Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Gland and Hormone Related Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Thyroid Diseases

Endocrine System Diseases

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

This is an observational, retrospective and monocentric study, conducted at the university Hospital of Brest The primary objective is to assess the association between the occurrence of thyroid dysfunction in patients treated with Nivolumab® for a non-small cell lung cancer and prognosis and therapeutic response The second objective is to assess prognosis and therapeutic response according to severity and subtype of thyroid dysfunction

Cohort characteristics

The patients' characteristics were collected from medicals records: age, gender, smoking status (absent, current or weaned), WHO performance index, neoplastic characteristics (tumor histology, history of brain metastasis, prior radiotherapy treatment, prior therapy lines (defined by the number of chemotherapy or immunotherapy regimens used before Nivolumab® treatment) We also recorded data about expression of tumor PD-L1, LDH levels and the lymphocyte to neutrophil ratio (dNLR) summarized in the LIPI score (Lung immune prognostic index), which distinguishes three categories: good prognosis (normal LDH, dNLR \<3), intermediate prognosis (abnormal LDH or dNLR\> 3), poor prognosis (abnormal LDH and dNLR\> 3),

Treatment schedule and morphological monitoring

Nivolumab® (3mg/kg mg) was administered as an IV infusion for 30 minutes every 2 weeks until disease progression, unacceptable toxicity, or death. Tumor assessment was performed every 2 months until disease progression. Tumor assessment was based on the results of the computerized tomodensitometry (CT) + injection of a radioiodine contrast agent and/or 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET/CT) (18FDG-PET/CT), according to the RECIST 1.1 or iRECIST 1.1 ((immune) Response Evaluation Criteria in Solid Tumors) criterion. In case of a dissociated response (response of a lesion associated with a progression of another lesion) or in case of suspicion of pseudo-progression (increase in size or appearance of new lesions linked to the influx of immune cells within the tumor), a new morphological evaluation after two additional cycles was taken into account.

Thyroid function screening and classification of thyroid dysfunction

Thyroid function screening was performed before (\<3 months) and during treatment with Nivolumab® (TSH, free T4 (fT4), free T3 (fT3) ± Anti-thyroid peroxidase antibodies (TPOAb) and/or TSH receptor antibodies (TRAbs) were measured by electrochemiluminescence (Reference laboratory values were: TSH, 0.27-4.20 mIU/L; fT4, 11.6-22.0 pmol/L; fT3, 4.0-6.8 pmol/L; TPOAb, \<34 kIU/L; and TRAb, \<1.75 U/L

For classification of thyroid dysfunction, the CTCAE classification was not taken into account because it is not adapted to thyroid dysfunction that is often asymptomatic. Only abnormalities of the thyroid function tests were considered as follow:

1. Patients with abnormalities of TSH level were classified in the group "Thyroid Dysfunction +" and those with normal TSH level were classified in the group "Thyroid Dysfunction -". In case of normal TSH with isolated abnormality of peripherical hormone fT4 and/or fT3, the patient was classified in the "Thyroid Dysfunction -" group;
2. Depending on the level of peripheral thyroid hormones (i.e. fT3 and fT4): subclinical thyroid dysfunction was defined by an abnormal TSH without abnormality of the peripheral hormones and overt thyroid dysfunction was defined by an abnormal TSH associated with at least one abnormality of the peripheral hormones T3 or T4L;
3. Depending on the TSH level: moderate thyroid dysfunction was defined by a TSH level between 0.1 mIU/L and 0.27 mIU/L or between 4.2 mIU/L and 10 mIU/L, and severe thyroid dysfunction was defined in case of TSH ≤ 0.1 mUI/L or ≥ 10 mUI/L, respectively for hyperthyroidism and hypothyroidism;
4. Depending on the type of thyroid dysfunction, we classified each patient in three categories isolated hypothyroidism, isolated thyrotoxicosis and thyroiditis (thyrotoxicosis then hypothyroidism).

Thyroid Dysfunction and Nivolumab Reponse in NSCLC

Thyroid Biological Toxicity and Tumor Response in Patients Treated With NIVOLUMAB 2nd Line in Non-small Cell Bronchopulmonary Cancer

All collected data that underlie results in a publication

OS was defined as the time between the introduction of Nivolumab® and death

The ORR was defined as a partial or complete response

DCR was defined as stability or as an objective response

PFS is defined as the time between the introduction of Nivolumab® and the date of progression or death.

University Hospital, Brest

Skin and Connective Tissue Diseases

Breast Neoplasms

Carcinoma

Breast Diseases

Skin Diseases

Central Nervous System Depressants

Other Dietary Supplements

Benzocaine

Tannic Acid

Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 \< 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).

Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.

Triiodothyronine (T3)

Shruti Trehan, MD

Up to one third of breast cancer patients have hypothyroidism or hyperthyroidism. L-thyroxine (T4), or Synthroid, is the most commonly prescribed agent for the management of hypothyroidism in the US. However, there are data suggesting that triiodothyronine (T3) may have benefits in preventing disease progression over l-thyroxine (T4).

It is estimated that there are approximately 155,000 living with metastatic breast cancer in the US and the number is estimated to increase over the next years (SEER data). Although their median survival has improved over the last 2 decades from 17 months to approximately 24 months attributed to newer treatments, there is an ongoing need for additional strategies and research to improve survival and quality of life.

Many studies have explored the connection between hypothyroidism and hyperthyroidism and breast cancer with varied results ranging up to one third prevalence. Low Triiodothyronine (T3) and elevated Thyroid-Stimulating Hormone (TSH) levels have been detected in newly diagnosed breast cancer patients. Other studies have suggested that some of the common symptoms reported by breast cancer survivors such as fatigue and depression can be attributed to subclinical hypothyroidism.

L-thyroxine (T4) is the most commonly prescribed agent for the management of hypothyroidism in the US. However, there are data suggesting that T4 is a potent pro-oncogenic agent. Proposed mechanisms include stimulation of mitogenesis, angiogenesis and resistance to apoptosis, opposition of anti-PDL-1 and radiation effects. It has been postulated that the avbeta3integrin that is universally expressed on cancer cells harbors a thyroid hormone receptor and T4 interacts with it.

Triiodothyronine (T3) on the other hand, is significantly less oncogenic and less mitogenic and is downstream of T4 which is a T3 pro-hormone. Therefore, exogenous supplementation of T3 would decrease the T4 levels creating the desired state of euthyroid hypothyroxinemia.

The rationale of this study is to replace L-thyroxine (T4) with Triiodothyronine (T3) in hypothyroid patients with metastatic breast carcinoma while they continue to receive standard systemic therapy, titrating the dose to achieve a state of euthyroid hypothyroxinemia which is turn would result in a lower risk of disease progression and improved survival by lowering the concentration of T4.

Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma

A Single Arm Phase II Pilot Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma

To prospectively evaluate the progression-free survival in hypothyroid patients with metastatic breast carcinoma who are rendered euthyroid and hypothyroxinemic. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the nadir sum of the longest diameter (SLD) of target lesions, or unequivocal progression (overall level of substantial worsening) in existing non-target lesions, or the appearance of one or more new lesions.

To quantitate the prevalence of hypothyroidism in metastatic breast cancer patients at a community oncology practice.

Functional Assessment of Cancer Therapy - Breast (FACT-B) Total Score comprised of Physical Well Being (PWB), Social Well Being (SWB), Emotional Well Being (EWB), Functional Well Being (FWB), and Breast Cancer Subscale (BCS). Range is 0-148. A higher score indicates higher quality of life. Missing scores were handled by prorating values.

Functional Assessment of Cancer Therapy - Breast (FACT-B) Lack of energy on 5 point Likert scale as measured on FACT-B Physical Well-being subscale. Score of 0 indicates no lack of energy with score of 4 indicating total lack of energy.

To study the average time required to achieve euthyroid hypothyroxinemia state in qualifying patients. Thyroid function laboratory testing was performed at baseline and then at every 4 weekly intervals until 12 weeks then every 3 monthly thereafter, unless thyroid-stimulating hormone (TSH) was abnormal. If a normal TSH level was not achieved by the 12 week visit, repeat TSH measurements were ordered every 4-6 weeks until the TSH value was within the laboratory normal reference range. Initial euthyroid state defined by number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value.

Aultman Health Foundation

Shruti Trehan MD

112/124 - 88.7% of adverse events were deemed to be related to underlying metastatic breast cancer and/or treatment thereof.

0 events reported definitely related to the study drug 14/124 -11.3% events reported as possible or probably related to the study drug Cause of mortality reported due to metastatic breast cancer.

Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 \< 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).

Triiodothyronine (T3): Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Duration of time since diagnosis of metastatic disease

Limitation is small sample size due to pandemic affecting clinical trial accrual. A larger sample is needed to adequately answer the research question.

Last enrolled subject was only able to be followed for 9 months due to early termination of study. Subject not included in primary outcome measure.

Number of Participants With Progression-free Survival at 12 Months Based Upon Clinical and Radiological Assessments Completed as Part of Routine Care

Outcome was number of practice patients with both metastatic breast cancer and hypothyroidism. Of the 26 identified, 7 patients consented to enroll on the study.

Number of Patients With Both Metastatic Breast Cancer and Hypothyroidism in All Screened Patients.

Baseline

At 3 months

At 6 months

At 9 months

At 12 months

Of the 7 subjects enrolled only 5 of the patients completed Quality of Life FACT-B questionnaires for all five timepoint. Two subjects did not complete the 12 months surveys due to death or premature study termination.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Thyroid Dysfunction and Nivolumab Reponse in NSCLC	NCT04470440	Non Small Cell ... Treatment Adver... Thyroid Dysfunc... Immune Checkpoi... Prognosis		18 Years -	University Hospital, Brest
Thyroid Dysfunction and Nivolumab Reponse in NSCLC	NCT04470440	Non Small Cell ... Treatment Adver... Thyroid Dysfunc... Immune Checkpoi... Prognosis		18 Years -	University Hospital, Brest
Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma	NCT03787303	Metastatic Brea... Thyroid Dysfunc...	Triiodothyronin...	18 Years - 105 Years	Aultman Health Foundation
Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma	NCT03787303	Metastatic Brea... Thyroid Dysfunc...	Triiodothyronin...	18 Years - 105 Years	Aultman Health Foundation

Spots Global Cancer Trial Database for thyroid dysfunction