;90(5):656-61  - Not a new idea - 1985
  • Surgery - Types - Sublobar Resection
    •     
    RJ Ginsberg, LV Rubinstein and Lung Cancer Study Group Ann Thorac Surg 1995;60:615-23 - Prospective, multi-institutional randomized trial - Lobectomy vs. Sublobar for Early Stage NSCLC = 1.26 & .016% = 4.7 & 2.52% = 3.83 & 1.3%
  • Surgery - Types - Sublobar Resection RJ Ginsberg, LV Rubinstein and Lung Cancer Study Group Ann Thorac Surg 1995;60:615-23 - Lobectomy vs. Sublobar for Early Stage NSCLC
  • Thermal Ablation Cryoablation (Cooltip) Microwave ablation
    •     
    Alternative Ablative Modalities
    • Retrospective Single Center
    • 420 Patients
    • 33% w/1o Lung, 67% w/Metastasis
    • 1000 Cool-tip RFAs
    Alternative Ablative Modalities AJR Am J Roentgenol. 2011 Oct;197(4):W576-80. Complications after 1000 lung radiofrequency ablation sessions in 420 patients: a single center's experiences. Kashima M, Yamakado K, Takaki H, Kodama H, Yamada T, Uraki J, Nakatsuka A.
    • Complications
    Alternative Ablative Modalities
  • Radiotherapy- Historical Perspective
    • Standard approach involves giving approximately 45-66 Gy total dose in 1.8-2.0 Gy fractions.
    • - Relationship in both survival and local control in these patients. - Review of 156 medically inoperable stage I NSCLC patients at Duke University between 1980 and 1995 demonstrated a five-year, cause-specific survival of 32% with radiotherapy alone.         
    •      Improved survival was significantly correlated with achieving local control and approached significance for higher radiotherapy dose (p=0.07).
    • - Historically treated area included regional lymphatics in the ipsilateral hilum and mediastinum. This “prophylactic” treatment was based on identified risk of occult nodal involvement from surgical series ranging up to 20%, and surgical data indicating better control with more extensive resections.
    • - Nonetheless, large  radiotherapy fields are potentially poorly tolerated in this population with limited pulmonary reserve. (Curran WJ, Moldofsky PJ, Solin LJ. Analysis of the influence of elective nodal irradiation on postirradiation pulmonary function. Cancer. 65:2488-93, 1990.)
    • Early technique used 1D-2D planning and didn’t:
      • visualize the target
      • had limitations in selection of beam directions
      • limitations in computational algorithms describing deposited dose.
    Sibley GS, Jamieson TA, Marks LB, Anscher MS, Prosnitz LR. Radiotherapy alone for medically inoperable stage I non-small cell lung cancer: The Duke experience. Int J Radiat Oncol Biol Phys. 40(1): 149-54, 1998.
  • Radiotherapy- Historical Perspective
    • Researchers at the Karolinska Hospital in Stockholm, Sweden developed an extracranial stereotactic frame and began treatment with the device in 1992.
    • - Blomgren, et al., reported on 17 patients treated with stereotactic radiotherapy for intrathoracic metastases with follow-up
    • of 3.5 to 25 months.
    • 25 Tumors ranged in size from 1.8 cm to 7.2 cm. 
    • Margin doses ranges from 20 Gy in one fraction to 45 Gy in three fractions.
    • Response was measured by repeat CT scans demonstrating:
    • Disappearance in 35%
    • Reduction in 41%
    • Stabilization in 18%
    • Progression in only one patient (the largest tumor treated in the report).
  • SBRT - Rationale
    • -Conventionally fractionated RT (ie, cGy per fraction) operates on a portion of the cell survival curve describing the logarithm of clonagenic survival as a function of dose called the shoulder. 
    • -In this shoulder region, an increasing dose per fraction corresponds to small decrements in cell survival due
    • to the ability of the tumor cell to repair modest damage (called sublethal damage). 
    • -At some point with the increasing dose per fraction, these repair mechanisms become overwhelmed, and the logarithm of clonagenic survival becomes linear with increasing doses (called exponential cell killing). 
    • -The dose per fraction and the total dose levels attained with ESR in this trial operated well beyond the shoulder, and its biological potency at disabling tumor clonogenicity should be significant.
  • SBRT
    •     Dose, Fractionation
    •     Outcomes
    •     Technique
    •     Dose Constraints 
    •     Side Effects/Complications
    •     Post Treatment Surveillance
  • SBRT Dose/Fractionation Phase 1 Dose Finding Study 37 Stage 1 NSCLC Patients 1o Objective: Est DLT/MTD 8Gy x 3 to the 80% IDL 10Gy x 3 12Gy x 3 14Gy x 3 16Gy x 3 18Gy x 3 20Gy x 3 @ 14Gy stratified to escalate dose independently for T1 & T2 tumors
  • SBRT Dose/Fractionation - Didnt reach MTD - No diff in Tox b/n T1 or T2 - No heterogeneity correction - No significant cardiopulmonary toxicity - 87% Objective RR, 27% CR - 6 failures in patients all <18Gy/fx 8Gy x 3 to the 80% IDL 10Gy x 3 12Gy x 3 14Gy x 3 16Gy x 3 18Gy x 3 20Gy x 3
  • SBRT Dose/Fractionation Retrospective Multicenter 257 Stage 1 NSCLC Patients Widely variable dose/fractionation: 18-75Gy, 1-22Fx
  • SBRT Dose/Fractionation
    • Phase II - Single Center
    • 70 Patients w/ T1,T2 N0 M0 
    • Tx: 60-66Gy / 3 Fx 
    • Median f/u 17.5 mo
    Robert Timmerman, and James Fletcher. J Clin Oncol 24:4833-4839. 2006 LC @ 2 years was 95%   Median OS 32.6 mo  2 yr OS 54.7%
  • SBRT Dose/Fractionation 2 yr freedom from toxicity -Central: 54% -Peripheral: 83% - Only additional predictor of toxicity was size of GTV, with > 10 cc tumors showing greater toxicity than smaller GTVs. - G3/4 Toxicity events occurred a median of 7.6 mo after completion of SBRT.
  • SBRT Dose/Fractionation
  • SBRT Dose/Fractionation Prospective Cohort 27 Patients w/Central NSCLC (Recurrent (14) or Stage 1 (13) Median f/u of 17 mo  - Prescribed dose of 40 Gy (n = 7) to the PTV - Escalated to 50 Gy (n = 20) in 4 consecutive days 1 patient experienced a brachial plexopathy       w/20% of plexus recieving >40Gy LC was poor w/<50Gy~ 3/7 failed Not powered for any objectives, limited conclusions can be drawn      - However 50Gy/4 fractions appears safe for central tumors     - <50Gy is associated w/a higher failure rate
  • SBRT Dose/Fractionation Central Dose Question is currently being evaluated prospectively w/: RTOG 0813     Phase I/II Study of SBRT in Medically Inoperable Patients w/Centrally Located Stage I NSCLC      Dose Escalation: 50Gy/5fx --> 52.5/5 --> 55/5 --> 57.5/5 --> 60Gy/5fx     - Has high dose conformality index requirements that necessitate noncoplanar beam arrangement     - OARs are limited to <105% of prescribed dose     - Low and High Dose spillage are highly restrictive
  • SBRT Dose/Fractionation - RTOG 0236
    • Phase 2 Multi-center Trial
    • Peripheral Stage 1 NSCLC - Medically Inoperable 
    • 1 o Objective: Eval Toxicity and Efficacy in high risk patients
    • Of 55 evaluable patients, 44 had T1 & 11 had T2 tumors. 
    • Tx: 60Gy /3 fx --> Didnt correct for tissue inhomogeneity but retrospective analysis 
    •      shows a total dose of 54Gy / 3 fx
    • Median f/u 34.4 mo
    • The study was activated in May 2004 and opened in 8 sites, after those sites had completed the         
    •      credentialing process.  RTOG 0236 was closed October 2006. 
  • SBRT Dose/Fractionation - RTOG 0236
    • 1o Failure =   2.4% @ 3yrs (CI 0.3-15.7%)
    • 1 patient
    • Involved Lobe Failure = Local failure - 1o Failure = 10.4%-2.4% = 8%
    • Local Failure = 1o failure + Involved lobe failure =   10.4% @ 3 yrs (CI 3.5-24%)
    • 3 patient (involved lobe 2nd 1o)
    • Regional Failure  = hilum + mediastinum = local regional - local failure = 12.8%-10.4% = 2.4%
    • 2 involved lobe & mediastinum, 1 hilum alone 
    •  
    • Local-regional Failure =1o Failure+Involved lobe+hilum+mediastinum= 12.8%@3yrs (CI 5.3%-29%)
    • Disseminated Failure =  22.1% @ 3yrs (CI 12.3%-37.8%)
    • 11 patients 
    •      1 mediastinum & dissem
    •      8 dissem alone
    •      2 NOS
    •    - 30.7% Adeno, 6% SCC 
  • SBRT Dose/Fractionation - RTOG 0236
    • - 3yr DFS 48.3% (95% CI, 34.4%-60.8%)
    •     - 34.4 Mo (95% CI 34.4 mo-NA)
    • - 3 yr OS 55.8% (95% CI, 41.6%-67.9%)
    •      - Median OS 48.1 mo (95% CI, 29.6- NA)
    •      10 patients died of lung cancer
    •     16 patients died of other causes
    •          5 of comorbid problems: - Stroke, MI, COPD exacerbation, & 2nd malignancy
    •          2 of nonprotocol medical interventions
    •         9 of unknown causes
  • SBRT Dose/Fractionation - RTOG 0236
    • Toxicities
    • Median f/u of 38.7 mo
    • - 1 (2%) G4 pulmonary
    • - 2/7 reported PFT decrease
    • - 1/7 reported cough/dyspnea
    • - 1 reported hypoxia
    • - 1 reported pneumonitis
    • - 1 reported cough
    • - 1 patient reported PNX 
    • - 1 G3 dermatitis 
    • - 1 G3 syncope reported as related to protocol treatment. 
    • - 7 (13%) G3 pulmonary/upper respiratory adverse events 2/2 protocol
    • *Median Time to Toxicity not evaluated
    • - No treatment related deaths have been reported.
  • SBRT Outcomes
    • Recently Closed
    • RTOG 0915 - Closed 3/22/2011 
    •      A Randomized Phase II Study Comparing 2 SBRT Schedules (48Gy/4fx vs. 34Gy/1) for Medically 
    •      Inoperable Patients with Stage I Peripheral Non-Small Cell Lung Cancer 
    • RTOG 0618 - Closed 5/17/10 - Analysis planned for 6/2012
    •      A Phase II Trial of SBRT in the Treatment of Patients with Operable Stage I/II NSCLC
    • ROSEL   - Closed 4/4/11 due to poor accrual
    •      Radiosurgery or Surgery for Operable Stage 1 NSCLC - Netherlands Trial 
  • SBRT Outcomes
    • Current Trials
    • ACOSOG RTOG 1021 
    •    Phase 3 Sublobar Resection +/- Brachytherapy vs. SBRT (54Gy/3fx)
    • STARS - 
    •     Phase 3 Randomized Study to Compare Cyberknife to Surgical Resection (any) in Stage 1 NSCLC
    •       Central lesion: 15 Gy x 4 fractions = 60 Gy; Peripheral lesion: 20 Gy x 3 fractions = 60 Gy  
  • SBRT Technique
    •  
  • SBRT Technique
    •  
  • SBRT Technique
    •  
    Composite 4d (MIP) Breath Hold CT
  • SBRT Technique
    •  
    Med Phys. 2004 Dec;31(12):3179-86. Four-dimensional (4D) PET/CT imaging of the thorax. Nehmeh SA, Erdi YE, Pan T, Pevsner A, Rosenzweig KE, Yorke E, Mageras GS, Schoder H, Vernon P, Squire O, Mostafavi H, Larson SM, Humm JL.
  • SBRT Technique
    •  
  • SBRT Technique - Constraints
    • AAPM Task Group 101 
    AAPM Task Group 101 SBRT Dose Constraints
  • SBRT Post Treatment Surveillance
    • Monitor for:
    • - Early treatment effects
    • - Late radiotherapy effects (median time to G3/4 tox ~8mo)
    • - Appearance of occult disease
    • - Failure at primary site
    • - Failure at distant site
  • SBRT Post Treatment Surveillance
    • Early Stage- f/u visits
    •      Post Tx: @ 2 mo then q4mo thereafter for 2 yrs
    •          2 mo visit to establish baseline CT prior to tx change
    •          q4mo visits: CT w/out contrast if no concerns
    •      2 Yrs Post Tx: q6mo for 5 yrs w/CT
    •      5 yrs Post Tx: q1yr w/CT
    • Monitor for: Early treatment effects
    • - PFT changes
    •     - No SS change in FEV1 or DLCO
    •     - If <6 mo out, pneumonitis possible
    SBRT Post Treatment Surveillance J Thorac Oncol. 2009 Jul;4(7):838-44. Comprehensive analysis of PFT changes after SBRT for stage I lung cancer in medically inoperable patients. Stephans KL, Djemil T, Reddy CA, Gajdos SM, Kolar M, Machuzak M, Mazzone P, Videtic GM.
  • SBRT Post Treatment Surveillance
    • Monitor for: Early treatment effects - PFT changes
    J Thorac Oncol. 2009 Jul;4(7):838-44. Comprehensive analysis of pulmonary function Test (PFT) changes after stereotactic body radiotherapy (SBRT) for stage I lung cancer in medically inoperable patients. Stephans KL, Djemil T, Reddy CA, Gajdos SM, Kolar M, Machuzak M, Mazzone P, Videtic GM.
  • SBRT Post Treatment Surveillance
    • Monitoring for Occult Disease
    •     - PET
    •          Sensitivity - 86%
    •         Specificity - 88%
    •     - Mediastinoscopy
    •         Sensitivity - 93%
    •         Specificity - 100%
    •     - EBUS
    •         Sensitivity - 76%
    •         Specificity - 97%
    Chest. 2003 Jan;123(1 Suppl):137S-146S. Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Toloza EM, Harpole L, McCrory DC. PET
  • SBRT Post Treatment Surveillance
    • Monitoring for Primary Site Failure
    • - Complicated by:
    •     - Post RT changes
    •         - Radiation pneumonitis
    •         - Radiation fibrosis
    •         - Effusion
    •     - Other disease processes w/in the lung
    •         - Infection/Pneumonia
    •         - Bronchiectasis
    •         - Atelectasis
    •     - Actual Treatment Failure
    •         - Local progression
    •         - Subclinical lyphmangitic spread
    Larici. Lung Abnormalities at Multimodality Imaging after Radiation Therapy for NSCLC. May 2011 RadioGraphics, 31, 771-789.
  • SBRT Post Treatment Surveillance
    • Monitoring for Primary Site Failure
    • Post Radiation Treatment Changes
    • - 1-6 mo RT Pneumonitis
    •     - Ground glass opacities, consolidation w/in radiation port
    •     - Potential ipsiateral pleural effusion
    •     - 4 patterns (Ikezoe)
    •         - ground glass opacities
    •         - patchy consolidation and ground glass opacities
    •         - patchy ground glass opacities
    •         - scar like 
    • - 6-12 mo Radiation Fibrosis
    •     - Well defined area of volume loss w/linear scar or
    • consolidation w/parenchymal distortiona and traction 
    •          bronchiectasis conforming to treatment portals
    Larici. Lung Abnormalities at Multimodality Imaging after Radiation Therapy for NSCLC. May 2011 RadioGraphics, 31, 771-789. 2 months 3 months 6 months Before
  • SBRT Post Treatment Surveillance
    • Monitoring for Primary Site Failure
    • Algorithm for post treatment CT surveillance
    Site Abnormality  - after comparison to prior CT scans Significant + in size w/no air bronchograms Moderate + in size PET Scan vs. Biopsy Short interval f/u w/CT Empiric Tx w/ roids & abtx Short interval f/u w/CT
  • SBRT Post Treatment Surveillance
    • Role of PET in f/u s/p SBRT
    •      Sensitivity and specificity of FDG-PET/CT for detecting recurrence has historically been estimated to
    • range from 93% to 100% and 82% to 92%, respectively
    • More recently found to be controversial
    Mac Manus MP, Ding Z, Hogg A, et al. Association between pulmonary uptake of fluorodeoxyglucose detected by positron emission tomography scanning after radiation therapy for nonsmall-cell lung cancer and radiation pneumonitis. Int J Radiat Oncol Biol Phys. [Epub ahead of print July 31, 2010].
  • SBRT Post Treatment Surveillance
    • Role of PET in f/u s/p SBRT
    • - Hoopes et al demonstrated that 
    •      moderate HM activity may persist
    •      for up to 2 yrs after completion of
    •      SBRT w/out definite evidence of
    •      recurrence. 
    • Validated prospectively w/a
    • small number of patients
    Mac Manus MP, Ding Z, Hogg A, et al. Association between pulmonary uptake of fluorodeoxyglucose detected by positron emission tomography scanning after radiation therapy for nonsmall-cell lung cancer and radiation pneumonitis. Int J Radiat Oncol Biol Phys. [Epub ahead of print July 31, 2010].
  • SBRT Post Treatment Surveillance
    • A study from the University of Pittsburgh demonstrated a significant correlation with mean SUV and treatment response. (mean SUV decreases)
    •      Complete responders, 94%, 
    •      Partial responders 48%, 
    •      Stable disease 28%
    • Patients with progressive disease had an SUV decrease of only 0.4%.
    • However this study only had once LR, so their definition of CR, PR, SD is arbitrary and w/out clinical
    • relevance
    Clin Lung Cancer. 2008 Jul;9(4):217-21. Fractionated stereotactic body radiation therapy in the treatment of primary, recurrent, and metastatic lung tumors: the role of positron emission tomography/computed tomography-based treatment planning. Coon D, Gokhale AS, Burton SA, Heron DE, Ozhasoglu C, Christie N.
  • SBRT Post Treatment Surveillance
    • Monitoring for Distant Failure
    • Evaluate bony, mediastinal windows for recurrence
    • - Mediastinal changes suspicious include + size of LAD or loss of fatty hilum
    • - Complicating factors can include associated comorbidities such as:
    •     - CHF exacerbation
    •     - Chronic Bronchitis
    •     - TB/MAC infection i.e. HIV patients
    • Algorithm for post treatment CT surveillance
    High Suspicion @ Primary Site  for recurrence Restage w/PET C/A/P
  • Fin
  • SBRT Treatment Failure - Salvage
    • To be discussed at a later date…
  •  
    • 1. maximal tolerated dose for peripheral primary tumors less than 7 cm is 60 to 66 Gy in three  fractions.
    • 2. The maximal tolerated dose for centrally located primary tumors less than 7 cm is unknown but is exceeded by doses of 60 to 66 Gy in three fractions. 
    • 3. A prescription dose less than 54 Gy in three frac- tions is associated with maximal local control of approximately 70% to 80% for patients treated in
    • prospective trials with adequate follow-up in North America and Europe.
    • 4. A prescription dose of 54 Gy or more in three fractions has been demonstrated to achieve local control in more than 90% of treated tumors in prospective testing.
    • 5. Despite clinical staging, isolated hilar and mediastinal nodal failures occur in less than 5% of patients after SBRT.
    • 6. Despite staging with whole body PET scans, ap- proximately 20% of patients develop distant meta- static disease.
    • 7. Although it is well-known that toxicity after large dose per fraction treatment occurs late, it is also recognized that tumor recurrence likewise occurs
    • late after treatment with the median time to recur- rence of 16 to 24 months after therapy. 
    • 8. Despite excellent local control after SBRT, patient survival for medically inoperable early-stage lung cancer is very poor, mainly due to severe and life- threatening coexisting morbidities and the eventual appearance of metastatic disease.
  •  
    • How do we stage early stage lung cancer patients who are planned for surgical eval?
    • Why do PET only staged patients who go for SBRT have lower regional failures?
    • What is the most appropriate group for comparing surgical vs. nonsurgical (SBRT) intervention for early stage lung cancer?
    •      - 20% to 25% of patients with earlystage lung cancer are not considered candidates for lobar resection
    •          because of concomitant severe cardiac or pulmonary comorbidities
    •     - Varying modilty of choice by location? 
    •         - Peripherally located tumors 3 cm, sublobar resection by an anatomic segmentectomy (rather than 
    •          a wedge resection) may result in OS & CSS ~ to lobectomy
    •         - Centrally located within a lobe or close to the lobar bronchi have no viable surgical option other than lobectomy which, in this patient population, may be associated with a prohibitive morbidity & higher mortality. 
  • SBRT Outcomes
    •  
    Timmerman, Journal of Thoracic Oncology • Vol. 2, No. 7, Supplement 3, July 2007
  • SBRT vs. Wedge Resection
  • Radiotherapy- Historical Perspective
    • A key issue that must be considered when comparing these modalities based on available literature is that the definitions of local recurrence, local control, and regional recurrence are not uniform. This has led to
    • different perceptions and interpretations of the published literature relating to these modalities. In the
    • surgical literature, local recurrence variably includes recurrence occurring within the same lobe, sometimes another lobe within the same ipsilateral lung, hilar and sometimes ipsilateral mediastinal lymph nodes [2,18,102]. 
    • In the SBRT literature, local recurrence usually is synonymous with primary tumor control, i.e., limited to recurrence within and sometimes within 1cm of the planning treatment volume (PTV) [12,101]. The more
    • appropriate convention for characterizing recurrence definitions is a reflection on the original TNM staging.
    • As such, a recurrence of the original primary tumor (originally characterized by the T of the TNM staging
    • including the primary tumor and involved lobe) is deemed a local recurrence. A recurrence in the primary
    • tumors draining lymph nodes (hilar and mediastinal as originally characterized by the N of the TNM staging) is deemed a regional recurrence. Finally, a recurrence in distant sites (originally characterized by the M of the TNM staging) is deemed a disseminated recurrence. By this convention, both the more recent surgical literature and SBRT literature have been guilty of inappropriate recurrence definitions making comparisons difficult.
  • Surgery -  -Lobectomy vs.  Sublobar Resection
    •     
    Sublobar resection for lung cancer.  SERIES ‘‘LUNG CANCER’’ Number 2 in this Series.   R. Rami-Porta* and M. Tsuboi#  Edited by C. Brambilla.  
  • Radiotherapy- Historical Perspective
    • At Indiana University, a phase I dose escalation protocol has been completed for the treatment of
    • medically inoperable patients with AJCC Stage I lung cancer. 26 SBRT (a.k.a. extracranial
    • stereotactic radioablation) with large doses per fraction was delivered in an extracranial
    • stereotactic body frame, which includes a system to decrease respiratory motion. The starting
    • dose was 8 Gy times 3 (24 Gy total), and fraction dose was escalated by 2 Gy per fraction for
    • each cohort. The target lesion was outlined by a physician and designated as the gross tumor
    • volume (GTV). An additional 0.5 cm in the axial plane and 1.0 cm in the longitudinal plane was
    • added to the GTV to constitute the PTV based on validation measurements for this commercially
    • available system.27-29 Typically, 7-10 non-coplanar beams were used to encompass the PTV.
    • Dose was prescribed to the 80% line; however, higher isodoses (hotspots) occurred within the
    • central core of the target mimicking the heterogenous dose profile common to intracranial
    • stereotactic radiosurgery. The higher dose in the tumor core is intended to give extra dose in
    • areas of presumed greatest tumor hypoxia and radioresistance. The treatment isocenter was
    • identified with 3-D coordinates defined stereotactically and localized on verniers attached to the
    • frame. No skin or bony landmarks were used to set the treatment isocenter, however; orthogonal
    • port films were used on a daily basis for isocenter verification. 30 Separate dose escalations were
    • carried out independently for patients with T1 versus T2 small (< 5 cm) versus T2 large (5-7 cm)
    • tumors at diagnosis.