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## Complete Summary

#### GUIDELINE TITLE

Nonsurgical, aggressive therapy for non-small-cell lung cancer.

#### BIBLIOGRAPHIC SOURCE(S)

Gewanter RM, Komaki RU, Movsas B, Bradley J, Gopal RS, Lee HK,
Rosenzweig KE, Thoms WW Jr, Kaiser LR, Schiller JH, Expert Panel on
Radiation Oncology-Lung. Nonsurgical, aggressive therapy for
non-small-cell lung cancer. \[online publication\]. Reston (VA):
American College of Radiology (ACR); 2006. 14 p. \[32 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Komaki R, Sause WT, Byhardt
RW, Curran WJ, Fuller D, Graham MV, Ko B, Weisenburger TH, Kaiser LR,
Leibel SA, Choi NC. Non-small cell lung cancer, nonsurgical, aggressive
therapy. American College of Radiology. ACR Appropriateness Criteria.
Radiology 2000 Jun;215(Suppl):1319-30.

The appropriateness criteria are reviewed annually and updated by the
panels as needed, depending on introduction of new and highly
significant scientific evidence.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Non-small-cell lung cancer

#### GUIDELINE CATEGORY

Treatment

#### CLINICAL SPECIALTY

Oncology\
Pulmonary Medicine\
Radiation Oncology\
Radiology

#### INTENDED USERS

Health Plans\
Hospitals\
Managed Care Organizations\
Physicians\
Utilization Management

#### GUIDELINE OBJECTIVE(S)

To evaluate the appropriateness of treatment procedures for patients
with non-small-cell lung cancer

#### TARGET POPULATION

Patients with non-small-cell lung cancer

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Irradiation planning

2.  Radiation therapy (RT) alone

3.  Chemotherapy (chemo) alone

4.  Combination therapy

    -   Concurrent chemo/RT

    -   Concurrent chemo/RT followed by chemo

    -   Chemo followed by RT

    -   Chemo followed by concurrent chemo/RT

    -   Chemo followed by RT, followed by more chemo

    -   RT followed by chemo

5.  Surgery

#### MAJOR OUTCOMES CONSIDERED

-   Progression-free, two-year, and five-year survival rate

-   Median survival time

-   Complications associated with treatment

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

The guideline developer performed literature searches of peer-reviewed
medical journals and the major applicable articles were identified and
collected.

#### NUMBER OF SOURCE DOCUMENTS

The total number of source documents identified as the result of the
literature search is not known.

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Not Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Not stated

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review with Evidence Tables

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

One or two topic leaders within a panel assume the responsibility of
developing an evidence table for each clinical condition, based on
analysis of the current literature. These tables serve as a basis for
developing a narrative specific to each clinical condition.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus (Delphi)

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Since data available from existing scientific studies are usually
insufficient for meta-analysis, broad-based consensus techniques are
needed for reaching agreement in the formulation of the appropriateness
criteria. The American College of Radiology (ACR) Appropriateness
Criteria panels use a modified Delphi technique to arrive at consensus.
Serial surveys are conducted by distributing questionnaires to
consolidate expert opinions within each panel. These questionnaires are
distributed to the participants along with the evidence table and
narrative as developed by the topic leader(s). Questionnaires are
completed by participants in their own professional setting without
influence of the other members. Voting is conducted using a scoring
system from 1-9, indicating the least to the most appropriate imaging
examination or therapeutic procedure. The survey results are collected,
tabulated in anonymous fashion, and redistributed after each round. A
maximum of three rounds is conducted and opinions are unified to the
highest degree possible. Eighty percent agreement is considered a
consensus. This modified Delphi technique enables individual, unbiased
expression, is economical, easy to understand, and relatively simple to
conduct.

If consensus cannot be reached by the Delphi technique, the panel is
convened and group consensus techniques are utilized. The strengths and
weaknesses of each test or procedure are discussed and consensus reached
whenever possible. If \"No consensus\" appears in the rating column,
reasons for this decision are added to the comment sections.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Not applicable

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Criteria developed by the Expert Panels are reviewed by the American
College of Radiology (ACR) Committee on Appropriateness Criteria.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

**ACR Appropriateness Criteria®**

**Clinical Condition: Nonsurgical, Aggressive Therapy for Non-Small-Cell
Lung Cancer**

**Variant 1: T1N3M0: 55-year-old patient with Stage IIIB (T1N3M0) poorly
differentiated adenocarcinoma with a 2 cm nodule in RLL and a palpable
supraclavicular lymph node. KPS \>70, weight loss \<5%.**

  ---------------------------------------------------------------------------
  **Treatment**        **Appropriateness   **Comments**
                       Rating**            
  -------------------- ------------------- ----------------------------------
  Radiation therapy    8                    
  plus chemotherapy                        

  RT alone             2                    

  Chemotherapy alone   2                    

  Surgery              2                    

  **Timing of                              
  Chemotherapy with                        
  RT---if given**                          

  Concurrent chemo/RT  8                    

  Concurrent chemo/RT  8                    
  followed by chemo                        

  Chemo followed by    7                    
  concurrent chemo/RT                      

  Chemo followed by RT 2                    

  Chemo followed by    2                    
  RT, followed by more                     
  chemo                                    

  RT followed by chemo 2                    

  **Local                                  
  Irradiation**                            

  60-70 Gy/6-7 ½ weeks 8                    
  or biological                            
  equivalent                               

  55 Gy/7-8 weeks      2                    
  (split course)                           

  50 Gy/5 weeks        2                    

  45 Gy/3 weeks        2                    

  40 Gy/4 weeks        2                    

  30 Gy/2 weeks        2                    

  **Radiotherapy                           
  Technique**                              

  Multifield technique 8                    

  AP/PA only           2                    

  **For Local                              
  Irradiation**                            

  Computer planning    8                    

  CT-based planning    8                    

  Complex blocking     8                    

  3D treatment         8                    
  planning                                 

  ***Appropriateness                       
  Criteria Scale*\                         
  1 2 3 4 5 6 7 8 9\                       
  1 = Least                                
  appropriate 9 = Most                     
  appropriate**                            
  ---------------------------------------------------------------------------

Note: Abbreviations used in the tables are listed at the end of the
\"Major Recommendations\" field.

**Variant 2: T2N3M0 (IIIB): 60-year-old male with NSCLC. Chest CT
revealed a 5 cm mass in RML APW node enlargement. The patient has
hoarseness due to paralyzed left vocal cord. KPS \>70, weight loss
\<5%.**

  ---------------------------------------------------------------------------
  **Treatment**        **Appropriateness   **Comments**
                       Rating**            
  -------------------- ------------------- ----------------------------------
  Radiation therapy    8                    
  plus chemotherapy                        

  RT alone             2                    

  Chemotherapy alone   2                    

  Surgery              2                    

  **Timing of                              
  Chemotherapy with                        
  RT---if given**                          

  Concurrent chemo/RT  8                    

  Concurrent chemo/RT  8                    
  followed by chemo                        

  Chemo followed by    6                    
  concurrent chemo/RT                      

  Chemo followed by RT 6                    

  Chemo followed by    4                    
  RT, followed by more                     
  chemo                                    

  RT followed by chemo 3                    

  **Local                                  
  Irradiation**                            

  60-70 Gy/6-7 ½ weeks 8                    
  or biological                            
  equivalent                               

  55 Gy/7-8 weeks      2                    
  (split course)                           

  50 Gy/5 weeks        2                    

  45 Gy/3 weeks        2                    

  40 Gy/4 weeks        2                    

  30 Gy/2 weeks        2                    

  **Radiotherapy                           
  Technique**                              

  Multifield technique 8                    

  AP/PA only           2                    

  **For Local                              
  Irradiation**                            

  Computer planning    8                    

  CT-based planning    8                    

  Complex blocking     8                    

  3D treatment         8                    
  planning                                 

  ***Appropriateness                       
  Criteria Scale*\                         
  1 2 3 4 5 6 7 8 9\                       
  1 = Least                                
  appropriate 9 = Most                     
  appropriate**                            
  ---------------------------------------------------------------------------

Note: Abbreviations used in the tables are listed at the end of the
\"Major Recommendations\" field.

**Variant 3: T3N3M0 (IIIB): 60-year-old patient NSCLC. Chest CT showed
right paratracheal adenopathy with post obstructive pneumonia due to
endobronchial lesion at the left mainstem. KPS \>70, weight loss \<5%.**

  ---------------------------------------------------------------------------
  **Treatment**        **Appropriateness   **Comments**
                       Rating**            
  -------------------- ------------------- ----------------------------------
  Radiation therapy    8                   Concurrent chemotherapy should be
  plus chemotherapy                        started once pneumonia clears.

  RT alone             2                    

  Chemotherapy alone   2                    

  Surgery              2                    

  **Timing of                              
  Chemotherapy with                        
  RT---if given**                          

  Concurrent chemo/RT  8                    

  Concurrent chemo/RT  8                    
  followed by chemo                        

  Chemo followed by    2                    
  concurrent chemo/RT                      

  Chemo followed by RT 2                    

  Chemo followed by    2                    
  RT, followed by more                     
  chemo                                    

  RT followed by chemo 2                    

  **Local                                  
  Irradiation**                            

  60-70 Gy/6-7 ½ weeks 8                    
  or biological                            
  equivalent                               

  55 Gy/7-8 weeks      2                    
  (split course)                           

  50 Gy/5 weeks        2                    

  45 Gy/3 weeks        2                    

  40 Gy/4 weeks        2                    

  30 Gy/2 weeks        2                    

  **Radiotherapy                           
  Technique**                              

  Multifield technique 8                    

  AP/PA only           2                    

  **For Local                              
  Irradiation**                            

  Computer planning    8                    

  CT-based planning    8                    

  Complex blocking     8                    

  3D treatment         8                    
  planning                                 

  ***Appropriateness                       
  Criteria Scale*\                         
  1 2 3 4 5 6 7 8 9\                       
  1 = Least                                
  appropriate 9 = Most                     
  appropriate**                            
  ---------------------------------------------------------------------------

Note: Abbreviations used in the tables are listed at the end of the
\"Major Recommendations\" field.

**Variant 4: T4N0M0 (IIIB): 60-year-old patient with left shoulder pain
radiating in an ulnar distribution to the left upper extremity,
accompanied by Horner syndrome. MRI of chest revealed a left superior
sulcus tumor (SST) with limited involvement of the C7 and T1 vertebral
bodies and left posterior 1st and 2nd ribs. Tumor was close to foramen
between C7 and T1. FNA of left SST showed poorly differentiated
adenocarcinoma. KPS \>70, weight loss \<5%.**

  ---------------------------------------------------------------------------
  **Treatment**        **Appropriateness   **Comments**
                       Rating**            
  -------------------- ------------------- ----------------------------------
  Radiation therapy    8                    
  plus chemotherapy                        

  RT alone             2                    

  Chemotherapy alone   2                    

  Surgery alone        2                   Neoadjuvant chemoradiation may be
                                           considered in selective cases.

  **Timing of                              
  Chemotherapy with                        
  RT---if given**                          

  Concurrent chemo/RT  8                    

  Concurrent chemo/RT  8                    
  followed by chemo                        

  Chemo followed by    2                    
  concurrent chemo/RT                      

  Chemo followed by RT 2                    

  Chemo followed by    2                    
  RT, followed by more                     
  chemo                                    

  RT followed by chemo 2                    

  **Local                                  
  Irradiation**                            

  60-70 Gy/6-7 ½ weeks 8                    
  or biological                            
  equivalent                               

  55 Gy/7-8 weeks      2                    
  (split course)                           

  50 Gy/5 weeks        2                    

  45 Gy/3 weeks        2                    

  40 Gy/4 weeks        2                    

  30 Gy/2 weeks        2                    

  **Radiotherapy                           
  Technique**                              

  Multifield technique 8                    

  AP/PA only           2                    

  **For Local                              
  Irradiation**                            

  Computer planning    8                    

  CT-based planning    8                    

  Complex blocking     8                    

  3D treatment         8                    
  planning                                 

  ***Appropriateness                       
  Criteria Scale*\                         
  1 2 3 4 5 6 7 8 9\                       
  1 = Least                                
  appropriate 9 = Most                     
  appropriate**                            
  ---------------------------------------------------------------------------

Note: Abbreviations used in the tables are listed at the end of the
\"Major Recommendations\" field.

**Variant 5: T4N1M0: 60-year-old male with a few weeks history of
superior vena caval obstruction (SVCO). Bronchoscopy revealed extrinsic
compression of RUL. FNA showed undifferentiated large cell carcinoma.
Chest CT showed 6 cm mass in RUL invading directly to mediastinum with
compression of SVC and right hilar enlargement. KPS \>70, weight loss
\<5%.**

  ---------------------------------------------------------------------------
  **Treatment**        **Appropriateness   **Comments**
                       Rating**            
  -------------------- ------------------- ----------------------------------
  Radiation therapy    8                    
  plus chemotherapy                        

  RT alone             2                    

  Chemotherapy alone   2                    

  Surgery              2                    

  **Timing of                              
  Chemotherapy with                        
  RT---if given**                          

  Concurrent chemo/RT  8                    

  Concurrent chemo/RT  8                    
  followed by chemo                        

  Chemo followed by    2                    
  concurrent chemo/RT                      

  Chemo followed by RT 2                    

  Chemo followed by    2                    
  RT, followed by more                     
  chemo                                    

  RT followed by chemo 2                    

  **Local                                  
  Irradiation**                            

  60-70 Gy/6-7 ½ weeks 8                    
  or biological                            
  equivalent                               

  55 Gy/7-8 weeks      2                    
  (split course)                           

  50 Gy/5 weeks        2                    

  45 Gy/3 weeks        2                    

  40 Gy/4 weeks        2                    

  30 Gy/2 weeks        2                    

  **Radiotherapy                           
  Technique**                              

  Multifield technique 8                    

  AP/PA only           2                    

  **For Local                              
  Irradiation**                            

  Computer planning    8                    

  CT-based planning    8                    

  Complex blocking     8                    

  3D treatment         8                    
  planning                                 

  ***Appropriateness                       
  Criteria Scale*\                         
  1 2 3 4 5 6 7 8 9\                       
  1 = Least                                
  appropriate 9 = Most                     
  appropriate**                            
  ---------------------------------------------------------------------------

Note: Abbreviations used in the tables are listed at the end of the
\"Major Recommendations\" field.

**Variant 6: T4N2M0: 63-year-old male with hemoptysis and chest pain.
Bronchoscopy revealed ulcerating carinal lesion. Biopsy showed SCC.
Chest CT showed subcarinal lymph node enlargement. KPS \>70, weight loss
\<5%.**

  ---------------------------------------------------------------------------
  **Treatment**        **Appropriateness   **Comments**
                       Rating**            
  -------------------- ------------------- ----------------------------------
  Radiation therapy    8                    
  plus chemotherapy                        

  RT alone             2                    

  Chemotherapy alone   2                    

  Surgery              2                    

  **Timing of                              
  Chemotherapy with                        
  RT---if given**                          

  Concurrent chemo/RT  8                    

  Concurrent chemo/RT  8                    
  followed by chemo                        

  Chemo followed by    2                    
  concurrent chemo/RT                      

  Chemo followed by RT 2                    

  Chemo followed by    2                    
  RT, followed by more                     
  chemo                                    

  RT followed by chemo 2                    

  **Local                                  
  Irradiation**                            

  60-70 Gy/6-7 ½ weeks 8                    
  or biological                            
  equivalent                               

  55 Gy/7-8 weeks      2                    
  (split course)                           

  50 Gy/5 weeks        2                    

  45 Gy/3 weeks        2                    

  40 Gy/4 weeks        2                    

  30 Gy/2 weeks        2                    

  **Radiotherapy                           
  Technique**                              

  Multifield technique 8                    

  AP/PA only           2                    

  **For Local                              
  Irradiation**                            

  Computer planning    8                    

  CT-based planning    8                    

  Complex blocking     8                    

  3D treatment         8                    
  planning                                 

  ***Appropriateness                       
  Criteria Scale*\                         
  1 2 3 4 5 6 7 8 9\                       
  1 = Least                                
  appropriate 9 = Most                     
  appropriate**                            
  ---------------------------------------------------------------------------

Note: Abbreviations used in the tables are listed at the end of the
\"Major Recommendations\" field.

**Variant 7: T4N3M0: 58-year-old patient with a palpable right
supraclavicular lymph node. Biopsy showed poorly differentiated NSCLC.
Chest CT showed a small right pleural effusion which is too small to be
tapped. KPS \>70, weight loss \<5%.**

  ---------------------------------------------------------------------------
  **Treatment**        **Appropriateness   **Comments**
                       Rating**            
  -------------------- ------------------- ----------------------------------
  Radiation therapy    8                    
  plus chemotherapy                        

  Chemotherapy alone   5                    

  RT alone             2                    

  Surgery              2                    

  **Timing of                              
  Chemotherapy with                        
  RT---if given**                          

  Concurrent chemo/RT  8                    

  Concurrent chemo/RT  8                    
  followed by chemo                        

  Chemo followed by    8                    
  concurrent chemo/RT                      

  Chemo followed by RT 5                    

  Chemo followed by    5                    
  RT, followed by more                     
  chemo                                    

  RT followed by chemo 2                    

  **Local                                  
  Irradiation**                            

  60-70 Gy/6-7 ½ weeks 8                    
  or biological                            
  equivalent                               

  55 Gy/7-8 weeks      2                    
  (split course)                           

  50 Gy/5 weeks        2                    

  40 Gy/10 fractions   2                    
  split course                             

  30 Gy/10 fractions   2                    

  20-24 Gy/3-5         2                    
  fractions                                

  **Radiotherapy                           
  Technique**                              

  Multifield technique 8                    

  AP/PA only           2                    

  **For Local                              
  Irradiation**                            

  Computer planning    8                    

  CT-based planning    8                    

  Complex blocking     8                    

  3D treatment         8                    
  planning                                 

  ***Appropriateness                       
  Criteria Scale*\                         
  1 2 3 4 5 6 7 8 9\                       
  1 = Least                                
  appropriate 9 = Most                     
  appropriate**                            
  ---------------------------------------------------------------------------

Note: Abbreviations used in the tables are listed at the end of the
\"Major Recommendations\" field.

**Variant 8: T1N0M0: 70-year-old male with long history of heavy smoking
and COPD. Routine chest x-ray showed nodule of LLL. FNA showed NSCLC.
(Medically inoperable). KPS \>70, weight loss \<5%.**

  ---------------------------------------------------------------------------
  **Treatment**        **Appropriateness   **Comments**
                       Rating**            
  -------------------- ------------------- ----------------------------------
  Radiation therapy    2                    
  plus chemotherapy                        

  RT alone             8                    

  Chemotherapy alone   2                    

  Surgery              1                    

  **Timing of                              
  Chemotherapy with                        
  RT---if given**                          

  Concurrent chemo/RT  2                    

  Concurrent chemo/RT  2                    
  followed by chemo                        

  Chemo followed by    2                    
  concurrent chemo/RT                      

  Chemo followed by RT 2                    

  Chemo followed by    2                    
  RT, followed by more                     
  chemo                                    

  RT followed by chemo 3                    

  **Local                                  
  Irradiation**                            

  60-70 Gy/6-7 ½ weeks 8                    
  or biological                            
  equivalent                               

  55 Gy/7-8 weeks      2                    
  (split course)                           

  50 Gy/5 weeks        2                    

  45 Gy/3 weeks        7                    

  40 Gy/4 weeks        2                    

  30 Gy/2 weeks        2                    

  **Radiotherapy                           
  Technique**                              

  Multifield technique 8                    

  AP/PA only           8                    

  Stereotactic RT      6                    

  **For Local                              
  Irradiation**                            

  Computer planning    8                    

  CT-based planning    8                    

  Complex blocking     8                    

  3D treatment         8                    
  planning                                 

  ***Appropriateness                       
  Criteria Scale*\                         
  1 2 3 4 5 6 7 8 9\                       
  1 = Least                                
  appropriate 9 = Most                     
  appropriate**                            
  ---------------------------------------------------------------------------

Note: Abbreviations used in the tables are listed at the end of the
\"Major Recommendations\" field.

**Summary of Literature Review**

Stage I through stage IIIA non-small-cell lung cancer (NSCLC) patients
can be operated on, with some advantage to receiving neoadjuvant or
adjuvant chemotherapy with or without radiation therapy (RT). However,
some patients with stage I through stage IIIA (surgically resectable)
but having poor lung function or other medically inoperable conditions
are candidates for aggressive RT with or without chemotherapy. These
patients should be treated with 3-dimensional conformal radiation
therapy (3DCRT) to minimize damage to surrounding normal tissue.

Stage IIIB includes patients with more extensive tumor invading the
mediastinum (T4) and/or with metastasis to the contralateral
mediastinum, contralateral hila, and ipsilateral or contralateral
supraclavicular (N3). They are considered to be surgically unresectable
and are usually treated by chemoradiation, RT alone, or chemotherapy
alone depending on their performance status and their symptoms. Those
patients who have better performance status and \<5% weight loss need to
be treated with a more aggressive approach, such as concurrent
chemotherapy and RT. Some patients in this group, especially T4N0-1
patients, may become resectable after neoadjuvant therapy. Those
patients who have pleural effusion are usually treated by chemotherapy
followed by palliative RT when indicated to relieve symptoms. Patients
with painful or obstructive lesions who are not otherwise candidates for
definitive radiation may require prompt palliative RT rather than
palliative chemotherapy alone.

**Radiation Therapy Alone: Standard Fractionation**

RT alone used to be considered the standard treatment for patients with
unresectable and locally advanced NSCLC. RTOG® 73-01tried to optimize
time/dose scheduling of RT alone for patients with unresectable and
locally advanced NSCLC, including those with poor performance status and
\>5% weight loss. This trial showed that better local control and 2-year
survival were achieved by a total dose of 60 Gy in 6 weeks compared to a
lower dose of RT alone. The investigators randomized 375 patients with
inoperable or unresectable stage II and stage III cancer to be treated
by 4 Gy/day x 5 days/week with a 2 week break and repeated 4 Gy/day x 5
days/week, giving a total dose of 40 Gy in 6 weeks (split course), 40 Gy
in 4 weeks, 50 Gy in 5 weeks, or 60 Gy in 6 weeks with continuous RT (2
Gy/day without split). The overall progression-free survival rates were
46% among the patients who received 40 Gy with a split course, 51% for
those who received 40 Gy continuous course, 65% for those who received
50 Gy, and 61% for those who received 60 Gy. The difference in the
response rates was statistically significant (49% vs. 63%) between the
groups who received 40 Gy and those who received 50--60 Gy. Two-year
survival rates were 14% among the patients who received 40 Gy in 4 weeks
with continuous course and 18% for those who received 50--60 Gy,
compared to only 10% among those who received a split course, although
this difference was not statistically significant. Patients who were
treated with 50--60 Gy with clinical tumor control had a survival rate
of 22% in 3 years compared to 10% if patients failed in the thorax. The
initial response rate was significantly better among patients with
adenocarcinoma and large cell carcinoma (69%) compared to those with
squamous cell carcinoma (50%).

**Altered Fractionation and Dose-Escalated Radiation Therapy**

Because of the poor 2-year survival and local control with standard
radiation doses and fractionation, a randomized dose escalation study
was initiated through RTOG® 83-11. This trial was an attempt to increase
local control by using higher total doses, while employing a twice-daily
fractionation regimen to avoid increasing toxicities of late responding
normal tissue. Eight hundred forty patients were treated with 1.2 Gy
twice-daily fractionation separated by 4--6 hours. They were randomized
to receive minimum total doses of 60 Gy, 64.8 Gy, and 69.6 Gy. After
acceptable acute toxicities, 74.4 Gy and 79.2 Gy arms were added. The
best arm received was 69.6 Gy in 6½ weeks and showed a 2-year survival
rate of 29% for patients with good performance status and \<5% weight
loss, which was significantly better compared to the survival rates
among patients who received lower doses.

The European Organisation for Research and Treatment of Cancer (EORTC)
conducted a randomized study for patients with inoperable or
unresectable stage II or III NSCLC who were treated by standard RT (60
Gy in 6 weeks) or continuous, accelerated, hyperfractionated RT (CHART).
The majority of the patients had squamous cell carcinoma on histology.
CHART was given at 1.5 Gy/fractions (Fx) 3 times a day, 7 days/week with
at least 6 hours interfractional interval. The large volume dose was
37.5 Gy in 25 fractions followed by 16.5 Gy in 11 fractions, giving a
total dose of 54 Gy. Their updated results showed improvement in
survival and local control with CHART compared to standard RT (3-year
survival rate with CHART was 20% vs. 13% with standard RT, and 3-year
local control with CHART was 17% vs. 12% with standard RT). More
moderate or severe acute dysphagia affected 49% of CHART cases, compared
with 19% of those treated conventionally. However, there was no
significant difference between the two arms in the rate of late
complications.

**Combined Chemotherapy and Radiation Therapy**

Given the poor outcome with RT alone and the high rate of metastatic
disease, combined chemotherapy and RT approaches were designed in an
attempt to improve outcomes. The Cancer and Leukemia Group B (CALGB)
randomized 155 patients with stage III NSCLC with good performance
status and \<5% weight loss who were treated with 2 cycles of
vinblastine and cisplatin followed by RT (60 Gy in 6 weeks) or with RT
alone (60 Gy in 6 weeks) Patients who were treated by induction
chemotherapy followed by RT had a median survival of 13.8 months (78
patients) compared to 9.7 months for those (77 patients) treated by RT
alone. The two-year survival rate was significantly better among the
patients who receive combined treatment compared to those who received
RT alone, 26% versus 13%. The longer follow-up of this study showed that
the 5-year survival rate of patients who receive combined treatment was
19%, compared to 7% for those who received RT alone.

The RTOG® 88-08 randomized 452 patients with stage III NSCLC, good
performance status, and \<5% weight loss to be treated in three arms.
Arm 1 received combined chemotherapy and radiotherapy (CRT). The
chemotherapy, using vinblastine and cisplatin, was administered in 2
cycles and was followed by RT with 60 Gy over 6½ weeks. Patients in the
other two arms received RT alone, one using 60 Gy of standard
fractionation (ST) RT in 6 weeks, the other using 69.6 Gy of
hyperfractionated (HFX) RT with a fraction size of 1.2 Gy. The median
survival was 13.2 months in the CRT arm compared to 11.4 months among
the patients who received ST RT. The two-year survival rate was 32%
among the patients who received combined treatment vs. 19% among the
patients who received ST RT alone. Outcome in the HFX RT arm was
intermediate between the other 2 arms (median survival= 12 months;
2-year overall survival rate 24%). Five-year survival rates, however,
were \<10% in all the study arms.

Other phase III trials have been reported since 1988, including an EORTC
study with a daily cisplatin and simultaneous RT arm, showing a
significantly improved 2-year survival rate, 26% compared to 13% among
the patients who received RT alone. However, the RT schedule was not
considered optimal as a standard of RT in the U.S. The control arm of RT
was given 3 Gy x 10 fractions with a 3- to 4-week break followed by 2.5
Gy x 10 Fx as a boost.

Other phase III trials have not found any significant improvement by
adding chemotherapy to RT. One study reported that giving cisplatin
concurrently with RT of 45 Gy in 3 weeks (3 Gy/day x 5 days/week) vs. RT
alone (45 Gy in 3 weeks) did not show any significant difference in
local control and survival. Another study randomized 121 patients to RT
alone vs. cyclophosphamide, doxorubicin, and cisplatin as induction
chemotherapy followed by RT. The latter did not provide any significant
improvement in median survival.

**Altered Fractionation Radiation Therapy Combined with Chemotherapy**

The North Central Cancer Treatment Group (NCCTG) conducted a 3-arm Phase
III randomized trial for patients with unresectable (stage III) NSCLC
treated with standard fractionated thoracic RT, accelerated
hyperfractionated thoracic RT, or HFX RT with concurrent etoposide and
cisplatin. The standard fractionation was 60 Gy in 30 Fx over 6 weeks.
HFX RT was given 1.5 Gy twice daily fractionation with a 2-week break
after initial 30 Gy in 2 weeks. This HFX RT was given alone or with
concomitant cisplatin (30 mg/m^2^, days 1-3 and 28-30) and etoposide
(100 mg/m^2^, days 1-3 and 28-30). The study group analyzed 99 eligible
patients out of the 110 patients entered. There was a suggestion of
improvement in the rate of freedom from local recurrence and survival
for patients with HFX RT with or without chemotherapy, compared to
standard RT. There was a significant improvement in survival with
accelerated and HFX RT (with or without chemotherapy) in the subgroup of
patients with non-squamous cell carcinoma. There was no difference in
freedom from distant metastasis or survival among the patients who
received HFX RT with or without concurrent chemotherapy. This study
suggested that the patients with stage III NSCLC treated with
accelerated HFX RT with or without chemotherapy may have better freedom
from local progression and survival compared to those receiving standard
RT, especially for patients with non-squamous-cell carcinoma.

The NCCTG next tested concurrent chemotherapy plus once-daily (qd) vs.
twice-daily (bid) RT. Both arms received cisplatin (30 mg/m^2^) and
etoposide (100 mg/m^2^) on days 1 and 28 concurrent with RT. Grade 3+
non-hematologic toxicity was slightly worse in the twice daily arm. At 2
years there was no difference in local control or overall survival.
Subgroup analysis suggested a survival benefit to twice daily in
non-squamous-cell histology, similar to previous findings by the NCCTG.
This was in distinction to findings from RTOG® 94-10 (see below) that
twice daily RT improved local control in squamous cancers.

RTOG® 91-06 combined the best arm of RTOG 83-11 (HFX RT to a total dose
of 69.6 Gy) with concurrent oral VP-16 (50 mg twice daily for 14 days
repeated every 29 days) and cisplatin (60 mg/m^2^ on days 1 and 8
repeated every 29 days). The study showed a 2-year survival rate of 40%
and median survival of 19.7 months among the patients with good
performance status and \<5% weight loss.

RTOG® 92-04 then compared the 91-06 regimen of immediate concurrent HFX
RT and chemotherapy in a randomized phase II study with induction
chemotherapy followed by concurrent chemotherapy and RT. Induction
chemotherapy consisted of vinblastine (5 mg/m^2^ intravenous bolus
weekly, weeks 1-5) and cisplatin (100 mg/m^2^ days 1 and 29 and 75
mg/m^2^ on days 50, 71, and 92) with standard RT initiated on day 50,
for a total tumor dose of 63 Gy in 34 fractions in 7 weeks. Arm 2
consisted of a total tumor dose of 69.6 Gy, 1.2 Gy/Fx twice-daily
fractionation with 6 hours interfractional interval with cisplatin (50
mg/m^2^ on days 1 and 2) and oral VP-16 (50 mg twice daily during the
first 10 days of RT). The chemotherapy was repeated every 29 days x 2.
One hundred sixty-eight patients were randomized and 160 were evaluable.
There was no difference between the two arms in regard to overall
survival. However, there was significant improvement in in-field
progression at four years in arm 2 (30%) vs arm 1 (49%) at 4 years.
There was significantly higher incidence of acute esophagitis among the
patients who received concurrent chemotherapy and HFX RT. The latter
regimen was included as one arm of the 3-arm phase III trial, RTOG®
94-10, described below.

RTOG® 98-01 was a randomized trial designed to test the hypothesis that
the cytoprotectant amifostine (AM) would reduce the incidence of
esophageal toxicity during concurrent chemotherapy and HFX RT. Patients
received 2 cycles of induction chemotherapy with paclitaxel (225
mg/m^2^) and carboplatin (area under the curve \[AUC\] 6) on days 1 and
22, followed by concurrent weekly paclitaxel (50 mg/m^2^) and
carboplatin (AUC 2) with HFX RT (1.2 Gy bid to 69.6 Gy). Patients were
randomized to receive or not to receive AM during the radiotherapy. The
AM was administered once daily, 4 days a week, before the afternoon
treatment. On RT-only days, AM was infused 15--30 minutes prior to RT
administration. On days when chemotherapy was given, RT was to be
administered not later than 180 minutes after AM administration. Acute
esophagitis was graded using the NCI Common Toxicity Criteria (CTC), and
patients kept a self-assessed swallowing diary. The results showed no
significant difference in the incidence of CTC grade [\>]{.underline} 3
esophagitis (30% with AM vs. 34% without AM); however, patient-reported
swallowing symptoms were significantly less severe with AM, particularly
in patients older than 65 years and in women. No differences in median
survival or median time to progression were seen between the 2 arms. The
authors concluded that while the trial did not support the hypothesis
that AM reduces esophagitis, the findings of the patient-derived
self-assessment suggested that further study of AM for non-squamous-cell
lung cancer is warranted.

**Sequential vs. Concurrent Chemotherapy and Radiation Therapy**

The West Japan Lung Cancer Group conducted a Phase III study to
investigate whether concurrent or sequential treatment with RT and
chemotherapy improves survival for patients with unresectable stage III
NSCLC. In the concurrent arm, chemotherapy consisted of cisplatin (80
mg/m^2^ on days 1 and 29), vindesine (3 mg/m^2^ on days 1, 8, 29, and
36), and mitomycin (8 mg/m^2^ on days 1 and 29). RT began on day 2 at a
dose of 28 Gy, 2 Gy/Fx, 5 Fx/week for a total of 14 fractions. This was
repeated after a rest period of 10 days; the total tumor dose was
therefore 56 Gy in 6 weeks. In the sequential arm, the same chemotherapy
was given with RT initiated after completing 2 cycles of chemotherapy.
RT consisted of 56 Gy, 2 Gy/Fx, and 5Fx/week with a total of 28
fractions. Three hundred twenty patients were entered in this study. The
response rate for the concurrent arm was significantly higher (84%)
compared to the sequential arm (66%). Median survival was significantly
improved in patients receiving concurrent chemotherapy and RT (16.5
months) compared with those receiving sequential therapy (13.3 months).
Two-, 3-, 4- and 5-year survival rates in the concurrent group were
34.6%, 22.3%, 16.9%, and 15.8%, respectively. The sequential group
showed 27.4%, 14.7%, 10.1% and 8.9% in 2-, 3-, 4- and 5-year survival,
respectively. Mild suppression was significantly greater among the
patients who received concurrent chemotherapy and RT. There was no
significant difference in regard to acute esophagitis between the two
groups.

RTOG® 94-10 was a three-arm randomized trial comparing sequential (SEQ)
chemotherapy followed by RT (once daily to 63 Gy), vs. two different
concurrent chemoradiotherapy regimens. The latter consisted of either
concurrent once-daily RT to 63 Gy (CON-QD), or concurrent twice-daily RT
to 69.6 Gy (CON-BID). The SEQ and CON-QD arms each included 2 cycles of
cisplatin and vinblastine. The CON-BID used 2 cycles of cisplatin and
VP-16 based on the experience in RTOG® 92-04. Acute toxicity was worst
in the CON-BID arm. Although time to in-field progression was best in
the CON-BID arm, this did not translate into a survival benefit. The
best survival was in the CON-QD arm, significantly better than the SEQ
arm. Median survivals in the three arms were 14.6 months (SEQ), 17
months (CON-QD), and 15.2 months (CON-BID).

**Role of Additional Chemotherapy before or after Concurrent
Chemotherapy and Radiation Therapy**

Several groups have studied the use of additional cycles of adjuvant
chemotherapy in an attempt to improve outcomes. The CALGB recently
presented initial results of trial 39801, in which patients with
unresectable stage III disease were randomized to concurrent weekly
carboplatin (AUC 2) and paclitaxel (50 mg/m^2^) and 66 Gy once-daily RT,
versus the same concurrent regimen preceded by 2 cycles of carboplatin
(AUC 6) and paclitaxel (200 mg/m^2^). A nonsignificant increase in
median survival was seen in the induction arm (14 vs. 11.4 months),
although the survival in both arms was poor compared with that seen in
other recent studies. Significant toxicity was more common on the
induction arm.

At the present time, combined treatment consisting of RT and
chemotherapy has given better 5-year survival than RT alone for patients
with medically inoperable and surgically unresectable stage III NSCLC.
More recent results showed that concurrent chemotherapy and RT improved
median survival and local control compared to sequential chemotherapy
followed by RT. HFX RT and concurrent chemotherapy appears to give
better local control, although survival has not been improved
significantly compared to induction chemotherapy followed by concurrent
low dose chemotherapy and daily RT. The risk of acute toxicity,
especially esophagitis, is increased when HFX RT is combined with
concurrent chemotherapy.

**Chemoradiation Alone vs. Neoadjuvant Chemoradiation Followed by
Surgery for pN2 Patients**

Patients with stage IIIA disease, with metastatic involvement of
ipsilateral mediastinal nodes (T1-3, N2) have traditionally been
considered inoperable due to poor outcomes following surgical resection.
Attempts have been made to improve the results of surgery in these
patients with the addition of neoadjuvant chemotherapy with and without
RT. Many consider chemoradiation alone to be the standard of care for
these patients, particularly those with bulky nodal disease. The North
American Intergroup 0139 (RTOG® 9309) trial was designed to compare
definitive chemoradiotherapy with neoadjuvant chemoradiation followed by
surgical resection. Patients in both arms received 2 cycles of cisplatin
and etoposide concurrent with 45 Gy of RT. Patients without progression
then went on to consolidation. Patients randomized to the surgery arm
underwent attempted surgical resection, followed by 2 additional cycles
of cisplatin/etoposide. Patients randomized to the chemoradiation arm
completed RT to 61 Gy concurrent with 2 additional cycles of
cisplatin/etoposide. Five-year progressive-free survival rate was
significantly improved in the surgery arm (24.4% vs. 11.1%), but due to
increased postoperative deaths, mainly following pneumonectomies, the
overall survival benefit did not reach statistical significance (27.2%
vs. 20.3% at 5 years). Patients downstaged to pN0 at surgery had a
5-year overall survival rate of 41%, compared to 24% in those with
pN1-3. The results of this trial suggest that surgery after
chemoradiation can be considered in fit patients, but that this approach
may not be optimal in patients requiring a pneumonectomy.

**Targeted Therapy**

Given the overall poor results with standard cytotoxic therapies, and
the number of advances that have been made recently in our understanding
of the biology of cancer, a strong interest has emerged in targeting
pathways unique to neoplastic cells or tumors. One such example is the
epidermal growth factor receptor (EGFr), which can be inhibited by
either monoclonal antibodies (e.g., cetuximab) or small molecule
tyrosine kinase inhibitors (erlotinib or gefitinib). Another example is
the area of angiogenesis, which can be inhibited with such drugs as
bevacizumab, a monoclonal antibody to vascular endothelial growth factor
(VEGF). Inhibition of both of these pathways (EGFr and VEGF) has been
shown in randomized studies to prolong survival of patients with
advanced NSCLC. However, in general little has been done with these
drugs in earlier stage disease, although adjuvant studies are being
planned with chemotherapy with or without erlotinib or bevacizumab.
Other studies are being conducted with these agents when given with
radiation therapy in inoperable stage III disease.

Neoadjuvant and adjuvant therapy are discussed more completely in the
American College of Radiology (ACR) Appropriateness Criteria® topic:
Induction and Adjuvant Therapy for N2 Non-Small-Cell Lung Cancer.

**Abbreviations**

-   AP/PA, anterior-posterior/posterior-anterior

-   APW, aortopulmonary window

-   C, cervical

-   COPD, chronic obstructive pulmonary disease

-   CT, computed tomography

-   3D, 3-dimensional

-   FNA, fine-needle aspiration

-   KPS, Karnofsky Performance Status

-   LLL, left lower lobe

-   MRI, magnetic resonance imaging

-   NSCLC, non-small-cell lung cancer

-   RLL, right lower lobe

-   RML, right middle lobe

-   RT, radiation therapy

-   RUL, right upper lobe

-   SCC, squamous cell carcinoma

-   SST, superior sulcus tumor

-   SVC, superior vena cava

-   SVCO, superior vena caval obstruction

-   T, thoracic vertebra

-   TNM, primary tumor, regional lymph node, and distant metastasis

#### CLINICAL ALGORITHM(S)

Algorithms were not developed from criteria guidelines.

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The recommendations are based on analysis of the current literature and
expert panel consensus.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

Selection of appropriate treatment procedures for patients with
non-small-cell lung cancer

#### POTENTIAL HARMS

-   Complications associated with radiotherapy (e.g., acute dysphagia,
    acute esophagitis) and chemotherapy

-   Morbidity and mortality associated with surgery

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

An American College of Radiology (ACR) Committee on Appropriateness
Criteria and its expert panels have developed criteria for determining
appropriate imaging examinations for diagnosis and treatment of
specified medical condition(s). These criteria are intended to guide
radiologists, radiation oncologists, and referring physicians in making
decisions regarding radiologic imaging and treatment. Generally, the
complexity and severity of a patient\'s clinical condition should
dictate the selection of appropriate imaging procedures or treatments.
Only those exams generally used for evaluation of the patient\'s
condition are ranked. Other imaging studies necessary to evaluate other
co-existent diseases or other medical consequences of this condition are
not considered in this document. The availability of equipment or
personnel may influence the selection of appropriate imaging procedures
or treatments. Imaging techniques classified as investigational by the
U.S. Food and Drug Administration (FDA) have not been considered in
developing these criteria; however, study of new equipment and
applications should be encouraged. The ultimate decision regarding the
appropriateness of any specific radiologic examination or treatment must
be made by the referring physician and radiologist in light of all the
circumstances presented in an individual examination.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Personal Digital Assistant (PDA) Downloads

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Gewanter RM, Komaki RU, Movsas B, Bradley J, Gopal RS, Lee HK,
Rosenzweig KE, Thoms WW Jr, Kaiser LR, Schiller JH, Expert Panel on
Radiation Oncology-Lung. Nonsurgical, aggressive therapy for
non-small-cell lung cancer. \[online publication\]. Reston (VA):
American College of Radiology (ACR); 2006. 14 p. \[32 references\]

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

1996 (revised 2006)

#### GUIDELINE DEVELOPER(S)

American College of Radiology - Medical Specialty Society

#### SOURCE(S) OF FUNDING

The American College of Radiology (ACR) provided the funding and the
resources for these ACR Appropriateness Criteria®.

#### GUIDELINE COMMITTEE

Committee on Appropriateness Criteria, Expert Panel on Radiation
Oncology---Lung

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Panel Members*: Richard M. Gewanter, MD; Ritsuko U. Komaki, MD;
Benjamin Movsas, MD; Jeff Bradley, MD; Ramesh S. Gopal, MD; Hoon Ku Lee,
MD; Kenneth E. Rosenzweig, MD; William W. Thoms, Jr, MD; Larry R.
Kaiser, MD; Joan H. Schiller, MD

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### GUIDELINE STATUS

This is the current release of the guideline.

This guideline updates a previous version: Komaki R, Sause WT, Byhardt
RW, Curran WJ, Fuller D, Graham MV, Ko B, Weisenburger TH, Kaiser LR,
Leibel SA, Choi NC. Non-small cell lung cancer, nonsurgical, aggressive
therapy. American College of Radiology. ACR Appropriateness Criteria.
Radiology 2000 Jun;215(Suppl):1319-30.

The appropriateness criteria are reviewed annually and updated by the
panels as needed, depending on introduction of new and highly
significant scientific evidence.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Portable Document Format (PDF) from the
[American College of Radiology (ACR) Web
site](http://www.acr.org/SecondaryMainMenuCategories/quality_safety/app_criteria/pdf/ExpertPanelonRadiationOncologyLungWorkGroup/NonsurgicalAggressiveTherapyforNonSmallCellLungCancerDoc4.aspx).

ACR Appropriateness Criteria® *Anytime*, *Anywhere*™ (PDA application).
Available from the [ACR Web
site](http://www.acr.org/SecondaryMainMenuCategories/ACRStore/FeaturedCategories/QualityandSafety/ac_pda.aspx).

Print copies: Available from the American College of Radiology, 1891
Preston White Drive, Reston, VA 20191. Telephone: (703) 648-8900.

#### AVAILABILITY OF COMPANION DOCUMENTS

The following is available:

-   ACR Appropriateness Criteria®. Background and development. Reston
    (VA): American College of Radiology; 2 p. Electronic copies:
    Available in Portable Document Format (PDF) from the [American
    College of Radiology (ACR) Web
    site](http://www.acr.org/SecondaryMainMenuCategories/quality_safety/app_criteria/pdf/background_dev.aspx).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI Institute on May 17, 2007.

#### COPYRIGHT STATEMENT

Instructions for downloading, use, and reproduction of the American
College of Radiology (ACR) Appropriateness Criteria® may be found on the
[ACR Web
site.](http://www.acr.org/SecondaryMainMenuCategories/quality_safety/app_criteria/ACRAppropriatenessCriteriaTermsandConditionsDoc1.aspx)

### DISCLAIMER

#### NGC DISCLAIMER

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Date Modified: 11/3/2008