# Radiation Oncology/NSCLC/Overview

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## Epidemiology

164,100 cases/yr. 156,900 deaths. Risk of lung cancer is 20X in heavy smokers than nonsmokers. Carcinogens: absestos, coal tar fumes, nickel, chromium, arsenic, radioactive material.
Lung cancer in non-smokers:
* PMID 17290054, 2007 — "Lung Cancer Incidence in Never Smokers." Wakelee HA et al. Journal of Clinical Oncology, Vol 25, No 5 (February 10), 2007: pp. 472-478.
** Large U.S.-based population database, ages 40-79, covering 1971-2003.
** Incidence 14.4-20.8 per 100,000 person-years in women, 4.8-13.7 in men. (By comparison, rates are 12-30 times higher in smokers). Adenocarcinoma higher in never smokers than in smokers.
** Conclusion: Lung cancer in never smokers is an important public health issue. Higher incidence in women.

## Presentation

At diagnosis: 15% N0M0 30% N1-3M0 55% M1

## Symptoms

Paraneoplastic syndromes:
* Gynecomastia - most commonly with large-cell
* Hypercalcemia - most commonly with squamous cell
* Hypertrophic pulmonary osteoarthropathy - presents as bilateral pain and tenderness in the legs, especially over the tibias. Bone scan positive. X-rays show elevated periosteum without cortical involvement. - most commonly with adenocarcinoma (secondary to PTHrp)
* Clubbing of digits
Syndromes according to tumor location:
* Pancoast syndrome (superior sulcus tumor) - lower brachial plexopathy, Horner's syndrome, shoulder/ulnar distribution of pain.
* Horner's syndrome - enophthalmos, ptosis, miosis, ipsilateral loss of sweating, hoarseness due to recurrent laryngeal nerve involvement
Second primary: Patients treated for upper aerodigestive tract tumors (lung, H&N, esophagus) have a 3%/year risk of developing a subsequent cancer.

## Pathology

* Adenocarcinoma - 40% (more common in those that do not smoke)
** Adenocarcinomas have a worse prognosis stage-for-stage.
** Bronchoalveolar is a subtype of adenocarcinoma.
*** Arises from type II pneumocytes, is least associated with smoking.
* Squamous cell carcinoma - 30% (more common in smokers)
* Large cell carcinoma - 15%
* Small cell carcinoma - 20% (see separate page)

## Workup

* Please also see Screening section
Patients with potentially resectable disease should undergo staging evaluation prior to therapy.
CT scans of the chest and abdomen through the adrenals should be performed. The sensitivity and specificity of CT scans for detecting involved mediastinal lymph nodes is only 60% and 77% with a PPV of 50% and NPV of 85% PMID 10551237. Thus, an enlarged lymph node (defined as >1cm) on CT contains cancer only 1/2 the time, and 15% of normal sized lymph nodes are cancerous.
PET has a sensitivity of 79%, specificity of 91%, PPV 90%, NPV 93% PMID 10551237. If both CT and PET are negative, the NPV is 97%. Thus, PET scans can reliably rule out N2 disease but surgical staging is required to confirm it.
Mediastinoscopy is used to detect N2 and N3 disease before surgical resection because if N3 disease is present, then surgery is not indicated, and if N2 disease is present, induction chemoradiation should be used prior to resection. Not all lymph nodes are evaluable by mediastinoscopy, so sensitivity is around 72-89%.
* Mediastinoscopy can be used to sample level 2 L/R, 4 L/R, and 7 nodal stations. For level 5 (AP window) and 6 lymph nodes, VATS or Chamberlain procedure (anterior mediastinotomy) can be used.
Enhanced MRI of the brain is recommended in some asymptomatic patients for the detection of occult brain mets. Brain metastases are present in 12-18% of all lung cancer patients, and there is a higher prevalence in nonsquamous histology and more advanced disease. In patients without neurologic symptoms, brain mets were detected in 4% of Stage I and II patients and 11.4% of Stage III patients PMID 10084481. It is also recommended that a brain MRI be repeated after induction chemotherapy and prior to thoracotomy to rule out disease progression.
Bone scan is not valuable unless there are focal symptoms or an elevated alkaline phosphatase. Furthermore, PET better for detection of bone metastases.
Pulmonary function tests if resection is being considered.

## Survival by stage

5-year survival data :
| Stage | TNM | Pathologic stage | Clinical stage |
| IA | T1,N0,M0 | 67% | 61% |
| IB | T2,N0,M0 | 57% | 38% |
| IIA | T1,N1,M0 | 55% | 34% |
| IIB | T2,N1,M0 | 39% | 24% |
| IIB | T3,N0,M0 | 38% | 22% |
| IIIA | T3,N1,M0 | 25% | 9% |
| IIIA | T1-3,N2,M0 | 23% | 13% |
Note the decreased survival for those clinically staged compared to those with pathologic staging, reflecting understaged disease.

## Prognostic factors
### Recursive partitioning analysis (RPA)

* RTOG RPA, 1997 - PMID 9213303 — "Recursive partitioning analysis of 1592 patients on four Radiation Therapy Oncology Group studies in inoperable non-small cell lung cancer." Scott C et al. Lung Cancer. 1997 Jun;17 Suppl 1:S59-74.
** RTOG 83-11, 83-21, 84-03, 84-07.
** KPS was most important on multivariate analysis (>80 median survival = 9.9 months vs <=70 MS = 5.9 months)
** Poor prognostic factors: KPS < =70 vs KPS = 80-100, wt loss <= 5% vs > 5%, age > 60, pleural effusion, higher T/N stage (from RTOG studies)
* RTOG RPA, 2000 - PMID 11121651 — "Recursive partitioning analysis of 1999 Radiation Therapy Oncology Group (RTOG) patients with locally-advanced non-small-cell lung cancer (LA-NSCLC): identification of five groups with different survival." Werner-Wasik M et al. Int J Radiat Oncol Biol Phys. 2000 Dec 1;48(5):1475-82.
** I: KPS>= 90% with chemotherapy - MS 16.2 months
** II: KPS>= 90%, no chemo, no pleural effusion - MS 11.9 months
** III: KPS < 90%, age < 70, non-large cell histology - MS 9.6 months
** IV: KPS >=90% with pleural effusion; KPS <90, age < 70, large cell; >70 without PE - MS 5.6-6.4 months
** V: Age > 70 with pleural effusion - MS 2.9 months

## Lymph node drainage

For primary tumor in a lobe, which lymph nodes does it drain to?
* Right upper lobe - ipsilateral mediastinum
* Left upper lobe - ipsilateral and contralateral mediastinum
* Right lower lobe - Subcarinal nodes -> right superior mediastinum -> right inferior mediastinum
* Left lower lobe - Subcarinal nodes -> right or left superior mediastinum -> right or left inferior mediastinum

## Natural history

* Also please see information in the Early Stage Inoperable page
* Split; 1994 (Croatia)(1980-1987) PMID 7988203 — "Survival analysis of untreated patients with non-small-cell lung cancer." (Vrdoljak E, Chest. 1994 Dec;106(6):1797-800.)
** Retrospective. 130 patients not treated with anti-cancer therapy
** Outcome: Median OS T2N0 17 months, T2N1 11 months, T2N2 10 months, other groups <8 months. Overall median OS 9 months. No patient (including T2N0) survived >3 years
** Subgroup analysis: Stage I (T2N0) better survival, all other stages comparable (worse) survival
** Conclusion: Lymph node involvement crucial factor in determining length of survival

## Economics

Cost-Effectiveness
* US Oncology; 2010 (2006-2007) No PMID JOP Abstract -- "Cost Effectiveness of Evidence-Based Treatment Guidelines for the Treatment of Non–Small-Cell Lung Cancer in the Community Setting" (Neubauer MA, Journal Oncol Pract 2010 Jan 6(1):12-18)
** Retrospective. Patients with NSCLC receiving chemotherapy, classified whether treated on Level I Pathway guidelines or not. 8 practices within US Oncology network. 12-month cost of care and overall survival
** Outcome: 12-month cost $18,042 vs. $27,737 (35% lower for on-Pathway patients). No difference in OS
** Conclusion: Treating patients according to evidence-based guidelines is a cost-effective strategy
RT Utilization
* Queen's University, 2001 (Canada) PMID 11240238 -- "Estimating the need for radiotherapy for lung cancer: an evidence-based, epidemiologic approach." (Tyldesley S, Int J Radiat Oncol Biol Phys. 2001 Mar 15;49(4):973-85.)
** Epidemiologic approach. Lit review to identify RT indications, then population estimates
** Overall: 61% have RT indication (45% initial, 16% progression)
** SCLC: 54% have RT indication (45% initial treatment, 8% progression)
** NSCLC: 64% have RT indication (46% initial treatment, 18% progression)
*** Stage I: 41%
*** Stage II: 55%
*** Stage III: 84%
*** Stage IV: 66%

## Patterns of failure

* RTOG, 1987
** PMID 3032394 — "Long-term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy." Perez CA et al. Cancer. 1987 Jun 1;59(11):1874-81.
** Based on two prospective studies:
*** RTOG 73-01: T1-3N0-2; randomized pts to 40 Gy split course (20 Gy in 5 fx, 2 weeks rest, repeat) or 40, 50, 60 Gy continuous course.
*** RTOG 73-02: T4 or N3; randomized to 30 Gy in 10 fx, 40 Gy split course, or 40 Gy std fx.
** Better control with 60 Gy. Adeno had better tumor control than squamous or large cell. Overall DM rate was the same, but for adenos DM appeared earlier and more likely to fail in the brain.

## Smoking

    See also: Cancer epidemiology
* PMID 16189363, 2005 — "Effect of smoking reduction on lung cancer." Godtfredsen NS et al. JAMA. 2005 Sep 28;294(12):1505-10.
** For those who smoke >15 cigarettes/day, smoking reduction by 50% reduces the risk of lung cancer (RR=0.73). In comparison, HR for quitters is 0.50.

## Radiation Injury

See Radiation Oncology/Normal tissue tolerance

## Other Resources

* ARRO Case - Locally Advanced NSCLC
* ASTRO/ARRO Journal Club Webinar 2012 - "Excessive toxicity when treating central tumors in a phase II study of SBRT for medically inoperative early-stage lung cancer" with Robert Timmerman, M.D
* ASTRO/ARRO Journal Club Webinar 2011 - "RTOG 9410: concurrent chemoradiation improves overall survival for inoperable stage III lung cancer" with Jeffrey Bradley, M.D.