Staging of Non-Small-Cell Lung Cancer

Table III.

Test	Accessible mediastinal stations	Reported Sensitivity	Limitations
Transbronchial needle aspiration biopsy (TBNA)	2, 4, 7	36-78%	Limited sensitivity for “low prevalence” disease, such as single-station or discrete adenopathy
Endobronchial ultrasound (EBUS)-guided TBNA	1, 2, 4, 7, 10, 11	69%	Requires special training
Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA)	2, 4, 5, 7, 8, 9	69%	Requires special training in upper endoscopy
Combined EBUS-TBNA and EUS-FNA	1, 2, 4, 5, 7, 8, 9, 10, 11	93%	Requires two procures, although both can be done in one setting
Cervical mediastinoscopy	1, 2, 3, 4, anterior 7	78-90%	Surgical procedure; general anesthesia; no access to posterior subcarinal, paraesophageal, and pulmonary ligament nodes
Anterior mediastinotomy	5, 6	63-86%	Surgical procedure; general anesthesia; no access to right-sided, subcarinal, paraesophageal, or pulmonary ligament lymph nodes
Video-assisted thoracoscopic surgical (VATS) biopsy	ipsilateral 2, 4, 5, 6, 7, 8, 9	75%	Not able to sample contralateral lymph nodes; surgical procedure; general anesthesia; requires single-lung ventilation

T staging is generally achieved by reviewing imaging – either by CT scan or PET-CT scan. N stage is determined definitely with biopsy procedures that can sample N1 or N2 nodal stations, and is often guided by CT and PET-CT results. M stage can be determined from imaging, including CT scans of the chest, abdomen and brain, and PET-CT scans. MRI of the brain has a higher sensitivity in locating brain metastases than CT scan of the head, although has not been shown to increase survival over CT scans, and is recommended for patients at higher risk of brain metastases, e.g., patients with large cell carcinoma or stage III/IV cancer. Accessible metastatic sites can be biopsied percutaneously or endoscopically (i.e, via EBUS or EUS).

Staging evaluation

Staging evaluation is tailored to the specific presentation of each patient. An initial computed tomography (CT) of the chest will guide subsequent investigations and should be performed in every patient with a suspicion of lung cancer. The chest CT should include cuts of the upper abdomen to visualize the liver and adrenal glands for evidence of metastatic disease. Abnormalities on chest CT can be used to establish a preliminary clinical stage (CT stage) that will then guide the remainder of the staging evaluation. (See “Classification.”) The most effective and efficient evaluations can subsequently be planned by considering the following guiding principles:

• Use symptoms, signs, and the results of chest CT to guide subsequent test selection.

• Obtain tissue confirmation of metastasis when results of imaging tests are positive.

• Perform as few procedures as necessary; try to establish diagnosis and stage with a single procedure.

• Select an accessible site for biopsy that will establish the highest-stage disease.

• Minimize risk by selecting the least invasive alternative for biopsy.

• Seek specialist or multidisciplinary input when there are two or more potential targets for biopsy.

• Maximize yield by using direct visualization.

Invasive Mediastinal Staging Guidelines

Staging of the mediastinum (i.e., testing N2 nodal stations for the presence of cancer using invasive techniques) is not required for all confirmed or suspected lung cancers. Generally, very early stage cancers (clinical T1, N0, with tumors located peripherally in the lung field) do not require pre-operative invasive mediastinal staging, and according to patient variables, patients with these tumors may proceed directly to surgery. Updated invasive mediastinal guidelines are directed at potentially resectable tumors, with the goal of avoiding surgery on patients with positive N2 lymph nodes. Recent guidelines are in agreement on the criteria required for invasive mediastinal staging. Both surgical and endoscopic techniques for staging the mediastinum are acceptable, depending on resource availability, operator skill and results. The specific guideline criteria include:

• Tumour more than 3cm on CT scan

• Tumour located proximally on CT scan

• N1 or N2 lymph nodes greater than 1cm on their greatest axis on CT scan

• N1 or N2 lymph nodes positive on PET-CT

Imaging results should be up-to-date at the time of decision-making for staging; although an absolute time frame has not been specified in the literature, less than 3 months has been proposed. Invasive mediastinal staging may also be performed in cases with more advanced disease, as discussed below.

Invasive mediastinal staging techniques include mediastinoscopy, EBUS-TBNA, EUS-TBNA combined EBUS-EUS TBNA, anterior chamberlain and VATS. Merits of techniques are discussed further below.

Classification:

Following a confirmed or suspected diagnosis of lung cancer, a preliminary clinical stage should be assigned based on the results of the initial CT scan of the chest to guide the subsequent evaluation.

Suspected stage IA

By definition, patients with clinical stage IA lung cancer have no evidence of mediastinal or distant metastasis. The risk of occult metastasis is relatively low (5-10%). Most suspected stage IA tumors are asymptomatic, and are detected incidentally. This group of tumors represented 16% of non-small cell lung cancers in the database that informed the new 8^th edition, and may increase as lung cancer screening programs develop. PET-CT should be performed to confirm the clinical stage, and invasive mediastinal staging is required for patients with proximal tumors according to staging guidelines.

These patients have the highest chance for cure by surgery, and thus referral to a surgeon to determine fitness for surgery should be initiated. Patients not suitable for surgery can be treated with stereotactic beam radiation therapy (SBRT), provided the appropriateness of tumor variables. Conventional radiation therapy remains another treatment modality option. The long-term outcomes of SBRT for curative intent of early NSCLC is currently under evaluation, and the role of SBRT in comparison to surgery in curing early stage lung cancers has yet to be determined.

Suspected Stages IB, IIA and IIB

In the new 8^th staging edition, patients with T2 tumors (those >3-5cm) and those with enlarged ipsilateral hilar lymph nodes on chest CT (N1) have clinical stage IB, IIA, or IIB disease. In addition, T3 tumors with negative nodes and T3 tumors based on endobronchial lesions being <2cm from the carina or based on criteria for atelectasis with N1 disease are also stage IIB. All guidelines support the use of PET in these patients, and invasive mediastinal staging is required to confirm the absence of N2 or N3 disease, and in the absence of significant comorbidities should be referred to a thoracic surgeon for consideration of surgical resection. Recent evidence supports surgery for patients in the past not deemed surgical candidates, based on increased uptake of minimally invasive techniques and improved operative and perioperative care, and thus the decision for surgery is best made by a thoracic surgeon. Patients who are not surgical candidates should be referred for radiation oncology consultation if they have good performance status.

If PET reveals one or more sites of possible metastasis, it is imperative to obtain histopathological confirmation of metastasis by invasive staging before excluding the patient from potentially curative surgery. Depending on the site of metastasis, biopsy options include percutaneous biopsy, bronchoscopy with blind TBNA or EBUS-guided TBNA, EUS-guided FNA, cervical mediastinoscopy, anterior mediastinotomy or VATS.

Ipsilateral hilar (N1 enlargement)

While ipsilateral hilar (N1) lymph node involvement can sometimes be confirmed preoperatively via EBUS-guided TBNA, such confirmation will not necessarily change management because such patients are still eligible for surgical resection. More often, the presence of N1 disease is established by pathological review of resection specimens. In either case, demonstration of N1 lymph node involvement has important implications for treatment because randomized, controlled trials have confirmed that post-operative adjuvant chemotherapy improves survival in stages IIA and IIB NSCLC, whereas adjuvant chemotherapy leads to worse outcomes in patients with stage IA disease and neither benefits nor harms patients with stage IB disease.

Suspected stage III

Clinical stage III NSCLC is a heterogeneous group, and in the new 8^th staging edition also includes the stage group IIIC for both tumors larger than 5cm, and T4 tumors with N3 disease.

In the absence of suspicion for N2, N3, or M1 lymph node involvement, confirmed with PET-CT scan and invasive mediastinal staging, patients with T2 with tumors >5-7cm, T3 and T4 tumors may have resectable disease and should be referred for thoracic surgical evaluation.

Mediastinal lymph node (N2 or N3) involvement has several different presentations, including: occult N2 disease identified at the time of surgery, limited N2 disease identified preoperatively, and bulky N2 and/or N3 lymph node involvement. Each of these presentations is managed differently, as described below.

Occult N2 disease identified at the time of surgery

By definition, these patients have ipsilateral mediastinal metastasis that was not identified during the preoperative staging evaluation, so they were upstaged at surgery from clinical stage I or II (N0 or N1) disease to pathological stage IIIA (N2) disease. Accordingly, they should be referred post-operatively for consideration for adjuvant combined chemoradiation.

Limited or N2 disease identified preoperatively

Patients with discrete, single-station lymphadenopathy and those with non-bulky, mildly enlarged nodes at two or more stations have limited N2 disease according to CT criteria. These patients require invasive mediastinal staging for histopathological confirmation of mediastinal metastases. Provided good performance status, these patients can be considered for neoadjuvant chemoradiation followed by surgery.

Bulky N2 or N3 disease

In patients with evidence of bulky mediastinal adenopathy or extensive mediastinal infiltration on chest CT, it is desirable but not mandatory to obtain histopathological confirmation of metastasis, especially when the pattern of involvement is consistent with lung cancer. For example, stage III disease can be safely assumed in an older patient with a smoking history and a large, right hilar mass that is accompanied by bulky involvement of right paratracheal and subcarinal lymph nodes.

In such a patient, the diagnosis (and stage) can be established by endobronchial ultrasound biopsy of the primary tumor, in which case the stage is inferred based on imaging, or confirmed by biopsy of involved lymph nodes. The choice of staging procedure is similar to that for patients with limited or discrete adenopathy, although many patients with bulky adenopathy will have involvement of the subcarinal space that can often be sampled successfully with blind TBNA.

Use of PET in suspected stage III

There is evidence to support routine use of PET scanning in patients with clinical stage III NSCLC. Several randomized, controlled trials have demonstrated that PET reduces the frequency of futile thoracotomy, defined as identification of unresectable or benign disease at the time of surgery, or recurrence or death within one year of surgery (van Tinteren et al., 2002; Maziak et al., 2009; Fischer et al., 2009). PET is necessary to complete the staging prior to radiation therapy since staging often changes after PET, and it is important to help guide radiation therapy targets. PET can also help to identify the most suitable target for invasive staging and can identify occult extrathoracic metastasis that would have otherwise gone undetected.

Suspected stage IV

In patients with suspected M1 disease on chest CT (preliminary clinical stage IV), a biopsy of one of the involved sites should be performed in an attempt to establish both the diagnosis and the presence of stage IV disease in a single procedure. When present, a moderate or large pleural effusion is an easily accessible target that can be sampled by simple thoracentesis. If the fluid is exudative and the cytology is negative, diagnostic thoracentesis should be repeated once. If cytopathological examination of the second sample is also negative and the extent of disease is otherwise resectable, video-assisted thoracoscopic surgical (VATS) pleural biopsy should be performed to exclude metastasis. Brain MRI, or CT head if MRI is not available, is recommended in patients with clinical stage IV lung cancer.

Other common sites of suspected M1 involvement that may be accessible via needle biopsy include the liver, the adrenal glands, and (sometimes) the bones. Liver and adrenal glands can also be accessible by EUS. Biopsy of brain lesions is rarely necessary, as these patients commonly have other sites of metastatic involvement. However, patients with a suspected isolated, solitary brain metastasis, or single metastasis to the adrenal gland should be evaluated for surgical resection.

Suspected stage IV, not amenable to biopsy

In some patients with suspected M1 disease on chest CT that is not accessible or too risky to biopsy, it is sufficient to establish the diagnosis by obtaining a biopsy from another site of disease involvement. In such patients, histopathological confirmation of stage IIIA or IIIB disease is preferred, but this is not always practical. In some cases, biopsy of the primary tumor exposes the patient to the least risk, and the presence of M1 disease can be assumed if there is overwhelming evidence of metastatic disease on imaging. While such metastatic involvement is usually grossly apparent on chest CT, sometimes positron emission tomography (PET) can help to clarify the extent of disease.

Suspected stage IV, based on symptoms, signs or laboratory abnormalities

Patients without obvious M1 disease on chest CT but with one or more of the following findings should undergo a clinically-directed evaluation for distant metastasis:

• Patients with altered mental status, headache, visual change, and/or focal motor weakness or sensory loss should undergo head CT or (preferably) MRI.

• Patients with back pain and/or incontinence should undergo CT or MRI of the spine.

• Patients with other bony pain, elevated serum alkaline phosphatase, and/or hypercalcemia should be evaluated with a bone scan, whole body PET scan, and/or x-rays of involved bones.

• While most patients with substantial unintended weight loss have obvious evidence of M1 disease on chest CT, it is reasonable to perform a PET scan if CT findings are subtle or absent.

Management of incidental lung nodules

The management of incidentally discovered lung nodules has gained increased attention with the advent of lung cancer screening programs and the need to manage nodules to reduce risk of cancer, while also minimizing the number of unnecessary follow-up examinations. Several guidelines for managing pulmonary nodules exist, including those recently updated from the Fleischner society and the ACCP. These seek to provide guidance while also allowing for discretion to the clinician, and patient to make decisions based on patient preferences for management.

Guidelines for incidentally-discovered nodules apply to patients over a certain age (generally age 35), and are not intended for patients with known lung cancer with increased risk of secondary tumors, or immune-compromised patients at increased risk of lung cancer. Nodule size as well as the number of nodules is important, and guidelines distinguish between solid and sub-solid lesions, and divide patients into low, intermediate or high risk for cancer depending on patient and nodule variables. Older patients who are either former or current smokers with spiculated lesions located in the upper lobes are at a higher risk for cancer.

For specific guideline criteria, the reader is directed to the Fleischner and ACCP guidelines. The more recent 2017 Fleischner guideline recommendations for single solid lung nodules, which minimize follow-up for small lesions, are summarized here. ACCP guidelines are similar except suggest a follow-up interval for lesions 4-6mm. All guidelines stress the importance of determining patient preferences for nodule management.

• Nodules >8mm with high clinical probability of cancer

  Repeat imaging in a short interval (3 months) which should consider PET-CT to further characterize the lesion. Biopsy can be considered.

• Nodules >8mm with low clinical probability of cancer

  Similar recommendations for high-probability of cancer: consider PET-CT to characterize the lesion, and biopsy can be considered.

• Nodules 6-8mm, high risk of cancer

  Repeat CT scans every 6-12 months for 2 years is recommended. If the nodule remains stable after 2 years, no further imaging is suggested.

• Nodules 6-8mm, low risk of cancer

  Repeat CT scan is recommended at 6 or 12 months, with consideration of another CT scan at 2 years. No further follow-up is recommended after 2 years.

Nodules less than 6mm do not require further follow-up for either low or high-risk patients, but in cases with increased suspicion based on nodule morphology or upper lobe location, a follow-up CT scan of the chest can be done at 12 months.

Are you sure your patient has non-small-cell lung cancer? What should you expect to find?

Please see the chapter, “Lung Cancer: General Considerations.”

Beware: there are other diseases that can mimic non-small-cell lung cancer:

Please see the chapter, “Lung Cancer: General Considerations.”

How and/or why did the patient develop non-small-cell lung cancer?

Please see the chapter, “Lung Cancer: General Considerations.”

Which individuals are of greatest risk of developing non-small-cell lung cancer?

Please see the chapter, “Lung Cancer: General Considerations.”

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

All patients with suspected or confirmed NSCLC should have a complete blood count and complete metabolic panel. The presence of anemia, liver function abnormalities, or hypercalcemia raises the suspicion for metastatic disease. Abnormal liver function tests are usually accompanied by the presence of gross hepatic involvement on CT. Hypercalcemia is usually due to paraneoplastic production of a parathyroid hormone-like substance by squamous cell carcinomas, but this finding can also be explained by bone metastasis, so it should be evaluated by bone imaging and confirmatory biopsy. When there is overwhelming evidence of metastasis on hepatic or bone imaging, histopathological confirmation is not mandatory, but patients with isolated or oligometastasis should undergo confirmatory biopsy.

What imaging studies will be helpful in making or excluding the diagnosis of non-small-cell lung cancer?

Non-invasive imaging studies that are commonly used for lung cancer staging include CT, PET, brain imaging with CT or MRI, and bone imaging with plain x-rays, CT or PET.

Chest CT

Chest CT is used to assign a preliminary stage in most patients with known or suspected NSCLC, and subsequent staging evaluation is guided by the CT results. For mediastinal staging, CT uses lymph node size as a proxy for metastatic involvement; a cut-point of 1 cm in short-axis diameter is usually applied to define abnormal lymph node enlargement. CT has limited sensitivity and specificity for identifying mediastinal metastasis because enlarged lymph nodes can be reactive and non-enlarged lymph nodes can harbor foci of metastasis. In a systematic review of forty-three studies of diagnostic accuracy, the sensitivity and specificity of CT for identifying mediastinal metastasis were 51 percent (95% CI 47-54%) and 86 percent (95% CI 84-88%), respectively (Silvestri et al., 2007).

CT is also imperfect for identifying extrathoracic metastatic disease, although some findings are highly specific, such as multiple areas of low attenuation in the liver and multiple lytic bone lesions.

PET and PET/CT

PET is a functional imaging test that uses hypermetabolism as a proxy for tumor involvement. PET imaging makes use of a radio-labelled glucose analog (fluorodeoxyglucose or FDG), which is selectively taken up by and subsequently trapped in metabolically active cells. False negative findings can be seen in small tumors and in those that are metabolically indolent, such as some bronchalveolar carcinomas and carcinoid tumors. False positive findings can be seen in virtually any infectious or inflammatory condition, some of which may co-exist with bronchogenic carcinoma. In a systematic review of forty-four studies of diagnostic accuracy, the sensitivity and specificity of PET for identifying mediastinal metastasis were 74 percent (95% CI 69-79%) and 85 percent (95% CI 82-88%), respectively (Silvestri et al., 2007).

In many clinical settings in the U.S., integrated PET/CT has largely replaced dedicated PET imaging. PET/CT is probably more accurate than dedicated PET in identifying metastasis, and it enables more precise localization of even minor hypermetabolic foci.

Whole-body PET identifies occult metastasis in up to 8 percent of patients with clinical (CT) stage 1 NSCLC and up to 20 percent of patients with stage II disease. In one study of 102 patients with potentially resectable NSCLC, the sensitivity and specificity of PET for identifying distant metastasis were 82 percent (95% CI 64-100%) and 93 percent (95% CI, 88-98%) (Pieterman et al., 2000).

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of non-small-cell lung cancer?

The peri-operative evaluation of patients with potentially resectable NSCLC should include pulmonary function testing. Most patients in whom the percent predicted post-operative FEV-1 and diffusing capacity (DLCO) are greater than 40 will be eligible for resection. In borderline cases, quantitative perfusion lung scanning and/or cardiopulmonary exercise testing may be indicated. Patients with limited pulmonary reserve who are unable to tolerate lobectomy may be candidates for sub-lobar resection. VATS resections also decrease the pulmonary risk for surgery rendering more patients operable than previously considered, particularly the elderly.

Pre-operative non-invasive cardiac evaluation should be reserved for patients with major cardiovascular risk factors, including those with unstable angina, decompensated heart failure, uncontrolled dysrhythmias or conduction disturbances, or severe valve disease.

What diagnostic procedures will be helpful in making or excluding the diagnosis of non-small-cell lung cancer?

Invasive staging is crucial in order to exclude mediastinal metastasis in patients with potentially resectable NSCLC. Invasive staging can be performed by using surgical or minimally invasive methods. Surgical methods include cervical mediastinoscopy, anterior mediastinoscopy, and video-assisted thoracoscopic surgery (VATS), while minimally-invasive staging methods include bronchoscopic “blind” TBNA, EBUS-guided TBNA, and EUS-guided FNA.

Cervical mediastinoscopy and anterior mediastinotomy

As summarized in Table III, cervical mediastinoscopy provides access to mediastinal stations 1, 2, 4, and 7, although posterior subcarinal (station 7) nodes may be difficult or impossible to approach. The sensitivity of video-assisted mediastinoscopy for identifying lymph node metastasis may be as high as 90 percent.

Anterior mediastinoscopy is useful in approaching the lymph nodes at stations 5 and 6 that are commonly involved in patients with left upper lobe tumors and that are difficult or impossible to access via other methods. When performed, anterior mediastinoscopy is commonly accompanied by cervical mediastinoscopy, and the reported sensitivity of the combined procedure for identifying metastasis is 87 percent. Surgical staging can also be performed by VATS, which enables sampling of ipsilateral, but not contralateral, lymph nodes.

Minimally-invasive staging methods: TBNA

A meta-analysis of thirteen studies of diagnostic accuracy reported that the sensitivity of blind TBNA was directly correlated with the prevalence (and perhaps the extent) of mediastinal metastasis. Pooled sensitivity was 40 percent in low-prevalence studies, compared with 84 percent in studies that reported a high prevalence of metastasis (Holty et al., 2005). Subcarinal lymph nodes are easiest to approach by blind TBNA, but skilled operators can also sample high and low paratracheal lymph nodes.

Minimally invasive staging methods: EBUS-TBNA

Endobronchial ultrasound (EBUS)-guided TBNA, which is more sensitive than blind TBNA, facilitates sampling of mediastinal, hilar, and intrapulmonary lymph nodes that are adjacent to the tracheobronchial tree (stations 1, 2, 3P and some 3A, 4, 7, 10, and 11) (Table I). EBUS-guided TBNA uses a linear (or convex) ultrasound probe to perform biopsy under real-time guidance. In a review of twelve studies of diagnostic accuracy, the pooled sensitivity was 93 percent (Gomez and Silvestri, 2009).

In most studies, the prevalence of metastasis was high, suggesting that many of these patients probably had bulky adenopathy. Nevertheless, two studies from a group with extensive experience in the technique reported high sensitivity even in lower-prevalence populations with non-enlarged or PET-negative lymph nodes (Herth et al., 2006; Herth et al., 2008).

Minimally invasive staging methods: EUS-FNA

Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is useful in sampling lymph nodes that are adjacent to the esophagus, including those at stations 2, 4, 5, 7, 8, and 9 (Table I). Techniques for sampling stations 5 and 6 are also described. While lymph nodes at stations 8 and 9 are less commonly involved than are nodes at other stations, they are accessible only by EUS-FNA or VATS.

Minimally invasive staging methods: combined EBUS-TBNA and EUS-FNA

In a study of 138 consecutive patients with known or suspected lung cancer and no proven extrathoracic metastasis, all patients underwent, in sequence, blind TBNA, EBUS-TBNA, and EUS-FNA under conscious sedation (Wallace et al., 2008). Reported sensitivities for identifying metastasis were 36 percent (95% CI 22-52%) for blind TBNA, 69 percent (95% CI 53-82%) for EBUS-TBNA, 69 percent (95% CI 53-82%) for EUS-FNA, and 93 percent (95% CI 81-99%) for the combination of EBUS-TBNA and EUS-FNA. Therefore, the combination of EBUS-TBNA and EUS-FNA appears to be highly sensitive for invasive staging, as also shown by further more recent studies (Liberman et al., 2014) and it can probably replace cervical mediastinoscopy if it is performed by experienced practitioners (Vilmann et al., 2015).

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of non-small-cell lung cancer?

Molecular markers that predict survival and treatment response have been identified. Mutations in the epidermal growth factor receptor (EGFR) are particularly common in non-smokers, Asians, and women with adenocarcinoma. Overall, these mutations are associated with a more favorable prognosis. More importantly, among patients with advanced-stage adenocarcinoma, several studies have reported an association between the presence of an EGFR mutation and a more favorable response to first-line treatment with tyrosine kinase inhibitors.

Another relatively common marker, KRAS, is more common in non-Asians and smokers than in others and is associated with resistance to therapy with tyrosine kinase inhibitors. Programmed death ligand 1 (PDL-1) inhibitors and targets for next generation sequencing are also becoming available. As we learn more about the molecular diversity of lung cancer, molecular staging and diagnosis will play an increasingly large role in the management of patients with NSCLC. Recently, an international expert panel recommended molecular testing for EGFR mutations in all patients with advanced adenocarcinoma (Travis et al., 2011).

If you decide the patient has non-small-cell lung cancer, how should the patient be managed?

Please see the chapter, “Lung Cancer: General Considerations.”

What is the prognosis for patients managed in the recommended ways?

Please see the chapter, “Lung Cancer: General Considerations.”

What other considerations exist for patients with non-small-cell lung cancer?

Please see the chapter, “Lung Cancer: General Considerations.”

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