Basic science V Surgical Oncology 28 29 - Antimetabolites Palliative care tumor suppressor genes

• A. Drugs directly acting on cells (Cytotoxic drugs)
• 1. Alkylating agents (cross link DNA) -Cyclophosphamide, Dacarbazine, Ifosfamide, Busulfan, Melphalan, Cisplatin, Temozolomide 
• 2. Antimetabolites  
• - Folate antagonist - Methotrexate
• - Purine antagonist: Cladribine, Fludarabine, Azathioprine, 6-Mercaptopurine
• - Pyrimidine antagonist: Ftorafur, 5-Fluorouracil, Cytarabine (cytosine arabinoside)
• 3. Vinca alkaloids (Inhibit microtubule function) - VINCristine (OnCoVIN), Vinblastine
• 4. Taxanes (Inhibit microtubule function) - Paclitaxel
• 5. Epipodophyllotoxin - Etoposide
• 6. Antibiotics
• - Actinomycin D 
• - Doxorubicin (aDriamicin), Daunorubicin - intercalate DNA
• - Mitomycin

B. Drugs altering hormonal milieu - Glucocorticoids, Tamoxifen, Flutamide, Finasteride

• Thiopurine - Risk of lymphoma
• Anthracyclines - Cardiotoxicity, Leukemia 
• Taxanes - Peripheral neuropathy
• Trastuzumab - Cardiac toxicity

• Potential to lower the volume of microscopic metastatic disease
• Decrease drug resistance by treating tumors before resistance has developed
• Increase the efficacy of treatment because the vascular system has not been disrupted by surgery
• Permit evaluation of the response to treatment in vivo.
• Response to neoadjuvant chemotherapy correlates with survival outcomes.
• Neoadjuvant chemotherapy eradicates microscopicdisease in the regional nodes

• The term nadir is used to represent the lowest level of a blood cell count while a patient is undergoing chemotherapy.
• A diagnosis of neutropenic nadir after chemotherapy typically lasts 7–10 days

• 1. Pre-chemotherapy assessment 
• - Performance status 
• - Physical examination, BMI 
• - Laboratory test 

• 2. Counselling
• - Treatment plans and side effects 
• - Aim of therapy most be clearly stated to patient - curative or palliative 
• - Obtain informed consent 

• 3. Modalities 
• - Neoadjuvant, adjuvant, multimodality 

• 4. Optimiation 
• - Anemia, Dehydration, De-worming 
• - Malnutrition, control of infection
• - Uremia 

• 5. Administration of chemotherapy 
• - Route
• - Dose 
• - Pre-medications 

• 6. Management of side effects 
• - Due to lysis of normal cells 
• - Rapidly dividing cells are more affected

• Tumor markers are indicators of cellular, biochemical, molecular, or genetic alterations by which neoplasia can be recognized.
• Not used for primary diagnosis of tumor. 
• Have prognostic value 
• Presence of tumor markers signify recurrence or residual tumors. 

• Classifications 
• A. Hormonal:
• Human chorionic gonadotrophin (HCG). — Trophoblastic tumour, nonseminomatous testicular tumour
• Calcitonin — Medullary carcinoma of thyroid
• Catecholamines and VMA. — Pheochromocytoma
• Ectopic hormones — In tumours of paraneoplastic syndromes

• B. IsoEnzymes:
• Prostatic acid phosphatase — Carcinoma prostate
• Neuron specific enolase — Small cell carcinoma lung, neuroblastoma

• C. Oncofetal antigens:
• Alpha feto protein — Liver cancer, nonseminomatous germ cell tumour
• Carcinoembryonic antigen (CEA) — Carcinoma colon (common). Carcinoma pancreas, lung, stomach and breast

• D. Mucin and other proteins:
• CA –125 (Carbohydrate antigen) — Ovarian cancer
• CA –15-3 — Breast cancer
• CA—19-9 — Pancreatic and colon cancer

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• The ideal tumor marker has three defining characteristics.
• 1. Should be expressed exclusively by the particular tumor.
• 2. Collection of the specimen for the tumor marker assay should be easy.
• 3. The assay itself should be reproducible, rapid, and inexpensive.

Currently, there is no one marker that fulfils all these criteria for any cancer, nor is there any specific cancer for which there are biomarkers that completely describe its behavior.

• It is an oncofetal protein that is normally present during fetal life but can be present in low concentrations in healthy adults.
• It is a glycoprotein with a molecular mass of 200 kDa and is a component of the glycocalyx, located on the luminal side of the cell membrane of normal epithelial intestinal cells.
• CEA is a member of a large family of proteins that are related to the immunoglobulin gene superfamily.
• The molecule itself is secreted into the circulation and is also found in the mucous secretions of the stomach, small intestine, and biliary tree.

• Level of CEA -
• Normal - < 2.5 ng/mL
• Borderline -  2.5 to 5.0 ng/mL
• Elevated - > 5.0 ng/mL

• Benign Conditions of Elevated CEA -
• - Benign disorders such as inflammatory bowel disease, pancreatitis, cirrhosis, and COPD.
• - Smoking - the upper limit of normal in smokers should be considered 5 ng/mL.

• Other malignant conditions in which CEA is raised 
• - Carcinoma stomach or pancreas. 
• - Carcinoma breast or lung
•  
• Screening- not useful as a screening test (low sensitivity in early-stage disease).

Elevated CEA levels reflect the burden of tumor, and therefore CEA levels have prognostic value, useful in monitoring response to chemotherapy in patients with metastatic cancer.

Preoperative serum CEA is an independent predictor of survival; the higher the preoperative serum level, the poorer the prognosis.

• Monitoring -
• The most common application of CEA is in monitoring of patients for recurrent disease.
• CEA is most sensitive for hepatic or retroperitoneal metastasis and relatively insensitive for local, pulmonary, or peritoneal involvement.
• About 75% of patients with recurrent colorectal cancer have an elevated serum CEA level before development of symptoms.
• A rising trend in CEA should prompt evaluation for recurrent disease.

• Carbohydrate antigen 19-9 (CA 19-9) is widely used as a serum marker of pancreatic cancer.
• Its use is limited to monitoring responses to therapy, not as a diagnostic marker.
• It is a mucin-type glycoprotein expressed on the surface of pancreatic cancer cells. 
• The CA 19-9 epitope is normally present within the biliary tree.

• Level of CA 19-9
• - Normal Level - < 37 U/mL
• - When a cutoff level of 100 U/mL is used,  sensitivity ranges from 60% to 84%, specificity for pancreas cancer is 95% or greater.
• - Levels above 1000 U/mL are almost diagnostic of pancreatic cancer.

• Limitations of CA 19-9
• - Patients with negative Lewis blood group antigen cannot synthesize CA 19-9, and therefore it should not be used as a serologic marker in these individuals, who make up about 10% of the population.
• - Patients with benign biliary tract disease can have levels of up to 400 U/mL, with 87% having concentrations above 70 U/mL.
• - Significant numbers of patients with pancreatitis, either acute or chronic, also have elevated levels. 
• - CA 19-9 levels are also elevated in patients with other cancers, including those of the biliary tree (95%), stomach (5%), colon (15%), liver (HCC, 7%), and lung (13%). 

• Screening
• - CA 19-9 is not useful as a screening modality because of its low sensitivity in early-stage disease. With increasing levels of CA 19-9, the diagnosis of pancreatic cancer becomes more accurate.
• - Because of its frequent elevation in benign biliary tract disease, CA 19-9 is not useful in distinguishing benign from malignant distal common bile duct strictures.

• Prognosis and Monitoring - 
• - The level has been shown to correlate with tumor burden.
• - Serial measurement of CA 19-9 is used to monitor response to therapy. 
• - In patients with unresectable or metastatic disease, failure of CA 19-9 levels to fall with chemotherapy reflects poor tumor response.

Palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial and spiritual. Palliative care:

• provides relief from pain and other distressing symptoms;
• affirms life and regards dying as a normal process;
• intends neither to hasten or postpone death;
• integrates the psychological and spiritual aspects of patient care;
• offers a support system to help patients live as actively as possible until death;
• offers a support system to help the family cope during the patients illness and in their own bereavement;
• uses a team approach to address the needs of patients and their families, including bereavement counselling, if indicated;
• will enhance quality of life, and may also positively influence the course of illness;
• is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications.

• 1. Pain management - follow WHO ladder 
• 2. Weakness and Immobility - Good nursing care, regular physiotherapy, steroids, special mattresses, wheelchair 
• 3. Anorexia - treat the cause, small portion and well presented food, considre progesterone or steroids for appetite stimulants. 
• 4. Nausea and vomiting - symptomatic treatment 
• 5. Bowel obstruction - treat constipations, treat cause 
• 6. Nutrition - TPN, PEG, FJ
• 7. Surgical Procedures

If pain occurs, there should be prompt oral administration of drugs in the following order: nonopioids (aspirin and paracetamol); then, as necessary, mild opioids (codeine); then strong opioids such as morphine, until the patient is free of pain. To calm fears and anxiety, additional drugs – “adjuvants” – should be used. Adjuvants include antidepressants and gabapentine. 

• Systematic approach to pain:
• – "By the ladder"
• – "By the clock"
• – "By the appropriate route"
• – "By the individual

• To maintain freedom from pain, drugs should be given “by the clock”, that is every 3-6 hours, rather than “on demand” This three-step approach of administering the right drug in the right dose at the right time is inexpensive and 80-90% effective. Surgical intervention on appropriate nerves may provide further pain relief if drugs are not wholly effective. 
• 

• In the case of cancer pain in children, WHO recommends a two step ladder. Codeine/tramadol is not recommended in children. 
• 

• A surgical procedure used with the primary intention of improving QOF or relieving symptoms caused by an advanced disease.
• The effectiveness of palliative surgery is judged by the presence and durability of patient-acknowledged symptom resolution.

• Surgical procedures
• • Drainage procedures for ascites, plural effusions or pericardial effusions.
• • Laparotomy/laparoscopy and bypass or resection for relief of biliary or bowel obstruction
• • Palliation of jaundice - Bypass, ERCP and stenting, PTBD
• • Resection of tumor (debulking) for relief of pain, constitutional symptoms, control of odor.
• • Endoscopic interventions for stenting an obstructed lumen, ablation of tumor, hemostasis.
• • Gastrostomy (PEG) placement for relief of obstruction, hunger or feeding.
• • Craniotomy for excision of symptomatic matastasis or for hemorrhage.
• • Fixation of pathological fracture.
• • Major amputation for painful, nonviable extremity.
• • Tumor embolization procedures.
• • Surgical procedures for metastatic spinal cord compression.
• • Suprapubic cystostomy for bladder outlet obstruction.
• • Simple mastectomy (toilet).
• • Tracheostomy.
• • Biopsy procedure to guide palliative treatment.
• • Vascular access procedures for medication administration, dialysis and parenteral nutrition.