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## Complete Summary

#### GUIDELINE TITLE

Non-small cell lung cancer.

#### BIBLIOGRAPHIC SOURCE(S)

Dutch Lung Cancer Study Group. Non-small cell lung cancer. Utrecht, The
Netherlands: Association of Comprehensive Cancer Centres (ACCC); 2004
Oct 15. 142 p. \[526 references\]

#### GUIDELINE STATUS

This is the current release of the guideline.

### COMPLETE SUMMARY CONTENT

 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 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 (NSCLC)

#### GUIDELINE CATEGORY

Diagnosis\
Evaluation\
Management\
Risk Assessment\
Screening\
Treatment

#### CLINICAL SPECIALTY

Family Practice\
Internal Medicine\
Nuclear Medicine\
Nursing\
Oncology\
Pathology\
Psychiatry\
Psychology\
Pulmonary Medicine\
Radiation Oncology\
Radiology\
Thoracic Surgery

#### INTENDED USERS

Advanced Practice Nurses\
Allied Health Personnel\
Health Care Providers\
Health Plans\
Hospitals\
Physician Assistants\
Physicians\
Psychologists/Non-physician Behavioral Health Clinicians\
Social Workers

#### GUIDELINE OBJECTIVE(S)

Generally:

-   To provide recommendations for the diagnosis treatment, follow-up,
    and types of support for patients with non-small cell lung cancer
    (NSCLC)

-   To facilitate the best care for patients with NSCLC

-   To offer an initial basis for developing transmural care or local
    protocols to promote guideline implementation

Specifically:

-   To specify the role of positron emission scans in the staging of
    lung carcinoma

-   To specify the role of induction chemotherapy for locally advanced
    lung carcinoma

-   To specify the role of concomitant chemotherapy and radiotherapy for
    lung carcinoma

-   To determine acceptable waiting times in diagnosis and treatment and
    assess the centralisation of certain healthcare services

-   To more precisely define various surgical options

#### TARGET POPULATION

Adults with non-small cell lung cancer

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Diagnosis/Evaluation**

1.  Patient history

2.  Physical examination

3.  Imaging (chest x-ray, bronchoscopy, computed tomography \[CT\]-scan
    of chest and upper abdomen, fluorodeoxyglucose positron emission
    tomography (FDG-PET)

4.  Laboratory evaluations

5.  Cytology/histology (transthoracic lung puncture, aspiration of
    pleural effusion, mediastinoscopy and biopsy, endoscopic ultrasound
    \[EUS\] with fine needle aspiration \[FNA\])

6.  Assessment of operability

    -   Age

    -   Cardiovascular status

    -   Lung function (forced expiratory volumes in 1 second \[FEV~1~\],
        diffusion capacity, maximum oxygen uptake)

    -   Intraoperative assessment of type of resection and resectability

    -   Intraoperative staging (intraoperative frozen section
        assessment, involvement of other organs/structures)

    -   Surgical and pathological documentation

7.  Diagnosis of metastases

    -   PET scan or skeletal scintigraphy, CT or magnetic resonance
        imaging (MRI) of brain

**Management/Treatment**

1.  Surgery

2.  Postoperative radiotherapy for resectable non-small cell lung cancer
    (NSCLC)

3.  Combination chemotherapy/radiotherapy for locally advanced NSCLC

4.  Chemoradiotherapy and/or surgery for superior sulcus tumors

5.  Chemotherapy/supportive care for Stage IIIB/IV NSCLC

6.  Follow-up

7.  Organization of care

    -   Maximum acceptable waiting times

    -   Treatment consultation and reporting

    -   Referral (lung surgery center requirements)

8.  Psychological care

    -   Physical, psychological, and social functioning

#### MAJOR OUTCOMES CONSIDERED

-   Relapse/recurrence rate

-   Response to treatment

-   Complications of treatment

-   Disease-free and overall survival

-   Quality of life

-   Sensitivity and specificity of diagnostic assessments

-   Correlation of waiting time to outcome

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Hand-searches of Published Literature (Primary Sources)\
Hand-searches of Published Literature (Secondary Sources)\
Searches of Electronic Databases

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

Relevant articles were found by performing systematic searches in the
Cochrane Library, Medline and Embase. Manual searches were also
performed. Other guidelines for lung carcinoma were also consulted. For
most chapters, searches covered the last 15 years, but in some cases
earlier records were searched. The articles were selected based on the
following criteria: (a) predominantly English or Dutch publications and
(b) full articles whenever possible. The quality of the articles was
evaluated by members of the study group using evidence-based guideline
development (evidence-based richtlijnontwikkeling \[EBRO\]) evaluation
forms. Articles of mediocre or poor quality were excluded. After this
selection process, the remaining articles were used as the basis for the
various conclusions stated in the guideline.

#### NUMBER OF SOURCE DOCUMENTS

-   11 articles on sleeve lobectomy

-   6 articles on pneumonectomy

-   8 articles on frozen section diagnosis

-   7 articles on mediastinal lymph node sampling or dissection

-   6 articles on pleural lavage cytology

-   12 articles on immunohistochemistry of lymph nodes

-   4 articles on the treatment of resectable non-small cell lung cancer
    (NSCLC)

-   5 articles on radiotherapy for locally advanced NSCLC

-   6 articles on neoadjuvant chemotherapy versus radiotherapy alone

-   8 articles on chemoradiotherapy versus radiotherapy alone

-   6 articles on waiting time and prognosis

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

Weighting According to a Rating Scheme (Scheme Given)

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

**Levels of Evidence**

  ---------------- -------------------------------------------------------------------
  **For Articles   
  Regarding        
  Intervention**   

  **A1**           Systematic reviews covering at least some A2-level studies in which
                   the results of the individual studies are consistent

  **A2**           Randomised comparative clinical studies of good quality
                   (double-blind, controlled), sufficient size and consistency

  **B**            Randomised clinical trials of moderate quality or insufficient
                   size, or other comparative studies (non-randomised, comparative
                   cohort studies, patient-control studies)

  **C**            Non-comparative studies

  **D**            Expert opinion from, for example, working group members

  **For Articles   
  Regarding        
  Diagnosis**      

  **A1**           Studies on the effects of diagnosis on clinical outcomes in a
                   prospectively followed, well-defined patient population with a
                   predefined protocol based on the results of the study test, or
                   decision theory studies on the effects of diagnosis on clinical
                   outcomes based on the results of A2-level studies with sufficient
                   consideration given to the interaction between diagnostic tests

  **A2**           Studies that include a reference test with predefined criteria for
                   the study test and the reference test and a good description of the
                   test and the clinical population studied; a sufficiently large
                   series of consecutive patients must be included, predefined cut-off
                   values must be used and the results of the test and the gold
                   standard must be evaluated independently. For situations in which
                   multiple diagnostic tests are involved, there is in principle
                   interaction and the analysis should take this into account by
                   using, for example, logistical regression

  **B**            Comparison with a reference test and description of the study test
                   and population, but lacking the other characteristics of A-level
                   studies

  **C**            Non-comparative studies

  **D**            Expert opinion from, for example, working group members
  ---------------- -------------------------------------------------------------------

#### METHODS USED TO ANALYZE THE EVIDENCE

Review of Published Meta-Analyses\
Systematic Review

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

The selected articles were graded according to the level of evidence.
Data derived from abstracts that were not (yet) published as full
articles are mentioned, but did not have any decisive weight in the
formulation of the conclusions and recommendations.

After the selection process, the remaining articles were used as the
basis for the various conclusions stated in the guideline. The selected
articles were then graded according to the level of evidence, in which
the following classification was used. Data derived from abstracts that
were not (yet) published as full articles are mentioned, but did not
have any decisive weight in the formulation of the conclusions and
recommendations.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

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

**Composition of the Working Group**

A multidisciplinary study group was formed that consisted of
representatives of all relevant specialties involved in the diagnosis
and treatment of on-small cell lung cancer (NSCLC) (see \"Assembling the
Study Group\" in the original guideline document). In creating the study
group, consideration was given to the geographic distribution of the
group members, the proportional representation of various concerned
associations and authorities, as well as distribution among those with
and without an academic background. In addition to the professional
groups, a representative from the Netherlands Epidemiological Society
(Vereniging voor Epidemiologie) was also present. Study group members
acted independently with authorisation from their associations.

**Formation of Basis Questions**

In spring 2002, the Dutch Lung Cancer Study Group (Landelijke Werkgroep
Longtumoren) conducted a survey to identify problem areas in the daily
practice and organisation of care for patients with NSCLC. Through this
process, a list of potential basis question was recorded. The list of
questions was sent to a random sample of clinicians with the request to
formulate their answers within their oncology boards. A total of 26
questionnaires were returned. A response was received from each region
with a comprehensive cancer centre. Both academic and non-academic
hospitals responded. Based on the results, the questions were
prioritised and a definitive list of 24 basis questions was created.
These questions focus on key problem areas in daily practice in the
Netherlands. The basis questions (see appendix 1 of the original
guideline document) form the foundation for the various chapters of the
guideline. Therefore, the guideline is not intended to be comprehensive.
Some additional instructional chapters have been included.

**Methods of the Working Group**

Given the scale of the task, the basis questions were divided into 14
clusters and a corresponding number of subgroups were formed with
representatives from relevant disciplines. In addition, an editorial
team that consisted of a chair, two vice-chairs, Centraal
Begeleidingsorgaan voor de Intercollegiale toetsing (CBO) advisors and a
project manager from the Vereniging voor Integrale Kanker Centra (VIKC)
was responsible for the coordination and mutual agreement among the
subgroups. The 14 subgroups worked over the period of approximately one
year on draft text related to a certain part of the guidelines. Study
group members wrote text individually or in subgroups that was discussed
during meetings and agreed upon after incorporation of comments. The
complete study group met seven times to intercorrelate the results of
the subgroups. The text created by the subgroups was combined by the
editorial team and standardised to create one document: the draft
guideline.

**Other Considerations**

In addition to the scientific evidence, there are often other important
aspects to consider in the development of a recommendation, including
patient preferences, the availability of special techniques or
expertise, organisational factors, social consequences and costs. These
factors are addressed in the section following the \'Conclusion\' (see
original guideline document). In this section, the conclusion that was
based on the literature is placed in the context of daily practice and
the advantages and disadvantages of the various protocol options are
weighed. The final formulated recommendation is the result of the
available evidence in combination with these considerations. The output
of this procedure and the structuring of the guideline in this format
are intended to enhance the transparency of the guideline. It allows for
efficient discussion during the study group meetings and also increases
the clarity for guideline users.

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

  ------------------------------------------------------------------------------------
  **Level of      
  Evidence for    
  Conclusions**   
  --------------- --------------------------------------------------------------------
  **1**           At least one systematic review (A1) or two independently conducted
                  A2-level studies

  **2**           At least two independently conducted B-level studies

  **3**           At least one A2-, B- or C-level study

  **4**           Expert opinion from, for example, working group members
  ------------------------------------------------------------------------------------

#### COST ANALYSIS

Published cost analyses were reviewed.

**Screening**

-   Screening should not be difficult for the patient or produce many
    false-positive results by which extra costs, alarm and anxiety are
    created.

-   Knowledge of the CT scan evidence before a bronchoscopy is
    cost-effective in patients with suspected lung cancer: the knowledge
    increases the diagnostic yield of invasive procedures and reduces
    the need for additional diagnostic testing.

**Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET)**

Nearly all data regarding costs are derived from model studies based on
decision theory analyses. Therefore it is possible to criticise the lack
of sensitivity analyses regarding the usual factors (costs, efficacy).
In one study, it appeared that the additional costs associated with PET
were negated by the reduction in the number of days hospitalised and the
number of operations.

**Surgery**

Sleeve resections were actually associated with a slightly higher local
recurrence rate than pneumonectomy, but the long-term results were
better. Moreover, the quality of life was better and sleeve resections
were more cost-effective.

**Chemotherapy versus Other**

-   For patients with stage IIIB/IV NSCLC and World Health Organization
    (WHO) performance status 0-1, the combination of best supportive
    care and chemotherapy as initial therapy improves 1-year survival
    and quality of life; this approach is viewed as cost-effective.

-   For patients with stage IIIB/IV NSCLC and WHO performance status 0-1
    with progression following platinum-containing chemotherapy,
    single-agent docetaxel plus best supportive care improves survival
    and quality of life; treatment is considered cost-effective.

**Radiation Therapy**

Multiple studies demonstrate that treatment with a fraction of 8 Gy is
as cost-effective as treatment with multiple fractions for a total of 24
Gy (for example, 6 x 4 Gy).

**Follow-up**

Intensive follow-up for a longer time period to detect second primary
lung tumours is not cost-effective, given the limited treatment options
for these patients.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

The draft guideline was presented for discussion at a national
guidelines meeting on 16 April 2004. For this meeting, all members of
the relevant professional groups were invited personally or via an
announcement in a medical journal. The comments from this meeting were
incorporated in the definitive guideline.

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

**Screening**

Screening for lung cancer in smokers using semi-annual cytological
sputum analysis and/or a chest x-ray is not indicated.

**Diagnostic Procedures**

**Patient History, Physical Examination, and Chest X-Ray**

For all patients with indications of lung carcinoma, a patient history
should be taken, a physical examination should be conducted and a chest
x-ray should be made.

**Laboratory Tests**

For all patients with suspected lung carcinoma, a limited laboratory
evaluation should be performed, including at least haemoglobin, calcium,
albumin, sodium, lactate dehydrogenase and alkaline phosphatase. A more
comprehensive laboratory evaluation is performed to assess organ
function prior to treatment.

**Bronchoscopy**

In principle, all patients with indications of lung cancer should
undergo bronchoscopy. Bronchoscopy is recommended for patients with a
peripheral tumour \<2 cm for staging purposes, rather than to diagnose a
lesion.

**Chest Computed Tomography (CT)-Scan**

All patients with suspected or confirmed non-small cell lung cancer
(NSCLC) should be considered for a CT scan of the chest and upper
abdomen, unless surgery, radiotherapy or chemotherapy is not being
considered. Performing the CT scan before bronchoscopy is recommended.

**Transthoracic Lung Puncture**

For patients with a lung lesion suspected of malignancy, transthoracic
lung puncture should be performed if the results could affect further
management.

**Pleural Effusion**

Aspiration of pleural effusion should occur in patients without distant
metastases. Puncturing should be repeated no more than twice if the
result is negative.

If the cytological assessment of the pleural effusion is negative,
supplemental thoracoscopy and possibly guided biopsy can be performed,
provided that the outcome may affect further management.

**Fluorodeoxyglucose Positron Emission Tomography (FDG-PET)**

Patients with NSCLC who are deemed candidates for intentionally curative
surgery should undergo FDG-PET scan after conventional evaluation for
metastatic disease and before mediastinoscopy.

See also the recommendations for mediastinoscopy.

**Mediastinoscopy**

During cervical mediastinoscopy, sufficient biopsies should be taken
from at least 4 of the 6 accessible lymph node stations, namely 2
ipsilateral stations, 1 contralateral station and node station 7.

Cervical mediastinoscopy should be performed in patients with (signs of)
NSCLC in whom no extrathoracic metastases are found, and in whom CT
and/or FDG-PET scans show evidence of lymph node involvement.

The imaging-based criteria that suggest (mediastinal) lymph node
involvement are (a) at least one lymph node with a short-axis diameter
\>1 cm on the CT scan or (b) a focus of increased activity in the hilus
or mediastinum on the FDG-PET scan.

In patients with a negative mediastinal FDG-PET scan, mediastinoscopy
can be omitted provided that the following 4 criteria are met:

-   There is clear uptake of FDG in the primary tumour

-   There is no evidence of hilar metastases on the PET scan

-   The tumour is not close to the mediastinum

-   The short-axis diameters of the nodes visible on the CT scan are
    less than 1 cm

**Endoscopic Ultrasound (EUS) with Needle Puncture**

The value of EUS with fine-needle aspiration (FNA) lies mainly in
detecting mediastinal lymph node metastases (particularly on the left
side or in the lower mediastinum) and possibly in determining whether
central tumours are unresectable (T4) (see the original guideline
document for the tumor/node/metastasis \[TNM\] staging definitions).

Although the definitive role of EUS-FNA in lung carcinoma is under
investigation, this procedure can be considered for:

-   Analysis of PET-positive lesions that are suspected of N2 or N3
    lymph node metastases

-   Mediastinal restaging following chemotherapy

-   Evidence of T4 mediastinum for central tumours on the left side

**Treatment Criteria**

**Criteria for Medical (In)operability**

*Age*

For patients aged 70 to 80 years, it appears that the increased surgical
risk due to age is not a reason to withhold lung surgery. It is advised
that these patients are evaluated for lung surgery in accordance with
the recommendations listed below with extra attention given to
comorbidity and general condition. Caution is warranted, however, when
considering right-side pneumonectomy.

Resection should also be considered as a possible treatment modality for
patients aged more than 80 years without relevant comorbidity and in
good condition, provided that the doctor and patient find the surgical
risk acceptable.

*Cardiovascular Evaluation*

Before surgery, cardiac disorders such as coronary disease, heart
failure, valve disease and rhythm disorders should be detected through
patient history, physical examination and ECG.

If lung surgery is planned for a patient with (signs of) heart disease,
a cardiologist or an anaesthesiologist should assess the perioperative
risk and advise on the perioperative protocol.

*Lung Function*

The surgical risk is not considered increased if the forced expiratory
volume in one second (FEV~1~) and the diffusion capacity (TLCO) are both
\>80% and there is no unforeseen exertional dyspnoea.

If these criteria are not met, it is advised to calculate the predicted
postoperative lung function using the calculation method (perfusion scan
with left-right proportion and, for lobectomy, supplemented with the
segment method).

If the operability of the patient is questioned based on the lung
function assessment and/or the patient history (unforeseen exertional
dyspnoea), an exertion test that includes determination of the maximum
oxygen uptake (VO~2~max) is advisable.

Use of the flowchart in Figure 2.1 in the original guideline document is
recommended for the evaluation of perioperative risk.

*General*

Before surgery, it should be determined what maximum degree of
parenchymal resection is prudent.

For patients with an increased surgical risk, alternatives such as
limited resection or chemotherapy and/or radiotherapy should be weighed
against the increased risk of surgery in a multidisciplinary
consultation.

**Intraoperative Assessment of the Type of Resection and Resectability**

For operable patients with NSCLC in whom tumour growth is limited to one
lobe, lobectomy is the treatment of choice. Intentionally curative
radiotherapy is a good alternative if the surgical risk is determined to
be (too) high.

Patients in whom lung function is so limited that lobectomy is not
possible may be considered for segment resection (preferred) or wedge
excision if complete resection using this method is possible.

In principle, if the lung tumour has spread from one lobe to another, a
lobectomy plus a wedge resection of the other lobe should be performed.
For central tumours, bilobectomy or pneumonectomy may be an option.

If a conventional lobectomy is not possible due to tumour growth up to
or past the level of the bronchial ostium, a sleeve lobectomy is
advisable because complete resection is possible with this technique
even when lung function precludes pneumonectomy.

A sleeve resection of the pulmonary artery should be performed only if
the patient cannot tolerate pneumonectomy due to lung function.

If there is tumour growth in the direction of the thoracic wall and it
is questionable whether the tumour has spread through the parietal
pleura, one should immediately opt for including the affected thoracic
wall en bloc.

If during surgery it appears that the tumour has spread to the
intrapericardially positioned portion of the pulmonary artery, it is
often possible to conduct a pneumonectomy.

If during surgery it appears that the tumour has spread to or into the
main carina, which precludes a conventional pneumonectomy, a sleeve
lobectomy may be attempted. If this is not possible, it should be
immediately ascertained whether a sleeve pneumonectomy can be performed
on the right side. On the left side, a sleeve pneumonectomy can occur in
2 phases. Referral to a treatment centre is indicated.

If during surgery it appears that the tumour is growing into the vena
cava superior, the adventitia of the aortic wall, the pericardium or the
diaphragm, primary resection should not be ruled out *a priori*.

If during surgery it appears that the tumour is growing into the spinal
column or into the left atrium substantially, it is seldom resectable.

If during surgery it appears that the tumour is growing into the
pulmonary trunk or through the entire aortic wall or has led to
pleuritis carcinomatosa, it is unresectable. This likely holds true also
for spread to the oesophagus.

If during surgery it appears that there are more tumours present in one
lobe, lobectomy is performed. If multiple tumours are present in
different lobes (M1), primary resection is an option.

*Requirements for Intraoperative Staging*

If before surgery there is no known tissue diagnosis, intraoperative
frozen section assessment of the tumour is recommended before proceeding
to lung resection.

Intraoperative frozen section assessment is recommended if macroscopic
findings of lymph nodes provide reason for it (indications of extranodal
growth or bulky disease). This is applicable if the result of the
assessment can influence the surgical procedure (lung resection and/or
mediastinal lymph node dissection).

For central tumours, intraoperative frozen section assessment of the
bronchial resection field is recommended, unless a positive result would
have no influence on the surgical procedure. Regardless of the location
of the tumour, all intrapulmonary and hilar lymph nodes (N1 node
stations 10, 11 and 12) should be removed en bloc with the resected
section if possible.

Regardless of the location of the tumour, all intrapulmonary and hilar
lymph nodes (N1 node stations 10, 11 and 12) should be removed en bloc
with the resected section if possible.

To determine the status of mediastinal lymph nodes (N2 stations), at
least the lymph node stations to which the tumour preferably drains
should be systematically sampled during surgery.

Specifically, this implies for tumours of the

-   Right upper and middle lobe: node stations 2R, 4R and 7

-   Right lower lobe: node stations 4R, 7, 8 and 9

-   Left upper lobe: node stations 5, 6 and 7

-   Left lower lobe: node stations 7, 8 and 9

*Requirements for Surgical Documentation*

Following an operation for NSCLC, the surgical documentation should
contain:

-   Surgical approach (thoracotomy, sternotomy, etc)

-   Tumour location, size, extent and distance from the main carina

-   Presence or absence of satellite lesions and metastases in other
    lobes

-   Lymph node stations (extranodal growth) and surgical technique used
    to evaluate mediastinal lymph nodes

-   Presence and characteristics of pleural effusion; pleural lavage
    (duration and method), if applicable

-   Result of frozen section assessment, if performed

-   Distance between the tumour and the resection field, particularly
    the bronchial resection field

-   Radicality of the resection (R0, R1 or R2)

-   Placement of clips to demarcate the resection field, if applicable

-   Perioperative consultation with other specialists

-   Complications, if applicable

-   Conclusion: procedure performed and intraoperative staging

*Requirements for Pathological Documentation*

The pathology report should include at least all evidence that allows
for indisputable conclusions regarding staging (pTNM stage) and the
completeness of resection.

The recommendation for pathological reporting calls for the use of a
checklist (see appendix 17 in the original guideline document ).

Removed lymph nodes should be assessed using hematoxylin and eosin (HE)
staining and immunohistochemical techniques.

**Treatment**

**Resectable NSCLC**

Postoperative radiotherapy is recommended if pathological assessment
reveals involvement of the resection field. Postoperative radiotherapy
should be considered for unexpected pN2 (possibly also pN3). The chance
of improved local control should be weighed against the risk of
radiotherapy-associated morbidity.

Postoperative radiotherapy is not indicated for pN0-1 nodes with R0
resection.

**Locally Advanced NSCLC**

Patients with locally advanced NSCLC (clinical stage III, based on cT4
and/or cN2-3) should be treated with combination therapy with curative
intent. Exceptions include patients with World Health Organization (WHO)
performance status 2, pleuritis carcinomatosa, extensive tumour invasion
(requiring a radiotherapy field that would be too large with respect to
lung function) or contralateral supraclavicular lymph node involvement.

Standard combination therapy consists of chemotherapy and radiotherapy.
The value of surgery in this setting, particularly for stage IIIA N2
disease, has not yet been confirmed.

Radiotherapy is given at a biological equivalent of at least 60 Gy over
6 weeks.

At this time, chemotherapy is preferably given sequentially before
radiotherapy. In accordance with the recommendations for advanced NSCLC,
induction chemotherapy consists of 2 to 4 cycles of cis- or carboplatin
in combination with a third generation cytostatic agent.

Chemotherapy can be given concomitantly with radiotherapy in selected
patients provided that the associated increased risk of toxicity appears
acceptable. For concomitant chemoradiotherapy, the chemotherapy regimen
used is preferably one that has been used in published studies, such as
cisplatin-containing chemotherapy in combination with vinca alkaloids,
with or without mitomycin.

**Superior Sulcus Tumors**

For patients with locally advanced superior sulcus NSCLC and a WHO
performance status 0-1, standard treatment consists of a multimodality
approach using chemoradiotherapy and/or surgery. On the one hand,
superior sulcus tumours can be considered the same as any other NSCLC.
On the other hand, a more aggressive approach is justified, given the
location and symptoms that are often difficult to treat if local control
is not achieved.

For patients with a superior sulcus tumour that does not appear to be
primarily resectable (stage cIII), sequential or concurrent
chemoradiotherapy is advisable, in accordance with the recommendation
for other NSCLC patients with stage III disease. If it is later
determined that the tumour is in fact small enough to be resected,
surgery can be considered for selected patients.

Treatment of patients with a superior sulcus tumour should occur in a
specialised treatment centre.

**Stage IIIB/IV**

*Chemotherapy Versus Supportive Care*

For patients with stage IIIB/IV NSCLC and a WHO performance status 0-1,
treatment should consist preferably of best supportive care and
chemotherapy.

*Choice of Chemotherapy*

For patients with stage IIIB/IV NSCLC and WHO performance status 0-1,
best supportive care and chemotherapy, consisting of cisplatin or
carboplatin in combination with a third generation cytostatic agent, is
preferred.

*Age \>70 Years*

For patients aged more than 70 years with stage IIIB/IV NSCLC and WHO
performance status 0-1, chemotherapy is preferred; comorbidity should be
taken into account.

*Number of Chemotherapy Cycles*

For patients with stage IIIB/IV NSCLC and WHO performance status 0-1, 3
to 4 cycles of chemotherapy is preferred; fewer may be given in the
event of disease progression or severe toxicity.

*Second-Line Treatment*

For patients with stage IIIB/IV NSCLC and WHO performance status 0-1
with progression following first-line chemotherapy, best supportive care
is preferred; additionally, patients may be considered for second-line
chemotherapy.

**Follow-Up**

Routine follow-up after treatment for patients with NSCLC should consist
of patient history, physical examination and possibly chest x-ray.

More intensive follow-up (additional imaging, tumour marker assessment,
bronchoscopy) should occur only in the context of a study protocol or in
a training or academic setting.

The study group recommends the following with regard to the frequency of
follow-up (alternating though different clinicians if desired):

-   For the first year: every 3 months

-   For the second year: every 6 months

-   After the second year: annually for a minimum of 5 years

**Diagnosis of Metastases**

Patients with clinical stage III NSCLC must undergo skeletal
scintigraphy (unless PET scan was performed and was negative) and CT or
magnetic resonance imaging (MRI) of the brain to avoid unnecessary
combination therapy.

**Organisation of Care**

**Maximum Acceptable Waiting Time**

The study group recommends the following maximum acceptable waiting
times:

-   General practitioner: 80% within 2 working days, maximal 3 working
    days

-   Pulmonologist: 80% within 5 working days for evidence of a lung
    tumour or abnormal chest image

-   Diagnosis (CT scan, bronchoscopy with pathological anatomy (PA),
    PET, mediastinoscopy): 80% with 3 weeks

-   PA: the result of the PA test should be known within 1 week unless
    hindered by special processing

-   Curative therapy: 80% within 2 weeks after the diagnosis is made

-   Palliative therapy: 80% within 1 week

Eighty percent of patients should be through the diagnostic trajectory
within 3 weeks. Within 5 weeks is acceptable if mediastinoscopy is
conducted.

If indicated, 80% of patients should undergo surgery and/or (the
preparation for) radiotherapy and/or start chemotherapy within 2 weeks
after the completion of the diagnostic trajectory.

**Treatment Consultation and Reporting**

All new patients should be discussed during a multidisciplinary (lung)
oncology review.

**Referral**

A lung surgery centre should meet the requirements set for academic
institutions for lung surgery as described in the report of the
Interdisciplinary Committee on Lung Surgery (Interdisciplinaire
Commissie Longchirurgie).

A treatment centre should be consulted in the following situations:

-   cT3 or cT4 disease

-   Increased pulmonary of cardiac comorbidity

-   Use of combined treatment modalities

As a minimum, a treatment centre should provide the support of
pulmonologists, radiation oncologists, (thoracic) surgeons, clinical
pathologists, radiologists and specialised nurses, in accordance with
the requirements set by the relevant professional societies.

A treatment centre should have a minimum of two specialists in each
discipline to ensure continuity.

A treatment centre should offer consultation to clinicians in other
hospitals.

**Psychosocial Care**

**Prevalence**

Based on the prevalence of psychosocial problems in patients with lung
cancer, the care providers involved should inquire about anxiety and
depression in every patient with lung cancer.

**Interventions**

From the beginning and throughout all phases of diagnosis and treatment,
medical specialists, general practitioners and/or (oncology) nurses
should be educated to inquire about and treat physical symptoms because
prompt medical and/or behavioural therapy for these symptoms may promote
psychosocial functioning and quality of life.

From the beginning and throughout all phases of diagnosis and treatment,
medical specialists, general practitioners and/or (oncology) nurses
should inquire about psychosocial stress factors and psychological
symptoms because prompt treatment may promote improved psychosocial
functioning and quality of life.

An (oncology) nurse should be involved in the process of care because he
or she is an integral link in the chain of treatment, care and early
signalling of somatic and psychological symptoms.

Care providers should pay attention to psychosocial problems in family
members and/or others close to the patient.

**Organisation**

General practitioners, medical specialists and (oncology) nurses should
be aware that basic psychosocial care must be offered from the initial
phases of diagnosis and treatment for NSCLC. This care consists of
customised education, adequate handling and temporary admission if
necessary.

Good psychosocial care requires the availability of adequate referral
options to care providers who are trained to address the psychosocial
needs of cancer patients, such as nursing specialists, social workers
(associated with the hospital), psychologists, psychiatrists and/or
specific patient programmes (discussion groups, relaxation groups,
rehabilitation programmes, patient associations).

#### CLINICAL ALGORITHM(S)

The original guideline document contains clinical algorithms for:

-   Recommended diagnostic tests and staging of patients with
    indications of lung cancer

-   Determining perioperative risk before lung surgery by means of lung
    function assessment

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is not identified or graded for each
recommendation.

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Avoidance of unnecessary therapy for non-small cell lung cancer

-   Improved outcomes

-   Reduction in treatment related adverse events

#### POTENTIAL HARMS

-   Adverse effects of treatment

-   Complications of surgical and other procedures

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

-   Transthoracic lung puncture is contraindicated in some patients,
    including those with pulmonary hypertension and increased bleeding
    tendency.

-   Palliation other than chemotherapy (e.g., surgical intervention
    followed by radiotherapy) for bone metastases is contraindicated for
    life expectancy less than four weeks and a general condition so poor
    that an operation cannot be performed safely.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

Guidelines are not legal requirements, but rather scientifically founded
and widely accepted views and recommendations to which healthcare
providers would have to adhere to provide quality care. Given that
guidelines are based on \'average patients\', healthcare providers can
deviate from the recommendations in the guideline as necessary in
individual cases. Deviation from the guideline is in fact sometimes
necessary if the patient\'s situation demands it. When there is
deviation from the guideline, however, it must be rationalised,
documented and, when necessary, discussed with the patient.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

During the various phases of development of the draft guideline,
consideration was given whenever possible to the implementation of the
guideline and the actual feasibility of the recommendations. The
guideline will be distributed to all hospitals and oncology boards,
scientific societies and Comprehensive Cancer Centres (Integrale Kanker
Centra). A summary of the guideline will also be published in the *Dutch
Journal of Medicine (Nederlands Tijdschrift voor Geneeskunde)* and
attention will be given to the guideline in various specialty journals.
In addition, the guideline will be reproduced on www.oncoline.nl. To
stimulate the implementation and evaluation of this guideline, the study
group will, as a next step, create an implementation plan and develop a
list of indicators through which implementation can be measured. In
general, indicators give healthcare providers the opportunity to assess
whether they are providing the desired level of care. They can also be
used to identify topics for improving the provision of care. The
guideline will be tested by end-users in different regions and
scientific societies, at which time on-site visits will also be
organised.

#### IMPLEMENTATION TOOLS

Clinical Algorithm\
Foreign Language Translations\
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

End of Life Care\
Living with Illness

#### IOM DOMAIN

Effectiveness\
Patient-centeredness\
Timeliness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Dutch Lung Cancer Study Group. Non-small cell lung cancer. Utrecht, The
Netherlands: Association of Comprehensive Cancer Centres (ACCC); 2004
Oct 15. 142 p. \[526 references\]

#### ADAPTATION

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

#### DATE RELEASED

2004 Oct

#### GUIDELINE DEVELOPER(S)

Association of Comprehensive Cancer Centres - Disease Specific Society

#### SOURCE(S) OF FUNDING

Association of Comprehensive Cancer Centres

#### GUIDELINE COMMITTEE

Dutch Lung Cancer Study Group

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Chief Editors*: Prof. dr. J.P. van Meerbeeck, pulmonologist,
Universitair Ziekenhuis Gent, België , chair; Mw. prof. dr. C.C.E.
Koning, radiation oncologist, Academisch Medisch Centrum,
Amsterdam,vice-chair; Mw. dr. V.C.G. Tjan-Heijnen, medical oncologist,
Radboud University Nijmegen Medical Centre, Nijmegen, vice-chair; Mw.
drs. J. Wittenberg, epidemiologist, Kwaliteitsinstituut voor de
Gezondheidszorg CBO,Utrecht, advisor (until October 2003); Mw. dr.
C.J.E. Kaandorp, physician, Kwaliteitsinstituut voor de Gezondheidszorg
CBO, Utrecht, advisor (as of October 2003); Dr. J.S. Burgers, general
practitioner, Kwaliteitsinstituut voor de Gezondheidszorg CBO, Utrecht,
senior advisor (as of October 2003); A.G. Boekema, medical officer,
Vereniging van Integrale Kankercentra, Utrecht,project manager; Drs.
V.K.Y. Ho, methodologist, Vereniging van Integrale Kankercentqra,
Utrecht, policy advisor for national guidelines

*Study Group Members*: J.T. Annema, pulmonologist, Leids Universitair
Medisch Centrum, Leiden; Dr. P. Baas, pulmonologist, Antoni van
Leeuwenhoek Ziekenhuis, Amsterdam; Dr. M. den Bakker, clinical
pathologist, Erasmus MC, Josephine Nefkens Instituut, Rotterdam; Mw. dr.
P.F.A. Bakker, cardiothoracic surgeon, Universitair Medisch Centrum,
Utrecht; Mw. J.S.A. Belderbos, radiation oncologist, Nederlands Kanker
Instituut-Antoni van Leeuwenhoek Ziekenhuis, Amsterdam; Dr. B. Biesma,
pulmonologist, Bosch Medicentrum, locatie Groot Ziekengasthuis,
\'sHertogenbosch; Dr. E.C.M. Bollen, surgeon, Atrium Medisch Centrum,
Heerlen; Dr. J. Bussink, radiation oncologist, Universitair Medisch
Centrum St. Radboud, Nijmegen; H.E. Codrington, pulmonologist,
Ziekenhuis Leyenburg, Den Haag; Mw. C.E. van Die, thoracic radiologist,
Universitair Medisch Centrum St. Radboud, Nijmegen; Prof. dr. H.J.M.
Groen, pulmonologist, Academisch Ziekenhuis Groningen, Groningen; Dr.
J.M.W. van Haarst, pulmonologist, Ziekenhuis Hilversum, Hilversum; Dr.
P.A. Helle, radiation oncologist, Medisch Spectrum Twente, Enschede A.G.
Hensens, cardiopulmonary surgeon, Universitair Medisch Centrum St.
Radboud, Nijmegen; Dr. F.M.J. Heijstraten, radiologist, Universitair
Medisch Centrum St. Radboud, Nijmegen; Dr. O.S. Hoekstra, nuclear
medicine physician, VU Medisch Centrum, Amsterdam; Dr. P.L. Jager,
nuclear medicine physician, Academisch Ziekenhuis Groningen, Groningen;
Mw. dr. M.L.G. Janssen-Heijnen, epidemiologist, Integraal Kankercentrum
Zuid, Eindhoven; Mw. dr. M.J.A. de Jonge, internist-oncologist, Erasmus
MC, locatie Dani.l, Rotterdam; G.W.P.M. Kramer, radiation oncologist,
Arnhems Radiotherapeutisch Instituut, Arnhem; Dr. H.B. Kwa,
pulmonologist, Onze Lieve Vrouwe Gasthuis, Amsterdam; Dr. W.B.
Lastdrager, surgeon, Gelre Ziekenhuizen, Apeldoorn; Dr. H.J. Mulder,
surgeon, Medisch Spectrum Twente, Enschede; Prof. dr. E.M. Noordijk,
radiation oncologist, Leids Universitair Medisch Centrum, Leiden; Dr.
B.P. Ponsioen, general practitioner, Brielle; Dr. J.W.G. van Putten,
pulmonologist, Martini Ziekenhuis, Groningen; Mw. A.M.C. Raat, general
practitioner, Amersfoort; P.T.R. Rodrigus, radiation oncologist,
Catharina-ziekenhuis, Eindhoven; Dr. W.J.G. Ros, social psychologist,
Universitair Medisch Centrum Utrecht, Utrecht; Mw. J.P. Salomé, nurse
practitioner, St. Franciscus Gasthuis, Rotterdam; N.J.J. Schl.sser,
pulmonologist, Centraal Militair Hospitaal, Utrecht; Dr. J.H. Schouwink,
pulmonologist, Medisch Spectrum Twente, Enschede; Mw. N.A.W.P. Schrama,
oncology nurse, Ziekenhuis Bernhoven, Veghel; Dr. F.M.H.H. Schramel,
pulmonologist, St. Antonius Ziekenhuis, Nieuwegein; Dr. E.F. Smit,
pulmonologist, Martini Ziekenhuis, Groningen and VU Medisch Centrum,
Amsterdam; A.H.M. van Straten, cardiothoracic surgeon, Catharina
Ziekenhuis, Eindhoven; Dr. J.R.M. van der Sijp, surgeon, VU Medisch
Centrum, Amsterdam; Dr. F.B.J.M. Thunnissen, pathologist, Nijmeegs
Interkonfessioneel Ziekenhuis Canisius-Wilhelmina, Nijmegen; Mw. A.L.J.
Uitterhoeve, radiation oncologist, Academisch Medisch Centrum,
Amsterdam; E.F. Ullmann, pulmonologist, Rijnstate Ziekenhuis, Arnhem;
Dr. G.P.M. ten Velde, pulmonologist, Academisch Ziekenhuis Maastricht,
Maastricht; A.F.T.M. Verhagen, cardiothoracic surgeon, Universitair
Medisch Centrum St. Radboud, Nijmegen; B.A. Verheij, general
practitioner, Huizen; M.I.M. Versteegh, cardiothoracic surgeon, Leids
Universitair Medisch Centrum, Leiden; Mw. M.S. Vos, psychiatrist,
Ziekenhuis Bronovo, Den Haag; S.L. Wanders, radiation oncologist,
MAASTRO Clinic, Heerlen; Dr. L.N.A. Willems, pulmonologist, Leids
Universitair Medisch Centrum, Leiden

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### ENDORSER(S)

Lung Cancer Information Centre (Longkanker Informatiecentrum) - Disease
Specific Society

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available in Available in English and Dutch from the
[Association of Comprehensive Cancer Centres Web
site](http://www.oncoline.nl/richtlijn/item/pagina.php?richtlijn_id=396).

Print copies: Available from Association of Comprehensive Cancer Centres
PO Box 19001, 3501 DA Utrecht, The Netherlands

#### AVAILABILITY OF COMPANION DOCUMENTS

A version of the guideline for Personal Digital Assistants (PDAs) is
available from the [Association of Comprehensive Cancer Centres Web
site](http://www.oncoline.nl/index.php?pagina=/richtlijn/item/pagina.php&richtlijn_id=396).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI Institute on May 6, 2008. The
information was verified by the guideline developer on August 18, 2008.

#### COPYRIGHT STATEMENT

This NGC summary is based on the original guideline, which is subject to
the guideline developer\'s copyright restrictions.

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
approve, or endorse the guidelines represented on this site.

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Guidelines represented on the NGC Web site are submitted by guideline
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<http://www.guideline.gov/about/inclusion.aspx> .

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Date Modified: 11/10/2008