Testing the Addition of High Dose, Targeted Radiation to the Usual Treatment for Locally-Advanced Inoperable Non-small Cell Lung Cancer
- Conditions
- Locally Advanced Lung Non-Small Cell CarcinomaStage IIB Lung Cancer AJCC v8Stage III Lung Cancer AJCC v8
- Interventions
- Procedure: Computed TomographyRadiation: Image Guided Radiation TherapyProcedure: Positron Emission TomographyOther: Questionnaire AdministrationRadiation: Stereotactic Body Radiation Therapy
- Registration Number
- NCT05624996
- Lead Sponsor
- NRG Oncology
- Brief Summary
This phase III trial compares the effect of adding stereotactic body radiation therapy (SBRT) to the usual treatment (conventional image guided radiation therapy \[IGRT\] and chemotherapy followed by immunotherapy with durvalumab or osimertinib) versus the usual treatment alone in treating patients with non-small cell lung cancer that has spread to nearby tissue or lymph nodes (locally advanced) and cannot be treated by surgery (inoperable). SBRT uses special equipment to position a patient and deliver radiation to tumors with high precision. This method may kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. IGRT is a type of radiation that uses a computer to create a picture of the tumor, to help guide the radiation beam during therapy, making it more accurate and causing less damage to healthy tissue. Usual chemotherapy used in this trial consists of combinations of the following drugs: cisplatin, carboplatin, paclitaxel, nab-paclitaxel, pemetrexed, and etoposide. Cisplatin and carboplatin are in a class of medications known as platinum-containing compounds. Cisplatin works by killing, stopping, or slowing the growth of tumor cells. Carboplatin works in a way similar to the anticancer drug cisplatin but may be better tolerated than cisplatin. Carboplatin works by killing, stopping, or slowing the growth of tumor cells as well. Paclitaxel is in a class of medications called antimicrotubule agents. It works by stopping the growth and spread of tumor cells. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Pemetrexed is in a class of medications called antifolate antineoplastic agents. It works by blocking the action of a certain substance in the body that may help tumor cells multiply. Etoposide is in a class of medications known as podophyllotoxin derivatives. It blocks a certain enzyme needed for cell division and deoxyribonucleic acid (DNA) repair and may kill tumor cells. Immunotherapy with durvalumab, may induce changes in the body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib is in a class of medications called kinase inhibitors. It works by blocking the action of a protein called EGFR that signals cancer cells to multiply. This helps slow or stop the spread of tumor cells. Adding SBRT to the usual treatment of IGRT with chemotherapy and immunotherapy may be more effective at treating patients with locally-advanced non-small cell lung cancer than giving the usual treatment alone.
- Detailed Description
PRIMARY OBJECTIVES:
I. To compare the overall survival in patients with stage II-IIIC inoperable node-positive non-small cell lung cancer (NSCLC) after image guided, motion-managed conventional radiotherapy to the primary tumor and nodal metastases (Arm 1) or after image guided, motion-managed stereotactic body radiation therapy (SBRT) to the primary tumor followed by conventionally fractionated radiotherapy to nodal metastases (Arm 2) both given with concurrent platinum-based chemotherapy.
II. To compare progression-free survival between the experimental arm (Arm 2) and control arm (Arm 1).
SECONDARY OBJECTIVES:
I. To compare objective response rate (as defined by Response Evaluation Criteria in Solid Tumors \[RECIST\] version \[v\] 1.1) between the experimental arm and control arm.
II. To compare the rate of local control between the experimental arm and control arm.
III. To compare patterns of failure (primary, locoregional, or distant) between the experimental arm and control arm.
IV. To compare changes in pulmonary function (forced expiratory volume in 1 second \[FEV1\] and diffusion capacity of the lung for carbon monoxide \[DLCO\] assessed at randomization and at 6- and 12- months following completion of radiation therapy) between the experimental arm and control arm.
V. To compare changes in quality of life and patient-reported outcomes assessed from pre-treatment to 3 months following radiation therapy of each treatment arm.
VI. To determine acute and late toxicity profiles of each treatment arm as measured by the Common Terminology Criteria for Adverse Events (CTCAE) v5.
EXPLORATORY OBJECTIVES:
I. To characterize and compare longitudinal quality of life and patient-reported outcomes of each treatment arm.
II. To collect biospecimens at baseline, after SBRT (for Arm 2 patients), during last 2 weeks of chemoradiation, and after first dose of consolidation therapy, to allow for future analyses.
III. To collect 4-dimensional (4D) computed tomography (CT) planning scans and radiation dose to calculate regional lung ventilation and explore pre-treatment 4D-CT based ventilation to predict pulmonary toxicity.
IV. To characterize clinical outcomes, toxicities and changes in pulmonary function and quality of life among patients receiving proton and photon radiotherapy.
V. To develop and characterize a machine learning/artificial intelligence algorithm for radiotherapy planning and/or quality assurance.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel intravenously (IV) followed by carboplatin IV weekly (Q7D) during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or positron emission tomography (PET)/CT during follow-up.
ARM II: Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
Patients are followed up every 3 months for 1 year, every 6 months during years 2 and 3, and then yearly after that for the duration of the study.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 474
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Pathologically (histologically or cytologically) proven diagnosis of non-operable stage IIB or III, node positive (American Joint Committee on Cancer [AJCC] eighth edition) non-small cell lung cancer (NSCLC) with known PD-L1 status prior to registration
- Patients must have an identified primary tumor and at least one nodal metastasis (peribronchial/hilar/intrapulmonary, mediastinal/subcarinal, supraclavicular/scalene)
- Up to 4 cycles of systemic therapy received prior to registration for the current study cancer is allowable; any prior chemotherapy for a different cancer is also permissible
- Patients who refuse surgery, in addition to those who are technically unresectable or medically inoperable, are eligible.
- Patients with separate tumor nodules in the same lobe of the primary tumor are eligible
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The patient must be deemed clinically appropriate for curative intent definitive combined modality therapy, based on the following staging assessments:
- History/physical examination prior to registration;
- Magnetic resonance imaging (MRI) scan of the brain (preferred) or CT scan of the brain (if available, contrast is preferred for all neuroimaging) prior to registration;
- CT chest with IV contrast (if contrast is available and unless contraindicated, such as for abnormal kidney function) prior to registration. PET/CT may be used if the CT portion is of identical diagnostic quality as achieved in a stand-alone CT
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No evidence of distant metastases based on FDG PET/CT scan obtained within 60 days of registration
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Primary tumor =< 7 cm
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Age >= 18
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Eastern Cooperative Oncology Group (ECOG) performance status 0-2
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Hematologic function (e.g. platelets, leukocytes, hemoglobin) amenable, at the discretion of the treating physician, to allow for treatment with chemotherapy and concurrent radiation therapy
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Creatinine clearance >= 25 mL/min by the Cockcroft-Gault (C-G) equation
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Subjects with non-malignant pleural effusion are eligible provided the effusion is not known or demonstrated to be an exudative effusion
-
If a pleural effusion is present, the following criteria must be met to exclude malignant involvement:
- When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative;
- Effusions that are minimal (i.e., not visible on chest x-ray) that are too small to safely tap are eligible
-
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Medical history consistent with the patient being amenable, at the discretion of the treating physician, to allow for treating with consolidation immunotherapy. Patients with known EGFR/ALK/other driver mutation at the time of registration are eligible, and these patients can be treated with consolidation systemic therapy at the discretion of the treating physician
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Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen
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Negative pregnancy test =< 14 days prior to registration for participants of childbearing potential
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The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
- Prior radiotherapy to the study cancer (local recurrence). Prior radiotherapy for a different cancer/condition to the region of the study cancer that would result in overlap of radiation therapy fields that is determined by the treating physician to impede the treatment of the study malignancy
- Patients without identifiable primary tumor and at least 1 pathologically enlarged lymph node are not eligible (T3-4N0 or T0N1-3 patients are not eligible). At least 1 radiographically-involved lymph node is required, but pathologic confirmation of involvement is not mandated
- Centrally located primary tumor < 2 cm from involved nodal disease that would result in significant overlap of the primary SBRT and nodal radiation fields. This does not include proximity to involved segmental and subsegmental lymph nodes (levels 13 and 14) that would not result in overlap of dose to the proximal bronchial tree or esophagus. Centrally located is defined as within or touching the zone of the proximal bronchial tree, which is a volume 2 cm in all directions around the proximal bronchial tree (carina, right and left main bronchi, right and left upper lobe bronchi, intermedius bronchus, right middle lobe bronchus, lingular bronchus right and left lower lobe bronchi)
- Participants who are pregnant or unwilling to discontinue nursing
- Participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) unwilling to use highly effective contraceptives during therapy and for the Food and Drug Administration (FDA)-labeled contraception timeframe required after the final dose of the selected systemic therapy regimen, because the treatment in this study may be significantly teratogenic
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm I (image guided RT, chemotherapy, immunotherapy) Carboplatin Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm I (image guided RT, chemotherapy, immunotherapy) Cisplatin Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm I (image guided RT, chemotherapy, immunotherapy) Computed Tomography Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm I (image guided RT, chemotherapy, immunotherapy) Durvalumab Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm I (image guided RT, chemotherapy, immunotherapy) Etoposide Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm I (image guided RT, chemotherapy, immunotherapy) Image Guided Radiation Therapy Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm I (image guided RT, chemotherapy, immunotherapy) Nab-paclitaxel Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm I (image guided RT, chemotherapy, immunotherapy) Paclitaxel Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm I (image guided RT, chemotherapy, immunotherapy) Pemetrexed Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm I (image guided RT, chemotherapy, immunotherapy) Positron Emission Tomography Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm I (image guided RT, chemotherapy, immunotherapy) Questionnaire Administration Patients undergo conventional IGRT and receive usual care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Carboplatin Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Cisplatin Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Computed Tomography Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Durvalumab Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Etoposide Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Image Guided Radiation Therapy Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Nab-paclitaxel Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Paclitaxel Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Pemetrexed Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Positron Emission Tomography Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Questionnaire Administration Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up. Arm II (SBRT, image guided RT, chemotherapy, immunotherapy) Stereotactic Body Radiation Therapy Patients undergo SBRT and conventional IGRT and receive standard-of-care chemotherapy consisting of paclitaxel IV followed by carboplatin IV Q7D during radiotherapy or pemetrexed IV followed by carboplatin IV every 21 days during radiotherapy or etoposide IV on days 1 to 5 and days 29 to 33 followed by cisplatin IV on days 1, 8, 29, and 36 or pemetrexed IV followed by cisplatin IV every 21 days during radiotherapy. Patients then receive consolidation durvalumab IV every 2 or 4 weeks for up to one year in the absence of disease progression or unacceptable toxicity. Patients also undergo CT and/or PET/CT during follow-up.
- Primary Outcome Measures
Name Time Method Overall survival (OS) Time between date of randomization and date of death due to any cause, assessed up to 8 years Non-inferiority (NI) between arm 2 and arm 1 (reference level) will be evaluated by comparing the upper bound of the 95% confidence interval for the hazard ratio to the pre-specified NI margin. NI of arm 2 will be concluded if the upper bound of the confidence interval is equal to, or falls below, the pre-specified margin at the final analysis. When evaluating the NI of arm 2 in OS, a Cox proportional hazards (PH) model stratified by stratification factors will be used to compute the hazard ratio and associated 95% confidence interval (CI). OS rates will be estimated using the Kaplan-Meier method. If the NI of arm 2 in OS is demonstrated, the superiority of arm 1 in OS will be tested at 1-sided significance level of 0.025 using a stratified log-rank test by adjusting for stratification factors.
Progression-free survival (PFS) Time between date of randomization and first date of documented progression or death due to any cause, assessed up to 8 years The PFS analysis will be conducted using the same methods and stratification factors as the OS analysis. The superiority of arm 2 in PFS will be tested at 1-sided significance level of 0.025 using a stratified log-rank test by adjusting for stratification factors. In the event that the NI of OS is not established, statistical inference of PFS will be considered exploratory in nature only. A Cox PH model stratified by stratification factors will be used to compute the hazard ratio and associated 95% CI.
- Secondary Outcome Measures
Name Time Method Objective response rate (ORR) Up to 8 years ORR (per Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1) is defined as the number (%) of patients with at least 1 visit response of complete response (CR) or partial response (PR) and will be based on all randomized patients who have measurable disease. Therefore, data obtained up until progression, or the last evaluable assessment in the absence of progression, will be included in the assessment of ORR. The ORR will be compared between arm 2 versus arm 1 using a Fisher's exact test. A binary response variable for ORR will be used for the analysis with the categories of CR and PR versus stable disease (SD), progressive disease (PD) and inevaluable (NE).
Time to progression Up to 8 years Local control also known as time to progression will be defined as freedom from local progression, in which a failure is defined as intrathoracic tumor progression (failure in the lobe of the primary tumor or mediastinal lymph nodes) by RECIST 1.1 criteria. Local control will be analyzed as competing risks data based on cause-specific hazards approaches, where deaths without local failure will be considered as a competing event and analyzed as "censoring" of local failure. The rates at various timepoints (e.g., every 6 months after randomization) and medians of PFS for each arm will be estimated using the Kaplan-Meier method. The associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Results from an unstratified analysis will also be provided.
Time to primary, locoregional, or distant failure Up to 8 years Competing risks analysis will be used to analyze times to primary failure, locoregional failure and distant failure as the first failure. Competing events include primary failure, locoregional failure, distant failure and deaths without any failures. Rates at various timepoints (i.e., every 6 months after randomization) for each arm will be estimated using the cumulative incidence function. The associated 95% CI will be calculated using the Delta method and based on a log-log transformation applied on the estimated cumulative incidence functions. Statistical inferences of the development of each failure between arms will be based on cause-specific hazards using the log-rank test and Cox proportional hazard model. In addition, Gray's test and the Fine-Gray model will also be used to provide statistical inferences between arms based on cumulative incidence functions and subdistribution hazards.
Changes in pulmonary function From randomization to 6 months or 12 months Includes forced expiratory volume in 1 second (FEV1) and diffusion capacity of the lung for carbon monoxide (DLCO). Changes in pulmonary function (FEV1 and DLCO) will be summarized with descriptive statistics, and compared with Wilcoxon rank-sum test. The descriptive statistics of changes in FEV1 and diffusion capacity before and after treatment will be reported by treatment arm and by response categories (complete response; partial response; stable disease; progressive disease). Linear regression will be used to model changes with adjustment for treatment arms and possibly other baseline covariates, if applicable. The grade 3-5 NRG Oncology Pulmonary Toxicity Scale for changes will be reported with the frequency and grade by arm. Logistic regression will be used to model the distribution of the NRG Oncology Pulmonary Toxicity Scale by arms with and without adjustment for covariates.
Patient reported outcomes-Common Terminology Criteria for Adverse Events (PRO-CTCAE) At 3, 12, and 24 months Adverse events will also be assessed using PRO-CTCAE items. The PRO-CTCAE is a patient-reported outcome measurement system developed to characterize the frequency, severity, and interference of symptomatic treatment toxicities. Items are scored on a Likert scale. For each symptom and each domain (i.e., frequency, severity, and interference), counts and frequencies will be summarized for the worst score experienced by the patient by the treatment arm. In addition, a composite grading algorithm (Basch 2021) will be used to derive a single numerical grade for each adverse event scored using PRO-CTCAE. PRO-CTCAE, the frequency of acute grade \>= 3 patient-reported toxicity will be compared to the corresponding rate of clinician-scored toxicity using a chi-square test or Fisher exact test, as appropriate. Distributions of clinician-reported and patient-reported adverse events will also be compared across study arms.
Functional Assessment of Cancer Therapy Lung (FACT-L) and Trial Outcome Index (TOI) At 3, 12, and 24 months FACT-L and TOI is a measure that sums the functional well-being (FWB - 7 items), physical well-being (PWB - 7), and the lung cancer subscale (LCS - 9 items) of FACT-L. Questionnaire trial outcome index deterioration rates at 3 months and associated 95% confidence interval will be calculated for each treatment group, based on all randomized subjects. In addition, to explore if higher QOL scores will be maintained at 12 and 24 months from the end of radiotherapy as well, longitudinal data analysis will also be performed to characterize the trend of scores over time across the two treatment groups using hierarchical formulation of the linear mixed model. The Clopper-Pearson method will be used for calculating 95% CI. The deterioration rates of each arm will also be compared using Cochran-Mantel-Haenszel Test, stratified by PD-L1 expression and T-stage.
European Quality of Life Five Dimension (EQ-5D) scale At 3, 12, and 24 months Subjects' overall health state on a visual analog scale (EQ-VAS) at each assessment time point will be summarized using descriptive statistics by treatment group, as randomized. Proportion of subjects reporting problems for the five EQ-5D dimensions at each assessment time point will be summarized by level of problem and by treatment group, as randomized. Percentages will be based on number subjects assessed at assessment time point.
Incidence of adverse events Up to 8 years For each patient, the maximum severity reported will be used in the summaries. Adverse events will be summarized regardless of relationship to protocol treatment as assessed by the investigator. Treatment-related adverse events using National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) will be presented in statistical analysis reports/publications in CTCAE version 5. Adverse event rates will be reported with the frequency and severity (e.g., type, grade, and attribution) by arm.
Trial Locations
- Locations (400)
Kingman Regional Medical Center
🇺🇸Kingman, Arizona, United States
Cancer Center at Saint Joseph's
🇺🇸Phoenix, Arizona, United States
Mayo Clinic Hospital in Arizona
🇺🇸Phoenix, Arizona, United States
Banner University Medical Center - Tucson
🇺🇸Tucson, Arizona, United States
University of Arizona Cancer Center-North Campus
🇺🇸Tucson, Arizona, United States
University of Arkansas for Medical Sciences
🇺🇸Little Rock, Arkansas, United States
AIS Cancer Center at San Joaquin Community Hospital
🇺🇸Bakersfield, California, United States
Mills-Peninsula Medical Center
🇺🇸Burlingame, California, United States
Palo Alto Medical Foundation-Fremont
🇺🇸Fremont, California, United States
Los Angeles General Medical Center
🇺🇸Los Angeles, California, United States
USC / Norris Comprehensive Cancer Center
🇺🇸Los Angeles, California, United States
Fremont - Rideout Cancer Center
🇺🇸Marysville, California, United States
Sutter Cancer Centers Radiation Oncology Services-Roseville
🇺🇸Roseville, California, United States
Memorial Medical Center
🇺🇸Modesto, California, United States
Sutter Roseville Medical Center
🇺🇸Roseville, California, United States
Sutter Medical Center Sacramento
🇺🇸Sacramento, California, United States
Mills Health Center
🇺🇸San Mateo, California, United States
Palo Alto Medical Foundation-Camino Division
🇺🇸Mountain View, California, United States
Palo Alto Medical Foundation Health Care
🇺🇸Palo Alto, California, United States
California Pacific Medical Center-Pacific Campus
🇺🇸San Francisco, California, United States
Sutter Pacific Medical Foundation
🇺🇸Santa Rosa, California, United States
Palo Alto Medical Foundation-Sunnyvale
🇺🇸Sunnyvale, California, United States
Sutter Solano Medical Center/Cancer Center
🇺🇸Vallejo, California, United States
UCHealth University of Colorado Hospital
🇺🇸Aurora, Colorado, United States
Rocky Mountain Cancer Centers-Penrose
🇺🇸Colorado Springs, Colorado, United States
UCHealth Memorial Hospital Central
🇺🇸Colorado Springs, Colorado, United States
Memorial Hospital North
🇺🇸Colorado Springs, Colorado, United States
UCHealth - Cherry Creek
🇺🇸Denver, Colorado, United States
Poudre Valley Hospital
🇺🇸Fort Collins, Colorado, United States
Cancer Care and Hematology-Fort Collins
🇺🇸Fort Collins, Colorado, United States
UCHealth Greeley Hospital
🇺🇸Greeley, Colorado, United States
UCHealth Highlands Ranch Hospital
🇺🇸Highlands Ranch, Colorado, United States
UCHealth Lone Tree Health Center
🇺🇸Lone Tree, Colorado, United States
Medical Center of the Rockies
🇺🇸Loveland, Colorado, United States
Beebe Medical Center
🇺🇸Lewes, Delaware, United States
Beebe South Coastal Health Campus
🇺🇸Millville, Delaware, United States
Helen F Graham Cancer Center
🇺🇸Newark, Delaware, United States
Medical Oncology Hematology Consultants PA
🇺🇸Newark, Delaware, United States
Christiana Care Health System-Christiana Hospital
🇺🇸Newark, Delaware, United States
Christiana Care Health System-Wilmington Hospital
🇺🇸Wilmington, Delaware, United States
Beebe Health Campus
🇺🇸Rehoboth Beach, Delaware, United States
Morton Plant Hospital
🇺🇸Clearwater, Florida, United States
Mayo Clinic in Florida
🇺🇸Jacksonville, Florida, United States
Jupiter Medical Center
🇺🇸Jupiter, Florida, United States
Orlando Health Cancer Institute
🇺🇸Orlando, Florida, United States
Saint Joseph's Hospital/Children's Hospital-Tampa
🇺🇸Tampa, Florida, United States
Winter Haven Hospital
🇺🇸Winter Haven, Florida, United States
Grady Health System
🇺🇸Atlanta, Georgia, United States
Emory Proton Therapy Center
🇺🇸Atlanta, Georgia, United States
Emory University Hospital Midtown
🇺🇸Atlanta, Georgia, United States
Emory University Hospital/Winship Cancer Institute
🇺🇸Atlanta, Georgia, United States
Emory Saint Joseph's Hospital
🇺🇸Atlanta, Georgia, United States
Augusta University Medical Center
🇺🇸Augusta, Georgia, United States
WellStar Cobb Hospital
🇺🇸Austell, Georgia, United States
Hamilton Medical Center - Peeples Cancer Institute
🇺🇸Dalton, Georgia, United States
CTCA at Southeastern Regional Medical Center
🇺🇸Newnan, Georgia, United States
Hawaii Cancer Care - Westridge
🇺🇸'Aiea, Hawaii, United States
Pali Momi Medical Center
🇺🇸'Aiea, Hawaii, United States
Hawaii Cancer Care Inc - Waterfront Plaza
🇺🇸Honolulu, Hawaii, United States
Queen's Cancer Cenrer - POB I
🇺🇸Honolulu, Hawaii, United States
Queen's Medical Center
🇺🇸Honolulu, Hawaii, United States
Straub Clinic and Hospital
🇺🇸Honolulu, Hawaii, United States
University of Hawaii Cancer Center
🇺🇸Honolulu, Hawaii, United States
Kuakini Medical Center
🇺🇸Honolulu, Hawaii, United States
Queen's Cancer Center - Kuakini
🇺🇸Honolulu, Hawaii, United States
The Cancer Center of Hawaii-Liliha
🇺🇸Honolulu, Hawaii, United States
Alton Memorial Hospital
🇺🇸Alton, Illinois, United States
Rush - Copley Medical Center
🇺🇸Aurora, Illinois, United States
Advocate Outpatient Center - Aurora
🇺🇸Aurora, Illinois, United States
Advocate Good Shepherd Hospital
🇺🇸Barrington, Illinois, United States
OSF Saint Joseph Medical Center
🇺🇸Bloomington, Illinois, United States
Illinois CancerCare-Bloomington
🇺🇸Bloomington, Illinois, United States
Illinois CancerCare-Canton
🇺🇸Canton, Illinois, United States
Illinois CancerCare-Carthage
🇺🇸Carthage, Illinois, United States
Centralia Oncology Clinic
🇺🇸Centralia, Illinois, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
Advocate Illinois Masonic Medical Center
🇺🇸Chicago, Illinois, United States
AMG Crystal Lake - Oncology
🇺🇸Crystal Lake, Illinois, United States
Carle at The Riverfront
🇺🇸Danville, Illinois, United States
Cancer Care Specialists of Illinois - Decatur
🇺🇸Decatur, Illinois, United States
Decatur Memorial Hospital
🇺🇸Decatur, Illinois, United States
Northwestern Medicine Cancer Center Kishwaukee
🇺🇸DeKalb, Illinois, United States
Advocate Good Samaritan Hospital
🇺🇸Downers Grove, Illinois, United States
Carle Physician Group-Effingham
🇺🇸Effingham, Illinois, United States
Crossroads Cancer Center
🇺🇸Effingham, Illinois, United States
Advocate Sherman Hospital
🇺🇸Elgin, Illinois, United States
Illinois CancerCare-Eureka
🇺🇸Eureka, Illinois, United States
Illinois CancerCare-Galesburg
🇺🇸Galesburg, Illinois, United States
Northwestern Medicine Cancer Center Delnor
🇺🇸Geneva, Illinois, United States
Advocate South Suburban Hospital
🇺🇸Hazel Crest, Illinois, United States
Illinois CancerCare-Kewanee Clinic
🇺🇸Kewanee, Illinois, United States
AMG Libertyville - Oncology
🇺🇸Libertyville, Illinois, United States
Condell Memorial Hospital
🇺🇸Libertyville, Illinois, United States
Illinois CancerCare-Macomb
🇺🇸Macomb, Illinois, United States
Carle Physician Group-Mattoon/Charleston
🇺🇸Mattoon, Illinois, United States
Cancer Care Center of O'Fallon
🇺🇸O'Fallon, Illinois, United States
HSHS Saint Elizabeth's Hospital
🇺🇸O'Fallon, Illinois, United States
Advocate Christ Medical Center
🇺🇸Oak Lawn, Illinois, United States
Illinois CancerCare-Ottawa Clinic
🇺🇸Ottawa, Illinois, United States
Advocate High Tech Medical Park
🇺🇸Palos Heights, Illinois, United States
Advocate Lutheran General Hospital
🇺🇸Park Ridge, Illinois, United States
Illinois CancerCare-Pekin
🇺🇸Pekin, Illinois, United States
Illinois CancerCare-Peoria
🇺🇸Peoria, Illinois, United States
OSF Saint Francis Radiation Oncology at Peoria Cancer Center
🇺🇸Peoria, Illinois, United States
Methodist Medical Center of Illinois
🇺🇸Peoria, Illinois, United States
OSF Saint Francis Medical Center
🇺🇸Peoria, Illinois, United States
Illinois CancerCare-Peru
🇺🇸Peru, Illinois, United States
Illinois CancerCare-Princeton
🇺🇸Princeton, Illinois, United States
UW Health Carbone Cancer Center Rockford
🇺🇸Rockford, Illinois, United States
Memorial Hospital East
🇺🇸Shiloh, Illinois, United States
Southern Illinois University School of Medicine
🇺🇸Springfield, Illinois, United States
Springfield Clinic
🇺🇸Springfield, Illinois, United States
Springfield Memorial Hospital
🇺🇸Springfield, Illinois, United States
Carle Cancer Center
🇺🇸Urbana, Illinois, United States
Northwestern Medicine Cancer Center Warrenville
🇺🇸Warrenville, Illinois, United States
Illinois CancerCare - Washington
🇺🇸Washington, Illinois, United States
Midwestern Regional Medical Center
🇺🇸Zion, Illinois, United States
Mary Greeley Medical Center
🇺🇸Ames, Iowa, United States
McFarland Clinic - Ames
🇺🇸Ames, Iowa, United States
UI Health Care Mission Cancer and Blood - Ankeny Clinic
🇺🇸Ankeny, Iowa, United States
Saint Luke's Hospital
🇺🇸Cedar Rapids, Iowa, United States
UI Health Care Mission Cancer and Blood - West Des Moines Clinic
🇺🇸Clive, Iowa, United States
Heartland Oncology and Hematology LLP
🇺🇸Council Bluffs, Iowa, United States
Methodist Jennie Edmundson Hospital
🇺🇸Council Bluffs, Iowa, United States
Iowa Methodist Medical Center
🇺🇸Des Moines, Iowa, United States
UI Health Care Mission Cancer and Blood - Des Moines Clinic
🇺🇸Des Moines, Iowa, United States
UI Health Care Mission Cancer and Blood - Laurel Clinic
🇺🇸Des Moines, Iowa, United States
UI Health Care Mission Cancer and Blood - Waukee Clinic
🇺🇸Waukee, Iowa, United States
University of Kansas Cancer Center
🇺🇸Kansas City, Kansas, United States
The University of Kansas Cancer Center - Olathe
🇺🇸Olathe, Kansas, United States
University of Kansas Cancer Center-Overland Park
🇺🇸Overland Park, Kansas, United States
Salina Regional Health Center
🇺🇸Salina, Kansas, United States
University of Kansas Health System Saint Francis Campus
🇺🇸Topeka, Kansas, United States
University of Kansas Hospital-Westwood Cancer Center
🇺🇸Westwood, Kansas, United States
Ascension Via Christi Hospitals Wichita
🇺🇸Wichita, Kansas, United States
University of Kentucky/Markey Cancer Center
🇺🇸Lexington, Kentucky, United States
Louisiana State University Health Science Center
🇺🇸New Orleans, Louisiana, United States
University Medical Center New Orleans
🇺🇸New Orleans, Louisiana, United States
Luminis Health Anne Arundel Medical Center
🇺🇸Annapolis, Maryland, United States
Sinai Hospital of Baltimore
🇺🇸Baltimore, Maryland, United States
TidalHealth Richard A Henson Cancer Institute
🇺🇸Ocean Pines, Maryland, United States
TidalHealth Peninsula Regional
🇺🇸Salisbury, Maryland, United States
William E Kahlert Regional Cancer Center/Sinai Hospital
🇺🇸Westminster, Maryland, United States
UMass Memorial Medical Center - University Campus
🇺🇸Worcester, Massachusetts, United States
Trinity Health Saint Joseph Mercy Hospital Ann Arbor
🇺🇸Ann Arbor, Michigan, United States
McLaren Cancer Institute-Bay City
🇺🇸Bay City, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Brighton
🇺🇸Brighton, Michigan, United States
Trinity Health Medical Center - Brighton
🇺🇸Brighton, Michigan, United States
Chelsea Hospital
🇺🇸Chelsea, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology - Chelsea Hospital
🇺🇸Chelsea, Michigan, United States
McLaren Cancer Institute-Clarkston
🇺🇸Clarkston, Michigan, United States
Michigan Healthcare Professionals Clarkston
🇺🇸Clarkston, Michigan, United States
Wayne State University/Karmanos Cancer Institute
🇺🇸Detroit, Michigan, United States
Michigan Healthcare Professionals Farmington
🇺🇸Farmington Hills, Michigan, United States
Weisberg Cancer Treatment Center
🇺🇸Farmington Hills, Michigan, United States
Corewell Health Farmington Hills Hospital
🇺🇸Farmington Hills, Michigan, United States
McLaren Cancer Institute-Flint
🇺🇸Flint, Michigan, United States
Trinity Health Grand Rapids Hospital
🇺🇸Grand Rapids, Michigan, United States
Bronson Methodist Hospital
🇺🇸Kalamazoo, Michigan, United States
West Michigan Cancer Center
🇺🇸Kalamazoo, Michigan, United States
Ascension Borgess Hospital
🇺🇸Kalamazoo, Michigan, United States
Karmanos Cancer Institute at McLaren Greater Lansing
🇺🇸Lansing, Michigan, United States
University of Michigan Health - Sparrow Lansing
🇺🇸Lansing, Michigan, United States
McLaren Cancer Institute-Lapeer Region
🇺🇸Lapeer, Michigan, United States
Trinity Health Saint Mary Mercy Livonia Hospital
🇺🇸Livonia, Michigan, United States
Michigan Healthcare Professionals Macomb
🇺🇸Macomb, Michigan, United States
Michigan Healthcare Professionals Madison Heights
🇺🇸Madison Heights, Michigan, United States
McLaren Cancer Institute-Macomb
🇺🇸Mount Clemens, Michigan, United States
McLaren Cancer Institute-Northern Michigan
🇺🇸Petoskey, Michigan, United States
Michigan Healthcare Professionals Pontiac
🇺🇸Pontiac, Michigan, United States
Trinity Health Saint Joseph Mercy Oakland Hospital
🇺🇸Pontiac, Michigan, United States
McLaren-Port Huron
🇺🇸Port Huron, Michigan, United States
Corewell Health William Beaumont University Hospital
🇺🇸Royal Oak, Michigan, United States
Munson Medical Center
🇺🇸Traverse City, Michigan, United States
Corewell Health Beaumont Troy Hospital
🇺🇸Troy, Michigan, United States
Michigan Healthcare Professionals Troy
🇺🇸Troy, Michigan, United States
Henry Ford Health Warren Hospital
🇺🇸Warren, Michigan, United States
University of Michigan Health - West
🇺🇸Wyoming, Michigan, United States
Trinity Health IHA Medical Group Hematology Oncology Ann Arbor Campus
🇺🇸Ypsilanti, Michigan, United States
Sanford Joe Lueken Cancer Center
🇺🇸Bemidji, Minnesota, United States
Essentia Health Saint Joseph's Medical Center
🇺🇸Brainerd, Minnesota, United States
Essentia Health - Deer River Clinic
🇺🇸Deer River, Minnesota, United States
Essentia Health Cancer Center
🇺🇸Duluth, Minnesota, United States
Essentia Health Saint Mary's Medical Center
🇺🇸Duluth, Minnesota, United States
Miller-Dwan Hospital
🇺🇸Duluth, Minnesota, United States
Essentia Health Hibbing Clinic
🇺🇸Hibbing, Minnesota, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States
Coborn Cancer Center at Saint Cloud Hospital
🇺🇸Saint Cloud, Minnesota, United States
Essentia Health Sandstone
🇺🇸Sandstone, Minnesota, United States
Essentia Health Virginia Clinic
🇺🇸Virginia, Minnesota, United States
Baptist Memorial Hospital and Cancer Center-Desoto
🇺🇸Southhaven, Mississippi, United States
Saint Francis Medical Center
🇺🇸Cape Girardeau, Missouri, United States
Siteman Cancer Center at West County Hospital
🇺🇸Creve Coeur, Missouri, United States
Parkland Health Center - Farmington
🇺🇸Farmington, Missouri, United States
Freeman Health System
🇺🇸Joplin, Missouri, United States
University of Kansas Cancer Center - North
🇺🇸Kansas City, Missouri, United States
University of Kansas Cancer Center - Lee's Summit
🇺🇸Lee's Summit, Missouri, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
Mercy Hospital South
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center-South County
🇺🇸Saint Louis, Missouri, United States
Missouri Baptist Medical Center
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center at Christian Hospital
🇺🇸Saint Louis, Missouri, United States
Mercy Hospital Saint Louis
🇺🇸Saint Louis, Missouri, United States
Siteman Cancer Center at Saint Peters Hospital
🇺🇸Saint Peters, Missouri, United States
Sainte Genevieve County Memorial Hospital
🇺🇸Sainte Genevieve, Missouri, United States
Mercy Hospital Springfield
🇺🇸Springfield, Missouri, United States
Missouri Baptist Sullivan Hospital
🇺🇸Sullivan, Missouri, United States
BJC Outpatient Center at Sunset Hills
🇺🇸Sunset Hills, Missouri, United States
Billings Clinic Cancer Center
🇺🇸Billings, Montana, United States
Bozeman Health Deaconess Hospital
🇺🇸Bozeman, Montana, United States
Benefis Sletten Cancer Institute
🇺🇸Great Falls, Montana, United States
Nebraska Cancer Specialists/Oncology Hematology West PC - MECC
🇺🇸Omaha, Nebraska, United States
Nebraska Methodist Hospital
🇺🇸Omaha, Nebraska, United States
Oncology Associates PC
🇺🇸Omaha, Nebraska, United States
Renown Regional Medical Center
🇺🇸Reno, Nevada, United States
Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
🇺🇸Lebanon, New Hampshire, United States
Memorial Sloan Kettering Basking Ridge
🇺🇸Basking Ridge, New Jersey, United States
Cooper Hospital University Medical Center
🇺🇸Camden, New Jersey, United States
Saint Barnabas Medical Center
🇺🇸Livingston, New Jersey, United States
Memorial Sloan Kettering Monmouth
🇺🇸Middletown, New Jersey, United States
Memorial Sloan Kettering Bergen
🇺🇸Montvale, New Jersey, United States
Rutgers Cancer Institute of New Jersey
🇺🇸New Brunswick, New Jersey, United States
Robert Wood Johnson University Hospital Somerset
🇺🇸Somerville, New Jersey, United States
Community Medical Center
🇺🇸Toms River, New Jersey, United States
Wilmot Cancer Center at Batavia
🇺🇸Batavia, New York, United States
Montefiore Medical Center-Einstein Campus
🇺🇸Bronx, New York, United States
Montefiore Medical Center-Weiler Hospital
🇺🇸Bronx, New York, United States
Montefiore Medical Center - Moses Campus
🇺🇸Bronx, New York, United States
Sands Cancer Center
🇺🇸Canandaigua, New York, United States
Memorial Sloan Kettering Commack
🇺🇸Commack, New York, United States
Glens Falls Hospital
🇺🇸Glens Falls, New York, United States
Memorial Sloan Kettering Westchester
🇺🇸Harrison, New York, United States
New York Proton Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Wilmot Cancer Institute Radiation Oncology at Greece
🇺🇸Rochester, New York, United States
Highland Hospital
🇺🇸Rochester, New York, United States
University of Rochester
🇺🇸Rochester, New York, United States
Stony Brook University Medical Center
🇺🇸Stony Brook, New York, United States
State University of New York Upstate Medical University
🇺🇸Syracuse, New York, United States
Memorial Sloan Kettering Nassau
🇺🇸Uniondale, New York, United States
Westchester Medical Center
🇺🇸Valhalla, New York, United States
Wilmot Cancer Institute at Webster
🇺🇸Webster, New York, United States
Atrium Health Stanly/LCI-Albemarle
🇺🇸Albemarle, North Carolina, United States
Duke Cancer Center Cary
🇺🇸Cary, North Carolina, United States
UNC Lineberger Comprehensive Cancer Center
🇺🇸Chapel Hill, North Carolina, United States
Carolinas Medical Center/Levine Cancer Institute
🇺🇸Charlotte, North Carolina, United States
Novant Health Presbyterian Medical Center
🇺🇸Charlotte, North Carolina, United States
Atrium Health Pineville/LCI-Pineville
🇺🇸Charlotte, North Carolina, United States
Atrium Health University City/LCI-University
🇺🇸Charlotte, North Carolina, United States
Wake Forest University at Clemmons
🇺🇸Clemmons, North Carolina, United States
Atrium Health Cabarrus/LCI-Concord
🇺🇸Concord, North Carolina, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Levine Cancer Institute - Rutherford
🇺🇸Forest City, North Carolina, United States
CaroMont Regional Medical Center
🇺🇸Gastonia, North Carolina, United States
Novant Health Cancer Institute - Huntersville
🇺🇸Huntersville, North Carolina, United States
Novant Health Presbyterian Medical Center Huntersville
🇺🇸Huntersville, North Carolina, United States
Novant Health Cancer Institute - Kernersville
🇺🇸Kernersville, North Carolina, United States
Levine Cancer Institute - Union West
🇺🇸Matthews, North Carolina, United States
Matthews Radiation Oncology Center
🇺🇸Matthews, North Carolina, United States
Novant Health Cancer Institute - Matthews
🇺🇸Matthews, North Carolina, United States
Atrium Health Union/LCI-Union
🇺🇸Monroe, North Carolina, United States
Novant Health Cancer Institute - Mooresville
🇺🇸Mooresville, North Carolina, United States
Novant Health Cancer Institute - Mount Airy
🇺🇸Mount Airy, North Carolina, United States
Novant Health Cancer Institute - Wilkesboro
🇺🇸North Wilkesboro, North Carolina, United States
Duke Cancer Center Raleigh
🇺🇸Raleigh, North Carolina, United States
Novant Health Cancer Institute - Rowan
🇺🇸Salisbury, North Carolina, United States
Rowan Regional Medical Center
🇺🇸Salisbury, North Carolina, United States
Atrium Health Cleveland/LCI-Cleveland
🇺🇸Shelby, North Carolina, United States
Novant Health Cancer Institute - Statesville
🇺🇸Statesville, North Carolina, United States
Wake Forest Baptist Health - Hematology Oncology - Statesville
🇺🇸Statesville, North Carolina, United States
Novant Cancer Institute Radiation Oncology - Supply
🇺🇸Supply, North Carolina, United States
Novant Health Cancer Institute - Thomasville
🇺🇸Thomasville, North Carolina, United States
Wake Forest Baptist Health - Wilkes Medical Center
🇺🇸Wilkesboro, North Carolina, United States
Novant Health Cancer Institute Radiation Oncology - Wilmington
🇺🇸Wilmington, North Carolina, United States
Novant Health New Hanover Regional Medical Center
🇺🇸Wilmington, North Carolina, United States
Novant Health Forsyth Medical Center
🇺🇸Winston-Salem, North Carolina, United States
Wake Forest University Health Sciences
🇺🇸Winston-Salem, North Carolina, United States
Sanford Bismarck Medical Center
🇺🇸Bismarck, North Dakota, United States
Sanford Broadway Medical Center
🇺🇸Fargo, North Dakota, United States
Sanford Roger Maris Cancer Center
🇺🇸Fargo, North Dakota, United States
Altru Cancer Center
🇺🇸Grand Forks, North Dakota, United States
Cleveland Clinic Akron General
🇺🇸Akron, Ohio, United States
UH Seidman Cancer Center at UH Avon Health Center
🇺🇸Avon, Ohio, United States
UHHS-Chagrin Highlands Medical Center
🇺🇸Beachwood, Ohio, United States
Cleveland Clinic Mercy Hospital
🇺🇸Canton, Ohio, United States
Aultman Health Foundation
🇺🇸Canton, Ohio, United States
Miami Valley Hospital South
🇺🇸Centerville, Ohio, United States
University of Cincinnati Cancer Center-UC Medical Center
🇺🇸Cincinnati, Ohio, United States
Case Western Reserve University
🇺🇸Cleveland, Ohio, United States
Riverside Methodist Hospital
🇺🇸Columbus, Ohio, United States
Grant Medical Center
🇺🇸Columbus, Ohio, United States
Doctors Hospital
🇺🇸Columbus, Ohio, United States
Miami Valley Hospital
🇺🇸Dayton, Ohio, United States
Premier Blood and Cancer Center
🇺🇸Dayton, Ohio, United States
Dayton Physician LLC - Englewood
🇺🇸Dayton, Ohio, United States
Miami Valley Hospital North
🇺🇸Dayton, Ohio, United States
Delaware Health Center-Grady Cancer Center
🇺🇸Delaware, Ohio, United States
Grady Memorial Hospital
🇺🇸Delaware, Ohio, United States
Dublin Methodist Hospital
🇺🇸Dublin, Ohio, United States
Atrium Medical Center-Middletown Regional Hospital
🇺🇸Franklin, Ohio, United States
Miami Valley Cancer Care and Infusion
🇺🇸Greenville, Ohio, United States
OhioHealth Mansfield Hospital
🇺🇸Mansfield, Ohio, United States
OhioHealth Marion General Hospital
🇺🇸Marion, Ohio, United States
UH Seidman Cancer Center at Lake Health Mentor Campus
🇺🇸Mentor, Ohio, United States
Mercy Health - Perrysburg Hospital
🇺🇸Perrysburg, Ohio, United States
Upper Valley Medical Center
🇺🇸Troy, Ohio, United States
University of Cincinnati Cancer Center-West Chester
🇺🇸West Chester, Ohio, United States
University of Oklahoma Health Sciences Center
🇺🇸Oklahoma City, Oklahoma, United States
Legacy Mount Hood Medical Center
🇺🇸Gresham, Oregon, United States
Legacy Good Samaritan Hospital and Medical Center
🇺🇸Portland, Oregon, United States
Legacy Meridian Park Hospital
🇺🇸Tualatin, Oregon, United States
Christiana Care Health System-Concord Health Center
🇺🇸Chadds Ford, Pennsylvania, United States
Chambersburg Hospital
🇺🇸Chambersburg, Pennsylvania, United States
Geisinger Medical Center
🇺🇸Danville, Pennsylvania, United States
Ephrata Cancer Center
🇺🇸Ephrata, Pennsylvania, United States
Adams Cancer Center
🇺🇸Gettysburg, Pennsylvania, United States
Penn State Milton S Hershey Medical Center
🇺🇸Hershey, Pennsylvania, United States
Lancaster General Ann B Barshinger Cancer Institute
🇺🇸Lancaster, Pennsylvania, United States
Sechler Family Cancer Center
🇺🇸Lebanon, Pennsylvania, United States
Geisinger Medical Oncology-Lewisburg
🇺🇸Lewisburg, Pennsylvania, United States
University of Pennsylvania/Abramson Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
Reading Hospital
🇺🇸West Reading, Pennsylvania, United States
Geisinger Wyoming Valley/Henry Cancer Center
🇺🇸Wilkes-Barre, Pennsylvania, United States
Asplundh Cancer Pavilion
🇺🇸Willow Grove, Pennsylvania, United States
Lankenau Medical Center
🇺🇸Wynnewood, Pennsylvania, United States
WellSpan Health-York Cancer Center
🇺🇸York, Pennsylvania, United States
WellSpan Health-York Hospital
🇺🇸York, Pennsylvania, United States
Gibbs Cancer Center-Gaffney
🇺🇸Gaffney, South Carolina, United States
Gibbs Cancer Center-Pelham
🇺🇸Greer, South Carolina, United States
Lancaster Radiation Therapy Center
🇺🇸Lancaster, South Carolina, United States
Rock Hill Radiation Therapy Center
🇺🇸Rock Hill, South Carolina, United States
Levine Cancer Institute-Rock Hill
🇺🇸Rock Hill, South Carolina, United States
Spartanburg Medical Center
🇺🇸Spartanburg, South Carolina, United States
SMC Center for Hematology Oncology Union
🇺🇸Union, South Carolina, United States
Sanford Cancer Center Oncology Clinic
🇺🇸Sioux Falls, South Dakota, United States
Sanford USD Medical Center - Sioux Falls
🇺🇸Sioux Falls, South Dakota, United States
Baptist Memorial Hospital and Cancer Center-Collierville
🇺🇸Collierville, Tennessee, United States
Baptist Memorial Hospital and Cancer Center-Memphis
🇺🇸Memphis, Tennessee, United States
MD Anderson in The Woodlands
🇺🇸Conroe, Texas, United States
M D Anderson Cancer Center
🇺🇸Houston, Texas, United States
MD Anderson West Houston
🇺🇸Houston, Texas, United States
MD Anderson League City
🇺🇸League City, Texas, United States
MD Anderson in Sugar Land
🇺🇸Sugar Land, Texas, United States
Central Vermont Medical Center/National Life Cancer Treatment
🇺🇸Berlin, Vermont, United States
University of Vermont Medical Center
🇺🇸Burlington, Vermont, United States
University of Vermont and State Agricultural College
🇺🇸Burlington, Vermont, United States
Dartmouth Cancer Center - North
🇺🇸Saint Johnsbury, Vermont, United States
Legacy Cancer Institute Medical Oncology and Day Treatment
🇺🇸Vancouver, Washington, United States
Legacy Salmon Creek Hospital
🇺🇸Vancouver, Washington, United States
Edwards Comprehensive Cancer Center
🇺🇸Huntington, West Virginia, United States
West Virginia University Healthcare
🇺🇸Morgantown, West Virginia, United States
Langlade Hospital and Cancer Center
🇺🇸Antigo, Wisconsin, United States
Duluth Clinic Ashland
🇺🇸Ashland, Wisconsin, United States
Northwest Wisconsin Cancer Center
🇺🇸Ashland, Wisconsin, United States
Aurora Cancer Care-Southern Lakes VLCC
🇺🇸Burlington, Wisconsin, United States
HSHS Sacred Heart Hospital
🇺🇸Eau Claire, Wisconsin, United States
Marshfield Medical Center-EC Cancer Center
🇺🇸Eau Claire, Wisconsin, United States
Aurora Health Care Germantown Health Center
🇺🇸Germantown, Wisconsin, United States
Aurora Cancer Care-Grafton
🇺🇸Grafton, Wisconsin, United States
Saint Vincent Hospital Cancer Center Green Bay
🇺🇸Green Bay, Wisconsin, United States
Aurora BayCare Medical Center
🇺🇸Green Bay, Wisconsin, United States
Essentia Health-Hayward Clinic
🇺🇸Hayward, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - Johnson Creek
🇺🇸Johnson Creek, Wisconsin, United States
Aurora Cancer Care-Kenosha South
🇺🇸Kenosha, Wisconsin, United States
William S Middleton VA Medical Center
🇺🇸Madison, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
🇺🇸Madison, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - University Hospital
🇺🇸Madison, Wisconsin, United States
Aurora Bay Area Medical Group-Marinette
🇺🇸Marinette, Wisconsin, United States
Marshfield Medical Center-Marshfield
🇺🇸Marshfield, Wisconsin, United States
Froedtert Menomonee Falls Hospital
🇺🇸Menomonee Falls, Wisconsin, United States
Aurora Cancer Care-Milwaukee
🇺🇸Milwaukee, Wisconsin, United States
Aurora Saint Luke's Medical Center
🇺🇸Milwaukee, Wisconsin, United States
Medical College of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Aurora Sinai Medical Center
🇺🇸Milwaukee, Wisconsin, United States
Zablocki Veterans Administration Medical Center
🇺🇸Milwaukee, Wisconsin, United States
Marshfield Medical Center - Minocqua
🇺🇸Minocqua, Wisconsin, United States
ProHealth D N Greenwald Center
🇺🇸Mukwonago, Wisconsin, United States
Drexel Town Square Health Center
🇺🇸Oak Creek, Wisconsin, United States
ProHealth Oconomowoc Memorial Hospital
🇺🇸Oconomowoc, Wisconsin, United States
Vince Lombardi Cancer Clinic - Oshkosh
🇺🇸Oshkosh, Wisconsin, United States
Aurora Cancer Care-Racine
🇺🇸Racine, Wisconsin, United States
Aspirus Cancer Care - James Beck Cancer Center
🇺🇸Rhinelander, Wisconsin, United States
Marshfield Medical Center-Rice Lake
🇺🇸Rice Lake, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Sheboygan
🇺🇸Sheboygan, Wisconsin, United States
Vince Lombardi Cancer Clinic-Sheboygan
🇺🇸Sheboygan, Wisconsin, United States
Essentia Health-Spooner Clinic
🇺🇸Spooner, Wisconsin, United States
Aspirus Cancer Care - Stevens Point
🇺🇸Stevens Point, Wisconsin, United States
Marshfield Medical Center-River Region at Stevens Point
🇺🇸Stevens Point, Wisconsin, United States
Saint Vincent Hospital Cancer Center at Sturgeon Bay
🇺🇸Sturgeon Bay, Wisconsin, United States
Aurora Medical Center in Summit
🇺🇸Summit, Wisconsin, United States
Essentia Health Saint Mary's Hospital - Superior
🇺🇸Superior, Wisconsin, United States
UW Cancer Center at ProHealth Care
🇺🇸Waukesha, Wisconsin, United States
Aspirus Regional Cancer Center
🇺🇸Wausau, Wisconsin, United States
Aurora Cancer Care-Milwaukee West
🇺🇸Wauwatosa, Wisconsin, United States
Aurora West Allis Medical Center
🇺🇸West Allis, Wisconsin, United States
Froedtert West Bend Hospital/Kraemer Cancer Center
🇺🇸West Bend, Wisconsin, United States
Marshfield Medical Center - Weston
🇺🇸Weston, Wisconsin, United States
Aspirus Cancer Care - Wisconsin Rapids
🇺🇸Wisconsin Rapids, Wisconsin, United States
Ottawa Hospital and Cancer Center-General Campus
🇨🇦Ottawa, Ontario, Canada