#1008New Strategies in Treatment of Lung Cancer

November 9 to 12

Patrick Ross, Jr. MD, PhDAssistant Professor of SurgeryDivision of Surgical Thoracic OncologyThe Ohio State University Medical Center &The James Cancer Hospital and Solove Research Institute

Gregory A. Otterson, MDAssociate Professor of Internal MedicineDivision of Hematology and OncologyThe Ohio State University Medical Center &The James Cancer Hospital and Solove Research Institute

Gregory A. Otterson, MDAssociate Professor of Internal Medicine

Division of Hematology and OncologyThe Ohio State University Medical Center &

The James Cancer Hospital and Solove Research Institute 11

Profile Profile

Mr. Perkins

• 55 year old male• Smoker• Hemoptosis• Photodynamic therapy• 2 cycles of chemotherapy

Diagnosis: Large T3 N2 tumor

Mr. Perkins

• 55 year old male• Smoker• Hemoptosis• Photodynamic therapy• 2 cycles of chemotherapy

Diagnosis: Large T3 N2 tumor 22

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New Treatment Strategies InThe Treatment Of Lung Cancer

New Treatment Strategies InThe Treatment Of Lung Cancer

• Multimodality treatment for locally advanced NSCLC - Surgery - Radiation - Chemotherapy

• Novel agents - SCLC - antisense bcl2 - NSCLC - farnesyltransferase inhibitors

• Multimodality treatment for locally advanced NSCLC - Surgery - Radiation - Chemotherapy

• Novel agents - SCLC - antisense bcl2 - NSCLC - farnesyltransferase inhibitors 44

Lung Cancer Statistics,1999

Lung Cancer Statistics,1999

• Greatest cause of cancer death worldwide - 921,000 deaths worldwide - 158,900 US deaths (90,900 men, 68,000 women)

• 28% of US cancer deaths (14% cancer cases)

• Greatest cause of cancer death worldwide - 921,000 deaths worldwide - 158,900 US deaths (90,900 men, 68,000 women)

• 28% of US cancer deaths (14% cancer cases)

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Lung Cancer Treatment -Stage And Type SpecificLung Cancer Treatment -Stage And Type Specific

• Non-small cell lung cancer (NSCLC) - ~80% of lung cancer - Principally surgically treated - Chemotherapy and radiation therapy added in specific circumstances

• Small cell lung cancer (SCLC) - ~20% of lung cancer - Principally chemotherapy +/- radiation therapy

• Non-small cell lung cancer (NSCLC) - ~80% of lung cancer - Principally surgically treated - Chemotherapy and radiation therapy added in specific circumstances

• Small cell lung cancer (SCLC) - ~20% of lung cancer - Principally chemotherapy +/- radiation therapy 66

Locally Advanced NSCLC Locally Advanced NSCLC

• Stage IIIB - Generally unresectable - Either bulky primary tumor involving critical mediastinal structures, pleural effusion or contralateral mediastinal lymph node involvement

• Chemotherapy added to radiation therapy improves control and survival - Concurrent vs. sequential?

• Stage IIIB - Generally unresectable - Either bulky primary tumor involving critical mediastinal structures, pleural effusion or contralateral mediastinal lymph node involvement

• Chemotherapy added to radiation therapy improves control and survival - Concurrent vs. sequential?

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Locally Advanced NSCLC Locally Advanced NSCLC

• Stage IIIA - Theoretically resectable - Ipsilateral mediastinal lymph nodes involved

• Surgery is principal modality in most centers - Post-operative radiation improves local controls

- Post-operative chemotherapy has not been dramatically successful

• Stage IIIA - Theoretically resectable - Ipsilateral mediastinal lymph nodes involved

• Surgery is principal modality in most centers - Post-operative radiation improves local controls

- Post-operative chemotherapy has not been dramatically successful

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Stage IIIA NSCLC Stage IIIA NSCLC

• Questions asked in clinical trials - ? Pre-op chemotherapy - ? Pre-op radiation therapy - ? Pre-op chemo-radiotherapy - ? Role of surgery

• These questions remain open

• Questions asked in clinical trials - ? Pre-op chemotherapy - ? Pre-op radiation therapy - ? Pre-op chemo-radiotherapy - ? Role of surgery

• These questions remain open

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Stage IIIA NSCLC Stage IIIA NSCLC

• Balance risks with benefits of aggressive treatment - Improved local / systemic control - Increased treatment related morbidity and mortality with combined treatment

• Prognostic / treatment factors - Weight loss (5-10%), performance status, age, comorbid conditions

• Balance risks with benefits of aggressive treatment - Improved local / systemic control - Increased treatment related morbidity and mortality with combined treatment

• Prognostic / treatment factors - Weight loss (5-10%), performance status, age, comorbid conditions

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OSU Trial For ResectableStage IIIA NSCLC

OSU Trial For ResectableStage IIIA NSCLC

• Pre-operative chemotherapy for three cycles (paclitaxel and carboplatin)

• Pre-operative radiation (to 4500 cGy) with a novel (Gadolinium-Texaphyrin) radiation sensitizer

• Curative resection planned after completion of radiation

• If incomplete resection, post-op radiation

• Pre-operative chemotherapy for three cycles (paclitaxel and carboplatin)

• Pre-operative radiation (to 4500 cGy) with a novel (Gadolinium-Texaphyrin) radiation sensitizer

• Curative resection planned after completion of radiation

• If incomplete resection, post-op radiation1111

Novel Drug Strategies Novel Drug Strategies

• Apoptosis - many chemotherapeutic drugs induce cell death by initiating a cellular suicide pathway in cancer cells (called apoptosis)

• Some cancers (including most SCLC) overexpress an oncogene (bcl2) that protects cells from apoptosis

• Apoptosis - many chemotherapeutic drugs induce cell death by initiating a cellular suicide pathway in cancer cells (called apoptosis)

• Some cancers (including most SCLC) overexpress an oncogene (bcl2) that protects cells from apoptosis

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Bcl2 Family Of Proteins Bcl2 Family Of Proteins

• Family of proteins that are involved in apoptotic pathways (some pro-, others anti-apoptotic)

• Bcl2 family members can homo- and hetero-dimerize with each other

• Susceptibility to programmed cell death (apoptosis) depends on relative ratio of homo- and hetero-dimers

• Family of proteins that are involved in apoptotic pathways (some pro-, others anti-apoptotic)

• Bcl2 family members can homo- and hetero-dimerize with each other

• Susceptibility to programmed cell death (apoptosis) depends on relative ratio of homo- and hetero-dimers

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Bcl2 Antisense Therapy Bcl2 Antisense Therapy

• Chemotherapy induces cell death through apoptosis

• Bcl2 protects cells from apoptotic death

• In theory, chemotherapy should be more effective if bcl2 is inhibited

• Therefore, use bcl2 antisense (synthetic oligonucleotide directed against the bcl2 messenger RNA molecule)

• Chemotherapy induces cell death through apoptosis

• Bcl2 protects cells from apoptotic death

• In theory, chemotherapy should be more effective if bcl2 is inhibited

• Therefore, use bcl2 antisense (synthetic oligonucleotide directed against the bcl2 messenger RNA molecule) 1515

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Bcl2 Antisense In SCLC Bcl2 Antisense In SCLC

• Patient population: resistant SCLS (Either progressive disease on treatment or relapse within 3 months)

• G3139 (bcl2 antisense) via continuous IV infusion X 7 days

• Paclitaxel 175 mg / m2 over 3 hours, day 6 q 3 weeks

• Patient population: resistant SCLS (Either progressive disease on treatment or relapse within 3 months)

• G3139 (bcl2 antisense) via continuous IV infusion X 7 days

• Paclitaxel 175 mg / m2 over 3 hours, day 6 q 3 weeks

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Novel Drug Strategies Novel Drug Strategies

• Ras is an oncogene that is mutated in many different cancers (~90% of pancreatic ca, ~50% of colon ca and ~30% of NSCLC)

• Ras (normal and mutant) requires association with the cell membrane via a cholesterol precurser for activity

• Ras is an oncogene that is mutated in many different cancers (~90% of pancreatic ca, ~50% of colon ca and ~30% of NSCLC)

• Ras (normal and mutant) requires association with the cell membrane via a cholesterol precurser for activity

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Inhibit Ras Activity ThroughIts Membrane Association

Inhibit Ras Activity ThroughIts Membrane Association

• HMG-CoA reductase inhibitors were attempted without remarkable success• Inhibition of the farnesyl-transferase enzyme has been pursued with better pre-clinical ad early clinical activity

• Single agent and combination trials are now underway (including one at OSU)

• HMG-CoA reductase inhibitors were attempted without remarkable success• Inhibition of the farnesyl-transferase enzyme has been pursued with better pre-clinical ad early clinical activity

• Single agent and combination trials are now underway (including one at OSU) 2020

Improvement InLung Cancer Survival?

Improvement InLung Cancer Survival?

• Better local control - Improved surgical technique - Improved preparation / selection of surgical patients - Improved radiotherapy technique and radiation sensitizers

• Better local control - Improved surgical technique - Improved preparation / selection of surgical patients - Improved radiotherapy technique and radiation sensitizers

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Improvement InLung Cancer Survival?

Improvement InLung Cancer Survival?

• Better control of systemic disease - Application of current chemotherapeutic agents in combination with surgery and / or radiation therapy - Novel chemotherapeutic agents, designed to attack specific genetic defects in tumor cells (for example, bcl2 antisense and farnesyltransferase inhibitors)

• Better control of systemic disease - Application of current chemotherapeutic agents in combination with surgery and / or radiation therapy - Novel chemotherapeutic agents, designed to attack specific genetic defects in tumor cells (for example, bcl2 antisense and farnesyltransferase inhibitors) 2222

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Summary Summary

Mr. PerkinsDiagnosis: IIIA non-small lung cancer

Treatment: - Photodynamic therapy - Chemotherapy - Right pneumonectomy

Follow-up: - Operation went smoothly - Further radiation and chemotherapy

Prognosis: Good

Mr. PerkinsDiagnosis: IIIA non-small lung cancer

Treatment: - Photodynamic therapy - Chemotherapy - Right pneumonectomy

Follow-up: - Operation went smoothly - Further radiation and chemotherapy

Prognosis: Good 2424

Patrick Ross, Jr. MD, PhDAssistant Professor of Surgery

Division of Surgical Thoracic OncologyThe Ohio State University Medical Center &

The James Cancer Hospital and Solove Research Institute 2525

Profile Profile

Joseph Tigerina• 61 year old male• Former smoker

• Newly identified left upper lobe mass

• Presented to family physician with left shoulder and back pain

Joseph Tigerina• 61 year old male• Former smoker

• Newly identified left upper lobe mass

• Presented to family physician with left shoulder and back pain

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Profile Profile

Joseph TigerinaSymptoms - No cough or hemoptsis - Some fatigue - No weight lossEvaluation - CT scan and CT needle guided biopsy - MRI - PET scanDiagnosis: Non small cell carcinoma

Joseph TigerinaSymptoms - No cough or hemoptsis - Some fatigue - No weight lossEvaluation - CT scan and CT needle guided biopsy - MRI - PET scanDiagnosis: Non small cell carcinoma

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Non Small CellLung Cancer

Non Small CellLung Cancer

• Can the tumor be resected?• Can the patient undergo resection?• What can be done to improve the outcome?

• Can the tumor be resected?• Can the patient undergo resection?• What can be done to improve the outcome?

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NSCLC: DiagnosisAnd Staging

NSCLC: DiagnosisAnd Staging

• Chest x-ray• CT scan chest• Distant metastasis evaluation• Bronchoscopy• Trans thoracic needle biopsy• Mediastinoscopy• VATS

• Chest x-ray• CT scan chest• Distant metastasis evaluation• Bronchoscopy• Trans thoracic needle biopsy• Mediastinoscopy• VATS 3030

Solitary Pulmonary Nodule:PET Scan

Solitary Pulmonary Nodule:PET Scan

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Surgical ManagementOf Stage 1 And 2

Surgical ManagementOf Stage 1 And 2

• Wedge resection vs lobectomy• Node sampling N1 and N2• Refer for adjuvant trials: evaluation of chemotherapy for early stage• Appropriate surveillance

• Wedge resection vs lobectomy• Node sampling N1 and N2• Refer for adjuvant trials: evaluation of chemotherapy for early stage• Appropriate surveillance

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Superior Sulcus TumorsSuperior Sulcus Tumors

• Arm pain • Arm parathesias

• Shoulder pain• Horner’s syndrome

• Arm pain • Arm parathesias

• Shoulder pain• Horner’s syndrome

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NSCLC Induction Therapy:Stage IIIA

NSCLC Induction Therapy:Stage IIIA

• Surgical staging

• Chemo or Radiation/chemo• Evaluate for distant disease• Nutrition

• Pulmonary rehab

• Surgical staging

• Chemo or Radiation/chemo• Evaluate for distant disease• Nutrition

• Pulmonary rehab

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Induction Therapy Induction Therapy

• Radiation alone

• Chemotherapy alone

• Radiation and chemotherapy: simultaneous vs sequential

• Radiation, and / or chemotherapy with PDT

• Pulmonary rehabilitation

• Radiation alone

• Chemotherapy alone

• Radiation and chemotherapy: simultaneous vs sequential

• Radiation, and / or chemotherapy with PDT

• Pulmonary rehabilitation3737

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Pulmonary Resection InThe High Risk Patient

Pulmonary Resection InThe High Risk Patient

• FEV 1 < 0.8• Hypoxemia• Hypercarbia• Steroid dependent• Elderly• Previous pulmonary resection

• FEV 1 < 0.8• Hypoxemia• Hypercarbia• Steroid dependent• Elderly• Previous pulmonary resection

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Pulmonary RehabilitationPulmonary Rehabilitation

• Prepare patient for resection • Decrease hospital stay• Enhance recovery• Promote sense of well being• Minimize impact of chronic illness

• Prepare patient for resection • Decrease hospital stay• Enhance recovery• Promote sense of well being• Minimize impact of chronic illness

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Summary Summary

Joseph Tigerina

Surgical procedure - Left upper lobe resection for non small cell cancer - Stage 1b lesion - all nodes were negative

Joseph Tigerina

Surgical procedure - Left upper lobe resection for non small cell cancer - Stage 1b lesion - all nodes were negative

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Summary Summary

Joseph Tigerina

Follow-up treatment• Given staging, treatment options are: - Surveillance - Adjunctive chemotherapy within a defined protocol

Prognosis: Good

Joseph Tigerina

Follow-up treatment• Given staging, treatment options are: - Surveillance - Adjunctive chemotherapy within a defined protocol

Prognosis: Good 51-A51-A

#1009 Evaluation & Management of Atrial Fibrillation

November 16 to 19

Stephen F. Schaal, MDProfessor of Internal MedicineDivision of CardiologyThe Ohio State University Medical Center

Robert Hoover, MDAssistant Professor of Internal MedicineDivision of CardiologyThe Ohio State University Medical Center

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