Research Reporting Standards for Percutaneous Thermal Ablation of Lung Neoplasms

Current Status of Research Reporting for Image-Guided Tumor Ablation 

In 2005, Goldberg and collaborators (47, 48), on behalf of the SIR Technology Assessment Committee and the International Working Group on Image-Guided Tumor Ablation (SIRTAC/IWGIGTA), published their updated consensus report on standardization of terminology and reporting criteria for generic image-guided tumor ablation. Because the editorial staffs of both Radiology and the Journal of Vascular and Interventional Radiology have agreed to adopt the recommendations offered by this group for publications, investigators in the field of image-guided thermal ablation are strongly encouraged to familiarize themselves with the content of this article and confirm that reports meet these standards. Brief highlights of their recommendations follow.

Tumor ablation is defined as “the direct application of chemical or thermal therapies to a specific focal tumor (or tumors) in an attempt to achieve eradication or substantial tumor destruction.” The generic term “image guidance” is preferred, as most tumor ablation can be performed with a variety of imaging modalities. Thermal ablation procedures are those that cause tumor destruction through application of thermal energy, either heat or cold.

Tumor ablation performed in one episode is termed a procedure or a session. A treatment refers to a completed effort to thoroughly ablate one or more tumors, and may involve more than one procedure or session. The number of sessions or procedures required to achieve a treatment should be reported.

The generic term used for thermal ablative device is “applicator.” Appropriate terms used for specific energy forms are “electrodes” for RF ablation applicators, “antennas” for microwave applicators, “fibers” for laser applicators, and “cryoprobes” for cryoablation applicators.

RF ablation refers to electromagnetic energy sources with frequencies less than 30 MHz. The specific devices, the algorithm of energy depositions, and adjuvant therapies, if employed, need to be specified. Recommended terms for specific types of RF electrodes include “multitined expandable electrodes,” “internally cooled electrodes” (either single or cluster), and “perfusion electrodes.” If adjuvant therapies are used, the rationale for use and specifics of technique should be detailed. Microwave ablation refers to electromagnetic tumor necrosis with devices that emit frequencies between 30 MHz and 30 GHz. Information provided should include the specific frequency and type and number of applicators used. “Laser ablation” is the appropriate term for ablation using light energy. Description of technique needs to include the laser light source, wavelength, description of the specific device employed, algorithms of energy application, laser power, duration of energy application, total energy applied, and type of energy application if multiple laser fibers are used. Focused ultrasound (US) ablation needs to be specified whether it is extracorporeal or directly introduced with applicators. Cryoablation applies to methods of tissue destruction using freezing. Reporting should include the low temperature achieved, gasses used, cryoprobe description and number, and numbers and duration of freeze/thaw cycles. If available, estimated distance between the location of the thermistor and the tip of the cryoprobe would be desirable.

Tissue blood flow affects all methods of thermal ablation. The heat-sink effect refers to alteration of ablation zone size, morphology, and homogeneity caused by blood flow in blood vessels greater than 1 mm in diameter. Perfusion-mediated tissue cooling (or warming in the case of cryoablation) refers to ablation zone alterations induced by blood flow both in vessels greater than 1 mm and in the microcirculation. If techniques are used to reduce the effect of blood flow on tumor ablation, the specific technique used should be reported.

The specific imaging modalities and techniques used to plan, target, monitor, control, and assess therapeutic response to tumor ablation should be included in the reports. Regarding assessment of outcome, the imaging strategy and diagnostic criteria need to be specified. Usually, imaging findings after ablation reflect zones of diminished perfusion (eg, absence of contrast enhancement) or alterations in tissue appearance of signal intensity, echogenicity, or attenuation. The cited SIRTAC/IWGIGTA publication (47, 48) details specific imaging findings during and after tumor ablation that should be addressed in reports of research results, including the presence of a transient hyperechoic zone, ablative margin, benign periablational enhancement, irregular peripheral enhancement, and involution of coagulation.

Specific recommendations were given regarding reporting tumor and ablation dimensions. The tumor targeted for ablation is referred to as the index tumor. As the time and effort expended to ablate tumors and the probability of complete tumor necrosis are highly dependent on tumor size, the actual dimensions of the index tumor, as well as the mean, SD, and range, should be included for the report. For the purposes of comparison of results between series or reports, tumors may be categorized as small when less than 3 cm in diameter, intermediate when between 3 and 5 cm in diameter, and large when exceeding 5 cm in diameter. Ideally, ablation zone descriptions would include all three dimensions. At a minimum, the short-axis diameter should be reported because that dimension is most closely related to the probability of ablation causing complete tumor necrosis and the number of applications required to completely ablate a tumor.

Technical success refers to the ability to treat the tumor per protocol with complete coverage. Alternatively, technique effectiveness refers to the ability to completely eradicate the index tumor(s) based on findings at follow-up. Complete tumor destruction may require more than one treatment session. Primary effectiveness rate is the percentage of tumors successfully eradicated by the initial procedure(s). Secondary or assisted effectiveness rates include those tumors thought initially to have been completely treated that developed local tumor progression that in turn was successfully eradicated by a repeated ablation. The SIRTAC/IWGIGTA committee recommended reporting only complete and incomplete status of tumor ablation. Given the absence of evidence of benefit for different degrees of incomplete tumor ablation, stratification based on the estimated portion of incomplete tumor ablation appears to be meaningless. In cases in which ablation is used for palliative symptom reduction, objective measures of symptom response should be used and presented in the reported results.

When tumor progression occurs after ablation, distinction should be made whether it involves local tumor progression, new tumors elsewhere within the treated organ, or distant metastases. Causes of mortality preferably differentiate those deaths caused by tumor progression from those caused by other comorbid conditions. They are also differentiated in the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (49, 50).

Complications are to be reported using the published SIR grading system (Table 3) as well as the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (49, 50). Deaths are to be reported on a per-patient basis with particular emphasis on deaths occurring within 30 days of an ablation procedure. The cause of mortality should be specified, including the likelihood of the death being procedure-related. Major complications are to be differentiated from minor complications, categorized according to SIR guidelines, and reported on a per–ablation procedure basis. Furthermore, the time of clinical manifestation preferably would be stratified as immediate (within 24 hours), periprocedural (within 30 days), or delayed (>30 days after ablation). For reporting pain following an ablation procedure, the committee proposed adoption of the Common Toxicity Criteria of the National Cancer Institute (50).

Table 3. SIR Definitions and Grading System of Complications

	Complication Category	Description
	Minor	Require no therapy, result in no consequence
		Require nominal therapy, result in no consequence; includes overnight admission for observation only
	Major	Require therapy and minor hospitalization (<48 h)
		Require major therapy, unplanned increase in level of care, prolonged hospitalization (>48 h)
		Result in permanent adverse sequelae
		Result in death

Clinical outcomes should include local tumor response, systemic tumor response, quality of life, and survival. When responding to quality of life outcomes, use of objective and preferably validated scales are encouraged. Imaging follow-up intervals should be specified. Imaging assessment of tumor control should include both the diameters of the index tumors and ablation zone as well as the presence or absence of tumor contrast enhancement. The appropriate length of follow-up will likely be a function of the tumor biology and aggressiveness. The report should include the mean and/or median length of follow-up as well as the ranges and/or SDs if appropriate.

To facilitate reproducibility of results, the SIRTAC/IWGIGTA committee recommended that investigators specify a number of technical details. This list included the device manufacturer, the type and duration of energy applied, the number of treatment sessions for each tumor, the type of approach (eg, percutaneous, open, or laparoscopic/endoscopic), whether general anesthesia or conscious sedation was used, type(s) of imaging guidance, whether the patient was hospitalized, the number of sessions required to achieve technical success, and rates of subsequent tumors requiring ablation. The reported patient population features should include inclusion and exclusion criteria; tumor type (including diagnostic proof), size, number, location, and stage; patient demographics and comorbidities; and the use, timing, and specific protocols of other oncologic therapies. Preferably, the report should include the number of patients, tumors, treatment sessions, and ablation procedures. The therapeutic goal (cure vs survival benefit vs palliation) should be stated.

Several recommendations were made regarding statistical evaluation. Primary and secondary endpoints should be clearly stated. Survival outcome should use Kaplan-Meier life-table analysis. In comparative studies, it is preferable to have patients randomized into treatment groups. Results should be reported on an intent-to-treat basis. Outcomes should be stratified by appropriate factors such as tumor type, grade, and stage, patient performance status, and comorbidities. Commonly reported outcomes used for comparison with alternative therapies include overall survival, disease-free survival, and quality of life.

The generic recommendations of the SIRTAC/IWGIGTA are to be followed. The remainder of the present article is intended to fine-tune reporting recommendations as they apply to thermal ablation of malignancies specifically located in the lungs. The topic of palliative thermal ablation of malignancies that arise within or invade the chest wall lies outside the scope of this report, and will be covered in a separate reporting standards publication on thermal ablation of musculoskeletal tumors.

Define Population 

Patients with malignancies in the lungs present a wide range of clinical scenarios. Tumors may be primary to the lungs or metastatic deposits from elsewhere. The biologic aggressiveness and patterns of dissemination are reflections of the tumor cell type and clinical stage. The tumor size, number, location, and pattern and degree of extrapulmonary spread are highly variable.

If anatomically and technically feasible, resection of the entire tumor burden—and in the case of patients with NSCLC, removal of draining lymphatic channels and regional lymph nodes that may harbor microscopic metastases—is usually the patient's best option for potential cure or prolonged survival. However, many such patients will not be optimal candidates for a surgical resection such as lobectomy with mediastinal lymph node sampling as a result of comorbid conditions such as chronic obstructive pulmonary disease, coronary artery disease, congestive heart failure, or advanced stages of malignancy. Some such patients may benefit from less invasive surgeries, thermal ablation, radiation therapy, or chemotherapy.

For clinicians, patients, and third-party payers to make rational evidence-based treatment decisions for patients who may have a wide range of clinical presentations, it is incumbent upon investigators to carefully define, describe, and stratify their subject populations. For both retrospectively accrued case series and prospectively enrolled series, thorough presentation of population demographics is necessary (discussed later). For studies that use prospective subject accrual, and for many case series, explicit description of enrollment inclusion and exclusion criteria should be given. Translatability of study results to other operators and centers, and over time, are central to advancement of lung cancer therapies.

Inclusion criteria are set to define the population believed most likely to benefit from the experimental therapy and are therefore eligible for treatment under the research protocol. Inclusion criteria should specify which tumor types are being studied. As tumor size and location strongly influence the probability of obtaining complete necrosis and causing complications, a definition of acceptable tumor diameter(s), number, and locations within the lungs needs to be stated. The method used to establish the diagnosis of lung malignancy, such as percutaneous biopsy, should be given. Demographic boundaries for enrollment of patient with lung cancers should be detailed. For example, a study may include patients with stage I NSCLC, ages between 18 and 85 years, with an Eastern Cooperative Oncology Group performance score of 0–2, and a life expectancy of at least 3 months. Because thermal ablation has not been established as standard first-line therapy for treatment of lung cancers, the reason patients are included in the study should be explained. As an example, patients with stage I NSCLC may be included if they were not candidates for resection as a result of advanced comorbid conditions or refusal to undergo surgery. Other cases of advanced symptomatic malignancies may have been refractory to radiation therapy, chemotherapy, or opioid analgesics. A randomized controlled trial would need to carefully define those patients amenable to be enrolled in the experimental arm of thermal ablation and the control arm of standard therapy.

Exclusion criteria are necessary to maintain maximal patient safety and purity of data analysis. Patient factors may include extremes of age, advanced comorbidities, specific device risks such as cardiac pacemakers in patients undergoing RF ablation, history of allergies or contraindications to agents involved in performing the ablation or assessment of outcome (eg, iodinated contrast agent reactions or renal insufficiency), and potential risk to unborn fetuses. Other exclusion criteria exist to protect dependent patients such as minors, incarcerated patients, or patients unable to provide informed consent. Some exclusion criteria are in place to protect patients for whom benefit is unrealistic, such as a poor performance status (Table 4), limited life expectancy, or significant extrapulmonary malignant disease. Exclusionary limits on tumor number and size need to be stated. Some tumors may occur in locations likely to result in mechanical or thermal injury of critical nontargeted structures such as the heart, mediastinum, central airways, or brachial plexus. Criteria used to exclude treatment based on tumor location need to be specified. Patients with cancer frequently receive a variety of interdisciplinary therapies at different times during the course of their disease. These multiple therapies may confound interpretation of outcome responses and complications. If limitations are placed on permissible antecedent, concurrent, or subsequent therapy to thermal ablation, these exclusions need to be presented.

Table 4. Eastern Cooperative Oncology Group/Zubrod Performance Status Scale

	Status	Description
	0	Asymptomatic and fully active
	1	Symptomatic; fully ambulatory; restricted in physical strenuous activity
	2	Symptomatic; ambulatory; capable of self-care; >50% of waking hours are spent out of bed
	3	Symptomatic; limited self-care; spends >50% of time in bed, but not bedridden
	4	Completely disabled; no self-care; 100% bedridden

Define Outcome of Therapy 

Establishing the trial endpoints is both a function of the type of trial and a determinant of how the trial is to be structured. The appropriate measure of outcome will depend on the specific trial design and relative phase in the course of data maturity. Early phase prospective trials, analogous to chemotherapy phase I trials, usually evaluate issues of safety and, when relevant, most appropriate parameter or dose of an agent that has a potential range of operational or dose parameters. Outcome measures frequently include toxicity according to the Common Toxicity Criteria of the National Cancer Institute (50) and complications according to SIR guidelines (49), including mortality. Intermediate-phase prospective trials, analogous to phase II pharmaceutical trials, incorporate measures of therapeutic efficacy, typically as single arm trials. Common examples include complete necrosis or tumor response to treatment based on Response Evaluation Criteria In Solid Tumors, World Health Organization, or other anatomic imaging guidelines; tumor response based on serologic markers; tumor response based on surrogate functional imaging parameters such as contrast-enhanced computed tomography (CT) or magnetic resonance (MR) imaging, diffusion-weighted MR imaging, or positron emission tomography (PET) scanning; time to progression locally, within the treated organ, or overall; and tumor-free survival or overall survival. Late-phase trials, analogous to phase III pharmaceuticals trials, evaluate safety and efficacy comparing a group of patients undergoing the experimental therapy versus a comparable, preferably randomized, group of patients undergoing standard therapy.

In these prospectively enrolled trials, the primary endpoint is the outcome measure that is used to prove safety or efficacy and for which the trial is statistically powered to demonstrate significance. Ideally, the selected outcome measure is directly a function of the safety and efficacy of the therapeutic agent with few confounding variables. Secondary endpoints are the other important patient care efficacy and safety outcome measures that are concomitantly collected and evaluated, but for which the study is not powered to assess significance. Frequently, secondary endpoints include outcome measures such as overall survival that depend not only on the response of the index tumor to ablative therapy, but also on disease spread to other locations, additional therapies the patient receives, and comorbid conditions. Specific primary and secondary endpoints need to be detailed in all reported prospective trials.

Retrospective case series are usually less stringent but frequently less useful as well. Data collected will include those of primary or secondary interest to test a given hypothesis. However, primary endpoints are not strictly relevant because the trial is not powered prospectively. Nevertheless, the specific outcome data collected and analyzed should be listed.

Pretreatment Evaluation 

Patient Evaluation 

Pretreatment evaluation of patients for thermal ablation must include assessment of demographics (age, sex, and any other variables relevant to risk of disease or complications). Any known or putative risk factors for lung cancer should be noted, such as smoking, occupational exposure, and interstitial lung disease. Because a large percentage of patients with NSCLC have a heavy smoking history, chronic pulmonary obstructive disease and other pulmonary and cardiac comorbidities are common and should be reported. These comorbidities are common reasons that patients with NSCLC cannot undergo lobectomy and are therefore candidates for thermal ablative therapy and other less invasive options (Table 5). Conversely, these same cardiopulmonary comorbidities frequently place these patients at higher risk of complications from ablative therapy. Other comorbidities must be reported, including essential hypertension, cerebrovascular disease, diabetes mellitus, and/or other malignancies. In addition to risk stratification for future treatment algorithms, this enables identification of patients who may have a lower tolerance for procedural complications.

Table 5. Criteria for Surgical Lobectomy for NSCLC

	Major Criteria
	FEV1 ≤50%
	DLCO ≤50%
	Minor Criteria
	Age ≥75 y
	FEV1 51%–60% predicted
	DLCO 51%–60% predicted
	Pulmonary hypertension (defined as a pulmonary artery systolic pressure >40 mm Hg) as estimated by echocardiography or right heart catheterization
	Poor left ventricular function (defined as an ejection fraction ≤40%)
	Resting or exercise arterial pO2 ≤55 mm Hg or SpO2 ≤88%
	pCO2 >45 mm Hg

Note.—Fulfillment of one major criterion or at least two minor criteria usually prevent a patient from being a candidate for surgical lobectomy for NSCLC. DLCO = carbon monoxide diffusing capacity; FEV1 = forced expiratory volume in 1 second; pO2 = partial O2 pressure; SpO2 = O2 saturation.

Treatment Description 

Posttreatment Evaluation 

Analysis of Outcomes 

Complications 

All complications of the ablation procedure should be reported, including those that do not appear related to the procedure. Recognized and/or potential complications of lung thermal ablation are given in Table 6. Complications within 30 days are presumed to be procedure-related. Complications beyond 30 days may be procedure-related and also need to be reported. The classification system used by SIR (49) for grading complications and the National Cancer Institute Common Terminology Criteria for Adverse Events (50) must be used (Table 3).

Table 6. Classification of Complications of Percutaneous Lung RF Ablation

	Complication	Class
	Abscess	Infectious/inflammatory
	Allergic/anaphylactoid reaction	Contrast-related
	Angina/coronary ischemia	Cardiac
	Bronchopleural fistula	General nonvascular
	Death related to procedure	Death
	Death unrelated to procedure (30-day mortality)	Death
	Empyema	Infectious/inflammatory
	Hypotension	Cardiac
	Hematoma bleeding, pleural	Vascular
	Hematoma bleeding, puncture site	Vascular
	Idiosyncratic reaction	Medication-related
	Myocardial infarction	Cardiac
	Nerve injury	Neurologic
	Pleural effusion	Respiratory/pulmonary
	Pneumothorax	Respiratory/pulmonary
	Pulmonary embolism	Vascular
	Respiratory failure	Respiratory/pulmonary
	Sepsis	Infectious/inflammatory
	Skin burn	Device-related
	Stroke	Neurologic
	Tumor seeding	General nonvascular
	Unintended perforation of hollow viscus	General nonvascular
	Vagal reaction	Cardiac

Quality of Life 

A validated instrument for measuring quality of life should be used at baseline and during each follow-up encounter, such as the Short Form 36, European Organisation for the Research and Treatment of Cancer QLQ-C30 instrument, or Functional Assessment of Cancer Therapy–General questionnaire.

Costs and Cost Effectiveness 

When reporting costs of lung ablation, authors should report direct costs associated with the procedure (eg, thermal applicators, CT interventional suite time, and hospital stay) and indirect costs (eg, need for increased imaging follow-up to detect residual or recurrent disease). These costs are then combined for a study patient cohort as a cumulative numerator for measurement of cost effectiveness. The denominator of cost effectiveness is the number of quality-adjusted life-years derived for the study population, yielding the cost-effectiveness ratio of dollars per quality-adjusted life-year. This should also include sensitivity analysis and discounting. These cost-effectiveness data will become critical in comparing percutaneous thermal ablation with other ablative and nonsurgical therapies.

Recommendations 

Disease-free and overall survival should be determined with the Kaplan-Meier technique. An initial intent-to-treat basis should be used for evaluating patient outcomes after randomization. Comparison with other nonsurgical approaches is ideal, rather than case series of patients treated only with thermal ablation. A thorough description of complications, both in the immediate periprocedual period and within 30 days of the procedure, is needed. Measurement of quality of life should be performed with a previously validated instrument, preferably one that has been developed for oncology patients. Determination of costs and cost effectiveness is recommended. A summary of recommended items to be included in reported trials of thermal ablation of lung cancers is presented in Table 7.

Table 7. Recommendations for Reporting Standards

	Procedure	Required	Highly Recommended	Recommended
	Preablation evaluation	☒	□	□
	Population description	☒	□	□
	Clinical indication for RF ablation	☒	□	□
	Anatomic location of tumor	☒	□	□
	Tumor staging	☒	□	□
	Biopsy	☒	□	□
	Study design
	Inclusion criteria	☒	□	□
	Exclusion criteria	☒	□	□
	Comorbid diseases	☒	□	□
	Functional status	☒	□	□
	Ablation description
	Ablation device description	☒	□	□
	Treatment endpoint	☒	□	□
	Energy and duration of RF ablation	☒	□	□
	Number of ablation zones	☒	□	□
	Method of targeting and monitoring	☒	□	□
	Adjunctive techniques	☒	□	□
	Anesthesia	☒	□	□
	Hospital days	☒	□	□
	Complications
	Immediate	☒	□	□
	30-day	☒	□	□
	Late complications	☒	□	□
	Postablation evaluation
	Follow-up imaging at regular intervals	☒	□	□
	Follow-up of clinical status	☒	□	□
	Technique effectiveness	☒	□	□
	Tumor progression	☒	□	□
	Survival	☒	□	□
	Disease-free survival	□	☒	□
	Quality of life assessment	□	☒	□
	Uniform duration of follow-up	□	☒	□
	Need for additional ablation	□	☒	□
	Costs	□	□	☒
	Cost effectiveness	□	□	☒

Conclusion 

Percutaneous ablation of lung tumors is becoming an established, minimally invasive therapy for many patients in whom conventional therapy fails or who are poor surgical candidates. To optimize its clinical potential, percutaneous thermal ablation ultimately must be supported by compelling randomized prospective trials in which it is used alone and in combination with other modalities. Rigorous earlier-phase trials are important to optimize ablation technique and lay the necessary research groundwork before large, expensive, lengthy definitive randomized controlled trials are performed. The goal of this document is to provide recommended definitions to enable uniform reporting of these trials.(58)