Dose Limiting Toxicity (DLT) and Common Toxicity Criteria (CTC) / Common Terminology Criteria for Adverse Events (CTCAE)

For the early clinical phase trials, especially first-in-man oncology studies, the major objective is usually to identify a safe dose, such as the MTD (maximal tolerated dose),  the highest dose that can be given with acceptable toxicity, and establish the safety profile. To identify the MTD, dose escalation studies are usually conducted. The determination of the MTD is based on the occurrence of the DLT (dose limiting toxicity), Dose-Limiting toxicity is defined to be a toxicity that prevents further administration of the agent at that dose level. One of the criteria for FDA to approve a Breakthrough Therapy designation for an experimental drug is that the experimental drug can significantly improve safety profile compared to available therapy (e.g., less dose-limiting toxicity for an oncology agent), with evidence of similar efficacy.

The choice of DLT (dose-limiting toxicity) may vary from study to study based on the natural history of the disease and the level of toxicity expected from standard therapy. For example, one might accept a greater degree of toxicity for a patient with end-stage cancer who has no other options, but less toxicity for a healthy individual getting a preventive medicine. 

The DLT has close relationship with the CTC (common toxicity criteria) and CTCAE (common terminology criteria for adverse events).

CTC (Common Toxicity Criteria) is the precursor of what is today named the Common Terminology Criteria for Adverse Events (CTCAE). The original CTC was developed by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) in 1983 to aid in the documentation and analysis of adverse effects of chemotherapy. CTC, like CTCAE, included terms and a severity grading scale with descriptions of the allowed grades of each term. Starting from v3, the CTC was replaced by CTCAE v3.

CTCAE is a list of terms (adverse events) commonly encountered in oncology interventions. Each AE term is defined and associated with a rating scale of severity that indicates the severity of the AE. The rating scale is used in the definition of protocols parameters (Eligibility; Maximum Tolerated Dose; Dose modification; etc) and indicates what is reasonable to document, report, and analyze for patient safety oversight based on current oncology research interventions. CTCAE is available only in English and the most recent version of CTCAE is verion 4.0. In the new CTCAE v4.0, the AE terms are organized by the System Organ Classes (SOCs) defined by the Medical Dictionary for Regulatory Activities (MedDRA). CTCAE has been developed from the earlier vocabulary known as CTC (Common Toxicity Criteria).

While CTC / CTCAE were developed by NCI, they were being used for clinical trials outside cancer trials such as AIDS/HIV trials, hypertension trials, and others.

The definition of Dose-limiting Toxicity (DLT) is determined by the individual protocol, not the CTC or CTCAE. Although it would be convenient to assume that all Grade 3 adverse events based on CTC or CTCAE represent dose limiting toxicities, this may not be appropriate. Grade 3 or 4 adverse events (based on CTC or CTCAE) of complications such as nausea and vomiting can be controlled with appropriate supportive care measures and may not constitute DLTs. Prolonged grade 2 toxicities can be considered DLTs depending on the schedule of drug administration. Acceptable DLTs or adverse events vary with the patient population and the anticipated outcome of the treatment. More severe adverse events may be acceptable with a potentially curative regimen than with a palliative treatment.

Typically in clinical trials, investigators will base their clinical judgment to grade all reported adverse events (AEs) during the study with three categories: mild, moderate, and severe.

Mild: An event that is easily tolerated by the subject, causing minimal discomfort and not             interfering with everyday activities.

Moderate: An event that is sufficiently discomforting to interfere with normal everyday activities.

Severe: An event that prevents normal everyday activities.

For oncology trials, the Grading should be based on CTCAE as following:

Grade 0 No Adverse Event	Sign/symptom within normal limits
Grade 1 Mild Adverse Event	Minor Mild symptoms and intervention not indicated Non-prescription intervention indicated No specific medical intervention Asymptomatic laboratory finding only Radiographic finding only Marginal clinical relevance
Grade 2 Moderate Adverse Event	Intervention indicated Minimal, local, noninvasive intervention (e.g. packing, cautery) Limiting instrumental ADL (e.g., shopping; laundry; transportation; ability to conduct finances)
Grade 3 Severe Adverse Event	Medically significant but not life-threatening Inpatient or prolongation of hospitalization indicated Important medical event that does not result in hospitalization but may jeopardize the patient or may require intervention either to prevent hospitalization or to prevent the AE from becoming life-threatening or potentially resulting in death Disabling - results in persistent or significant disability or incapacity Limiting self care ADL (e.g., getting in and out of bed; dressing; eating; getting around inside; bathing; using the toilet)
Grade 4 Life-threatening Adverse Event	Life-threatening consequences       Urgent intervention indicated Urgent operative intervention indicated Patient is at risk of death at the time of the event if immediate intervention is not undertaken
Grade 5 Fatal Adverse Event	Death

To map the CTCAE grading to AE severity / intensity, any AE graded as 1 using CTCAE can be categorized as mild, 2 be categorized as moderate and ≥3 be categorized as severe.

There are considerable discussions about the standardization in determining the dose limiting toxicities.

§         Towards new methods for the determination of dose limiting toxicities and the assessment of the recommended dose for further studies of molecularly targeted agents – Dose-Limiting Toxicity and Toxicity Assessment Recommendation Group for Early Trials of Targeted therapies, an European Organisation for Research and Treatment of Cancer-led study

§         Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: Results of a DLT-TARGETT international survey

§         Definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents

§         Heterogeneity in the definition of dose-limiting toxicity in phase I cancer clinical trials of molecularly targeted agents: A review of the literature

§         Criteria for defining dose-limiting criteria

In a paper by Paoletti et al “Defining dose-limiting toxicity for phase 1 trials of molecularly targeted agents: Results of a DLT-TARGETT international survey”, it was stated “DLT is traditionally defined as any grade 3–4 non-haematological or grade 4 haematological toxicity at least possibly related to the treatment, occurring during the first cycle of treatment. Some adjustments to this definition have been widely accepted, such as febrile neutropenia, or neutropenia grade 4 lasting more than 7 days or abnormal laboratory values rated as a DLT only in the presence of clinical symptoms.”

In study by Angevin et al “Phase I Study of Dovitinib (TKI258), an Oral FGFR, VEGFR, and PDGFR Inhibitor, in Advanced or Metastatic Renal Cell Carcinoma”, the following DLT criteria were provided in the study protocol appendix.