Chapter 51 Lung Cancer Flashcards
Among male Lung cancer is the most commonly diagnosed cancer and leading cause of cancer death!
Among female worldwide, lung cancer is third most commonly diagnosed cancer and second leading cause of death!
True
False(4th most commonly diagnosed cancer and 2nd leading cause of cancer death)
What is the 5-year survival rate of lung cancer?
16%
What is the most common cause of lung cancer?
Cigarette smoking
Voluntary or involuntary cigarette smoking accounts for what percentage of lung cancer?
80-90%
What percentage of lung cancer increase in risk from secondhand smoke exposure living with a smoker?
30%
What are the other known risk factors exposure for lung cancer besides cigarette smoking?
Asbestos
Arsenic
Polycyclic aromatic hydrocarbon
Which structure in left lung is homologous to right middle lobe?
Lingula located in left upper lobe of left lung
What is the functional unit of lung?
Bronchopulmonary segment defined by segmental bronchi
How are structures entering and exiting the bronchopulmonary segment arranged?
Structures entering bronchopulmonary segment(bronchus and artery) lie centrally and structures leaving the segment(veins and lymphatics) lie in the periphery
Describe lymphatic drainage of bronchopulmonary segment
Main lymphatic drainage for each segment follows vasculature and airways towards hilum where it ultimately drains into mediastinum.
What does IASLC(International Association for the study of Lung Cancer) lymph node mapping depends on?
Precise anatomic definition for all lymph node stations
Describe the pattern of spread of lung cancer
Locally by direct extension 15%
Regionally by lymphatics 22%
Distantly by invasion of vascular channels 56%
Unknown 7%
Describe the presentation of NSCLC and SCLC
NSCLC half present with localized or locally advanced disease
SCLC 20-30% locally advanced, 70-80% advanced disease
Describe 8 clinical presentations of lung cancer
- Cough 50-75%
- Hemoptysis, dyspnoea 25%
- Chest pain 20%
- Malignant pleural effusion 10-15%
- Hoarseness recurrent laryngeal nerve involvement
- Hiccup, SOB irritation of phrenic nerve with progression leading to unilateral paralysis of diaphragm
- Fullness of head, dyspnoea, jugular venous distension, swelling of face and arm SVC syndrome
- Shoulder pain, horner’s syndrome, brachial plexopathy (Pancoast’s syndrome) - tumor arising from superior sulcus
SVC syndrome is more common in which lung tumor type?
SCLC
Pancoast’s syndrome is common in which lung tumor type?
NSCLC
What are the sites of distant extra thoracic spread of lung cancer?
Contralateral lung Liver Bone Adrenals Brain
What are the evidence of liver metastasis in CT, PET-CT, autopsy in lung cancer?
CT 3%
PET-CT 4%
Autopsy >50%
What is the presentation of bone metastasis in lung cancer at presentation?
NSCLC 20%
SCLC 30-40%
What is the most common sites of bone metastasis in lung cancer?
Vertebral bodies
Which type of bone metastasis is more common in lung cancer?
Osteolytic
What percentage of adrenal biopsies showed metastatic involvement despite having a normal CT scan in lung cancer?
17%
40% at autopsy series
Isolated adrenal metastasis with limited thoracic disease in lung cancer. What is the management?
Aggressive definitive management
Frequency of brain metastasis is greatest in adenocarcinoma or SCC lung?
Adenocarcinoma lung
What are the tumor factors which increase the risk of brain metastasis in lung cancer?
Primary tumor size
Regional node involvement
What is the percentage of brain metastasis at presentation in SCLC?
20-30%
80% in autopsy series
What is the incidence of metastatic relapse in brain without prophylactic irradiation in lung cancer?
One-half patient within 2 years
Describe lymphatic drainage of bronchopulmonary segment
Main lymphatic drainage for each segment follows vasculature and airways towards hilum where it ultimately drains into mediastinum.
What does IASLC(International Association for the study of Lung Cancer) lymph node mapping depends on?
Precise anatomic definition for all lymph node stations
Describe the pattern of spread of lung cancer
Locally by direct extension 15%
Regionally by lymphatics 22%
Distantly by invasion of vascular channels 56%
Unknown 7%
Describe the presentation of NSCLC and SCLC
NSCLC half present with localized or locally advanced disease
SCLC 20-30% locally advanced, 70-80% advanced disease
Describe 8 clinical presentations of lung cancer
- Cough 50-75%
- Hemoptysis, dyspnoea 25%
- Chest pain 20%
- Malignant pleural effusion 10-15%
- Hoarseness recurrent laryngeal nerve involvement
- Hiccup, SOB irritation of phrenic nerve with progression leading to unilateral paralysis of diaphragm
- Fullness of head, dyspnoea, jugular venous distension, swelling of face and arm SVC syndrome
- Shoulder pain, horner’s syndrome, brachial plexopathy (Pancoast’s syndrome) - tumor arising from superior sulcus
SVC syndrome is more common in which lung tumor type?
SCLC
Pancoast’s syndrome is common in which lung tumor type?
NSCLC
What are the sites of distant extra thoracic spread of lung cancer?
Contralateral lung Liver Bone Adrenals Brain
What are the evidence of liver metastasis in CT, PET-CT, autopsy in lung cancer?
CT 3%
PET-CT 4%
Autopsy >50%
What is the presentation of bone metastasis in lung cancer at presentation?
NSCLC 20%
SCLC 30-40%
What is the most common sites of bone metastasis in lung cancer?
Vertebral bodies
Which type of bone metastasis is more common in lung cancer?
Osteolytic
What percentage of adrenal biopsies showed metastatic involvement despite having a normal CT scan in lung cancer?
17%
40% at autopsy series
Isolated adrenal metastasis with limited thoracic disease in lung cancer. What is the management?
Aggressive definitive management
Frequency of brain metastasis is greatest in adenocarcinoma or SCC lung?
Adenocarcinoma lung
What are the tumor factors the increase the risk of brain metastasis in lung cancer?
Primary tumor size
Regional node involvement
What is the percentage of brain metastasis at presentation in SCLC?
20-30%
80% in autopsy series
What is the incidence of metastatic relapse in brain without prophylactic irradiation in lung cancer?
One-half patient within 2 years
Describe Paraneoplastic syndrome
Disease or symptom that is a consequence of cancer cells in the body, mediated by humoral factors secreted by tumor cells or immune response against tumor. Treating the cancer usually resolves the syndrome
What is the etiology of Cushing’s syndrome?
Ectopic production of ACTH
What percentage of patient with SCLC exhibit SIADH?
10%
SCLC accounts for what percentage of all SIADH?
75%
What is the management of SIADH?
Treat underlying cancer
Demeclocycline is agent of choice
What percentage of lung cancer patients have hypercalcemia?
6%
What is the difference between Lambert-Eaton Myasthenic Syndrome and Myasthenia Gravis?
Lambert Eaton is characterized by muscle weakness of limbs that improves with repeated testing
Myasthenia Gravis worsen with repetition
What percentage of patient with SCLC exhibit LEMS?
3%
SCLC accounts for what percentage of all LEMS?
60%
In what percentage of patients does neurologic symptoms of LEMS precede the diagnosis of SCLC?
> 80%
Hypertrophic Pulmonary Osteoarthropathy(HPO) is frequently associated with what type of lung cancer?
Adenocarcinoma
Describe the Hypertrophic Pulmonary Osteoarthropathy
Clubbing and periosteal proliferation of tubular bones
Characterized by symmetrical painful arthropathy involves ankles, knees, wrists, elbows.
Describe findings of Landmark National Lung Screeing Trial
Low dose helical CT scan had relative reduction in risk of death caused by lung cancer compared to control radiography group
All-cause mortality was reduced in CT screening group by 6.7% when compared with control group
What percentage of weight loss from baseline has direct prognostic implications for survival in lung cancer?
> 5%
Meta-analysis, sensitivity and specificity for CT and PET for mediastinal nodal metastasis?
CT
Sensitivity 59%
Specificity 79%
PET
Sensitivity 81%
Specificity 90%
What is the sensitivity of sputum cytology in the setting of established lung cancers?
65%
What is the risk of pneumothorax from percutaneous FNA?
25%
What percentage of patient would need chest tube while performing percutaneous FNA?
5%
What is the percentage of overall diagnostic yield during percutaneous FNA?
80%
When no visible lesion is identified during bronchoscopy, what could be done?
Bronchus draining the area of suspicion can be lavaged for cytologic analysis.
What level of mediastinal lymph nodes FNA sampling could be done through EBUS-TBNA(EndoBronchial Ultrasound guided TransBronchial Needle Aspiration?
Levels 2 and 4 Paratracheal
Level 7 Subcarinal
Level 10 Hilar
What level of mediastinal lymph nodes FNA sampling could be done through EUS-FNA(Trans-Esophageal Endoscopic Ultrasound guided Fine Needle Aspiration?
Level 3 Retrotracheal
Level 7 Subcarinal
Level 8 Paraesophageal
Level 9 Pulmonary ligament lymph nodes
What percentage of lung cancer can be diagnosed by thoracocentesis?
70-80%
Multiple tap of fluid consistently bloody or exudative should be considered as?
Malignant
What levels of mediastinal lymph nodes sampling could be done through Mediastinoscopy?
Upper and lower Paratracheal station 2 and 4 Prevascular station 3a Retrotracheal station 3p Subcarinal station 7 Hilar station 7
What are the level of mediastinal lymph nodes sampling could be done through anterior mediastinotomy(Chamberlain procedure)?
Station 5 Lymph nodes within aortopulmonary window
Station 6 lymph node along ascending aorta
What are the indication of thoracoscopy in lung cancer?
- Peripheral nodules can be identified and excised
- Valuable for evaluation of suspected pleural disease when thoracocentesis has been nondiagnostic
- it can reach mediastinal nodes not accessible by standard mediastinoscopy, EBUS-TBNA, EUS-FNA
What are the 5 factors to consider while T-staging in lung cancer?
Tumor size Endobronchial extension Local invasion Seperate tumor nodule Post obstructive pneumonitis or atelectesis
Describe T-stage lung cancer in tumor size
T1 2-3cm
T2 3-7cm
T3 >7cm
T4 any size with characteristic local invasion
Describe T-stage lung cancer in endobronchial extension
T1 no bronchoscopic evidence
T2 bronchus involvement atleast 2 cm proximal from carina
T3 bronchus involvement
Define T-stage lung cancer with local invasion
T1 no local invasion
T2 invades visceral pleura
T3 invades chest wall, diaphragm, phrenic nerve, parietal pericardium, mediastinal pleura,
T4 invades mediastinum, heart, great vessels, carina, trachea, esophagus, vertebral body
Define T-stage lung cancer with seperate tumor nodule
T1 None
T2 None
T3 seperate nodule in same lobe as primary tumor
T4 seperate nodule in seperate lobe of ipsilateral lung
Define T-stage lung cancer with postobstructive pneumonitis or atelectesis
T1 None
T2 Partial postobstructive pneumonitis or atelectesis
T3 Total postobstructive pneumonitis or atelectesis
T4 None
Define N1 stage in lung cancer
Involvement of ipsilateral intra pulmonary, peribronchial, hilar lymph nodes
Define N2 stage of lung cancer
Involvement of mediastinal or Subcarinal lymph nodes
Define N3 stage of lung cancer
Involvement of contralateral mediastinal or hilar lymph nodes
Involvement of ipsilateral or contralateral scalene or supraclavicular nodes
Define M1a stage of lung cancer
Malignant pleural effusion, pericardial effusion, pleural nodule, or metastatic nodule in contralateral lung
T4N2M0 what is the stage?
Stage IIIB
N2 with T1-3 what is the stage?
Stage IIIA
N3 with T1-4 what stage is it?
Stage IIIB
T4 with N0-1 what stage is it?
Stage IIIA
T3N0M0
T3N1M0
What stage is it?
IIB
IIIA
What are 4 major classification of lung cancer?
Squamous cell carcinoma
Adenocarcinoma
Small cell carcinoma
Large cell carcinoma
In non squamous histology (Adenocarcinoma, large cell carcinoma) lung cancer, which agents showed statistically significant survival benefit ?
Bevacizumab combined with standard chemotherapy
Pemetrexed combined with platinum based chemotherapy
Define Bevacizumab?
Monoclonal antibody targeting VEGF
Name 2 mutation types associated with Adenocarcinoma lung
EGFR mutation
Echinoderm micro tubule associated protein like 4(EML4) and Anaplastic lymphoma kinase(AKL) translocation
Name 3 tumor related prognostic and predictive factors in lung cancer?
- Excision repair cross-complementation group 1(ERCC-1)
(+) prognostic : ERCC-1 positivity predicts improved survival after surgical resection
(-) predictive : low levels ERCC-1 predicts response to Cisplatin - EGFR
(+) Predictive : response to therapy with EGFR inhibitors(Gefinitib) - Thymidylate synthase(TS) target enzyme for antifolate drugs
(+) predictive : response to therapy with antifolate drugs(pemetrexed) in combination with Cisplatin
Name patient related prognostic and predictive factors in lung cancer
Prognostic for survival : age, gender, marital status
Predictive for survival : performance status, weight loss in 6 months, QOL
General management of NSCLC per stage
Stage I/II : complete surgical resection with possible addition of adjuvant chemotherapy
Stage IIIA(Resectable) : neoadjuvant chemo or ChemoRT
Stage III(Unresectable/fit patient) : concurrent ChemoRT
Stage III(Unresectable/unfit patient) : sequential chemo and RT
Stage IV without urgency : initial systemic chemo
Stage IV with urgency(SVC, Hemoptysis, Cord compression) : Palliative RT followed by systemic chemo
Stage IV with poor prognosis : early referral to hospice
What percentage of patient present with evidence of hematogenous dissemination at the time of diagnosis in NSCLC?
50%
Lung cancer study group
Lobectomy vs limited surgical resection(wedge resection or through segmentectomy)
What was the risk of local recurrence?
Lobectomy Limited resection
Risk of LR 6% 17%
5 years survival with lobectomy or pneumonectomy with mediastinal nodal dissection
pN0?
pN1?
pN0 60%
pN1 40%
MSKCC, Martini et al.
Lobectomy or pneumonectomy with complete mediastinal nodal dissection
1. What is the survival rate at 5 and 10 years in T1N0?
2. What is the survival rate at 5 and 10 years in T2N0?
3. What is the survival rate at 5 and 10 years who didn’t undergo LN dissection?
4. What is the survival rate at 5 and 10 years with wedge resection or segmentectomy?
5. What was the percentage of second primary cancer in long term survivors?
- 82% and 74%
- 68% and 60%
- 59% and 32%
- 59% and 35%
- 34%
ACOSOG Z0030 trial(1,111 pts)
Early stage NSCLC, N0-N1
Mediastinal lymph node sampling vs complete lymphadectomy
What was the 5 years disease free survival?
Mediastinal LN sampling 69%
Complete lymphadenectomy 68%
No difference in LocoRegional and distant recurrence
Okada et al.(567 pts) restrospective study
cT1N0M0
Sub lobar resection vs lobar resection
What was the 5 years OS?
Sublobar resection 89.6%
Lobar resection 89.1%
Name 2 prospective randomized trials examining the role of sublobar resection in early stage disease?
CALGB 140503
ACOSOG Z4032
What are 4 major classification of lung cancer?
Squamous cell carcinoma
Adenocarcinoma
Small cell carcinoma
Large cell carcinoma
In non squamous histology (Adenocarcinoma, large cell carcinoma) lung cancer, which agents showed statistically significant survival benefit ?
Bevacizumab combined with standard chemotherapy
Pemetrexed combined with platinum based chemotherapy
Define Bevacizumab?
Monoclonal antibody targeting VEGF
Name 2 mutation types associated with Adenocarcinoma lung
EGFR mutation
Echinoderm micro tubule associated protein like 4(EML4) and Anaplastic lymphoma kinase(AKL) translocation p
Name 3 tumor related prognostic and predictive factors in lung cancer?
- Excision repair cross-complementation group 1(ERCC-1)
(+) prognostic : ERCC-1 positivity predicts improved survival after surgical resection
(-) predictive : low levels ERCC-1 predicts response to Cisplatin - EGFR
(+) Predictive : response to therapy with EGFR inhibitors(Gefinitib) - Thymidylate synthase(TS) target enzyme for antifolate drugs
(+) predictive : response to therapy with antifolate drugs(pemetrexed) in combination with Cisplatin
Name patient related prognostic and predictive factors in lung cancer
Prognostic for survival : age, gender, marital status
Predictive for survival : performance status, weight loss in 6 months, QOL
General management of NSCLC per stage
Stage I/II : complete surgical resection with possible addition of adjuvant chemotherapy
Stage IIIA(Resectable) : neoadjuvant chemo or ChemoRT
Stage III(Unresectable/fit patient) : concurrent ChemoRT
Stage III(Unresectable/unfit patient) : sequential chemo and RT
Stage IV without urgency : initial systemic chemo
Stage IV with urgency(SVC, Hemoptysis, Cord compression) : Palliative RT followed by systemic chemo
Stage IV with poor prognosis : early referral to hospice
What percentage of patient present with evidence of hematogenous dissemination at the time of diagnosis in NSCLC?
50%
Lung cancer study group
Lobectomy vs limited surgical resection(wedge resection or through segmentectomy)
What was the risk of local recurrence?
Lobectomy Limited resection
Risk of LR 6% 17%
5 years survival with lobectomy or pneumonectomy with mediastinal nodal dissection
pN0?
pN1?
pN0 60%
pN1 40%
MSKCC, Martini et al.
Lobectomy or pneumonectomy with complete mediastinal nodal dissection
1. What is the survival rate at 5 and 10 years in T1N0?
2. What is the survival rate at 5 and 10 years in T2N0?
3. What is the survival rate at 5 and 10 years who didn’t undergo LN dissection?
4. What is the survival rate at 5 and 10 years with wedge resection or segmentectomy?
5. What was the percentage of second primary cancer in long term survivors?
- 82% and 74%
- 68% and 60%
- 59% and 32%
- 59% and 35%
- 34%
ACOSOG Z0030 trial(1,111 pts)
Early stage NSCLC, N0-N1
Mediastinal lymph node sampling vs complete lymphadectomy
What was the 5 years disease free survival?
Mediastinal LN sampling 69%
Complete lymphadenectomy 68%
No difference in LocoRegional and distant recurrence
Okada et al.(567 pts) restrospective study
cT1N0M0
Sub lobar resection vs lobar resection
What was the 5 years OS?
Sublobar resection 89.6%
Lobar resection 89.1%
Name 2 prospective randomized trials examining the role of sublobar resection in early stage disease?
CALGB 140503
ACOSOG Z4032
Stage III NSCLC role of surgery in N2 is still controversial
Martini et al. What was the outcome in favor of surgery in survival rate?
At 3 years 47%
At 4 years 38%
But better survival was also associated with
Adenocarcinoma histology
Small primary
No bulky mediastinal LN
Most patients received postoperative mediastinal irradiation
Van Meerbeeck et al. EORTC phase III randomized trial
Surgery vs RT after induction chemo in pN2 NSCLC
What was the median and 5 year OS?
Median OS 16.4 vs 17.5 months
5 year OS 15.7 vs 14 months
Author concluded RT is preferred owing to lower rates of treatment related morbidity and mortality.
Stage III NSCLC role of surgery in N2 is still controversial
Martini et al. What was the outcome in favor of surgery in survival rate?
At 3 years 47%
At 4 years 38%
But better survival was also associated with
Adenocarcinoma histology
Small primary
No bulky mediastinal LN
Most patients received postoperative mediastinal irradiation
Van Meerbeeck et al. EORTC phase III randomized trial
Surgery vs RT after induction chemo in pN2 NSCLC
What was the median and 5 year OS?
Median OS 16.4 vs 17.5 months
5 year OS 15.7 vs 14 months
Author concluded RT is preferred owing to lower rates of treatment related morbidity and mortality.
Pass et al. pN2 disease
Preoperative chemo(Etoposide and Cisplatin (EP)followed by Sx vs immediate Sx followed by postoperative RT
What was the median survival and 2 and 3 year survival rates?
Median survival
64 months perioperative chemo and surgery
11 months immediate surgery
2 and 3 years survival
60% and 56% perioperative chemo and surgery
25% and 15% immediate surgery
Preoperative chemoradiotherapy followed by surgery in stage III NSCLC.what was the outcome of Intergroup randomized phase III trial in OS?
Median OS
23.6 months in concurrent chemoRT(45Gy) followed by Sx
22.2 months in concurrent chemoRT(45Gy) followed by RT(61Gy to complete)
PFS
12.8 months in concurrent chemoRT(45Gy) followed by Sx
10.5 months in concurrent chemoRT(45Gy) followed by RT(61Gy to complete)
pN0 median OS 22.6 months
#Negative trial
What is the percentage of LRR in NSCLC in stage I and stage III?
Stage I 20%
Stage III 50%
MRC(Medical Research Council) 1998 meta-analysis
What was the outcome for pN1 and pN2 NSCLC with PORT?
pN1 decrease survival attributed to excessive RT induced morbidity exceeding any benefit
pN2 No survival difference
SEER meta-analysis PORT in stage II/III NSCLC.what was the 5-year OS for pN1 and pN2?
5 year OS
pN1 reduced OS
pN2 improved OS(27% vs 20%)
# this finding supported by ANITA(Adjuvant Navelbine International Trialist Association) trial
# Lung-ART PORT trial (Europe)observation with chemo vs ChemoRT (54Gy) is ongoing
Name trials in favor of postoperative chemotherapy in improved survival vs observation in NSCLC
Non-small cell Lung Cancer Collaborative Group
IALT(International Adjuvant Lung Cancer Trial)
National Cancer Institute of Canada JBR.10 trial
ANITA(Adjuvant Navelbine International Trialist Association) trial
LACE(Lung Adjuvant Cisplatin Evaluation) trial
#Cisplatin based chemo has improved survival Benefit of chemo decreased over time with more deaths
RTOG 9705 Phase II trial for stage II and IIIA NSCLC postoperative ChemoRT(Carboplatin + Paclitaxel / 50.4 + 10.8Gy boost to Extranodal extension).
What was the outcome of median OS and PFS?
Median OS 56.3 months Survival rates 1 year 86% 2 year 70% 3 year 61% PFS 1 year 70% 2 year 57% 3 year 50% # Fox Chase Cancer Center has similar results
What are the indications of adjuvant chemotherapy in NSCLC?
Node positive stage IIA, IIB, IIIA
What are the conditions where PORT is not indicated in NSCLC?
Completed resected stage I and II
Clinically early stage NSCLC with pathology confirmed clear margin with pN2. What should be the next step of management?
Adjuvant chemotherapy first because of known survival
Followed by PORT because of reported local control benefit
Clinically early stage NSCLC with positive microscopic margin or residual macroscopic disease. What should be the next step of management?
RT should start earlier as local failure is most common cause of failure in this group
Stage I/II inoperable NSCLC due to comorbidities.what should be the line of management?
Conventionally fractionated definitive RT alone SBRT hypofractionation(standard of care in medically inoperable patients)
RTOG multi institutional dose escalation study inoperable early stage NSCLC using 3D-CRT. What are the local control and OS rates?
1 year LC 76% (86.8Gy)
5 year OS 10-30% (102.9Gy Hayman et al.)
Timmerman et al. RTOG 0236 phase II SBRT trial in medically inoperable T1-T2 tumors 54Gy/18Gyx3 fxs . What were the outcomes.
3 years LC 90.6% LRC 87.2% Distant failure 22.1% DFS 48.3% OS 55.8% Median OS 48.1 months
Kubota et al. prospective randomized trial stage III inoperable NSCLC Chemo vs Chemo+RT
What were the survival outcomes?
Chemo+RT Chemo only
1 year 58% 66%
2 year 36% 9%
3 year 29% 3%
RTOG 7301 what is the recommended dose fractionation with RT alone in unresectable stage III NSCLC?
60Gy standard fractionation
Less tumor recurrence with no difference in 5 year survival rate when compared with other arms
RTOG 8311 randomized Phase I/II what is the recommended altered dose fractionation in unresectable stage III NSCLC?
- 2Gy twice daily 60-79.2Gy
69. 6Gy standard altered fractionation
Surgical studies report what percentage of patient with clinically negative NSCLC have evidence of occult mediastinal metastasis on lymph node dissection?
10-35%
FDG-PET what is the percentage of false negative rate in lymph node
25%
Inoperable stage III NSCLC Rosenzweig et al. What was the elective nodal control rate with IFRT?
92.4%
Inoperable stage III NSCLC Kepka et al. Stage with FDG PET and treated with elective nodal irradiation. What was the reported 2 year elective nodal control rate?
88%
Yuan et al. Only prospective trial ENI vs IFRT. What was the outcome of the trial?
Increase in LC with IFRT of 8% and 15% at 2 and 5 years
Improved OS with IFRT 39.4% vs 25.6% at 2 years
Significantly higher Pneumonitis rates with ENI 29% vs 17%
What is the dominant pattern of failure in locally advanced NSCLC and how much?
Distant dissemination
75-80%
CALGB phase III randomized trial unresectable stage III NSCLC with excellent performance status and minimal weight loss RT alone vs sequential ChemoRT. What was the median survival and 5 year survival outcome?
Median survival
Induction chemo 13.7 months
RT alone 9.6 months
5 years survival
Induction chemo improved from 6% to 17%
What was the outcome of Intergroup trial in inoperable stage III locally advanced NSCLC in favor of sequential ChemoRT?
Median survival
Induction chemo 13.8 months
Standard RT 11.4 months
Hyperfractionated RT 12.3 months
What was the outcome of Le Chevalier et al. in inoperable stage III locally advanced NSCLC in favor of sequential ChemoRT?
2 year survival rate
RT alone 14%
Sequential ChemoRT 21%
Distant metastasis was significantly lowered in induction chemo
O’Rourke et al. Meta analysis to examine concurrent ChemoRT in definitive management of NSCLC vs RT alone. What was the outcome?
Reduced overall risk of death (HR 0.69) with concurrent ChemoRT
Increased acute toxicity esp severe oesophagitis (RR 4.96)
Furuse et al. Phase III randomized trial concurrent vs sequential ChemoRT(MVP - Mitomycin, Vindesine, Cisplatin). What was the outcome?
Median survival
Concurrent 16.5 months
Sequential 13.3 months
5-year survival
Concurrent 15.8 months
Sequential 8.9 months
Who are the candidates of concurrent ChemoRT as standard approach in inoperable stage III locally advanced NSCLC
Good performance status
Minimal weight loss
Improved OS and LRC at expense of greater toxicity (severe oesophagitis)
What is the standard of care for ChemoRT in stage III locally advanced NSCLC?
Cisplatin based 60mg/m2 every 3 weeks
In combination with Etoposide 80-120mg/m2 daily every 3 weeks(North America)
RT 60Gy
In older patient with significant co morbidities with renal insufficiency, hearing loss, CHF, severe COPD, what are the alternative chemo instead of EP?
Carboplatin instead of Cisplatin
Paclitaxel instead of Etoposide
Name the only phase III trial to address question about the use of platinum in locally advanced NSCLC?
WJOGT 0105(West Japan Oncology Group Trial)
WJTOF 0105 in locally advanced NSCLC. What was the outcome?
Paclitaxel-Carboplatin
less toxic, equivalent survival at 5 year 19.5%
MVP 17.5%
Irinotecan-Carboplatin 17.8%
Consolidation chemotherapy after ChemoRT in locally advanced NSCLC. Name trials that proved to be negative.
SWOG trial
Hoosier Oncology Group Trial(Phase III randomized)
CALGB phase II study in higher risk locally advanced NSCLS evaluating Carboplatin and Paclitaxel followed by concurrent XRT and Gefitinib. What was the outcome in median OS?
19 months
CALGB phase II study in higher risk locally advanced NSCLS evaluating Carboplatin and Paclitaxel followed by concurrent XRT and Bevacizumab. What was the outcome in adverse events?
Tracheoesophageal fistula
Pulmonary hemorrhage
Lineberger Comprehensive Cancer Center Group single institution phase I dose escalation(60Gy to 74Gy)study with concurrent chemoradiation(Carbo-Paclitaxel) in locally advanced NSCLC. What was the outcome?
Median survival 24 months
5 year survival 25%
Patient number were small!!!
Dose escalation with concurrent ChemoRT in locally advanced NSCLC. RTOG 0617 closed early to accrual. What was the reason?
Initial result presented in ASTRO 2011 showed statistically significant detriment to survival with 74Gy
60Gy remains the standard
What are the most common tumors of superior sulcus?
Bronchogenic SCCA followed by Adenocarcinoma
What is the most common symptom among Superior Sulcus Tumor patients?
Pain in shoulder radiate down the arm due to direct invasion of tumor to,parietal pleura, vertebral body, ribs 1 through 3, brachial plexus.
What percentage of superior sulcus tumor may present with invasion of neural foramina causing spinal cord compression?
25%
Define Horner’s syndrome
Involvement of stellate ganglion
Triad of ptosis, papillary miosis, facial anhidrosis
Define Pancoast’s syndrome
Constellation of signs and syndromes
Shoulder/Arm pain
Horner’s syndrome
Unilateral upper extremity weakness.
What is the management of Non-Small Cell Superior Sulcus Tumors?
Lobectomy with en bloc resection of chest wall which may accompany resection of portion of parasympathetic chain, stellate ganglion, lower trunks of brachial plexus, subclavian artery, portion of vertebral bodies.
What is the management of Small Cell Superior Sulcus Tumors?
Concurrent ChemoRT for limited stage disease
Chemotherapy for extensive stage disease
Name the trials in favor of multimodality therapy(induction ChemoRT followed by surgery)for superior sulcus tumor?
SWOG 9416/Intergroup 0160
Japan Clinical Oncology Group(JCOG)
Single-institution French study
Prospective trial at the University of Texas MD Anderson Cancer Center(surgery followed by concurrent ChemoRT)
Unresectable localized Superior Sulcus Tumor and those with stage III disease and bulky N2/N3 nodal disease. What is the management?
Definitive ChemoRT
Harris et al. Lung windowing should be used for delineation of primary tumor GTV. What was the measured Hounsfield units reported in measurement of pulmonary nodules using standard lung windowing width and length?
Width of 850 Hounsfield units
Length of -750 Hounsfield units
Chapet al. University of Michigan what was the percentage accuracy of CT scan in correctly identifying location and size of nodal disease.
60%
Dwamena et at. Meta-analysis of FDG-PET and CT scan for identification of mediastinal nodal disease in lung cancer. What was the mean sensitivity and specificity for PET and CT scan?
PET
Sensitivity 0.79
Specificity 0.91
CT
Sensitivity 0.60
Specificity 0.77
What is the gold standard for identification of mediastinal nodal disease?
Invasive staging
Cervical mediastinoscopy
Endobronchial ultrasound with transbronchial needle aspiration
Define CTV margin for primary tumor and nodal disease in lung cancer
Accounts 95% of microscopic extension of disease
Adenocarcinoma 8 mm
SCC 6 mm
Nodal disease 2 cm larger margin than 3 mm
Define ITV(Internal Target Volume) in lung cancer
CTV + Respiratory motion
Define iGTV in lung cancer
Gross disease with motion as measured on 4D simulation CT scan
Define iCTV in lung cancer
iGTV expanded to encompass microscopic disease and involved lymph nodes, consideration of remainder involved lymph node station
What is the QUANTEC dose constraint for lung
Mean Lung Dose(MLD)
What is the QUANTEC dose constraint for esophagus
Volume treated at >40-50Gy correlate with acute symptoms
What is the QUANTEC dose constraint for heart and pericardial dose
V25
What is the QUANTEC dose constraint Brachial Plexus
Point maximum limit 66Gy(RTOG 0617)
V20
Anatomic region scanned during treatment simulation for lung cancer
From level of cricoid cartilage to second lumbar vertebrae to include both lungs
AAPM(American Association of Physicist in Medicine) Task Group Report No. 76273 recommends motion management strategy with what range of motion in lung cancer?
> 5 mm in any direction
What are the management of tumor motion while planning in lung cancer?
4D-CT scans Slow CT scans(4seconds per slice) Shallow breathing using abdominal compression device Deep inspiration breath hold technique Automatic breathing control technique Respiratory gating technique Tumor tracking technique
ICRU Report 38 what is PTV margin with and without use of ITV as motion compensation or IGRT in advanced staged NSCLC?
PTV margin
With ITV or IGRT 5-10mm
Without ITV or IGRT 10-20mm
SBRT based treatment with motion management and IGRT, what is the recommended PTV margin in advanced staged NSCLC?
3-6mm
What is the cumulative PTV dose range when AP-PA beams are implied in late staged NSCLC and why?
45-50Gy at 1.8-2Gy
Because of spinal cord tolerance
What are the points that must be considered to properly evaluate treatment plan prior to radiation delivery in lung cancer?
- Organ contours and dose-volume based organ constraints
- Planning margins for targets and OARs
- Intrafraction motion and impact on margins
- Inhomogeneity correction
- Dose uniformity and hot or cold spots in target regions
- Normal tissue tolerance doses
- Plan deliverability-presence of many low intensity segments that could possibly be removed without compromising plan quality
- Unusual beam orientation that might involve collision during gantry rotation
Phase III studies demonstrated survival advantages with agents compatible with platinum based chemotherapy in NSCLC. What are these agents?
Paclitaxel Docetaxel Gemcitabine Vinorelbine Irinotecan I
Name the combination chemotherapy agents in non-squamous lung cancer that improved both response and survival.
Pemetrexed with platinum based chemotherapy
Median PFS 7.8 months
Median survival 14.1 months
Name the chemotherapy agent in Squamous NSCLC proven to be more effective than pemetrexed
Gemcitabine
Phase III randomized trials name the chemotherapy agents approved for use as maintainence therapy for those who haven’t progressed on standard platinum based treatment
Pemetrexed nonsquamous histology
Erlotinib any histologic subtypes
IPASS(Iressa Pan Asia Study) Phase III multicenter randomized trial, advanced adenocarcinoma lung, EGFR mutation vs Wild type mutation. What was the outcome in terms of response rate, PFS, OS with respect to EGFR TKIs?
EGFR TKI(Gefitinib) has favorable outcome with respect to response rate and PFS in EGFR mutation than wild type but no change in OS.
Define Crizotinib
Selective inhibitor of ALK and MET tyrosine kinase
What is the percentage of KRAS mutation with advanced NSCLC?
20-25%
What is the percentage of BRAF and HER2Neu with advanced adenocarcinoma lung?
1-3%
What is the percentage of Fibroblast Growth Factor Receptor present in SCC lung?
20-25%
What is the most common palliative site in lung cancer?
Thorax
Bone
Brain
What symptoms might benefit from palliative RT in progression of intrathoracic lung cancer?
Cough Hemoptysis Chest wall pain SVC syndrome Dyspnoea from airway obstruction Hoarseness from involvement of recurrent laryngeal nerve
What is the recommended palliative dose to obstructive component for intrathoracic disease?
30-45Gy in 2.5-3Gy over 2-3 weeks
What are the characteristic signs of superior venacava syndrome?
Cyanosis
Plethora
Distension of subcutaneous veins
Edema of head, neck, arm
Is SVC syndrome a medical emergency?
No
When should immediate intervention warranted in SVC syndrome?
When symptoms are life threatening eg
cerebral edema leading to altered mental status,
stridor,
clinically significant hemodynamic compromise
What should be the initial management of extensive stage SCLC and SVC syndrome?
Start chemotherapy after staging evaluation
What should be the initial management of limited stage SCLC and SVC syndrome with bulky disease?
Start with a cycle of chemotherapy then add radiotherapy
What should be the initial management with NSCLC and SVC syndrome?
Start Radiotherapy as less likely to respond to chemotherapy
Name tumors with histologically small round blue cells
Small Cell Lung Cancer
Neuroblastoma
Rhabdomyosarcoma
Markel Cell Carcinoma
What are the markers positive in SCLC?
100% Keratin and epithelial membrane antigen
80% TTF-1(Thyroid Transcription Factor-1)
Majority Synaptophysin, Chromogranin A, Neuron specific enolase, CD56
What is the most clinically important prognostic factor in SCLC?
Stage Limited vs Extensive
What are the prognostic factors with improved survival in SCLC?
Good performance status
Female gender
Normal LDH level
What is the median survival for SCLC with limited and extended disease?
Limited disease 23 months
Extended disease 8-9 months
Regardless of stage, what work up should be done if patient is diagnosed with SCLC and why?
Brain MRI with gadolinium or Head CT scan with contrast
To evaluate for brain metastasis
What are the harmonally active peptides elaborated by SCLC?
ACTH(Cushing syndrome)
Vasopressin(SIADH)
SCLC is the most common tumor associated with SIADH. What percentage of patients meet the clinical criteria for SIADH?
10%
What type of paraneoplastic syndromes are more common in SCLC?
Neurologic
Early stage(T1-2N0) SCLC, what is the OS associated with lobectomy without adjuvant radiation?
50%
In SCLC, what should be done prior to surgical resection?
Given the propensity of early nodal dissemination, invasive staging of mediastinum should be performed prior to surgical resection.
What is the primary mode the failure after surgical resection in SCLC?
Distant dissemination
JCOG 9101 Lung cancer study group multi institutional phase II prospective trial stage I-III SCLC, adjuvant EP after surgical resection. What was the 3-years OS each stage?
Stage I 68%
Stage II 56%
Stage III 13%
In limited stage SCLC, what is the advantage of combined modality therapy(RT+Chemo)?
2 meta analysis have demonstrated thoracic control and absolute survival of 5%
In extensive stage SCLC, what should be the treatment?
Chemotherapy alone
In extensive stage SCLC, what is the indication of consolidation thoracic RT?
Good performance status with complete resolution of extra thoracic tumor burden
What are the indications of prophylactic Cranial Irradiation(PCI) in SCLC?
Early stage SCLC
Selective patients with extensive stage SCLC who respond to initial therapy
Meta analysis(7 randomized trials) by Fried et al. limited stage SCLC evaluating timing of RT with concurrent chemo, what was the outcome?
Early use of RT with chemotherapy improved 2 years OS compared to delayed or sequential RT with chemotherapy.
What is the standard of care for limited stage SCLC?
EP administered concurrently with thoracic RT
SCLC is highly sensitive and has a high proliferative index. What fractionation scheme will you suggest?
Radiosensitive hyperfractionation could be employed to reduce late normal tissue toxicity
High proliferative index accelerated treatment to counteract repopulation
Intergroup trial(417 patients enrolled)limited stage SCLC concurrent accelerated hyperfractionation,45Gy 1.5Gy x 2 vs standard 45Gy, 4 cycles EP. What was the outcome?
accelerated hyperfractionation vs standard OS at 5 years 26% vs 16% Local recurrence 36% vs 52% Grade 3 acute esophagitis 26% vs 11% No difference between late toxicity
Dose escalation altered fractionation limited staged SCLC in RTOG trial. What was the outcome?
19 months follow up
2 years OS 37%
2 years LRC 80%
Optimal dose and fractionation for SCLC remains to be defined. Name some ongoing trials with dose and fractionation
Intergroup trial(CALGB 30610, RTOG 0538, NTC00632858) 3 randomized arms 45Gy 30 fnxs 3 wks 61.2Gy in 5 wks 70Gy 35 fnx 7 wks
CONVERT trial Concurrent Once-daily Versus Twice-daily Radiotherapy Phase III trial 2 randomized arms
45Gy 30 fnx twice daily
66Gy 33 fnx once daily
Describe CONVERT(Concurrent Once-daily Versus Twice daily Radiotherapy) trial in SCLC.
Randomized phase III trial 45Gy in 30 fnx twice daily 66Gy in 33 fnx once daily All patients receive EP RT begins with cycle 2
Limited stage SCLC with bulky initial presentation. Describe SWOG study to address RT volume after induction chemotherapy to achieve cytoreduction of disease.
Randomized study
191 pts with partial response or stable disease after 6 weeks of induction chemotherapy
RT 48Gy split course to pre induction or post induction volume
Local recurrence
32% pre induction chemo
28% post induction chemo
Extensive stage SCLC with good performance status. Describe the role of thoracic radiotherapy.
Single institution prospective randomized trial in Yugoslavia
209 pts, treated with 3 cycles of EP
110 pts partial response in chest and complete response outside chest randomized to thoracic RT(54Gy in 36 fnx over 12 days) with concurrent EP followed by 2 cycles of EP VS 4 cycles of EP alone
All eligible pts received PCI
OS with RT 9%
with chemo alone 4%
Name 2 prospective trials studying the role of thoracic RT in extensive stage disease .
RTOG 0937
Phase II trial
Extensive disease with more than 3 extra thoracic sites of disease
45Gy thoracic RT in 30 twice daily fnx followed by PCI vs PCI alone after chemotherapy
CREST trial(Chest Irradiation in Extensive Stage Small Cell Lung Cancer) conducted by Dutch Lung Cancer Study Group Chemotherapy responder randomized to thoracic RT 30Gy in 10 fnx and PCI vs PCI alone
What percentage of patients present with brain metastasis at diagnosis in SCLC?
20%
Describe meta-analysis supporting PCI in limited stage SCLC.
987 pts treated in 7 randomized trials enrolled between 1977 and 1995
PCI vs Observation following complete response to initial therapy
PCI 8Gy single fnx to 40Gy in 20 fnx
Incidence of brain mets in 3 years decreased to 59% vs 33%
OS improved 21% vs 15%
Describe EORTC trial supporting PCI in extensive stage SCLC.
286 pts
Randomized to PCI or Observation after any response to 4-6 cycles of chemotherapy
1 year cumulative incidence of brain mets decrease d to 15% vs 40%
1 year OS increased to 27% vs 13%
PCI dose 25 to 39Gy
Describe multi-institutional Intergroup trial to define optimal dose for PCI in SCLC
Limited stage SCLC with complete response to ChemoRT
Standard dose 25Gy in 10 fnx
High dose 36Gy in 18 fnx or 24 twice daily fnx
720 pts
Cumulative incidence of brain mets at 2 years
29% standard dose
23% high dose
OS at 2 years
42% standard arm
36% high dose
Wolfson et al assessed neuropsychological test along with QOL in patients after PCI in SCLC. What was the outcome?
Increased incidence of chronic neurotoxicity at 12 months after PCI in 36Gy cohort
Which regimen is preferred to deliver PCI in SCLC?
25Gy at 2.5Gy in 10 fnx
What is the percentage of clinically significant Radiation Pneumonitis that happens in patients receiving radiation for lung cancer?
5-20%
What is the peak incidence of Radiation Induced Pneumonitis post treatment?
2-6 months post treatment
What are the most common clinical presentation of Radiation induced Pneumonitis?
Persistent non productive cough
Dyspnoea
Low grade fever
Fatigue
Mention x-ray changes over time in lung due to radiation induced Pneumonitis.
2-6 months ground glass opacification
4-12 months Patchy consolidation
10 months or more Fibrosis
Describe the dose constraint of lung for conventional fractionated scheme
QUANTEC
RP<20% when the MLD is less than approx 20Gy
RP is <20% for
V20 <30 to 35 Gy
V5 <60%
Describe dose constraint of lung in conformal RT
SBRT, large series
risk of grade 2 or greater RP 17% when MLD >4Gy vs 4% for lower dose
risk of RP 16% when v20 >4% vs 4% for lower values
AAMP task group Bilateral lung 7.4Gy for 10-15cc 7Gy for single fraction SBRT 12.4 and 11.6Gy for 3-fraction SBRT 13.5 and 12.5Gy for 5-fraction SBRT
What are the causes of radiation induced dyspnea?
RP Pleural and Pericardial effusion Restrictive Pericarditis Cardiomyopathy Bronchial stenosis or Bronchiectasis
What is the QUANTEC recommendation of dose constrain for major airways?
Caution for dose>80Gy
What is the recommended dose of AAMP task group for proximal bronchi in SBRT?
Max dose to 4cc and max point dose
10.5 and 20.2Gy for single fraction SBRT
15 and 30Gy for 3-fraction SBRT
16.5 and 40Gy for 5-fraction SBRT
What are the patient and treatment related factors impact risk of RP independent of dose and volume shown in RTOG trials?
Tumors in lower lung fields
Old age
Smoking
Chemo agents Docetaxel and Gemcitabine
What is the dose prescription of Glucocorticoid used to treat developing RP?
Prednisone
Starting dose 60mg or 1mg/kg given for 1-2 weeks
Slow taper over 4-8 weeks
Name some drugs used in development of RP in lung cancer.
- Pentoxifylline improves microvascular blood flow - significantly reduced grade 2 or 3 pulmonary toxicity
- Amifostine mixed results
- Captopril positive results in rats but not shown in humans
What is the percentage of grade 3 or greater acute esophagitis occurs in patients during OS shortly after Chemoradiation?
15-25%
What are the factors contributing to esophageal toxicity in treating lung cancer?
Dose and volume of irradiation Size, anatomic arrangement, proximity of target structures Accelerated fractionation Older age Use of concurrent chemotherapy
What is the combination of ChemoRadiation has shown the unexpectedly high risk of teacheoesophageal fistula in treatment lung cancer?
Concurrent chemotherapy with Bevacizumab
What is the primary treatment of acute esophagitis while treatment lung cancer with RT?
Supportive care with
Topical agents
Dietary changes
Narcotic pain management
Empirical antifungal agents with proton pump inhibitor for comorbid reflux disease
Radioprotectant Amifostine
Repeated dilations for esophageal stricture
Stenting or surgical management for esophageal fistula
What are the RT induced cardiac toxicities?
- Acute pericarditis which can progress to chronic pericardial fibrosis, effusion, rarely constrictive pericarditis
- Ischemic changes in cardiac muscle after long latency may lead to congestive heart failure
- Valvular heart disease owing to late fibrotic changes
Describe dose-volume constrain for cardiac toxicities during treatment of lung cancer
risk of pericardial toxicities with treatment of >50% heart contour in 2D planning volume receiving >=30Gy in 3D planning QUANTEC v25
What are the factors increasing the risk of RT induced cardiac toxicities?
Dose volume tolerance of heart Hypertension Diabetes Obesity Genetic predisposition Age >60 years Smoking Sequential use of anthracycline and concurrent use of Paclitaxel
Describe RT induced brachial plexopathy
Early transient plexopathy during or within months of RT at relatively low dose and resolve spontaneously
Late plexopathy manifest years after RT to supraclavicular area
Brachial plexus is a serial organ or parallel organ?
Serial organ
What is the proposed brachial plexus dose constrain for standard fractionated RT
RTOG 0617 point max limit of 66Gy
RTOG 0972/ CALGB 36050 limits the V20 to ≤35%
What is the proposed brachial plexus dose constrain for SBRT
Cumulative risk of grade 2 to 4 plexopathy 46% with >26Gy vs 8% when the plexus received ≤26 Gy
Name 2 validated QOL instruments?
FACT-L Functional Assessment of Cancer Therapy-Lung
EORTC QOL Questionaire Core -30(QLQ-C30) and QLQ-LC13
Temel et al. assessed impact of early palliative care on QOL among patients with newly diagnosed metastatic NSCLC randomized to early palliative care and standard care. What was the outcome?
Early palliative care not only had significant improvement in QOL with less depression or anxiety but also had longer median survival
PRO-CTCAE
Patient Reported Outcome version of Common Terminology Criteria for Adverse Events
