Thoracic tumors, Treatment By Dr. Emad KORRAA Professor of Pulmonology, Chest Department, Ain Shams University

Thoracic tumors include: -Lung cancer -Mediastinal tumors (esophageal, Neural, ….) -Pleural tumors

How is non-small cell lung cancer staged? - Staging is the process of finding out how far a cancer has spread. - Your treatment and prognosis (outlook) depend, to a large extent, on the cancer's stage. - The clinical and pathologic stages may be different in some cases. For example, during surgery the doctor may find cancer in an area that did not show up on imaging tests, which might give the cancer a more advanced pathologic stage. - Because many patients with NSCLC do not have surgery, the clinical stage is often used when describing the extent of this cancer. However, when it is available, the pathologic stage is likely to be more accurate than the clinical stage, as it uses the additional information obtained at surgery.

The TNM staging system The system used to describe the growth and spread of NSCLC is the American Joint Committee on Cancer (AJCC) TNM staging system. The TNM system is based on 3 key pieces of information: T indicates the size of the main (primary) tumor and whether it has grown into nearby areas. N describes the spread of cancer to nearby (regional) lymph nodes M metastasis. (brain, bones, adrenal glands, liver, kidneys, and the other lung.)

T categories for lung cancer TX: The main (primary) tumor can't be assessed, or cancer cells were seen on sputum cytology but no tumor can be found. T0: There is no evidence of a primary tumor. Tis: carcinoma in situ. T1: The tumor is ≤ 3 cm in greatest dimension, has not reached the visceral pleura, and does not affect the main branches of the bronchi. T1a If the tumor is ≤ 2 cm in greatest dimension. T1b If the tumor is > 2 cm but < 3 cm in greatest dimension.

T2: The tumor has 1 or more of the following features: -It is > 3 cm and ≤ 7 cm in greatest dimension. -It involves a main bronchus, ≥ 2 cm distal to the carina. -It has grown into the visceral pleura. -The tumor partially clogs the airways, but this has not caused the entire lung to collapse or develop pneumonia. T2a the tumor is ≤ 5 cm in greatest dimension. T2b the tumor is > 5 cm in greatest dimension but < 7 cm.

T3: The tumor has 1 or more of the following features: -> 7 cm in greatest dimension. -has grown into the chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium. -invades a main bronchus and is < 2 cm to the carina, but it does not involve the carina itself. -has grown into the airways enough to cause an entire lung to collapse or to cause pneumonia in the entire lung. -or more separate tumor nodules are present in the same lobe of a lung. T4: The cancer has 1 or more of the following features: -tumor of any size has grown into the mediastinum, heart, large blood vessels, trachea, esophagus, vertebral body, or the carina -or more separate tumor nodules are present in different lobes of the same lung.

N categories for lung cancer NX: Nearby lymph nodes cannot be assessed. N0: There is no spread to nearby lymph nodes. N1: The cancer has spread to ipsilateral peribronchial lymph nodes and/or the ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension. N2: The cancer has spread to subcarinal lymph nodes and/or ipsilateral mediastinum lymph nodes. N3: The cancer has spread to the contalateral hilar or madiastinal lymph nodes and/or ipsilateral or contralateral scalene or supraclavicular LNs.

M categories for lung cancer M0: No metastasis. This includes the other lung, lymph nodes further away than those mentioned in the N stages above, and other organs or tissues such as the liver, bones, or brain. M1: Distant metastasis M1a: Any of the following: -cancer has spread to the other lung. -malignant pleural or pericardial effusion. M1b: The cancer has spread to distant lymph nodes or to other organs such as the liver, bones, or brain.

Primary tumor (T) TXPrimary tumor cannot be assessed, or the tumor is proven by the presence of malignant cells in sputum or bronchial washing but is not visualized by imaging or bronchoscopy T0No evidence of primary tumor TisCarcinoma in situ T1Tumor ≤ 3 cm in greatest dimension, surrounded by lung or visceral pleura, no bronchoscopic evidence of invasion, more proximal than the lobar bronchus (not in the main bronchus); superficial spreading of tumor in the central airways (confined to the wall of the trachea or mainstem bronchus) T1aTumor ≤ 2 cm in the greatest dimension T1bTumor > 2 cm but ≤ 3 cm in the greatest dimension T2Tumor > 3 cm but ≤ 7 cm or tumor with any of the following:  Invades visceral pleura  Involves the main bronchus ≥ 2 cm distal to the carina  Associated with atelectasis/obstructive pneumonitis extending to hilar region but not involving the entire lung T2aTumor > 3 cm but ≤ 5 cm in the greatest dimension T2bTumor > 5 cm but ≤ 7 cm in the greatest dimension T3Tumor > 7 cm or one that directly invades any of the following:  Chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, or parietal pericardium  Tumor in the main bronchus < 2 cm distal to the carina but without involvement of the carina  Associated atelectasis/obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe T4Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, or carina; separate tumor nodule(s) in a different ipsilateral lobe Regional lymph nodes (N) NXRegional lymph nodes cannot be assessed N0No regional node metastasis N1Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N2Metastasis in the ipsilateral mediastinal and/or subcarinal lymph node(s) N3Metastasis in the contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph nodes Distant metastasis (M) MXDistant metastasis cannot be assessed M0No distant metastasis M1Distant metastasis M1aSeparate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusion M1bDistant metastasis

Stage grouping for lung cancer The stages identify cancers that have a similar prognosis and thus are treated in a similar way. Patients with lower stage numbers tend to have a better prognosis. Occult cancer TX, N0, M0: Cancer cells are seen in a sample of sputum or other lung fluids, but the cancer isn't found with other tests, so its location can't be determined. Stage 0 Tis, N0, M0: The cancer is found only in the top layers of cells lining the air passages. It has not invaded deeper into other lung tissues and has not spread to lymph nodes or distant sites.

Stage IA T1a/T1b, N0, M0: The tumor is ≤ 3 cm in greatest dimension, has not reached the visceral pleura, and does not affect the main branches of the bronchi. It has not spread to LNs or distant sites. Stage IB T2a, N0, M0: The tumor has 1 or more of the following : main tumor is > 3 cm and ≤ 5 cm in greatest dimension. tumor has grown into a main bronchus, but is not within 2 cm of the carina. tumor has grown into the visceral pleura tumor is partially clogging the airways. No spread to lymph nodes or distant sites.

Stage IIA 3 main combinations of categories make up this stage. T1a/T1b, N1, M0: The cancer is ≤ 3 cm in greatest dimension, has not grown into the visceral pleura, and does not affect the main branches of the bronchi. It has spread to ipsilateral hilar LNs. No spread to distant sites. OR T2a, N1, M0: The cancer has 1 or more of the following : main tumor is between 3 and 5 cm in greatest dimension. tumor has grown into a main bronchus, but is not within 2 cm of the carina. tumor has grown into the visceral pleura & is partially clogging the airways. The cancer has also spread to ipsilateral hilar LNs. No spread to distant sites. OR T2b, N0, M0: The cancer has 1 or more of the following : main tumor is between 5 and 7 cm in greatest dimension. tumor has grown into a main bronchus, but is not within 2 cm of the carina. tumor has grown into the visceral pleura & is partially clogging the airways. No spread to lymph nodes or distant sites.

Stage IIB Two combinations of categories make up this stage. T2b, N1, M0: The cancer has 1 or more of the following : main tumor is between 5 and 7 cm in greatest dimension. tumor has grown into a main bronchus, but is not within 2 cm of the carina. tumor has grown into the visceral pleura and is partially clogging the airways. It has also spread to lymph nodes within the ipsilateral hilar lymph nodes. It has not spread to distant sites. OR T3, N0, M0: The tumor has 1 or more of the following: is > 7 cm in greatest dimension. has grown into the chest wall, diaphragm, mediastinal pleura, or parietal pericardium. invades a main bronchus and is closer than 2 cm to the carina, but it does not involve the carina itself. has grown into the airways enough to cause pneumonia or collapse to the entire lung. or more separate tumor nodules are present in the same lobe of a lung. No spread to lymph nodes or distant sites.

Stage IIIA: 3 main combinations of categories make up this stage. T1 to T3, N2, M0: The tumor can be any size. Not grown into the mediastinum, heart, large blood vessels, trachea, esophagus, vertebrae, or the carina. Not spread to different lobes of same lung. The cancer has spread to subcarinal or ipsilateral mediastinal LNs. No distant metastasis. OR T3, N1, M0: The cancer has 1 or more of the following : is >7 cm in greatest dimension. has grown into the chest wall, diaphragm, mediastinal pleura, or parietal pericardium. invades a main bronchus and is closer than 2 cm to the carina, sparing the carina itself. or more separate tumor nodules in the same lobe of a lung. has grown into the airways enough to cause an entire lung pneumonia or collapse. It has also spread to LNs within the lung and/or ipsilateral hilar LNs. No distant metastasis. OR T4, N0 or N1, M0: has 1 or more of the following features: tumor of any size has grown into the mediastinum, heart, large blood vessels, trachea, esophagus, vertebrae, or carina. or more separate tumor nodules in different lobes of the same lung. It may or may not have spread to LNs within the lung and/or ipsilateral hilar LNs. No distant metastasis.

Stage IIIB (Advanced) Two combinations of categories make up this stage. Any T, N3, M0: The cancer can be of any size. It may or may not have grown into nearby structures or caused pneumonia or lung collapse. It has spread to lymph nodes near the collarbone on either side, and/or has spread to contralateral hilar or mediastinal LNs. The cancer has not spread to distant sites. OR T4, N2, M0: The cancer has 1 or more of the following : tumor of any size has grown into the mediastinum, heart, large blood vessels, trachea, esophagus, vertebrae, or the carina. or more separate tumor nodules are present in different lobes of the same lung. The cancer has also spread to subcarinal or the ipsilateral mediastinal LNs. No distant sites.

Stage IV (advanced) Two combinations of categories make up this stage. Any T, any N, M1a: The cancer can be any size and may or may not have grown into nearby structures or reached nearby lymph nodes. In addition, any of the following is true: -cancer has spread to the other lung. - malignant pleural or pericardial effusion. OR Any T, any N, M1b: The cancer can be any size and may or may not have grown into nearby structures or reached nearby lymph nodes. It has spread to distant lymph nodes or to other organs such as the liver, bones, or brain.

How is Lung Cancer Treated? Treatment depends on the stage and type of lung cancer Surgery Radiation therapy Chemotherapy (options include a combination of drugs) Targeted therapy Lung cancer is usually treated with a combination of therapies

Treatment depends on: 1.Cell Type: SCLC or NSCLC 2.Disease stage: Resectable or not 3.General condition: Tolerability to surgery 4.Associated comorbidity: an end stage chronic disease present or not.

Cancer Treatment: Surgery The tumor and the nearby lymph nodes in the chest are typically removed to offer the best chance for cure Lobectomy (removal of the entire lobe where the tumor is located), has shown to be most effective in NSCLC Surgery may not be possible in some patients

Cancer Treatment: Chemotherapy A combination of medications is often used May be prescribed before or after surgery, or before, during, or after radiation therapy Can improve survival and lessen lung cancer symptoms in all patients, even those with widespread lung cancer

Cancer Treatment: Radiation Therapy The use of high-energy x-rays or other particles to destroy cancer cells Side effects include fatigue, malaise, loss of appetite, and skin irritation at the treatment site Radiation pneumonitis occurs in 15% of patients It is important that the radiation treatments avoid the healthy parts of the lung

Stage I Non-Small Cell Lung Cancer Patient is operable: Pneumonectomy, lobectomy or segmentectomy with mediastinal LN sampling Patient is inoperable (or refuses surgery): Curative radiation therapy: 13-39% 5 year survival

Stage II Non-Small Cell Lung Cancer The cancer has spread to lymph nodes in the lung Treatment is as stage I + adjuvant chemotherapy for operable patients

Stage III Non-Small Cell Lung Cancer The cancer has spread to the lymph nodes located in the center of the chest, outside the lung Stage IIIA: Surgery + adjuvant (neo or post ) chemotherapy. Bulky N1 & N2: concurrent or sequential chemoradiotherapy. Stage IIIB: Chemoradiotherapy: concurrent is better

Stage IV Non-Small Cell Lung Cancer The cancer has spread to different lobes of the lung or to other organs, such as the brain, bones, and liver. Palliative treatment.

concurrent systemic therapy refers to administering medical treatments at the same time as other therapies, adjuvant therapy, is treatment that is given in addition to the primary, main or initial treatment. Neoadjuvant therapyNeoadjuvant therapy, in contrast to adjuvant therapy, is given before the main treatment

Diagnosis and Management of Lung Cancer: ACCP Guidelines, 2012 Bronchial Intraepithelial Neoplasia/Early Central Airways Lung Cancer 1.For patients with severe dysplasia, CIS, or carcinoma in sputum cytology but with chest imaging studies showing no localizing abnormality, standard white light bronchoscopy is recommended. AF bronchoscopy should be used when available.(1B) 2.For patients being considered for curative endobronchial therapy to treat CIS in centers where it is available, AF bronchoscopy may be considered to guide therapy. (2C) 3.For patients with known severe dysplasia or CIS in the central airways, standard white light bronchoscopy is recommended at periodic intervals (3 to 6 months) for follow-up. Autofluorescence bronchoscopy should be used when available.(2C) 4. For patients with superficial squamous cell carcinoma who are not surgical candidates, photodynamic therapy, electrocautery, cryotherapy, and brachytherapy are recommended as treatment options. Use of Nd:YAG laser therapy is not recommended because of the risk of perforation. (1C)

Treatment of NSCLC Stage I and II 1.For patients with clinical stage I and II NSCLC and no medical contraindication to operative intervention, surgical resection is recommended. (1A) 2.For patients with clinical stage I and II NSCLC, it is recommended that they be evaluated by a thoracic surgical oncologist with a prominent part of his/her practice focused on lung cancer, even if the patients are being considered for nonsurgical therapies such as percutaneous ablation or stereotactic body radiation therapy. (1B) 3.In patients with stage I and II NSCLC who are medically fit for conventional surgical resection, lobectomy or greater resection are recommended rather than sublobar resections (wedge or segmentectomy). (1A) 4.In patients with stage I NSCLC who may tolerate operative intervention but not a lobar or greater lung resection due to comorbid disease or decreased pulmonary function, sublobar resection is recommended over nonsurgical interventions. (1B)

5.In patients with stage I NSCLC who are considered appropriate candidates for thoracoscopic anatomic lung resection (lobectomy or segmentectomy), the use of video- assisted thoracic surgery by surgeons experienced in these techniques is an acceptable alternative to open thoracotomy. (1B) 6.In patients undergoing resection for stage I and II NSCLC, it is recommended that intraoperative systematic mediastinal lymph node sampling or dissection be performed for accurate pathologic staging. (1B) 7.For patients with centrally or locally advanced NSCLC in whom a complete resection can be achieved, sleeve lobectomy is recommended over pneumonectomy. (1B) 8.For patients with N1 lymph node metastases (stage II NSCLC) in whom a complete resection can be achieved with either technique, sleeve lobectomy is recommended over pneumonectomy. (1B) 9.For patients with completely resected stage IA NSCLC, the use of adjuvant chemotherapy is not recommended for routine use outside the setting of a clinical trial. (1A)

10.For patients with completely resected stage IB NSCLC, the use of adjuvant chemotherapy is not recommended for routine use. (1B) 11.For patients with completely resected stage II NSCLC and good performance status (PS), the use of platinum-based adjuvant chemotherapy is recommended. (1A) 12.For patients with stage I or II NSCLC who are not candidates for surgery (“medically inoperable”) or who refuse surgery, curative intent fractionated radiotherapy is recommended. (1B) 13.For patients with completely resected stage IA or IB NSCLC, postoperative radiotherapy is associated with a decreased survival and is not recommended. (1B) 14.For patients with completely resected stage II NSCLC, postoperative radiotherapy decreases local recurrence but a survival benefit has not been clearly shown, and therefore postoperative radiotherapy is not recommended. (1B)

Treatment of NSCLC Stage IIIA: Incidental (Occult) N2 Disease Found at Thoracotomy (Stage IIIA1–2) Surgical Considerations 1.In patients with NSCLC who have incidental (occult) N2 disease (IIIA2) found at surgical resection and in whom complete resection of the LNs and primary tumor is technically possible, completion of the planned lung resection and mediastinal lymphadenectomy is recommended. (2C) 2.In patients with NSCLC undergoing surgical resection, systematic mediastinal lymph node sampling or complete mediastinal lymph node dissection is recommended. (1B) Adjuvant Chemotherapy 3.In patients with resected NSCLC who were found to have incidental (occult) N2 disease (IIIA1–2) and have good PS, adjuvant platinum-based chemotherapy is recommended. (1A) Adjuvant Radiotherapy 4.In patients with resected NSCLC who were found to have incidental (occult) N2 disease (IIIA1– 2), adjuvant postoperative radiotherapy should be considered after adjuvant chemotherapy to reduce local recurrence. (2C) Adjuvant Chemoradiotherapy 5.In patients with resected NSCLC who were found to have incidental (occult) N2 disease (IIIA1– 2), combined postoperative concurrent chemotherapy and radiotherapy is not recommended except as part of a clinical trial. (1B)

Treatment of NSCLC Stage IIIA: Potentially Resectable N2 Disease (Stage IIIA3) 6. In NSCLC patients with N2 disease identified preoperatively (IIIA3), referral for multidisciplinary evaluation (which includes a thoracic surgeon) is recommended before embarking on definitive treatment. (1C) 7. In NSCLC patients with N2 disease identified preoperatively (IIIA3), induction therapy followed by surgery is not recommended except as part of a clinical trial. (1C) 8. In NSCLC patients with N2 disease identified preoperatively (IIIA3) who do receive induction chemoradiotherapy as part of a clinical trial, pneumonectomy is not recommended. The subsequent surgical resection in this setting should be limited to a lobectomy. If after induction chemoradiotherapy it appears that a pneumonectomy will be needed, it is recommended that pneumonectomy not be performed and treatment should be continued with full-dose radiotherapy. (1B) 9. In NSCLC patients with N2 disease identified preoperatively (IIIA3), primary surgical resection followed by adjuvant therapy is not recommended except as part of a clinical trial. (1C) 10. In NSCLC patients with N2 disease identified preoperatively (IIIA3), surgery alone is not recommended. (1A) 11. In NSCLC patients with N2 disease identified preoperatively (IIIA3), platinum-based combination chemoradiotherapy is recommended as primary treatment. (1B) Surgical Considerations 12. In NSCLC patients with N2 disease identified preoperatively (IIIA3), surgical debulking procedures are not recommended. (1A) 13. In NSCLC patients with N2 disease identified preoperatively (IIIA3) who have incomplete resections, postoperative platinum-based chemoradiotherapy is recommended. (1C)

Treatment of NSCLC Stage IIIA: Unresectable, Bulky N2 Disease (Stage IIIA4) 14. In patients with NSCLC who have bulky N2 disease (IIIA4) and good PS, radiotherapy alone is not recommended. (1A) 15. In patients with NSCLC who have bulky N2 disease (IIIA4) and good PS, combination platinum-based chemotherapy and radiotherapy are recommended. (1A) 16. In patients with NSCLC who have bulky N2 disease (IIIA4), good PS, and minimal weight loss, concurrent chemoradiotherapy is recommended over sequential chemoradiotherapy. (1A)

Treatment of NSCLC Stage IIIB 1.In selected patients with clinical T4N0-1 NSCLC due to satellite tumor nodule(s) in the same lobe, carinal involvement, or superior vena cava (SVC) invasion, it is recommended that evaluation be performed by a multidisciplinary team that includes a thoracic surgeon with lung cancer expertise to determine if the patient is operable. Surgery is not recommended if there is N2 involvement. (1C) 2.For patients with stage IIIB NSCLC due to N3 disease, treatment with neoadjuvant (induction) chemotherapy or chemoradiotherapy followed by surgery is not recommended. (1C) 3.For patients with stage IIIB disease without malignant pleural effusions, PS of 0 or 1, and minimal weight loss (< 5%), platinum-based combination chemotherapy is recommended. (1A) 4.In patients with stage IIIB NSCLC and PS of 2 or those with substantial weight loss (10%), chemoradiotherapy is recommended only after careful consideration. (1C)

5.For stage IIIB NSCLC patients with PS of 0 or 1 and minimal weight loss (< 5%), concurrent chemoradiotherapy is recommended. (1A) 6.The most efficacious chemotherapy drugs to be combined with thoracic radiotherapy and the number of cycles of chemotherapy needed to yield the best results is currently uncertain. No one combination chemotherapy regimen can be recommended. (2C) 7.For patients with stage IIIB NSCLC, once-daily thoracic radiotherapy plus chemotherapy is recommended. (1B) 8.For stage IIIB patients and either poor PS or disease too extensive to treat with curative intent and symptoms due to chest disease, palliative radiotherapy is recommended. The fractionation pattern should be chosen based on the physician’s judgment and patient’s needs. (1A)

Treatment of NSCLC Stage IV 1.In patients with stage IV NSCLC and a good PS, two-drug combination chemotherapy is recommended. The addition of a third cytotoxic chemotherapeutic agent is not recommended because it provides no survival benefit and may be harmful. (1A) 2.Bevacizumab improves survival combined with carboplatin and paclitaxel in a clinically selected subset of the good PS, stage IV NSCLC (nonsquamous histology, lack of brain metastases, and no hemoptysis). In these patients, bevacizumab added to carboplatin and paclitaxel should be considered a therapeutic option. (1A) 3.In patients with stage IV NSCLC who are elderly (> 70 to 79 years) single-agent chemotherapy is recommended for most patients. (1A) 4.However, in patients with stage IV NSCLC who are elderly (> 70 to 79 years) and have a good PS and lack significant comorbidities, two-drug combination chemotherapy is recommended as an option. (1B)

5.In patients with stage IV NSCLC who are > 80 years old, the benefit of chemotherapy is unclear and should be decided on based on individual circumstances. (2C) 6.In patients with stage IV NSCLC and a PS of 2, chemotherapy is recommended based on defined response rates and symptom palliation. (1B) 7.In patients with stage IV NSCLC and a PS of 2, no specific recommendation can be given with regard to the optimal chemotherapeutic strategy. A single phase III trial showed a survival benefit to a carboplatinbased doublet compared to a single agent in a prospectively planned subset analysis. (2C) 8.It is recommended that patient-reported health-related quality of life be measured using the FACT-L or European Organization for Research and Treatment of Cancer QLQ- C30 questionnaire because it is a significant prognostic factor for survival. (1A) 9.It is recommended that patients with stage IV NSCLC receive adequate education abou the risks and benefits of chemotherapy to enable active participation in the decision- making process regarding treatment selection. (1C)

Small Cell Lung Cancer–All Stages Patients with limited stage (confined to one hemithorax, ipsilateral supraclavicular LNs) small cell lung cancer are treated with simultaneous radiation therapy and chemotherapy Patients with extensive stage (not confined to one area of the chest) small cell lung cancer are treated with chemotherapy only Because small cell lung cancer can spread to the brain, preventative radiation therapy to the brain is routinely recommended to all patients whose tumors disappear following chemotherapy and radiation therapy

SCLC Limited Stage Defined as tumor involvement of one lung, the mediastinum and ipsilateral and/or contralateral supraclavicular lymph nodes or disease that can be encompassed in a single radiotherapy port. Extensive Stage Defined as tumor that has spread beyond one lung, mediastinum, and supraclavicular lymph nodes. Common distant sites of metastases are the adrenals, bone, liver, bone marrow, and brain.

Paraneoplastic Syndromes Cushing’s syndrome Treatment: -Adrenal enzyme inhibitors: metyrapone ( mg tdsday oral), aminoglutethemide ( mgday oral, ketoconazol ( mgday oral). -Good response in few weeks, may induce hypofunction -Chemotherapy or resection. Inappropriate ADH secretion: Treatment: -Mild: Fluid restriction: ml/day. -Moderate –severe: Democlocycline: mg/day.

Hypercalcemia: Treatment: -Rehydrate if the patient is dehydrated. -Mild cases ( 20 mg/dl) are not treated. -Biphosphonate (Zolidronate, Zometa): 4 mg min iv/day (10-40 days); inhibits bone resorption. -Clcitonin: weak but rapid onset (4-6 hrs), additive to biphosphonate. -Chemotherapy or resection. Musculoskeletal (Clubbing, HPO, Polymyositis-dermatomyositis) : Treatment: -NSAD, Biphosphonate.

Neurologic effecys (Somatic neuropathy, Autonomic neuropathy, Eaton-Lambert syndrome) : Treatment: -Diaminopyridine (increase acetyle choline release). Hematologic effects (Anemia, Thrombocytosis, leukocytosis, esinophilia) : Treatment: -Fractionated heparin (LMWH). -Vitamin K antagonists (not effective). Dermatologic effects (Hypertrichosis lanuinosa, Acanthosis nigricans, Dermatomyositis) : Treatment: -Of the tumor.