Chemotherapy of Head and neck cancers seminar

describes the principles , modalities and various chemotherapeutic agents

1. CANCER CHEMOTHERAPY

2. Contents Introduction Normal cell cycle and tumour cell kinetics Chemotherapeutic treatment modalities Classification of chemotherapeutic agents Agents employed in HNCs Oral management of patients on chemotherapy Conclusion

3. INTRODUCTION: Cancer -uncontrolled growth of cells coupled with malignant behavior: invasion and metastasis. A normal cell suddenly turns into A ROGUE- development of solid lumps (tumors) -abnormal rise in the number of dispersed cells like the blood corpuscles. interaction between genetic susceptibility and environmental toxins, which can occur in any part of the body and in any organ or tissue .

4. Chemotherapy- In popular usage- refers to antineoplastic drugs used to treat cancer or the combination of these drugs into a cytotoxic standardized treatment regimen. In its non- oncological use-refer to antibiotics (antibacterial chemotherapy). term was coined/shaped 1906 by Paul Ehrlich.

5. Normal cell cycle Inherent to cytokinetic principles is the concept of the cell cycle. Daughter cells formed as a result of mitosis consist of three subpopulations: (1) cells that are non-dividing and terminally differentiated, (2) cells that are continually proliferating, (3) cells that are resting but may be recruited into the cell cycle ( ie , stem cells). All three populations exist simultaneously in tumors .

6. Agents that are cell-cycle-phase–nonspecific have a linear dose-response curve- the greater the dose of drug, the greater is the fraction of cell kill. cell-cycle-phase–specific drugs have a plateau with respect to cell killing ability- cell kill will not increase with further increases in drug dosage

7. Tumour kinetics The rate of growth of a tumor is a reflection of: proportion of actively dividing cells (the growth fraction) length of the cell cycle (doubling time) rate of cell loss. Variations in these three factors are responsible for the variable rates of tumor growth observed among tumors of differing histologies , metastatic and primary tumors of the same histology Tumors characteristically exhibit a sigmoid-shaped Gompertzian growth curve

8. TREATMENT MODALITIES: Three major modalities used in treating cancer: surgical resection, radiation therapy and chemotherapy . Depending on the type of cancer and its stage, patients are treated with one, two or three modalities concurrently or consecutively. Surgery and radiation therapy -local/definitive therapies - do not address the issue of distant metastasis-can only be achieved with chemotherapy . Chemotherapy is used in following three settings Induction chemotherapy Concurrent chemotherapy/ Chemoradiotherapy Adjuvant chemotherapy

9. Induction Chemotherapy Term first used by Dr. Frei in 1982, using chemotherapy before definitive therapy (radiation therapy or surgery) often used in patients with locally advanced disease and in patients with advanced nodal disease (i.e. N2 and N3)

10. Potential benefits of induction chemotherapy: Cytoreduction or down staging of the tumor -facilitate the use of a more conservative approach for surgical procedure or radiotherapy- the possibility of organ preservation Avoids the potential for poor drug distribution due to a compromised vascularization from surgery or radiation therapy- Intact vascular bed allows for better drug delivery. Response to preoperative chemotherapy - prognostic importance as to overall outcome - important in selecting patients for additional postoperative adjunctive therapy decrease the manual manipulation of tumor.

11. Potential adverse effects of induction chemo: development of drug resistant cells increased toxicity with subsequent drugs inability of chemotherapy agent to produce significant reduction in tumor loss of the advantage to attack micro metastases after surgery when they may exhibit more favorable cell kinetics. proper determination of extend of surgery may be difficult

12. Concurrent chemotherapy Given during radiation therapy usually in an effort to achieve radio sensitization. Rationale for the addition of chemotherapy with radiotherapy is: SPATIAL COOPERATION Chemotherapy also acts against radioresistent hypoxic tumor cells principal settings of chemo radiotherapy can be: Uninterrupted radiation therapy, with the addition of one to three dose of (single – agent) chemotherapy. Simultaneous chemo radiotherapy, with scheduled breaks to allow for recovery of normal tissues. Rapidly alternating chemo radiotherapy, with one modality immediately following other.

13. Adjuvant Chemotherapy Despite an apparently complete surgical resection of primary tumour - high risk of developing recurrent disease at distant sites. Such cases,-consider the benefit of prophylactic or adjuvant chemotherapy after surgical removal of tumor and lymphnode . The need of adjuvant therapy arises: For the high recurrence rate after surgery of apparently localized solid tumors. Failure of chemotherapy or combined modality treatment to cure these patients after recurrence of disease. neoplasms are more sensitive to chemotherapy at their earliest stage of growth.- higher growth fraction and shorter cell cycle time, with resulting greater fractional cell kill for a given dose of drug

14. CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS : ALKYLATING AGENTS Cisplastin Carboplatin Oxaliplatin   ANTIMETABOLITES 5- fluorouracil Levcovorin ANTITUMOR ANTIBIOTICS Actinomycin D Bleomycin Dounorubicin Doroxubicin TOPOISOMERASE INHIBITORS Etoposide Irinotecan MITOTIC SPINDLE AGENTS PaclitaxeL Docetoxel Vinblastine Vincristine Vinolesine Vinorelbine  

15. CLASSIFICATION OF CHEMOTHERAPEUTIC AGENTS: TYROSIN KINASE INHIBITORS CYP34A inhibitors and inducers Imtinib Dasatinib Erlotinib Gefitinib Lapatinib MONOCLONAL ANTIBODIES CetuximAB Panitumumab RituximAB HORMONAL AGENTS Adernocorticoids Adrenal inhibitors : mitotane Androgens Antiandrogens Aromatase inhibitors LHRH agents Progestins   CYTOPROTECTIVE AGENTS Amifostine Dexrozonane MISCELLANEOUS AGENTS Interferon Interlukins Lenalidomide Retinoic acid receptor inhibitors

16. Chemotherapeutic agents commonly employed in HNCs Cis-platin Carboplatin 5-Fluorouracil Methotrexate Bleomycin Taxoids Vinca alkaloids Monoclonal anitbodies Tyrosine kinase inhibitors

17. Alkylating agents Alkylating agents are antitumour agents that act through covalent bonding of alkyl group to cellular molecules. sulfur nitrogen mustard 0.4 mg/kg IV in single or divided doses in patients with lymphomas - found to produce lymphoid aplasia in addition to expected irritation to lung and mucous membrane. subsequent investigations - improvement in therapeutic index, offer specific alterations in drug disposition, cellular uptake, reactivity, and resistance, with resultant differences in efficacy and toxicity .

18. Cisplatin Trade Name: Platinol Other name: CDDP available as 10 and 50mg vials for iv use with mannitol , NaCl and Hclto minimize nephrotoxicity -diluted to 1mg/ mL with 10 & 50 ml sterile water injection Cisplatin - inorganic metal complex -neutral platinum complexes inhibited division and induced filamentous growth of Escherichia coli. Several platinum analogs have been subsequently synthesized. Combination therapy involoving cis-platin and 5-FU is the most common regimen used in most HNCs Most acceptable regimen : Cisplatin 75-100 mg/m 2 /day IV on day 1 and 22  plus  5-FU 750-1000 mg/m 2 /day by continuous IV infusion on days 1-4 and 22-25 [ Soo KC, Tan EH, Wee J, et al. Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison.  Br J Cancer . 2005 Aug 8. 93(3):279-86

19. Acute toxixity : Chiefly nausea and vomiting- managed by premedication with emetics like domperidone Delayed toxicity: Nephrotoxicity , ototoxicity , peripheral sensory neuropathy, Nerve dysfunction and hypersensitivity reaction including urticaria , angioneurotic edema, and anaphylaxis which can be managed with antihistamine and corticosteroids. cardiac-function deterioration, myocardial injury, increased LDH, CK, -Rx with resveratrol hindered the adverse effects of cisplatin in a dose-dependent manner Wang J, He D, Zhang Q, Han Y, Jin S,  Qi F. Resveratrol protects against cisplatin -induced cardiotoxicity by alleviating oxidative damage. Cancer Biother Radiopharm 2009;24 (6):675-80  

20. Carboplatin : Trade name: Biocarb , blastocarb,blastoplatin,paraplatin Availability: sterile lyophilized powder in vials that contain 50, 150, or 450mg carboplatin with an equal weight of mannitol . reconstituted by dilution to 10mg/ mL sterile water and futher diluted to 0.5mg/ mL with 5% dextrose. can be maintained for up to 8hrs without refrigeration. main dose-limiting toxicity is less than cisplastin -Intravenous hydration is not required widely replaced cisplatin in combination chemotherapy regimens

21. Delayed toxicity: Myelosuppression - Thrombocytopenia and neutropenia are maximum between days 21 and 25 resulting in infection and/or bleeding. Anemia - cumulative and may require transfusion support rarely peripheral neuropathy, renal toxicity, and hepatic dysfunction are seen. Anaphylactic-like reaction have been reported. Epinephrine, corticosteroids, and antihistamines have been employed

22. Anti-Metabolites biochemical pathways proved to be most vulnerable to antimetabolites - relating to nucleotide and nucleic acid synthesis. an enzyme is known to have a major effect on pathways leading to cell replication-inhibitors of the reaction it catalyzes have proved to be useful anticancer drugs. Two most common antimetabolites commonly employed in HNCs are Methotrexate and 5-fluoro Uraci l

23. Methotrexate Trade name: Biotrexate , imutrex,oncotrex Availabilty : Methotrexate sodium tablets contain 2.5mg methotrexate in bottles of 100. Methotrexate sodium for injection, preservative protected, is available at 25mg per mL (50mg) and 10mL(250mg)vials. reconstituted with sterile water, D5W, or 0.9%saline to a concentration not greater then 25mg/ mL. Routes : administered by the intravenous, intrathecal , or oral route. 90% of oral dose excreted through urine within 12 hours Not metabolised -serum level proportional to dose The effects of methotrexate can be reversed by administration of the reduced folate leucovorin . used in conjunction with high-dose methotrexate therapy to rescue normal cells from undue toxicity and in cases of accidental drug overdose.

24. Mechanism of action: MTX- folic acid antagonist that binds to the active catalytic site of DHFR-interfering-interrupts the de novo synthesis of thymidylate , purine nucleotides, and the amino acids serine and methionine - interfering with the formation of DNA, RNA, and key cellular proteins. Resistance to methotrexate can be due to (1) decreased drug transport, (2) decreased formation of cytotoxic MTX polyglutamates , (3) synthesis of increased levels of DHFR through gene amplification (4) altered DHFR with reduced affinity for methotrexate . Dosage: 2.5-5 mg/d orally ; 10 mg intrathecally once or twice weekly. Doses in excess of 80mg/wk generally required leucovorin rescue to reduce systemic toxicity.

25. Toxicity: Mucositis seen 3-5days after Rx diarrhea is severe and when occur with neutropenia place the patient at high risk for sepsis and death bone marrow depression with leukopenia and thrombocytopenia. Nadir usually occur 10days after drug administration, with recovery by 14 to 21 days Renal toxicity is due to precipitation of methotrexate metabolite 7-OH in kidney-diminished vis alkanization o,f urine and hydration.

26. 5-FluoroUracil: Trade name: inj fludin , inj fluracil , inj oncouracil MOA: 5-FU acts principally as a  thymidylate synthase (TS) inhibitor –blocks thymine synthesis- inhbits DNA replication- thymineless death Availabilty : . Fluorouracil injection in 10mL vials contains 500mg 5-FU- compatible with either D5W or 0.9% saline, and infusion solution can be used for 24hrs after preparation. Dosage: Part of one of the most commonly employed combination regimen with cispplaytin - : Cisplatin 75-100 mg/m 2 /day IV on days 1 and 22  plus  5-FU 1000 mg/m 2 /day by continuous IV infusion on days 1-4 and 22-25 [ As a single agent(in chemoradiotherapy ): 5-FU 800 mg/m 2  by continuous IV infusion on days 1-5 given on the days of radiation (50 to 60 Gy )

27. Toxicity Nausea & diarrhea with mucositis is an early sign of severe toxicity indicate need to delay further treatment, bone marrow depression with nadir occurring between days 9 – 14dys with recovery usually occurs by day 30. Mild alopecia, increased sensitivity to sunlight, and hyperpigmentation of nail beds and skin are common. Hand and foot syndrome with 5-flurouracil- palmer- plantar erythrodysesthesia associated with the continuous infusion of 5-FU and has been improved with pyridoxine 5-FU can cause fetal harm when administration to a pregnant women.

28. Anti-Tumor antibiotics Many of these antibiotics bind to DNA through intercalation between specific bases-block the synthesis of RNA, DNA, or both- cause DNA strand scission- interfere with cell replication .

29. Bleomycin : small peptide that contains a DNA-binding region and an iron-binding domain at opposite ends of the molecule. Trade Name: bleocare , bleochem MOA:acts by binding to DNA- single-strand and double-strand breaks following free radical formation- inhibition of DNA biosynthesis. Dosage: Up to 15 units/m 2 IV twice weekly to a total dose of 200-250 units it can be given SC, IM or IV Elimination via renal excretion. Acute Tocxicity : Allergic reactions, fever, hypotension.

30. Delayed Toxicity: Almost every patient experience fever - first 4-12hrs after bleomycin injection-usually brief and not clinically troublesome Skin toxicity common - toxic free radicals producing DNA damage: -managed by topical steroids Pulmonary toxicity - dose-limiting- pneumonitis with cough, dyspnoea , dry inspiratory crackles on physical examination, and infiltrates on chest x-ray

31. TAXANES Paclitaxel : alkaloid ester derived -the Pacific yew ( Taxus brevifolia ) and the European yew ( Taxus baccata ). MOA: mitotic spindle poison through high-affinity binding to microtubules with enhancement of tubulin polymerization-arresting mitosis. Trade name:Abraxane,Adpaxil,Altaxel Availability: conc. sterile solution of 5mL, 16.7ml, and 50ml, multidose vials. Each ml- 6mg paclitaxel in polyoxyethylated castor oil. diluted before use in 0.9%sodium chloride injection or 5% dextrose to final concentration of 0.3-1.2mg/ml. stable for to 27hrs at RT. Dosage:130-170 mg/m 2 IV over 24 hours q 3-4 weeks- prevent hypersensitive reaction premedication with dexamethasone 20mg orally /iv 6-12hr before Rx &H 1 antagonist diphenhydramine 50mg iv 30mts before Rx .

32. Acute toxicity: Nausea, vomiting, hypotension, arrhythmias, and hypersensitivity reactions-5% of patients within first 2-3 minutes after first or second dose- incidence reduced by premedication with dexamethasone , diphenhydramine , and H 2 blocker. Delayed toxicity: Peripheral sensory neuropathy is seen which is dose- and time-dependent 59 . Bone marrow depression albumin-bound paclitaxel formulation ( Abraxane )- not associated with HS rexns -premedication not required significantly reduced myelosuppressive effects neurotoxicity - more readily reversible

33. Docetaxel : Trade name: Inj docemax 20/80/120mg semisynthetic taxane -European yew tree. MOA, metabolism, and elimination are identical to those of paclitaxel Packaged together with an accompanying dilutent 0.5mL for the 20mg /0.5mL vial or 2mL for the 80mg per 2mL vial Dosage:60 - 100 mg/m 2 IV over 1 hour every 3 weeks. premedication - dexamethasone 8mg orally BID for 3-5days before docetaxel , with/without H 1 or H 2 antagonists given intravenously 30mts before docetaxel . Docetaxel combined Cisplatin and 5-Fluorouracil (TPF), is now acknowledged as gold standard of induction treatment. Oncol Rep.2010 Nov;24(5):1213-6.

34. Acute Toxicity: HSRs-during first two courses and within minutes after start of Rx- dyspnea , bronchospasum , and hypotension. Delayed Toxicity: Alopecia, macularpapular rashes, Neurotoxicity, fluid retention -managed by aggressive & early use of progressive more potent diuretics , major dose-limiting toxicity (DLT) was dose- but not   schedule-dependent neutropenia and mucositis induces palmar plantar erythrodysesthesia ,- cooling or pyridoxine, 50mg orally tid .

35. Plant Alkaloids Vinblastin alkaloid derived from the periwinkle plant Vinca rosea Trade Name: Cytoblastin , Uniblastin , Vblastin . MOA: inhibition of tubulin polymerization- disrupts assembly of microtubules-mitotic arrest Availability: 10mg vials at concentration of 1mg/ mL preservatives phenol or benzyl alcohol and 0.9% sodium chloride diluents Dosage: 0.1-0.2 mg/kg IV weekly. doses of 18.5mg/m 2 in adults and 12.5mg/m 2 in children are not to be exceeded

36. Acute toxicity: Nausea and vomiting Delayed Toxicity: Alopecia, loss of reflexes, bone marrow depression with neutropenia are the principle toxicity . nadir occurs within 4-10dys with recovery in 7-21dys. Gastrointestinal toxicity pain, diarrhea, and hemorrhagic entrocolities - more common in high single doses >20mg -in combination with other neurotoxic agents like cisplastin . In one long term follow-up study of patients- received vinblastine , cisplastin and bleomycin - symptomatic Raynaud phenomena developed in 44% cases . Vesicant- extravasation of drug into dermal tissues - necrosis, cellulitis and sloughing

37. Vincristine : Trade Name:Alcrist , Biocristin,Oncocristin -AQ MOA: be identical to that of vinblastine Availability: 1mL, 2mL, and 5mL vials for IV. Each mL contains 1mg of vincristine sulfate, preservatives methylparaben or benzyl alcohol, citric acid/sodium citrate both for pH adjustment, water and mannitol . Dosage: 1.5 mg/m 2 IV (maximum: 2 mg weekly). Doses of 0.25 to 0.5mg/m 2 per day as a continuous iv for 5days generally well tolerated. Dose regulation needed for hepatic dysfucntion .

38. Toxicity: Include muscle weakness, peripheral neuritis, paralytic ileus , mild bone marrow depression, alopecia. The main dose-limiting toxicity is neurotoxicity -peripheral sensory neuropath autonomic nervous system dysfunction with orthostatic hypotension, sphincter problems, and paralytic ileus cranial nerve palsies, ataxia, seizures, and coma- Higher dose myelosuppression can occur,- milder and much less significant than with vinblastine . syndrome of inappropriate secretion of antidiuretic hormone (SIADH)

39. Growth Factor Receptor Inhibitors Epidermal growth factor receptor (EGFR) member of the erb -B family of growth factor receptors-over expressed in a number of solid tumors. Activation of the EGFR signaling pathway downstream activation of several key cellular events - cellular growth and proliferation, invasion and metastasis, and angiogenesis.  Mutations affecting EGFR expression or activity could result in cancer inhibits the cytotoxic activity of various anticancer agents and radiation therapy- suppression of key apoptotic mechanisms-cellular drug resistance.

40. Cetuximab : Trade Name: ERBITUX a monoclonal antibody directed against the extracellular domain of the EGFR Availability: A s vials of 10 ml, 20 ml, 50 ml or 100 ml solution. Each ml of solution for infusion contains 5 mg cetuximab . Dosage :400 mg/m 2 IV as loading dose followed by 250 mg/m 2 IV weekly. For the initial dose infusion period is 120 minutes-subsequent weekly doses,it is 60 minutes combination with platinum-based chemotherapy is used as 1st line treatment of recurrent and/or metastatic carcinoma.

41. Acute toxicity: Infusion reaction include: fevers, chills, rigors,  urticaria ,  pruritis , rashes, hypotension, bronchospasm , dyspnea , wheezing, angioedema , dizziness,anaphylaxis , and cardiac arrest-pretreatment with  diphenhydramine  30-60 min. Delayed toxicity:  acne-like rash-rarely leads to dose reductions or termination of therapy photosensitivity, hypomagnesaemia due to magnesium wasting and less commonly pulmonary and cardiac toxicity.

42. Molecular Targeted Cancer Therapies Molecular targeted therapies -work specifically on the parts of cells that lead to abnormal growth and the development of cancer. Act by specifically inhibiting a certain enzyme - characteristic of a particular cancer cell- rather than non-specifically inhibiting and killing all rapidly dividing cells recognize that the molecules on the surface of a cancer cell are different from those on a healthy cell recognize the molecular signals a cancer cell sends out to tell the body to build blood vessels that will feed a tumor- intercept them can cause side effects, but these are generally more moderate than those caused by other types of treatments They chiefly include Tyrosine kinase inhibitors and targetd monoclonal antibodies.

43. Tyrosine Kinase Inhibitors: Receptor tyrosine kinases are transmembrane glycoprotienes regulate cell proliferation, differentiation, and signaling Activity of tyrosine kinases implicated in many cancers and other proliferative disease such as atherosclerosis and psoriasis. Chief example is imatinib

44. Imatinib : Trade name:Marketed inetrnationally as glivec In india - celonib,imalak,imatib -Alpha(100/400mg) MOA:The genetic abnormality causing chronic myelogenous leukemia (CML)- Philadelphia chromosomal translocation-creates an abnormal fusion protein kinase BCR-ABL- leading to uncontrolled proliferation of the leukemia cells. Imatinib inhibits this kinase 7 Dosage: The recommended dose of Gleevec is 400 mg/day for adult patients in chronic phase CML and 600 mg/day for adult -accelerated phase or blast crisis.

45. Toxicity: generally very well tolerated. side effects such as edema, nausea, rash and musculoskeletal pain are common but mild. Severe congestive cardiac failure - uncommon but recognized smice treated with large doses of imatinib show toxic damage to their myocardium.

46. Rituximab Rituxan is an unconjugated chimeric anti-CD20 monoclonal antibody Trade name:Reditux and Mabthera (100/500mgper 50ml vials) first monoclonal antibody approved by the FDA - treatment of relapsed low grade or follicular non- hodgkin’s lymphoma MOA: Binds with protein CD20, primarily found on the surface of B cells-promote apoptosis phase II trial of the combination of rituximab and cyclophosphamide , doxorubicin, vincristine , and prednisone (CHOP) chemotherapy was reported with overall response rate of 95% 79 .

47. Toxicity: mild, consisting of infusion related reactions- nausea, fever, bronchospasm , rash and pruritus , mainly with first infusion. Myelosuppression and infection were minor complications

48. Oral management of patients on chemotherapy Oral complication a occurs during and following course of Chemo & comb chemo-radiotherapy. Acute reactions - during the course of therapy, primarily caused by direct toxicity, and resolve over weeks to months - completion of therapy. Chronic / late reaction occurs months and years after chemotherapy. change in vascular supply fibrosis in connective tissue muscle neuropathy mucosal atrophy change in cellularity of tissues

49. ORAL MUCOSITIS a common acute complication resulting from chemotherapy typically manifests as erythema or ulceration of the oral mucosa- 2weeks after initiation of chemotherapy and heals within 3-4weeks after the last dose. painful and debilitating -dose and rate-limiting toxicity of cancer therapy

50. Grading of mucositis World Health Organization (WHO) scale for oral mucositis Grade 0 = No oral mucositis Grade 1 = Erythema and Soreness Grade 2 = Ulcers, able to eat solids Grade 3 = Ulcers, requires liquid diet (due to mucositis ) Grade 4 = Ulcers, alimentation not possible (due to mucositis )

51. Management of oral mucositis : Pain control: topical mouth rinse -2% viscous lidocaine to reduce pain. mixed with equal volume of diphenhydramine to prevent infection. Sucralfate form protective coating over ulcerated mucosa there by reducing pain Nutrition support:severely compromised by pain associated with mucositis . soft and liquid diet supplement is recommendated . severe mucositis -total parenteral nutrition via indwelling catheter Oral decontamination: microbial colonization of oral mucositis lesion exacerbates the severity of oral mucositis and septicemia. achieved by using soft toothbrush, flossing and use of nonmedicated rinses like saline or sodium bicarbonate.

52. Other modalities: Cryotherapy : (topical application of ice chips in the mouth 5minuted before- beginning of chemo admin) Decreases delivery of agent to the oral mucosa-mediated through local vasoconstriction and reduced blood flow Recombinant Human Keratinocytes Growth Factor – I: Also known as palifermin Stimulates cell proliferation, differentiation, and upregulation of cytoprotective mechanisms Given IV bolus.Dose : 60 μ g/kg/day. 3 days before and 3 days after chemo Glutamine: Reduce production of proinflammatory cytokines ,cytokine-related apoptosis - increasing fibroblast and collagen synthesis. 10gms in 240ml of water- first day till 14 days after last dose

53. XEROSTOMIA: Chemo agents may cause transient damage to salivary glands. 40% of patients will report this side effect during therapy. usually short term- complete recovery is noted 2 to 8weeks after therapy , hyposalivation lead to dysphagia , dysgeusia and dysosmia - reduce appetite - nutritional compromise Sequelae from hyposalivation also include erythema of the oral soft tissues, a furrowed and desiccated tonguec shift in oral microflora - cariogenic organisms, periodontal diseases and fungal infections

54. Management Maintenance of oral hygiene via fluoride agents and antimicrobials to prevent dental caries and oral infections Saliva Substitutes And Mouth Wetting Agents Hydroxyethylcellulose , Hydroxypropylcellulose Or Carboxymethylcellulose - attempt to relive the discomfort of xerostomia - do not replace the antimicrobial and immunologic protection of saliva. Sialogogues : stimulate saliva production from residual gland Pilocarpine -stimulation of muscarinic /cholinergic receptors of salivary gland acinar cells doses of 5 to 10mg TID- increased secretion occurs within 30mts of ingestion.-continue for 8 -12 weeks Cevimeline and bethanechol –other sialogogues

55. Chemotherapy induced peripheral neuropathy (CIPN) resolves with or without Rx some patients - evolve into a chronic painful condition resulting in sensory and motor changes. Prevalence is variable with agents, the intensity of treatment (dose intensity and cumulative dose), other ongoing therapies such as surgery and RT, age of the patients, the use of combination of CT agents. Commonly used neurotoxic agents such as taxins , vinca alkaloids, and Pt- based compounds -most responsible for precipitating CIPN. managed -proper selection of agents - reduce the intensity of neuropathy.

56. Conclusion

57. References Cancer of head and neck-5th edn-Myers,Suen,Myers ,Hanna Cancer Management – multidsciplinary approach-Ray Page and Chris Takimoto Forasteire et al. Induction Chemotherapy Meta-Analysis in Head andNeck Cancer: Right Answer, Wrong Question , j clin onc ol,2013(31):23 O'Brien SG,   Guilhot F,   Larson RA,   Gathmann I,   Baccarani M,   Cervantes F. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348(11):994-1004. Mclaughlin P, grillo-lopaz AJ, LinkBK , et al. Rituximab chimeric anti CD20 monoclonal antibody for relapsed indolent lymphoma; half of the patient respond to a four – dose treatment program. J Clin Oncol 1998;16(8):2825-2833. Various other journal articles