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Radiation Oncology/Supportive care/Randomized

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Head & Neck Supportive Care Randomized Evidence

Hypoxia

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Erythropoietin

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  • Multi-National (Europe, North America, Australia)(2004-2006) -- General cancer
    • Randomized. 989 patients. Non-myeloid malignancies (NSCL 18%, breast 13%), anemia Hgb <11 (mean 9.5), not receiving chemo or RT. Arm 1) placebo vs. Arm 2) darbepoetin alfa 6.75 ug/kg q4w x 16 weeks
    • 2008 PMID 18227526 -- "Darbepoetin Alfa for the Treatment of Anemia in Patients With Active Cancer Not Receiving Chemotherapy or Radiotherapy: Results of a Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study." (Smith RE Jr, J Clin Oncol. 2008 Jan 28 [Epub ahead of print])
      • Outcome: Transfusions week 5-17 similar. Median OS DA 8.5 months vs. placebo 10.8 months (SS)
      • Toxicity: more cardiovascular, thromboembolic events, more deaths
      • Conclusion: Darbepoetin no impact on transfusions, worse survival
  • RTOG 99-03 (2000-2003) -- H&N Cancer
    • Randomized. Closed early due to other data suggesting worse locoregional control. 141 patients (40% of goal) with SCCHN, Stage I-IV. Hemoglobin men <13.5 g/DL and women <12.5 g/dL. RT +/- erythropoietin 40K units weeily. If Stage III-IV, concurrent chemo-RT and/or accelerated RT.
    • 2007 PMID 17716826 -- "Radiotherapy With or Without Erythropoietin for Anemic Patients With Head and Neck Cancer: A Randomized Trial of the Radiation Therapy Oncology Group (RTOG 99-03)." (Machtay M, Int J Radiat Oncol Biol Phys. 2007 Nov 15;69(4):1008-17. Epub 2007 Aug 23.). Median F/U 2.5 years
      • Hemoglobin: at 4 weeks control -0.2 g/dL vs. Epo +1.7 g/dL
      • Outcome: 3-year LRF control 36% vs. Epo 44% (NS). No difference in OS (52% vs. 47%) or toxicity
      • Conclusion: Addition of Epo did not improve outcomes
  • BEST Trial (Multi-national: Canada, Europe, Australia, South Africa)(2000-2002) -- Breast cancer
    • Randomized. Stopped early due to adverse outcomes. 939 patients, metastatic breast CA. Arm 1) placebo vs. Arm 2) Epo to maintain Hgb 12-14 g/dL, and initiated if Hgb <13 g/dL
    • 2005 PMID 16087945 -- "Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study." (Leyland-Jones B, J Clin Oncol. 2005 Sep 1;23(25):5960-72. Epub 2005 Aug 8.)
      • Outcome: 1-year OS placebo 76% vs. Epo 70% (SS); no difference in tumor response
      • Conclusion: Epo use to maintain high Hgb was associated with decreased survival
  • Canada (2001-2003) -- NSCLC
    • Randomized. Stopped early due to unplanned safety analysis. 70 patients assigned (out of 300 planned). NSCLC unsuitable for curative therapy, baseline Hgb <12.1 g/dL. Arm 1) placebo vs. Arm 2) Epo weekly to maintain Hgb 12-14 g/dL
    • 2007 PMID 17312332 -- "Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia." (Wright JR, J Clin Oncol. 2007 Mar 20;25(9):1027-32. Epub 2007 Feb 20.)
      • Outcome: at analysis, median OS placebo 4.2 months vs. Epo 2 months (SS)
      • Conclusion: Decreased overall survival on unplanned safety analysis
  • European Multinational (1997-2001) -- H&N Cancer
    • Randomized. 351 patients with oral cavity, oropharynx, hypopharynx, larynx. Hemoglobin <13.0 g/dL men, <12.0 g/dL women. RT 60-70 Gy +/- Epo 300 U/kg 3x weekly
    • 2003 PMID 14575968 -- "Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial" (Henke M, Lancet. 2003 Oct 18;362(9392):1255-60.)
      • Hemoglobin: 82% given Epo reached >14.0 (men) or >15 (women) compared with 15% control
      • Outcome: LR failure placebo 54% vs. Epo 64% (SS), median PFS 2.0 years vs. 1.1 years (SS); OS 48% vs. 39% (same 34% mortality from cancer but worse cardiac/general mortality for Epo)
      • Conclusion: Significantly worse LR control and survival with Epo

Iron

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  • Italy (2004-2006) -- darbepoetin +/- IV iron
    • 2008 PMID 18375891 -- "Randomized trial of intravenous iron supplementation in patients with chemotherapy-related anemia without iron deficiency treated with darbepoetin alpha." (Pedrazzoli P, J Clin Oncol. 2008 Apr 1;26(10):1619-25.)
    • Randomized. 149 patients with lung, GYN, BCA, and CRC; Hb <=11 g/L and no iron deficiency. Treated with darbepoetin and Arm 1) control vs. Arm 2) IV iron (sodium ferric gluconate) 125mg IV Q1W x6 weeks
      • Outcome: Hematopoietic response EPO 62% vs. EPO + Iron 77% (SS)
      • Toxicity: Comparable
      • Conclusion: IV supplementation reduces treatment failures to darbepoetin
  • European Multi-Institutional -- darbepoetin +/- IV iron
    • Randomized. 396 patients with non-myeloid malignancies, Hb <11 g/dL. Treated with darboepoetin 500 ug and Arm 1) control vs. Arm 2) IV iron (sodium ferric gluconate or iron sucrose) 200 mg Q3W x 4 months
    • 2008 PMID 18375890 -- "Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia." (Bastit L, J Clin Oncol. 2008 Apr 1;26(10):1611-8.)
      • Outcome: Hematopoietic response EPO 73% vs. EPO + Iron 86% (SS); also fewer transfusions 20% vs. 9% (SS)
      • Toxicity: No difference in adverse events; iron-related were GI
      • Conclusion: Addition of IV iron to darbepoetin improved Hb control and decreased number of transfusions
  • Sundsvall (2003-2005) -- EPO +/- IV iron
    • Randomized. 67 patients, lymphoproliferative malignancy, Hb 9-11 g/dL. Treated with epoetin 30,000 IU Q1W and Arm 1) control vs. Arm 2) IV iron 100 mg QW
    • 2007 PMID 17252006 -- "Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study." (Hedenus M, Leukemia. 2007 Apr;21(4):627-32. Epub 2007 Jan 25.)
      • Outcome: Hb response EPO 53% vs. EPO + IV iron 93%; mean weekly EPO dose lower >25% in IV iron group by week 15 (p=0.05)
      • Conclusion: Hb reponse significantly improved with IV iron
  • Karnell Cancer Center -- epoetin +/- oral iron or IV iron
    • 2007 PMID 17296819 -- "Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy." (Henry DH, Oncologist. 2007 Feb;12(2):231-42.)
    • Randomized. 129 patients, Hb <11 g/d, ferritin >= 100 ng/ml, transferring >=15%. Treated with epoetin 40,000 U and Arm 1) control vs. Arm 2)oral ferrous sulfacte 325 mg TID vs. Arm 3) IV ferric gluconate 125 mg IV Q1W
      • Outcome: Hb response EPO 41% vs. EPO + oral iron 46% vs. EPO + IV iron 73% (SS)
      • Toxicity: Well tolerated
      • Conclusion: IV iron in addition to epoetin produces significantly greater Hb response
  • Averbach Hematology-Oncology -- rHuEPO +/- oral iron or IV iron
    • Randomized. 157 patients, Hb <=10.5 g/dL or ferritin <=450 pmol/L or transferring <=19%. Treated with rHuEPO 40,000 U QW and Arm 1) control vs. Arm 2) oral iron 325 mg BID vs. Arm 3) IV iron (iron dextran) 100 mg bolus vs. Arm 4) IV iron (iron dextran) 100 mg infusion
    • 2004 PMID 15051778 -- "Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial." (Auerbach M, J Clin Oncol. 2004 Apr 1;22(7):1301-7.)
      • Outcome: Hematopoietic response EPO 25% vs. EPO + oral iron 36% vs. EPO + IV iron 68% (both groups). IV iron groups had improved energy, activity and QoL, oral iron group no difference, and no iron worsening
      • Conclusion: IV iron improves effect of EPO

Etanidazole

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  • RTOG 85-27 (1988-1991)
    • Randomized. 521 pts. Stage III-IV. Randomized to RT 66-74 Gy alone or RT + etanidazole (ETA) 3x/week.
    • 1995 PMID 7790241 -- "Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas." (Lee DJ, Int J Radiat Oncol Biol Phys. 1995 Jun 15;32(3):567-76.)
      • Outcome: 2-year LRC control 40% vs etanidazole 40% (NS); OS 41% vs 43%. For N0-1 patients, advantage for ETA for LRC 55% vs 37% (SS).
      • Conclusion: No benefit for etanidazole overall, subset benefit in N0-1 disease
    • 1998 PMID 9869231 -- "Anemia is associated with decreased survival and increased locoregional failure in patients with locally advanced head and neck carcinoma: a secondary analysis of RTOG 85-27." (Lee WR, Int J Radiat Oncol Biol Phys. 1998 Dec 1;42(5):1069-75.)
      • Subset of 451 patients. 46% normal Hgb (men >14.5, women >13), 64% anemic
      • Outcome: 5-year OS normal Hgb 36% vs. anemic 22% (SS); LRFR 52% vs. 68% (SS)
      • Toxicity: Grade 3+ normal Hgb 20% vs. 13% (NS)
      • Conclusion: Low Hgb levels result in worse survival and LR failure


Misonidazole

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  • RTOG 79-15 (1979-1983)
    • Randomized. 206 patients, 42% oropharynx, 78% T3-T4, 84% N+. Arm 1) RT + placebo vs. Arm 2) RT + misonidazole 2.0 gm/m2 weekly (on day of misonidazole, RT given BID)
    • 1987 PMID 3301758 -- "Failure of misonidazole-sensitized radiotherapy to impact upon outcome among stage III-IV squamous cancers of the head and neck." (Fazekas J, Int J Radiat Oncol Biol Phys. 1987 Aug;13(8):1155-60.)
      • Outcome: 2-year LR rate placebo 26% vs. misonidazole 22% (NS); 3-year OS 22% in both groups
      • Conclusion: No benefit
    • 1989 PMID 2689395 -- "The role of hemoglobin concentration in the outcome of misonidazole-sensitized radiotherapy of head and neck cancers: based on RTOG trial #79-15." (Fazekas JT, Int J Radiat Oncol Biol Phys. 1989 Dec;17(6):1177-81.)
      • Outcome: No difference

Psychotherapeutic Support

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  • Hamburg, 2007 (Germany)(1991-1993) PMID 17602075 -- "Impact of psychotherapeutic support for patients with gastrointestinal cancer undergoing surgery: 10-year survival results of a randomized trial." (Kuchler T, J Clin Oncol. 2007 Jul 1;25(19):2702-8.)
    • Randomized. 271 patients, prelim Dx of esophagus, stomach, liver/GB, pancreas, or CRC randomly assigned to standard care vs. formal psychotherapeutic support during hospital stay. 25% cross-over
    • 10-year survival: psychotherapy 21% vs. control 10% (SS). Local disease 57% vs. 21%; regional disease 13% vs. 2%; DM 5% vs. 5%
    • Conclusion: Benefit of formal psychotherapeutic support during inpatient stay


Stress Management

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  • South Florida; 2007 PMID 17876009 -- "Self-administered stress management training in patients undergoing radiotherapy." (Krischer MM, J Clin Oncol. 2007 Oct 10;25(29):4657-62.)
    • Randomized. 310 patients, prior to start of RT. Randomized to Arm 1) usual care or 2) self-administered stress management training. QOL assessments
    • Outcome: No difference; subset analysis showed improvement in patients with >average psychological distress
    • Conclusion: Self-administered stress management effective only in stressed patients


Exercise

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Prostate Cancer

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  • Houston VA; 2007 PMID 17964881 -- "Exercise prevents fatigue and improves quality of life in prostate cancer patients undergoing radiotherapy." (Monga U, Arch Phys Med Rehabil. 2007 Nov;88(11):1416-22.)
    • Randomized. 21 patients with localized PCA, undergoing therapy. Arm 1) RT + aerobic exercise 3x/week x8 weeks vs. Arm 2) RT only
    • Outcome: Significant benefit in fatigue, cardiac fitness, strength, flexibility, FACT-P, physical well-being, social well-being, and functional well-being
    • Conclusion: 8-week cardiovascular program during RT improves fatigues, well-being, and fitness

Breast Cancer

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  • Bangalore, India -- brief supportive therapy vs. yoga
    • 2009 PMID 19114222 -- "Anxiolytic effects of a yoga program in early breast cancer patients undergoing conventional treatment: a randomized controlled trial." (Rao MR, Complement Ther Med. 2009 Jan;17(1):1-8. Epub 2008 Oct 14.)
    • Randomized. 38 patients, Stage II-III breast cancer, who received surgery, adjuvant RT and adjuvant chemotherapy. Arm 1) routine supportive therapy vs. Arm 2) yoga 60 min daily. Evaluated at baseline, after surgery, before/during/after RT and chemotherapy
      • Outcome: yoga group decreased self-reported anxiety and trait anxiety (SS), positively correlated with symptom severity during RT
      • Conclusion: Yoga can be used for managing treatment-related symptoms and anxiety in BCA patients
  • Sungkyunkwan, Seoul -- moderate intensity exercise vs. observation
    • Randomized. 40 women after adjuvant RT for breast cancer. Arm 1) supervised moderate-intensity exercise (50 min 3x/week x5 weeks, including stretching, shoulder exercises, and aerobic exercise) vs. Arm 2) observation
    • 2008 PMID 18581595 -- "Effects of supervised exercise therapy in patients receiving radiotherapy for breast cancer." (Hwang JH, Yonsei Med J. 2008 Jun 30;49(3):443-50.)
      • Outcome: Exercise group increased QoL, shoulder ROM, decreased fatigue, decreased fatigue. Control group worse than baseline in QoL, shoulder ROM, fatigue, pain
      • Conclusion: Patients receiving RT for breast CA may benefit from supervised moderate-intensity exercise
  • Alberta (2003-2005) -- usual care vs. resistance exercise vs. aerobic exercise
    • Randomized. 242 patients undergoing adjuvant chemo. Arm 1) usual care, vs. Arm 2) supervised resistance exercise vs. Arm 3) supervised aerobic exercise. Adherence 70%
    • 2007 PMID 17785708 -- "Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial." (Courneya KS, J Clin Oncol. 2007 Oct 1;25(28):4396-404.)
      • Outcome: Aerobic exercise significantly superior for self-esteem, fitness, and % body fat. Resistance exercise significantly superior for self-esteem, strength, lean body mass, and chemo completion rate. No difference in cancer-specific QoL
      • Conclusion: No difference in either regimen on cancer-specific QoL, but improvement in self-esteem, physical fitness, and body composition
  • Albert Einstein; 2007 -- yoga vs. observation
    • Randomized. 128 patients (42% black, 31% hispanic), ~50% on treatment. Arm 1) 12-week yoga vs. Arm 2) control
    • 2007 PMID 17785709 -- "Randomized controlled trial of yoga among a multiethnic sample of breast cancer patients: effects on quality of life." (Moadel AB, J Clin Oncol. 2007 Oct 1;25(28):4387-95.)
      • Outcome: yoga group better social well-being (SS). However, limited adherance, worse with increased fatigue, RT, younger age, and no anti-estrogens
      • Conclusion: Yoga associated with beneficial effects on social functioning
  • Birmingham, UK -- supervised aerobic exercise vs. exercise-placebo vs. usual care
    • Randomized. 108 women treated for BCA 1-3 year previously. Assigned to 1) supervised aerobic exercise vs. 2) exercise-placebo vs. 3) usual care. Exercise 3x/week x 8 weeks
    • 2007 PMID 17470863 -- "Randomized trial of exercise therapy in women treated for breast cancer." (Daley AJ, J Clin Oncol. 2007 May 1;25(13):1713-21.)
      • Outcome: Significant benefit in functional outcome and QoL in Arm 1, but not Arm 2 (therefore not result of attention)
      • Conclusion: Exercise had large, clinically meaningful benefit on QoL

Fatigue

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Anti-cholinergics

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Donepezil (Aricept)

  • MD Anderson; 2007 PMID 17687152 -- "Donepezil for cancer fatigue: a double-blind, randomized, placebo-controlled trial." (Bruera E, J Clin Oncol. 2007 Aug 10;25(23):3475-81.)
    • Randomized. 103/142 patients with fatigue score >=4 (scale 0-10) for more than 1 week. Treated with 1) donepezil 5mg x 7days vs. 2) placebo. Everyone donepezil open label second week
    • Outcome: No difference by FACIT-F or ESAS
    • Conclusion: No difference from placebo


Psychostimulants

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Methylphenidate (Ritalin)

  • MD Anderson; 2006 - PMID 16648508 — "Patient-Controlled Methylphenidate for Cancer Fatigue: A Double-Blind, Randomized, Placebo-Controlled Trial." Bruera E et al. JCO May 1 2006: 2073–2078.
    • Randomized to 5 mg methylphenidate q2h as needed (patient controlled) vs placebo.
    • No significant difference from placebo.


Antidepresants

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Paroxetine (Paxil)

  • Rochester; 2003 PMID 14673053 -- "Differential effects of paroxetine on fatigue and depression: a randomized, double-blind trial from the University of Rochester Cancer Center Community Clinical Oncology Program." (Morrow GR, J Clin Oncol. 2003 Dec 15;21(24):4635-41.)
    • Randomized. 479/549 patients undergoing chemo for the first time, and reported fatigue at their 2nd cycle. Treated with 1) oral paroxetine 20mg qd x8 weeks vs. 2) placebo
    • Outcome: No difference in fatigue between groups; but benefit in depression score
    • Conclusion: No impact on fatigue


Hot Flashes

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Estrogens

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  • HABITS (1997-2003)
    • Randomized. Stopped prematuredly for increased risk of breast cancer. 434 women randomized/345 at least one follow-up. DCIS to Stage II BCA. Tamoxifen allowed. Arm 1) Hormone replacement therapy (choice allowed locally) x2 years vs. Arm 2) control. HRT given as estrogen only (21%), continuously combined regimens (46%), sequential regimens (26%), and non-protocol treatments or no HRT (6%). In non-HRT group, 18% exposed to HRT
    • 2004 PMID 14962527 -- "HABITS (hormonal replacement therapy after breast cancer--is it safe?), a randomised comparison: trial stopped." (Holmberg L, Lancet. 2004 Feb 7;363(9407):453-5.) Median F/U 2.1 years
      • Outcome: new breast cancer event HRT 15% vs. non-HRT 5% (SS). LR 6% vs. 1%, DM 6% vs. 3%, contralateral 3% vs. 0.6%
      • Conclusion: Hormone-replacement therapy for menopausal symptoms represents unacceptable risk for new breast cancer events

Progestins

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  • NCCTG N99C7 (2002-2004) -- Medroxyprogesterone 400 mg IM vs venlafaxine 75 mg PO
    • Randomized. 227 patients with bothersome hot flashes. Tamoxifen, raloxifene, and AI allowed, antineoplastics, androgens, and estrogens not allowed. Arm 1) Medroxyprogesterone (MPA) 400 mg IM x1 vs Arm 2) MPA 500 mg IM x3 Q2W vs Arm 3 venlafaxine 37.5 mg QD x 1 week, then 75 mg QD. Due to slow accrual, Arm 2 was discontinued.
    • 2006 PMID 16505409 — "Phase III Comparison of Depomedroxyprogesterone Acetate to Venlafaxine for Managing Hot Flashes: North Central Cancer Treatment Group Trial N99C7." (Loprinzi CL, JCO 2006 Mar 20;24(9):1409-14.)
      • Outcome: reduction in hot flashes MPA 79% vs. venlafaxine 55% (SS), reduction by >50% MPA 74% vs. venlafaxine 46% (SS)
      • Toxicity: Better in MPA arm
      • Conclusion: Single MPA dose well tolerated and more effective than venlafaxine
  • SWOG 9626 (1998-2000) -- placebo vs. megestrol 20 mg vs. megestrol 40 mg
    • 2008 PMID 18375894 -- "Phase III randomized placebo-controlled trial of two doses of megestrol acetate as treatment for menopausal symptoms in women with breast cancer: Southwest Oncology Group Study 9626." (Goodwin JW, J Clin Oncol. 2008 Apr 1;26(10):1650-6.)
    • Randomized. 288 women with T1-3N01, at least 10 hot flashes/week. Tamoxifen allowed (85%). Arm 1) placebo vs. Arm 2) megestrol acetate (MA) 20 mg QD vs. Arm 3) MA 40 mg QD x3 months. Success at 3 months defined as >= 75% reduction
      • Outcome: 3 months success placebo 14% vs. MA 20 mg 65% (SS) vs MA 40 mg 48% (SS). 6 months success 77% vs. 81%
      • Conclusion: megestrol significantly reduced hot flashes with durable benefit. MA 20 mg/d is preferred dose
  • Italy (1996-1998) -- medroxyprogesterone 500 mg vs. megestrol 40 mg
    • Randomized. 71 postmenopausal patients with BCA. Arm 1) depot medroxyprogesterone (MPA) IM 500 mg day 1, 14 and 28 vs. Arm 2) oral megestrol 40 mg QD x6 weeks
    • 2002 PMID 12123333 -- "Intramuscular depot medroxyprogesterone versus oral megestrol for the control of postmenopausal hot flashes in breast cancer patients: a randomized study." (Bertelli G, Ann Oncol. 2002 Jun;13(6):883-8.)
      • Outcome: At week 6, hot flash reduction MPA 75% vs. oral megestrol 67% (NS); at week 24, MPA 89% vs. oral megestrol 45% (SS)
      • Toxicity: vaginal dryness, dyspareunia, fatigue, night sweats, but most relatively minor
      • Conclusion: Short cycle of IM MPA injections provide significant and long-lasting relief
  • Mayo Clinic (1992-1993) -- placebo vs. megestrol 40 mg
    • Randomized, cross-over. 163 patients (97 women with breast CA and 66 men with prostate), with bothersome hot flashes. Arm 1) placebo vs. Arm 2) megestrol 40 mg x4, then crossed over
    • 1994 PMID 8028614 -- "Megestrol acetate for the prevention of hot flashes." (Loprinzi CL, N Engl J Med. 1994 Aug 11;331(6):347-52.)
      • Outcome: At 4 weeks, hot flash reduction placebo 21% vs. megestrol 85% (SS), >50% reduction placebo 20% vs. megestrol 74% (SS). Efficacy similar in men and women
      • Toxicity: well tolerated
      • Cross-over portion not analyzed due to longer-term benefit from megestrol in patients initially treated with megestrol vs. placebo
      • Conclusion: Low-dose megestrol well tolerated and efficacious in men and women
    • 1998 PMID 9576302 -- "Long term use of megestrol acetate by cancer survivors for the treatment of hot flashes." (Quella SK, Cancer. 1998 May 1;82(9):1784-8.)
      • Retrospective. 132/163 patients. Long-term follow-up for the initial cohort
      • Outcome: 45% continued megestrol >3 years after conclusion of study; 75% utilizing <=20 mg/day
      • Toxicities: chills, appetite stimulation, weight gain, vaginal bleeding, and carpal tunnel
      • Conclusion: Substantial proportion of patients continue to use megestrol; treatment relatively well tolerated

Antidepressants

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Paroxetine (Paxil)

  • US Multi-Institutional (2001-2002) -- placebo vs. paroxetine 12.5 vs. paroxetine 25 mg
    • 2003 PMID 12783913 -- "Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial." (Stearns V, JAMA. 2003 Jun 4;289(21):2827-34.)
    • Randomized. 165 women, functionally menopausal. No hormonal therapy. Arm 1) placebo vs. Arm 2) paroxetine CR 12.5 mg/d vs. Arm 3) paroxetine CR 25 mg/d
      • Outcome: 6 week mean reduction placebo 38% vs. paroxetine 12.5 62% vs. paroxetine 25 65%
      • Toxicity: Not different from placebo (54% vs. 58%)
      • Conclusion: Paroxetine CR may be effective and acceptable alternative
  • US Multi-Institutional (1999-2002) -- placebo vs. paroxetine 10 mg vs. paroxetine 20 mg
    • Randomized, 2 cross-over studies. 151 women, with or without h/o BCA, not candidate for HRT, with troublesome hot flashes. Arm 1) paroxetine 10 mg x4 weeks then placebo 4 weeks vs. Arm 2) paroxetine 20 mg x4 weeks then placebo 4 weeks vs. Arm 3) placebo x4 weeks then paroxetine 10 mg x4 weeks vs. Arm 4) placebo x4 weeks then paroxetine 20 mg
    • 2005 PMID 16192581 -- "Paroxetine is an effective treatment for hot flashes: results from a prospective randomized clinical trial." (Stearns V, J Clin Oncol. 2005 Oct 1;23(28):6919-30.)
      • Outcome: Reduction in hot flashes placebo 14% vs. paroxetine 10 46% (SS) vs. paroxetine 20 56% (SS). Also significant benefit in sleep
      • Toxicity: Women more likely to discontinue paroxetine 20 mg
      • Conclusion: Paroxetine effective treatment for hot flashes


Venlafaxine (Effexor)

  • NCCTG N99C7 (2002-2004) -- Medroxyprogesterone 400 mg IM vs venlafaxine 75 mg PO
    • Randomized. 227 patients with bothersome hot flashes. Tamoxifen, raloxifene, and AI allowed, antineoplastics, androgens, and estrogens not allowed. Arm 1) Medroxyprogesterone (MPA) 400 mg IM x1 vs Arm 2) MPA 500 mg IM x3 Q2W vs Arm 3 venlafaxine 37.5 mg QD x 1 week, then 75 mg QD. Due to slow accrual, Arm 2 was discontinued.
    • 2006 PMID 16505409 — "Phase III Comparison of Depomedroxyprogesterone Acetate to Venlafaxine for Managing Hot Flashes: North Central Cancer Treatment Group Trial N99C7." (Loprinzi CL, JCO 2006 Mar 20;24(9):1409-14.)
      • Outcome: reduction in hot flashes MPA 79% vs. venlafaxine 55% (SS), reduction by >50% MPA 74% vs. venlafaxine 46% (SS)
      • Toxicity: Better in MPA arm
      • Conclusion: Single MPA dose well tolerated and more effective than venlafaxine 75 mg
  • US Multi-Institutional (1999) -- placebo vs. venlafaxine 37.5 mg vs. 75 mg vs. 150 mg
    • Randomized. 191 patients, h/o BCA or concerned about developing BCA. Tamoxifen, raloxifene and AI allowed. Androgens, estrogens not allowed. Arm 1) placebo vs. Arm 2) venlafaxine 37.5 mg vs. Arm 3) venlafaxine 75 mg vs. Arm 4) venlafaxine 150 mg, taken x4 weeks
    • 2000 PMID 11145492 -- "Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial." (Loprinizi CL, Lancet. 2000 Dec 16;356(9247):2059-63.)
      • Outcome: After 4 weeks, median hot flash reduced by placebo 27% vs 37.5 mg 37% vs 75 mg 61% vs. 150 mg 61%
      • Toxicity: mouth dryness, decreased appetite, nausea, constipation worse in 75 mg and 150 mg groups
      • Outcome: Venlafaxine effective, favor 75 mg QD dose


Fluoxetine (Prozac)

  • Mayo Clinic (1998-2000) -- placebo vs. fluoxetine 20 mg
    • Randomized, cross-over. 81 patients with h/o BCA or perceived increased risk of BCA, bothersome hot flashes. Tamoxifen or raloxifene allowed. No androgens, estrogens, progestational drugs or chemotherapy. Arm 1) placebo vs. Arm 2) fluoxetine 20 mg x4 weeks. After 4 weeks, cross-over.
    • 2002 PMID 11896107 -- "Phase III evaluation of fluoxetine for treatment of hot flashes." (Loprinzi CL, J Clin Oncol. 2002 Mar 15;20(6):1578-83.)
      • Outcome: After 4 weeks (cross-over), hot flash decrease placebo 36% vs. fluoxetine 50% (NS); after cross-over fluoxetine arm better (SS)
      • Conclusion: Fluoxetine 20 mg modestly effective

Citalopram (Celexa)

  • NCCTG -- citalopram 10 mg, 20 mg, 30 mg, vs placebo
    • Randomized. 254 postmenopausal women.
    • 2010 PMID 20498389 -- "Phase III, Placebo-Controlled Trial of Three Doses of Citalopram for the Treatment of Hot Flashes: NCCTG Trial N05C9." (Barton DL, J Clin Oncol. 2010 July 10;28(20):3278-83.)
      • Reduction in mean hot flash score 23% (placebo), 49%, 50%, 55% (10,20,30 mg). Secondary outcomes superior in 20 mg arm.
      • Citalopram is effective.

Antiseizure medications

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Gabapentin

  • NCCTG N03C5 -- antidepresant + gabapentin vs. gabapentin alone
    • Randomized. 188 patients, inadequate hot flash control on an antidepressant. Randomized to Arm 1) antidepressant + addition of gabapentin vs. Arm 2) tapering of antidepressant + addition of gabapentin. Observation x5 weeks
    • 2007 PMID 17146104 -- "Phase III trial of gabapentin alone or in conjunction with an antidepressant in the management of hot flashes in women who have inadequate control with an antidepressant alone: NCCTG N03C5." (Loprinzi CL, J Clin Oncol. 2007 Jan 20;25(3):308-12. Epub 2006 Dec 4.)
      • 5-week outcome: antidepressant + gabapentin 54% reduction vs. gabapentin 49% (NS)
      • Conclusion: Gabapentin decreases hot flashes by ~50%, regardless of concurrent antidepressant
  • Rochester (2002-4) -- estrogens, gabapentin, vs. placebo
    • 2006 PMID 16816054 — "Gabapentin, estrogen, and placebo for treating hot flushes: a randomized controlled trial." (Reddy SY, Obstet Gynecol. 2006 Jul;108(1):41-8.)
      • Randomized, double blind. 60 postmenopausal women w/ moderate to severe hot flashes. Randomized to 1) conjugated estrogens, 2) gabapentin (to 2400 mg/d), or 3) placebo.
      • Hot flash score reduced by 72% (estrogen), 71% (gabapentin), and 54% (placebo) over 12 week period. Difference between arms 1 & 2 not significant.
      • Conclusion: similar efficacy of gabapentin and estrogens
  • Rochester (2001-3) -- high dose (900 mg/d) vs low dose (300 mg/d) gabapentin vs placebo
    • 2005 PMID 16139656 — "Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial." (Pandya KJ, Lancet. 2005 Sep 3-9;366(9488):818-24.)
      • Randomized, double blind. 420 women with history of breast cancer. Randomized to 1) gabapentin 100 mg TID, 2) gabapentin 300 mg TID, or 3) placebo.
      • Hot flash severity score decreased by 31% (300 mg), 46% (900 mg), and 15% (placebo) over 8 week period; difference between 300 mg and 900 mg doses is S.S.
      • Conclusion: gabapentin is effective at reducing hot flashes at the 900 mg/d dose but not at 300 mg/d.
  • Rochester (2000-1) -- low dose gabapentin (900 mg/d) vs placebo
    • 2003 PMID 12576259 — "Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial." (Guttuso T Jr, Obstet Gynecol. 2003 Feb;101(2):337-45.)
      • Randomized, double blind. 59 postmenopausal women. Randomized to 1) gabapentin (100 mg TID) or 2) placebo. After 12 week period, pts optionally could enroll in open-label study of gabapentin, titrating up to 2700 mg/d.
      • At 12 weeks, gabapentin associated with 45% reduction in hot flash frequency and 54% reduction in hot flash composite score vs 29% and 31% for placebo. Higher reduction in symptoms with higher dose in open-label study.
      • Conclusion: gabapentin is effective at reducing hot flashes in postmenopausal women

Pregabalin

  • NCCTG/Mayo -- 75 mg BID vs 150 mg BID vs placebo
    • 2010 PMID 19901102 -- "Phase III, Randomized, Double-Blind, Placebo-Controlled Evaluation of Pregabalin for Alleviating Hot Flashes, N07C1" (Loprinzi CL, J Clin Oncol. 2010 Feb 1;28(4):641-7.)
      • Randomized. 163 pts. Assessed at week 6.
      • Hot flash score decreased by 50% (placebo), 65% (75mg) and 71% (150mg); SS vs placebo. Pregabalin was well tolerated.
      • Conclusion: pregabalin decreases hot flashes and is well tolerated.

Acupuncture

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  • Henry Ford Health System (2004-2007) -- acupuncture vs venlafaxine
    • Randomized. 50 patients with Stage 0-III breast cancer, pre- or postmenopausal, on TAM or arimidex, ≥ 14 hot flashes/week, finished chemotherapy. Arm 1) acupuncture x12 weeks vs Arm 2) venlafaxine 75 mg QD x12 weeks. Primary outcome hot flash frequency
    • 2010 PMID 20038728 -- "Acupuncture versus venlafaxine for the management of vasomotor symptoms in patients with hormone receptor-positive breast cancer: a randomized controlled trial" (Walker EM, J Clin Oncol. 2010 Feb 1;28(4):634-40. Epub 2009 Dec 28.)
      • Outcome: No difference in hot flashes, depressive symptoms, and QoL. By 2 weeks after treatment, venlafaxine group significant increase in hot flashes but no increase for acupuncture group. In addition, acupuncture improved sex drive and well-being
      • Toxicity: Venlafaxine 18 incidences of adverse effects vs none in acupuncture group
      • Conclusion: Acupuncture appears equivalent to drug therapy for vasomotory symptoms due to hormone therapy
  • MSKCC (2002-2005) -- acupuncture vs. sham
    • Randomized. 72 women with 3+ hot flashes/day. Arm 1) acupuncture vs. Arm 2) sham acupuncture, twice/week x4 weeks. Cross-over at 4 weeks
    • 2007 PMID 18065731 -- "Randomized, controlled trial of acupuncture for the treatment of hot flashes in breast cancer patients." (Deng G, J Clin Oncol. 2007 Dec 10;25(35):5584-90.)
      • Outcome: mean reduction acupuncture 2.5 vs. sham 2.6 hot flashes/day (NS), at 6 weeks difference of 0.8 hot flashes/day (NS)
      • Conclusion: No difference between acupuncture and sham, both groups showed reduction

Hypnosis

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  • Multi-Institutional -- hypnosis vs control
    • Randomized. 51/60 patients. Breast cancer survivors, no detectable disease, hot flashes >14 per week. Arm 1) hypnosis 5 sessions x50 minutes QW vs Arm 2) no treatment. 20% withdrew or lost to follow up
    • 2008 PMID 18809612 -- "Randomized Trial of a Hypnosis Intervention for Treatment of Hot Flashes Among Breast Cancer Survivors." (Elkins G, J Clin Oncol. 2008 Sep 22. [Epub ahead of print])
      • Outcome: Hot flashes (frequency x severity score) decreased by 68%. Sleep, and mood significantly better with hypnosis
      • Conclusion: Hypnosis appears to reduce perceived hot flashes, and my have additional benefits such as reduced anxiety, depression, and improved sleep

Comparisons

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  • Hamilton, Ontario -- venlafaxine vs gabapentin
    • Randomized, cross-over trial. 66 pts (breast cancer survivors). 4 weeks of gabapentin (300 mg TID) vs venlafaxine (75 mg qd). Primary end point: patient preference.
    • 2010 PMID 21060031 -- "Multicenter, Randomized, Cross-Over Clinical Trial of Venlafaxine Versus Gabapentin for the Management of Hot Flashes in Breast Cancer Survivors." (Bordeleau L, J Clin Oncol. 2010 Nov 8. [Epub ahead of print])
      • 56 of 66 pts indicated a preference - 68% venlafaxine, 32% gabapentin. 10 pts no response (8 dropped out, 2 no preference).
      • 66% reduction of hot flashes in both arms.
      • Conclusion: Breast cancer survivors prefer venlafaxine over gabapentin for treatment of hot flashes

Cognitive function

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Methylphenidate (d-MPH)

  • Wake Forest; 2007 PMID 17869448 -- "A Phase III, Double-Blind, Placebo-Controlled Prospective Randomized Clinical Trial of d-threo-methylphenidate HCl in Brain Tumor Patients Receiving Radiation Therapy." (Butler JM Jr, Int J Radiat Oncol Biol Phys. 2007 Sep 13; [Epub ahead of print])
    • Randomized. 68 patients with primary or metastatic brain tumors. Arm 1) prophylactic d-MPH 5mg BID -> 15mg BID vs. Arm 2) observation. Outcome measure QOL and cognitive function
    • Outcome: No difference in fatigue, QOL, or cognitive function
    • Conclusion: Prophylactic d-MPH not beneficial in brain tumor patients

Libido

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  • NCCTG N02C3 (2004-2005)
    • Randomized, cross-over. 150 postmenopausal women, history of cancer but NED, reported decrease in sexual desire, and a sexual partner. None on hormone replacement. Arm 1) 2% testosterone in Vanicream for 10 mg/day x4 weeks vs. Arm 2) placebo Vanicream, then crossed over for additional 4 weeks. Primary endpoint sexual desire/libido assessed at 4 and 8 weeks
    • 2007 PMID 17470735 -- "Randomized controlled trial to evaluate transdermal testosterone in female cancer survivors with decreased libido; North Central Cancer Treatment Group protocol N02C3." (Barton DL, J Natl Cancer Inst. 2007 May 2;99(9):672-9.
      • Outcome: mean testosterone significantly increased, but average libido change no different
      • Conclusion: No benefit, possibly because women on study were estrogen depleted


Gynecomastia

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  • Italy (2002-2004) -- observation vs. tamoxifen vs RT
    • Randomized, 3 arms. 5 centers. 151 patients with prostate cancer, any TN, M0, no gynecomastia/breast pain. Arm 1) bicalutamide 150 mg alone vs. Arm 2) bicalutamide 150 mg + tamoxifen 10 mg x24 weeks vs. Arm 3) bicalutamide 150 mg + RT 12/1. RT given as electrons to 5cm diameter of tissue around each nipple, 6-12 MeV to deliver 90% between skin and chest wall. In observation patients who developed gynecomastia (35/50), subsequently randomized to TAM or RT
    • 2005 PMID 15863377 -- "Efficacy of tamoxifen and radiotherapy for prevention and treatment of gynaecomastia and breast pain caused by bicalutamide in prostate cancer: a randomised controlled trial." (Perdona S, Lancet Oncol. 2005 May;6(5):295-300.)
      • Outcome: Gynecomastia observation 69% vs. TAM 8% (SS) vs. RT 34% (SS). Breast pain observation 57% vs. TAM 6% (SS) vs. RT 30% (SS). In observation patients randomized secondarily, gynecomastia TAM 12% vs. RT 56% (SS)
      • Toxicity: both TAM and RT well tolerated
      • Conclusion: Antiestrogen treatment with TAM appears superior to RT
  • Italy (2002-2004) -- observation vs. tamoxifen vs RT
    • Randomized. 102 patients, treated with RP for localized or locally advanced PCA. Treated with adjuvant bicalutamide and Arm 1) observation vs. Arm 2) tamoxifen 10 mg vs. Arm 3) RT. Arm 1 failures subsequently randomized to TAM vs. RT
    • 2005 PMID 16280763 -- "Gynecomastia and breast pain induced by adjuvant therapy with bicalutamide after radical prostatectomy in patients with prostate cancer: the role of tamoxifen and radiotherapy." (DiLorenzo G, J Urol. 2005 Dec;174(6):2197-203.)
      • Outcome: Gynecomastia observation 67% vs. TAM 8% (SS) vs. RT 34% (SS). Breast pain 58% vs. 7% vs. 30%
      • Toxicity: No difference in QoL between TAM and RT
      • Conclusion: Gynecomastia and breast pain induced by bicalutamide after RP can be prevented. Tamoxifen more effective than RT
  • Italy (2000-2002) -- observation vs. tamoxifen vs. anastrozole
    • Randomized. 114 patients with localized, locally advanced, or recurrent prostate cancer. Treated with bicalutamide 150 mg. Arm 1) placebo vs. Arm 2) tamoxifen 20 mg/d vs. Arm 3) anastrozole 1 mg/d x 48 weeks
    • 2005 PMID 15681525 -- "Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer." (Boccardo F, J Clin Oncol. 2005 Feb 1;23(4):808-15.)
      • Outcome: Gynecomastia observation 73% vs TAM 10% vs. anastrozole 51% (SS). Breast pain 39% vs. 6% vs. 27% (SS).
      • Toxicity: No difference in PSA response. Adverse events 37% vs. 35% vs. 69% (SS). No difference in sexual function
      • Conclusion: Tamoxifen was effective, no significant benefit for anastrozole
  • US Multi-institutional -- placebo vs. tamoxifen vs. anastrozole
    • Randomized, 3 arms. 107 patients with prostate cancer, T1-4 any NM0 (T2-3 in 92%), on bicalutamide 150 mg/d. Arm 1) observation vs. Arm 2) tamoxifen 20 mg/d vs. Arm 3) anastrozole 1 mg/d x3 months. Excluded if gynecomastia >2cm or breast discomfort
    • 2005 PMID 15685254 -- "Prevention and management of bicalutamide-induced gynecomastia and breast pain: randomized endocrinologic and clinical studies with tamoxifen and anastrozole." (Saltzstein D, Prostate Cancer Prostatic Dis. 2005;8(1):75-83.)
      • Outcome: 3-month gynecomastia TAM 12% (SS) vs. anastrozole 64% (NS) vs. placebo 69%
      • Toxicity: PSA decreased in all groups
      • Conclusion: Incidence of gynecomastia reduced by tamoxifen; anastrozole 1mg/d not a viable option
  • European (1999-2001) -- RT 10/1 vs. sham
    • Randomized. 106 patients, prostate cancer (T1b-T4NxM0), Casodex 150 mg/d x1 year. Arm 1) RT 10/1 electrons vs. Arm 2) sham RT.
    • 2004 PMID 15380582 -- "Prophylactic breast irradiation with a single dose of electron beam radiotherapy (10 Gy) significantly reduces the incidence of bicalutamide-induced gynecomastia." (Tyrrell CJ, Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):476-83.)
      • Outcome: Gynecomastia RT 52% vs. sham 85% (SS), fewer were >5 cm (11% vs. 50%) and fewer were moderate/severe (21% vs 48%). Breast pain 83% vs. 91% (NS)
      • Conclusion: Prophylactic breast RT is effective and well tolerated for prevention of gynecomastia

Skin Care

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Acute Radiation Dermatitis

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  • Quebec; 2009 PMID 19327906 -- "Use of axillary deodorant and effect on acute skin toxicity during radiotherapy for breast cancer: a prospective randomized noninferiority trial." (Theberge V, Int J Radiat Oncol Biol Phys. 2009 Nov 15;75(4):1048-52. Epub 2009 Mar 26.)
    • Randomized, non-inferiority trial. 84 patients with breast RT. Arm 1) deodorant use vs. Arm 2) no deodorant.
    • Outcome: Grade 2 axilla dermatitis deodorant 23% vs. no deodorant 30% (NS); Grade 2 breast dermatitis 30% vs. 34% (NS); no Grade 3+ dermatitis. Sweating deodorant 18% vs no deodorant 39% (SS)
    • Conclusion: No evidence to prohibit deodorant use during breast RT
  • St. Jude's; 2007 PMID 18093332 -- "A phase III trial comparing an anionic phospholipid-based cream and aloe vera-based gel in the prevention of radiation dermatitis in pediatric patients." (Merchant TE, Radiat Oncol. 2007 Dec 19;2:45.)
    • Randomized. 45 patients, irradiated to at least 23.4 Gy (mean 34 Gy), age >3 years. Two creams applied to each patient by nursing staff, site randomly chosen prior to treatment. Arm 1) anionic polar phospholipid (APP) based cream (made by Ocular Research of Boston, Boston, MA) vs. Arm 2) aloe vera-based cream
    • Outcome: Grouped scores better for APP cream. Dryness and peely skin also better for APP cream
    • Conclusion: APP cream is more effective than aloe-vera based gel
  • Edinburgh; 2007 (UK) PMID 17363185 -- "Randomized comparison of dry dressings versus hydrogel in management of radiation-induced moist desquamation." (Macmillan MS, Int J Radiat Oncol Biol Phys. 2007 Jul 1;68(3):864-72. Epub 2007 Mar 23.)
    • Randomized. 357 patients with breast (63%), H&N (30%) or anorectal CA. Arm 1) simple dry dressings vs. Arm 2) hydrogel (Intrasite). Started using from onset of moist desquammation. Prevalence of moist desquammation 28%, mean 32 days after starting treatment
    • Outcome: Time-to-healing significantly worse. No impact on subjective symptoms (pain, burning, sleep). Compliance significantly better with hydrogel dressing (93% vs. 63%)
    • Conclusion: Hydrogel dressing are worse than dry dressings, with prolonged healing time
  • RTOG 99-13; 2006 (2000-2002) PMID 16648511 -- "Phase III Trial of an emulsion containing trolamine for the prevention of radiation dermatitis in patients with advanced squamous cell carcinoma of the head and neck: results of Radiation Therapy Oncology Group Trial 99-13." (Elliott EA, J Clin Oncol. 2006 May 1;24(13):2092-7.)
    • Randomized, 3 arms. 547 patients with locally advanced H&N cancers. RT >=50 Gy. Arm 1) prophylactic trolamin emulsion TID starting 1st day of RT vs. Arm 2) interventional trolamine emulsion once symptomatic vs. Arm 3) declared instituional management (14 different products: Aquaphor 39%, gel 24%, cream 16%, corticosteroid 11%, other 10%)
    • Outcome: Grade 2+ radiation dermatitis prophylactic arm 79% vs. interventional arm 77% vs. institutional management 79% (NS)
    • Conclusion: No advantage for use of trolamin (Biafine) in reducing RT dermatitis over local standard of care
  • Rome; 2006 PMID 16980242 -- "A double-blind, vehicle-controlled clinical study to evaluate the efficacy of MAS065D (XClair), a hyaluronic acid-based formulation, in the management of radiation-induced dermatitis." (Primavera G, Cutan Ocul Toxicol. 2006;25(3):165-71.)
    • Randomized. Patients with BCA. Arm 1) control vs. Arm 2) Xclair
    • Outcome: Xclair significantly better for radiation dermatitis and erythema. No difference in pain and itch. Both patients and inverstigators preferred Xclair
    • Conclusion: Xclair can be an effective option for managing radiation dermatitis
  • Ratan Hospital; 2006 (India) PMID 17192690 -- "Prophylactic beclomethasone spray to the skin during postoperative radiotherapy of carcinoma breast: a prospective randomized study." (Shukla PN, Indian J Cancer. 2006 Oct-Dec;43(4):180-4.)
    • Randomized. 60 patients with BCA treated with 50/25, randomized to beclomethasone spray to irradiated axilla vs. observation
    • Wet desquammation: beclomethasone spray 13% vs. observation 37% (SS)
    • Conclusion: Topical steroid spray during RT reduces risk of wet desquammation
  • Prince of Wales; 2005 (Hong Kong)(2001-2003) PMID 16330964 -- "A comparison of wound treatments in nasopharyngeal cancer patients receiving radiation therapy." (Mak SS, Cancer Nurs. 2005 Nov-Dec;28(6):436-45.)
    • Randomized. 146 patients with nasopharyngeal CA, who developed moist desquammation. Arm 1) nonadherent absorbent dressings vs. Arm 2) gentian violet (control). Daily cleansing with 0.9% saline. Evaluated wound healing, presence of infectin, social isolation, sleep, neck mobility
    • Outcome: No difference in any outcome; trend to higher wound pain with gentian violet
    • Conclusion: Nonadherent absorbent dressing can be considered for moist desquamation
  • Dundee; 2004 (UK) PMID 15542162 -- "Does aqueous or sucralfate cream affect the severity of erythematous radiation skin reactions? A randomised controlled trial." (Wells M, Radiother Oncol. 2004 Nov;73(2):153-62.)
    • Randomized, 3 arms. 357 patients with H&N, breast, or anorectal CA. Arm 1) aqueous cream vs. Arm 2) sucralfate cream vs. Arm 3) no creme. Start first day of RT. Wash using unperfumed soap
    • Outcome: No difference among 3 groups. Predictors smoking, higher BMI, concurrent chemo, or bolus
    • Conclusion: No benefit for prophylactic aqueous or sucralfate cream
  • Munich; 2004 (Germany)(2002) PMID 15127162 -- "Thêta-Cream versus Bepanthol lotion in breast cancer patients under radiotherapy. A new prophylactic agent in skin care?" (Roper B, Strahlenther Onkol. 2004 May;180(5):315-22.)
    • Randomized. 20 patients with BCA. Arm 1) Theta-Cream vs. Arm 2) Bepanthol lotion (control). Evaluated by modified RTOG criteria and photography
    • Outcome: No difference between groups. Theta-Cream trend to worse skin markings, and mild itchiness
    • Conclusion: Theta-Cream not better, more expensive, and trend to worse outcome
  • Lyon; 2004 (France)(1999-2001) PMID 15084618 -- "Phase III randomized trial of Calendula officinalis compared with trolamine for the prevention of acute dermatitis during irradiation for breast cancer." (Pommier P, J Clin Oncol. 2004 Apr 15;22(8):1447-53.)
    • Randomized. 254 patients with BCA. Arm 1) Biafine (control) vs. Arm 2) calendula.
    • Outcome: Grade 2+ acute dermatitis calendula 41% vs. Biafine 63% (SS); also less frequent interruption of RT. Calendula more difficult to apply but self-assessed satisfaction greater
    • Conclusion: Calendula highly effective for prevention of acute Grade 2+ dermatitis
  • Tuebingen; 2002 PMID 12122788 -- "Intraindividual comparison of two different skin care conceptions in patients undergoing radiotherapy of the head-and-neck region. Creme or powder?" (Schreck U, Strahlenther Onkol. 2002 Jun;178(6):321-9.)
    • Randomized. 12 patients with H&N. Arm 1) creme vs. Arm 2) powder. Each patient would treat 1/2 neck with creme and other half with powder.
    • Outcome: No difference
    • Conclusion: No difference between cream and powder
  • Uppsala; 2001 (Sweden) PMID 11369066 -- "Potent corticosteroid cream (mometasone furoate) significantly reduces acute radiation dermatitis: results from a double-blind, randomized study." (Bostrom A, Radiother Oncol. 2001 Jun;59(3):257-65.)
    • Randomized. 49 patients with BCA. Arm 1) mometasone furoate cream (moderately potent) vs. Arm 2) emollient cream. Applied twice/week until 12th fraction, then daily. Both groups non-blinded emollient cream daily
    • Outcome: MMF decreased acute radiation dermatitis (SS); no difference in pigmentation
    • Conclusion: Adding MMF to emollient is more effective than emollient alone
  • Miami; 2001 PMID 11338761 -- "The effect of aloe vera gel/mild soap versus mild soap alone in preventing skin reactions in patients undergoing radiation therapy." (Olsen DL, Oncol Nurs Forum. 2001 Apr;28(3):543-7.)
    • Randomized. Arm 1) skin clense with mild unscented soap vs. Arm 2) soap + aloe very multiple times daily.
    • Outcome: No difference if dose <27 Gy; for dose >27 Gy, longer time-to-skin change soap 3 weeks vs. soap + aloe 5 weeks
    • Conclusion: Protective effect for adding aloe to soap
  • Beilinson; 2001 (Israel) PMID 11182045 -- "Topical Biafine and Lipiderm for the prevention of radiation dermatitis: a randomized prospective trial." (Fenig E, Oncol Rep. 2001 Mar-Apr;8(2):305-9.)
    • Randomized. 74 patients with BCA. Arm 1) Biafine vs. Arm 2) Lipiderm vs. Arm 3) no treatment. Ointments started 10 days prior to RT, applied BID. Endpoints evaluated were maximal skin toxicity, gaps in RT, impression of patients, subjective skin reaction, RN score and MD score.
    • Outcome: No difference in all endpoints among all 3 groups
    • Conclusion: Neither Biafine nor Lipiderm have a radioprotective effect
  • Quebec; 2001 (Canada) PMID 11230896 -- "The impact of skin washing with water and soap during breast irradiation: a randomized study." (Roy I, Radiother Oncol. 2001 Mar;58(3):333-9.)
    • Randomized. 99 patients with BCA. Arm 1) no washing vs. Arm 2) washing with water/soap.
    • Outcome: Moist desquamation no washing 33% vs. washing 14%. Median scores for pain, itching, burning higher in no washing group though (NS)
    • Conclusion: Washing irradiated skin during RT should not be discouraged
  • Royal Marsden; 2000 (UK) PMID 10699472 -- "Advice on hair and scalp care during cranial radiotherapy: a prospective randomized trial." (Westbury C, Radiother Oncol. 2000 Feb;54(2):109-16.)
    • Randomized. 109 patients undergoing cranial RT. Arm 1) no hair washing vs. Arm 2) routine hair washing. Recorded diary card showed lower frequency in Arm 1
    • Outcome: No difference in acute skin reactions
    • Conclusion: Normal hair washing does not increase adverse skin reactions
  • RTOG 97-13; 2000 PMID 11121627 -- "Randomized phase III study comparing Best Supportive Care to Biafine as a prophylactic agent for radiation-induced skin toxicity for women undergoing breast irradiation: Radiation Therapy Oncology Group (RTOG) 97-13." (Fisher J, nt J Radiat Oncol Biol Phys. 2000 Dec 1;48(5):1307-10.)
    • Randomized. 172 patients with BCA. Arm 1) Biafine vs. Arm 2) best supportive care (typically Aquaphor or Aloe Vera). Biafine applied TID, starting after first treatment.
    • Outcome: No difference. RTOG 0 Biafene 9% vs. BCS 7%; RTOG 1 50% vs. 58%; RTOG 2 41% vs. 32%; RTOG 3 0% vs. 3% (NS).
    • Large breast size: Biafine better. RTOG 0 Biafene 52% vs. BCS 10%; RTOG 1 48% vs. 80%; RTOG 2 0% vs. 10%
    • Conclusion: No overall difference between Biafine and best supportive care
  • Prince of Wales; 2000 (Hong Kong) PMID 10851773 -- "The effects of hydrocolloid dressing and gentian violet on radiation-induced moist desquamation wound healing." (Mak SS, Cancer Nurs. 2000 Jun;23(3):220-9.)
    • Randomized. 39 patients, 60 moist desquamation wounds. Arm 1) hydrocolloid (moist) dressing vs. Arm 2) gentian violet (control).
    • Outcome: No difference between the groups; substantially worse patient satisfaction with gentian violet due to discoloration and drying
    • Conclusion: No difference; patients should decide which they prefer
  • Switzerland; 1997 PMID 9106924 -- "Double-blind, randomized clinical study comparing hyaluronic acid cream to placebo in patients treated with radiotherapy." (Liguori V, Radiother Oncol. 1997 Feb;42(2):155-61.)
    • Randomized. 134 patients with H&N, breast, or pelvic CA. Arm 1) hyaluronic acid cream vs. Arm 2) placebo. mean RT dose 62 Gy
    • Outcome: acute radio-epithelitis significantly lower with hyaluronic acid. Both patient and physician preference for hyaluronic acid. No difference in tolerance
    • Conclusion: Prophylacit hyaluronic acid reduces high grade dermatitis
  • NCCTG; 1996 (1990-1991, 1992-1993) PMID 8892458 -- "Phase III double-blind evaluation of an aloe vera gel as a prophylactic agent for radiation-induced skin toxicity." (Williams MS, Int J Radiat Oncol Biol Phys. 1996 Sep 1;36(2):345-9.Related Articles, Links
    • Randomized. Breast cancer patients. Two separate randomizations: Trial 1 (n=194): Arm 1) aloe vera gel vs. Arm 2) placebo gel. After negative result, Trial 2 (n=108): Arm 1) aloe vera gel vs. Arm 2) no treatment. Minimum RT dose 50 Gy. Gel applied BID on starting RT. Skin dermatitis scored weekly by patients and health-care providers
    • Outcome: Trial 1: no difference between aloe vera gel and placebo. Trial 2: no difference between aloe vera gel and no treatment
    • Conclusion: Aloe vera gel (and placebo gel) do not protect against radiation-induced dermatitis
  • Norwegian Radium Hospital; 1996 PMID 9023388 -- "Skin treatment with bepanthen cream versus no cream during radiotherapy--a randomized controlled trial." (Lokkevik E, Acta Oncol. 1996;35(8):1021-6.)
    • Randomized. 79 patients, breast (n=63) and H&N (n=16). Arm 1) dexpanthenol cream vs. Arm 2) nothing. Applied on parts of treatment field for each patient.
    • Outcome: No difference by EORTC/RTOG grade or itching/pain
    • Conclusion: No clinically important benefit for using Bepanthen cream
  • CNS Cancer Consortium; 1993 PMID 8514538 -- "A double-blind, randomized, prospective trial to evaluate topical vitamin C solution for the prevention of radiation dermatitis. CNS Cancer Consortium." (Halperin EC, Int J Radiat Oncol Biol Phys. 1993 Jun 15;26(3):413-6.)
    • Randomized. 65 patients with primary/metastatic brain tumors. Arm 1) topical ascorbic acid solution vs. Arm 2) control. All patients both treatments; applied on one vs. other side of head.
    • Outcome: No difference in patient preference, or toxicity score
    • Conclusion: No benefit for ascorbic acid
  • Clatterbridge; 1992 (UK) PMID 1554631 -- "Can patients wash during radiotherapy to the breast or chest wall? A randomized controlled trial." (Campbell IR, Clin Oncol (R Coll Radiol). 1992 Mar;4(2):78-82.)
    • Randomized, 3 arms. 99 patients with BCA, some treated with bolus. Arm 1) not washing vs. Arm 2) washing with water alone vs. Arm 3) washing with soap and water.
    • Outcome: Subjective and objective measurements less in the two groups randomized to washing, regardless of bolus
    • Conclusion: Washing of skin should be encouraged in low skin doses

Skin Fibrosis

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  • Montpellier; 2008 (France) PMID 18211604 -- "A randomized, prospective study using the LPG((R)) technique in treating radiation-induced skin fibrosis: clinical and profilometric analysis." (Bourgeois JF, Skin Res Technol. 2008 Feb;14(1):71-6.)
    • Randomized. 20 women, s/p BCS + RT 6-16 months prior. Arm 1) LPG((R)) massage vs. Arm 2) observation
    • Outcome: LPG massage improved erythema, decreased pain and pruritus, decreased feeling of induration, and improved skin softness
    • Conclusion: Improvement after clinical signs after LPG massage

Diarrhea

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Selenium

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  • Lippe Hospital, Germany (2000-2006) -- selenium vs control
    • Randomized. 81 patients with uterine (88%) or cervical (12%) cancer. If pretreatment selenium <84 ug/l randomized to Arm 1) selenium 500 ug PO daily vs Arm 2) control. Primary endpoint: efficiency of supplementation
    • 2010 PMID 20133068 -- "Multicenter, Phase 3 Trial Comparing Selenium Supplementation With Observation in Gynecologic Radiation Oncology." (Muecke R, Int J Radiat Oncol Biol Phys. 2010 Feb 2. [Epub ahead of print])
      • Outcome: Selenium level post RT significantly higher with supplement. Grade 2+ diarrhea selenium 20% vs no selenium 44% (SS). No difference in other measures
      • Conclusion: Selenium supplementation effective in improving blood selenium status in deficient patients, and reduces RT-induced diarrhea

Octreotide

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  • RTOG 0315 (2003-2006) -- octreotide vs placebo
    • Randomized. 215 patients, rectal or anal cancer. Arm 1) long-acting octreotide 30 mg given 4-7 days before RT, and again day 22 vs Arm 2) placebo. Primary endpoint Grade 2+ diarrhea
    • 2010 PMID 20339140 -- "Octreotide acetate in prevention of chemoradiation-induced diarrhea in anorectal cancer: randomized RTOG trial 0315." (Zachariah B, J Natl Cancer Inst. 2010 Apr 21;102(8):547-56. Epub 2010 Mar 25.) Median F/U 10 months
      • Outcome: Grade 2-4 acute diarrhea octreotide 44% vs placebo 49% (NS). No difference in chemotherapy delivery, RT delivery, medical resource utilization, bowel function or QoL
      • Conclusion: Prophylactic use of octreotide had no benefit

Radiation Proctitis

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Acute radiation proctitis

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Sucralfate Prophylactic

  • Multi-institutional, 2001 (Australia)(1995-1997) PMID 11597802 -- "The effect of oral sucralfate on the acute proctitis associated with prostate radiotherapy: a double-blind, randomized trial." (Kneebone A, Int J Radiat Oncol Biol Phys. 2001 Nov 1;51(3):628-35.)
    • Randomized. 338 patients with localized prostate CA. Randomized to 1) 3g oral sucralfate suspension BID during RT or placebo; balanced but placebo group more liquid baseline stools
    • Outcome: No difference in stool frequency, consistency, flatus, mucus, or pain. More bleeding in sucralfate group (64% vs. 47%, SS)
    • Conclusion: No difference for oral sucralfate
  • North Central Cancer Treatment Group, 2000 PMID 10715293 -- "Sucralfate in the prevention of treatment-induced diarrhea in patients receiving pelvic radiation therapy: A North Central Cancer Treatment Group phase III double-blind placebo-controlled trial." (Martenson JA, J Clin Oncol. 2000 Mar;18(6):1239-45.)
    • Randomized. 123 patients, pelvic RT to minimum 45 Gy +/- oral sucralfate 1.5g q6 hours
    • Outcome: fecal incontinence (16% vs. 34%, SS), need for protective clothing (8% vs. 23%, SS) worse with sucralfate, otherwise no difference
    • Conclusion: sucralfate didn't improve bowel toxicity, and may have aggravated some GI symptoms
  • TROG, 1997 (Australia) PMID 9424000 -- "A phase III double-blind randomised study of rectal sucralfate suspension in the prevention of acute radiation proctitis." (O'Brien PC, Radiother Oncol. 1997 Nov;45(2):117-23.
    • Randomized. 86 patients with localized prostate CA. Treated with 1) daily 3.0g sucralfate enema in 15 mL suspension vs. 2) suspension alone. RT 64/32. (See below for long-term proctitis results)
    • Outcome: Grade 2 proctitis sucralfate 61% vs. placebo 71% (NS). No difference in time-to-onset or duration, or quality of life
    • Conclusion: Sucralfate enema not helpful in reducing acute radiation proctitis


Misoprostol Prophylactic

  • Goettingen, 2005 (Germany) PMID 16137837 -- "A phase III randomized, placebo-controlled, double-blind study of misoprostol rectal suppositories to prevent acute radiation proctitis in patients with prostate cancer." (Hille A, Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1488-93.)
    • Randomized. 100 patients with prostate CA. RT +/- misoprostol suppositories
    • Outcome: No differences in proctitis symptoms, onset, or duration. More rectal bleeding in misoprostol group
    • Conclusion: Misoprostol not helpful


Chronic radiation proctitis

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Sucralfate Prophylactic

  • TROG, 2002 (Australia)(1995-1996) PMID 12243820 -- "Acute symptoms, not rectally administered sucralfate, predict for late radiation proctitis: longer term follow-up of a phase III trial--Trans-Tasman Radiation Oncology Group. (O'Brien PC, Int J Radiat Oncol Biol Phys. 2002 Oct 1;54(2):442-9.)
    • Randomized. 86 patients with localized prostate CA. Treated with 1) daily 3.0g sucralfate enema in 15 mL suspension vs. 2) suspension alone. RT 64/32. Median F/U 5 years (see above for acute proctitis results)
    • Outcome: Grade 2 toxicity sucralfate 5% vs. placebo 12% (NS); late rectal bleeding 54% vs. 59% (NS)
    • Conclusion: No benefit


Sucralfate Therapeutic

  • Chandigarh, 1991 (India) PMID 1670631 -- "Radiation-induced proctosigmoiditis. Prospective, randomized, double-blind controlled trial of oral sulfasalazine plus rectal steroids versus rectal sucralfate." (Kochhar R, Dig Dis Sci. 1991 Jan;36(1):103-7.)
    • Randomized. 37 patients with RT-induced proctosigmoiditis. Treate with 1) 3.0g oral sulfasalazine x4 weeks + 20 mg BID rectal prednisolone enama vs. 2) 2.0g BID rectal sucralfate enema
    • 4-week outcome: both groups significant clinical and endoscopic improvement; sucralfate enema clinically significantly better clinically, same endoscopically
    • Conclusion: both treatments effective; sucralfate enemas better clinical response and cheaper


Pentoxifylline

  • Royal Marsden; 2008 PMID 18339525 -- "Pentoxifylline to treat radiation proctitis: a small and inconclusive randomised trial." (Venkitaraman R, Clin Oncol (R Coll Radiol). 2008 May;20(4):288-92. Epub 2008 Mar 12.)
    • Randomized. 40 patients. Arm 1) standard treatment vs. Arm 2) pentoxifylline x6 months
    • Outcome: No difference
    • Conclusion: No advantage for prevention of late rectal bleeding with pentoxifylline

Oral Mucositis

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Honey

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  • Egypt (2005-2006) -- chemo-RT +/- honey
    • Randomized. 40 patients with H&N cancer, treated with chemo-RT with significant area of oral or oropharynx mucosa in treatment field. Arm 1) topical application of pure natural honey vs. Arm 2) no honey. Evaluated weekly, aerobic cultures and candida colonisation assessed
    • 2008 PMID 18485252 -- "Honey as topical prophylaxis against radiochemotherapy-induced mucositis in head and neck cancer." (Rashad UM, J Laryngol Otol. 2008 May 19:1-6. [Epub ahead of print])
      • Outcome: Grade 3-4 mucositis honey 15% vs. no honey 65% (SS); candidiasis 15% vs. 60% (SS); aerobic pathogens 15% vs. 65% (SS)
      • Conclusion: Prophylaxis with pure natural honey effective in reducing mucositis

Caphosol

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  • Tufts -- caphosol + fluoride vs. fluoride alone
    • Randomized. 95 patients undergoing stem cell transplant. Arm 1) Caphosol + fluoride vs. Arm 2) fluoride alone
    • 2003 PMID 12692611 -- "A prospective, randomized trial for the prevention of mucositis in patients undergoing hematopoietic stem cell transplantation." (Papas AS, Bone Marrow Transplant. 2003 Apr;31(8):705-12.)
      • Outcome: Mucositis days Caphosol 3.7 days vs. control 7.2 days (SS); duration of pain 2.9 vs. 7.7 (SS); morphine dose 34 mg vs. 123 mg, days of morphine 1.3 days vs. 4.0 days (SS); and days to onset of ANC 11.1 days vs. 12.6 days
      • Conclusion: Caphosol is superior to fluoride rinse alone for oral mucositis

Iseganan

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  • Multi-National (2000-2001) -- iseganan vs. placebo vs supportive care
    • Randomized, 3 arms. 545 patients with RT for H&N cancer. Arm 1) iseganan solution (microbicidal solution) vs. Arm 2) placebo vs. Arm 3) standard oral care
    • 2004 PMID 14967419 -- "A multinational, randomized phase III trial of iseganan HCl oral solution for reducing the severity of oral mucositis in patients receiving radiotherapy for head-and-neck malignancy." (Trotti A, Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):674-81.)
      • Outcome: No ulcerative mucositis iseganan 9% vs. placebo 9% (NS) vs. supportive care 2% (SS). No difference in mouth pain or difficulty swallowing. Some benefit for nausea
      • Toxicity: No significant difference
      • Conclusion: Iseganan oral solution safe but didn't reduce risk of ulcerative mucositis

Antiseptic Mouth Rinse

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  • Complutense University, Spain -- antiseptic mouth rinse vs placebo
    • Randomized. 36 patients, RT for HNC. Arm 1) antiseptic mouth rinse vs Arm 2) placebo
    • 2010 PMID 20173709 -- "Mucositis in irradiated cancer patients: effects of an antiseptic mouthrinse." (Lanzos I, Med Oral Patol Oral Cir Bucal. 2010 Feb 21. [Epub ahead of print])
      • Outcome: No difference in degree of mucositis; 2-week mucositis worse in placebo group
      • Conclusion: Mouth rinse may lead to some improvement

Doxepin

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  • NCCTG N09C6, Alliance for Clinical Trials in Oncology (NCCTG/CALGB/ACOSOG) (2010-2012) -- doxepin rinse vs placebo
    see page at: Oral mucositis
    • Randomized, cross-over. 140 eligible pts undergoing definitive RT (>50 Gy, including > 1/3 of oral cavity) with oral mucositis pain rated >= 4/10. Randomized to doxepin oral rinse and spit (25 mg in 5 mL water). Pain assessed at baseline
    • 2012 Abstract - ASTRO 2012 LBA #1 PDF (Miller RC, Int J Radiat Oncol Biol Phys Vol. 85, Issue 1, Page 21)
      • Pain reduction AUC greater for doxepin (-9.1) vs placebo (-4.7), SS; similar crossover (-7.9 vs -5.6, SS). Doxepin well tolerated but caused stinging/burning, unpleasant taste, and drowsiness. 64% of pts continued on doxepin in the optional continuation phase.
      • Conclusion: "This study sets a new standard of care for the treatment of oral pain due to radiation-related oral mucositis."

Oral Candidiasis

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  • Genoa (Italy)
    • Randomized. 270 patients with H&N tumors. Arm 1) fluconazole 100 mg QD vs. Arm 2) placebo. Starting 6th treatment until end of treatment.
    • 2008 PMID 18419630 -- "Effects of fluconazole in the prophylaxis of oropharyngeal candidiasis in patients undergoing radiotherapy for head and neck tumour: results from a double-blind placebo-controlled trial." (Corvo R, Eur J Cancer Care (Engl). 2008 May;17(3):270-7.)
      • Outcome: candidiasis-free survival improved (SS); time-to-outbreak fluconazole 56 days vs. placebo 47 days; mean duration of RT fluconazole 39.9 days vs. placebo 43.5 days (SS)
      • Toxicity: fluconazole 70% vs. placebo 67% (NS)
      • Conclusion: Prophylaxis with fluconazole significantly reduces rate and improves time to development of oral candidiasis

Xerostomia

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Accupuncture

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  • South Korea
    • Randomized. 12 patients with H&N cancer and radiation-induced xerostomia. Arm 1) real acupuncture vs. Arm 2) sham acupuncture BIW x 6 weeks. Measured whole stimulated and unstimulated salivary flow rate, and questionnaire at 3 and 6 weeks after acupuncture
    • 2008 PMID 18532895 -- "Manual Acupuncture Improved Quality of Life in Cancer Patients with Radiation-Induced Xerostomia." (Cho JH, J Altern Complement Med. 2008 Jun 4. [Epub ahead of print])
      • Outcome: Whole salivary flow rate: no difference. Unstimulated flow rate: acupuncture significantly better. Subjective: acupuncture significantly less xerostomia
      • Conclusion: Significantly improved amelioration of subjective xerostomia

Hyperbaric Oxygen

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  • Erasmus Medical Center (2006-2007) -- RT +/- HBO
    • Randomized. Trial stopped prematurely due to slow accrual and lack of financial support. 19 of expected 132 patients, oropharynx or nasopharynx. Standard RT, then Arm 1) HBO vs. Arm 2) control. HBO given in 30 sessions @ 2.5 ATA x 90 minutes, started within 2 days after RT completion
    • 2009 PMID 19386439 -- "Early hyperbaric oxygen therapy for reducing radiotherapy side effects: early results of a randomized trial in oropharyngeal and nasopharyngeal cancer." (Teguh DN, Int J Radiat Oncol Biol Phys. 2009 Nov 1;75(3):711-6. Epub 2009 Apr 20.)
      • Outcome: Significant improvement in QoL for HBO, particularly swallowing, stickly saliva, xerostomia, and pain in mouth
      • Conclusion: HBO after RT results in better quality of life

Osteoradionecrosis

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Hyperbaric Oxygen

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  • French Multi-Institutional (1997-2001) -- hyperbaric oxygen vs. placebo
    • Randomized. Stopped early after 2nd interim analysis for lower HBO outcomes. 68 patients, history of RT for H&N cancer, with overt mandibular radionecrosis. Severe forms such as mandibular fracture or bony resorption excluded. Arm 1) 30 HBO exposures @ 2.4 ATM x90 min prior to surgery, with additional 10 HBO exposures post-operatively vs. Arm 2) placebo
    • 2004 PMID 15520052 -- "Hyperbaric oxygen therapy for radionecrosis of the jaw: a randomized, placebo-controlled, double-blind trial from the ORN96 study group." (Annane D, J Clin Oncol. 2004 Dec 15;22(24):4893-900. Epub 2004 Nov 1.)
      • Outcome: 1-year recovery HBO 19% vs. placebo 32% (NS)
      • Conclusion: Patients with overt mandibular osteoradionecrosis didn't benefit from HBO
  • University of Miami -- hyperbaric oxygen vs. penicillin
    • Randomized. High risk patients, history of RT, who required tooth removal. Arm 1) hyperbaric oxygen vs. Arm 2) penicillin
    • 1985 PMID 3897335 -- "Prevention of osteoradionecrosis: a randomized prospective clinical trial of hyperbaric oxygen versus penicillin." (Marx RE, J Am Dent Assoc. 1985 Jul;111(1):49-54.)
      • Outcome: incidence of ORN: HBO 5% vs. penicillin 30% (SS)
      • Conclusion: HBO should be considered a prophylactic measure when post-RT dental care involving trauma to tissue is necessary

Brachial Plexopathy

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Hyperbaric Oxygen

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  • UK MRC -- hyperbaric oxygen vs control
    • Randomized, Phase II. 34 patients, radiation-induced brachial plexopathy. Median time to onset 3 years, median time to HBO 11 years. Arm 1) hyperbaric oxygen: 100% oxygen @ 2.4 ATA x 100 minutes x 30 dives vs Arm 2) Control: same number and pressure, but gas mix equivalent to 100% oxygen at surface
    • 2001 PMID 11230889 -- "Double-blind randomized phase II study of hyperbaric oxygen in patients with radiation-induced brachial plexopathy." (Pritchard J, Radiother Oncol. 2001 Mar;58(3):279-86.)
      • Outcome: No difference up to 12 months post-treatment, though some improvement. Two cases with chronic lymphedema reported major and persistent improvement
      • Conclusion: HBO doesn't slow or reverse RIBP

Acute Esophagitis

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Sucralfate

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  • NCCTG (1993-1994) -- Sucralfate suspension vs placebo
    • Randomized. 97/100 patients undergoing mediastinal RT. Arm 1) Sucralfate suspension 1g/30 ml QID during and for 2 weeks after RT vs. Arm 2) placebo
    • 1997 PMID 9060568 -- "Placebo-controlled trial of sucralfate for inhibiting radiation-induced esophagitis." (McGinnis WL, J Clin Oncol. 1997 Mar;15(3):1239-43.)
      • Outcome: No difference in RTOG esophagitis score or self-reported questionnaire scores
      • Toxicity: GI toxicity sucralfate 58% vs. placebo 14% (SS); medication stopped 40% vs. 4% (SS)
      • Conclusion: No benefit for oral sucralfate solutions, with significant side effects

Amifostine

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  • Greece Multicenter (1997-1999) -- amifostine vs control
    • Randomized. 97 patients with advanced lung CA, undergoing definitive RT 55-60 Gy. No concurrent chemotherapy. Arm 1) amifostine 340 mg/m2 QD 15 min prior to RT vs. Arm 2) control
    • 2001 PMID 11704311 -- "Randomized phase III trial of radiation treatment +/- amifostine in patients with advanced-stage lung cancer." (Antonadou D, Int J Radiat Oncol Biol Phys. 2001 Nov 15;51(4):915-22.)
      • Pneumonitis: Grade 2+ amifostine 9% vs. control 43% (SS); Grade 2+ lung damage 16% vs. 49% (SS); 6-month rate of fibrosis 28% vs. 53% (SS)
      • Esophagitis: Grade 2+ amifostine 4% vs. 42% (SS)
      • Outcome: 2-month PR/CR amifostine 75% vs. control 76% (NS)
      • Conclusion: Amifostine reduces pneumonitis, lung fibrosis, and esophagitis without compromising efficacy

Joint Pain

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Aromatase Inhibitor-associated Arthralgias

  • Columbia University -- acupuncture vs sham
    • Randomized. 43 pts (38 eval). Postmenopausal women with musculoskeletal pain related to AIs. Acupuncture 2x/week for 6 weeks vs placebo.
    • 2010 PMID 20100963 -- "Randomized, Blinded, Sham-Controlled Trial of Acupuncture for the Management of Aromatase Inhibitor–Associated Joint Symptoms in Women With Early-Stage Breast Cancer." (Crew KD, J Clin Oncol. 2010 Mar 1;28(7):1154-60.)
      • Conclusion: significant improvement in joint pain and stiffness.


Lymphedema

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  • Royal Marsden PMID 15542159 -- "Double-blind placebo-controlled randomised trial of vitamin E and pentoxifylline in patients with chronic arm lymphoedema and fibrosis after surgery and radiotherapy for breast cancer" (Gothard L, Radiother Oncol. 2004 Nov;73(2):133-9. doi: 10.1016/j.radonc.2004.09.013.)
    • Randomized phase II. 68 patients, >20% arm volume at median 15 years after RT. 1) dl-alpha tocopheryl acetate (Vitamin E) 500 mg twice daily + pentoxifylline 400 mg twice daily x 6 months vs 2) placebo x 6 months. Primary endopoint volume of ipsilateral imb
    • Outcome: 1 year arm volume: Tx 2.5% vs placebo 1.2% (NS). No difference in tissue fibrosis, photographic appearance, or patient QoL
    • Conclusion: No benefit in this setting
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