IS
Naso-pharynx         Oro-pharynx          Oral CavityLarynx
Nasopharynx:Oral Cavity:1. Ant 2/3 Tongue2. Lip3. Floor of mouth4. Buccal mucosa5. Retromolar trigone6. Gum.Oro-pharynx:  ...
Larynx:I) Supra-Glottic: 1. Supra-hyoid epiglottis 2. Laryngeal aspect of AE Fold 3. Arytenoid 4. Infra-hyoid epiglottis 5...
HEAD AND NECK
WHY RT IMPORTANT• Usually localized disease at presentation.• Remains localized for long even after diagnosis.• Curable wi...
PRESENT STATUS HEAD AND NECK
PRESENT STATUS HEAD AND NECK• In developing countries most of the pt present in  stage IIIB – IV A• So we need intensive t...
Which are the intensive regimens ? – Altered fraction    • Hyperfractionatin/ Accelerated Fractionation/ CHART – CT+RT    ...
NEED ?                                        Toxicities   Local control• We need to device regimens which give  increase ...
Toxicities depends uponPatient Related     Treatment Related   Tumor Related       Physician RelatedKPS                 Po...
CONVENTIONAL RT• Conventional regimens    • 1.8 - 2 Gy/ #, 1 #/day & 5 days/week     • Weekly Dose accumulation of 9 -10 Gy
Altered fractionationsConventional fractionation:70Gy/35 F/ 7 W                                 HYPER                    ...
ALTERED FRACTIONATIONHYPERFRACTIONATION         ACCELERATED FRACTIONATION                               PURE      HYBRID  ...
Accelerated fractionation• Reduction in overall treatment time reduces the chance of  accelerated tumor cell repopulation•...
ACCELERATED TREATMENT   Pure accelerated             Hybrid accelerated fractionation• conventional total        •   ↓ ove...
Pure accelerated regimenRef             #/day        #      Dose   Results                             /wee               ...
DAHANCA 6&7         January, 1992 and December, 1999                726 stage I-IV 750Conventional                     Acc...
DAHANCA 6&7For the first time showed improved• 5 yr locoregional control (66% vs 57%). [p=0.005].• 5 yr disease free survi...
DAHANCA 6 and 7 trialsMucositis                Late Morbidity53% VS 33% P<0.0001                      Overgaard, Lancet 20...
ACCELERATION TYPE A          Fraction   Total dose    Tumour response        Complications          per day    (Gy)Dische ...
CHART - unique form of hybrid              fractionation.• 36 fractions over 12 consecutive days using 3  fractions per da...
CHART Regime• MRC Trial-918 patients.• Mostly Laryngeal cancers.• Non-significant improvement in disease free survival.• S...
Accelerated radiotherapy with delayed                    concomitant boost•   Initial target volume- conventional daily fr...
HYPERFRACTIONATION•   To further separate the early and late effects• overall treatment time 6-8 wks• two fractions / per ...
TRIALS OF HYPERFRACTIONATION           # per                      dose   Tumour response                 Complications    ...
Effect of time interval between two fractions                           Usually > 6 hrs of gap                           b...
Phase III Randomized Trial of Very Accelerated Radiation    Therapy Compared With Conventional Radiation Therapy  in Squam...
Phase III Randomized Trial of Very Accelerated Radiation  Therapy Compared With Conventional Radiation Therapyin Squamous ...
RTOG 9003 TRIAL (1073 PATIENTS)ARMS            Dose/#;     Dose     Rx time LRC     DFS     OS     Grade        Late      ...
Conclusion – Altered Fractionation• Local control and overall survival better at the  cost of increased toxicities.
CHEMORADIOTHERAPY (MACH-NC Update)• 24 new trials,87 in total( 50 concurrent), 16,000 patients• Absolute benefit (overall)...
A Three-arm Randomized Trial                    TMH Experience   Interim Analysis (Apr 2000 - Dec 2004, n= 150)        Con...
CONCLUSION         (TMH Experience Interim Analysis (Apr 2000 - Dec 2004, n= 150)• Accelerated fractionation and Concomita...
Combination of altered fractionation and                chemotherapy Several trials evaluated altered fractionation with ...
Randomized study -concurrent twice-a-day RT andchemotherapy (BIRCF) : results at 2 years (FNCLCC-                   GORTEC...
Hyper fractionated accelerated radiotherapy alone       and with concomitant chemotherapy                             • 4 ...
INTENSIVE RADIOTHERAPY ± CHEMOTHERAPY PROTOCOLS•   Leads to ↑ LRC and OS•   Allow for Organ Preservation•   By minimizing ...
INTENSIVE RADIOTHERAPY ± CHEMOTHERAPY PROTOCOLS• While on t/t performance and functional status  decline dramatically• Cor...
INTENSIVE RADIOTHERAPY ± CHEMOTHERAPY PROTOCOLS• The most salient persistent difficulties :  – Dry mouth  – Taste  – Stick...
TOXICITIES• Not unique with intensive protocols• Also seen in XRT or Sx+RT• In general, comparison across studies is diffi...
TOXICITIES
TOXICITIES•   Unfortunately Late effects also•   Just now being studied•   Validated tools•   Objective measures•   Profou...
Patient Selection for Aggressive Treatment Regimens• Careful Selection of pts• Who are capable of withstanding added toxic...
Patient Selection for Aggressive Treatment Regimens• Age• Performance score ( KPS)• Education/ Literacy• Stage and Histolo...
Patient Selection for Aggressive Treatment RegimensTreatment Benefit Decreases With Increasing Age          2 meta-analys...
Patient Selection for Aggressive Treatment Regimens "How do we generalize clinical trial results to the broader head and n...
NUTRITION• Significant proportion of pts. are malnourished at  presentation• Malnutrition has significant impact on morbid...
NUTRITION• ↓ intake may be due to  – Alcohol & Tobacco  – Poor dentition  – Partial or complete obstruction of aerodigesti...
NUTRITION• ↑ Demand due to acute metabolic stress.• Stage III/IV head & neck cancer treated with multiple  modalities—the ...
NUTRITION• Impact:   – Immunocompetence   – Inability to tolerate antineoplastic treatments   – Toxicities more severe—tre...
NUTRITION• Symptomatic treatment   –   Mucositis : Oral hygiene   –   Dental care   –   Nausea Vomiting: Ondensetron/ Gran...
NUTRITION• Oral Supplementation: Commercially available : Costly• Enteral nutrition   – Nasogastric tube feeding :      • ...
NUTRITION• Gastrostomy/Jejunostomy feeding tube:  – Appropriate for patients who will need longer-term enteral feeds    (a...
NUTRITION
NUTRITION• Impact of nutritional support:• Scolapio, et al showed that PEG placement before XRT  resulted in prevention of...
Does the Use of a Percutaneous Endoscopic Gastrostomy (Peg) Improve Complianceto Intensive Chemo-Radiotherapy (Crt) Protoc...
Resultsintensive CRT protocols are feasible provided there is a doable and effective nutritionsupportive system (i.e. PEG)...
Patterns of change over timeLikert Scale
MUCOSITIS• Most devastating Acute toxicity• Physical manifestation of tissue damage• Incidence (Gr 3-4) ↑  – 30-40%( RT al...
MUCOSITIS• Grading requires visual examination• Predominantly based on presence of erythema and  ulceration• Only visualiz...
MUCOSITIS• Underlying inflammation has many profound physiologic,  functional, and symptom control implications• Not captu...
MUCOSITIS• Pt. self administered tool by Epstein and colleagues       – Oral Mucositis Weekly Questionnaire -- Head and Ne...
MUCOSITIS• Used prospectively in 75 pts undergoing CCR       – ↑Oral pain from baseline to week 6       – 76% by the end o...
MUCOSITIS• No proven agents available to treat• Oral hygeine and pain is the dominant factor• Salt and soda gargles: cost ...
MUCOSITIS• Wobe-Mugos comprised papain 100 mg, trypsin 40 mg, and  chymotrypsin 40 mg• Efficacy of Wobe-Mugos((R)) E for R...
MUCOSITIS•   GM-CSF:phase III study by RTOG 9901•   Aim: reduce the severity and duration of mucositis•   SC injection of ...
MUCOSITISHow To Control and reduce the severity and duration of mucositis?
SKIN REACTIONS
SKIN REACTIONS•Prophylactic : Pt. education and self care instructions•Avoid tight clothes: Friction•Oral intake of fluids...
SKIN REACTIONS•   Dry desquamation: Flaky peeling of epidermis•   Cracks and fissures are common•   Sense of pain and prur...
SKIN REACTIONS• Moist desq: Maintain hygiene  – Prevent secondary infection  – Promote reepithelization• Ulceration/necros...
SKIN REACTIONS
SKIN REACTIONS• Dini and colleagues: mixture of staeric acid,  propylene glycol, glycerol & polysaturated alcohols• Hydrop...
SKIN REACTIONSTo delay the occurrence and reduces the grade of acute skinreactions.
DENTAL CARE• Radiation induced decay, necrosis and subsequent  need for dental extraction• Prophylactic care reduces incid...
DENTAL CARE• Normal salivation acts as buffer• Prevention of salivary function may be useful• Use of Fluoride toothpaste
LORHAN• Prospective development of Longitudinal Oncology  Registry of Head and Neck Carcinoma  – document the outcome (tum...
LORHAN– identify supportive care received   •   for managing nutrition   •   Pain   •   Nausea   •   other complications s...
LORHAN    – Approximately 25,000 patients will be enrolled on the      registry over the next 10 years    – FU for at leas...
Patients forget acute toxicities when they are  cured                    ANDDoctors forget late toxicities when they are t...
Pre-treatment and treatment related risk factors for severe latetoxicity after chemo-RT for head and neck cancer: an RTOG ...
Pre-treatment and treatment related risk factors for severe latetoxicity after chemo-RT for head and neck cancer: an RTOG ...
Pre-treatment and treatment related risk factors for severe latetoxicity after chemo-RT for head and neck cancer: an RTOG ...
OTHER CHALLENGES• Normal tissue complication probability    – Eg. cord tolerance    – Due to addition of chemo•   Second m...
But,Activity does notalways meanprogress                    89
norProgress is anhypothesis….                 90
Thank youProgress is definitegain in knowledgefor the future….       91
Purpose: safety and efficacy of CBRT and concurrent Cisplat in Advanced H&N cancers      Feb 2000 to June 2001, n= 95CBRT ...
ConclusionOn present evidence, in the settings of a developingcountry, CBRT with concurrent cisplatin cannot berecommended...
Some other useful data
Author                    No. of patients                                            T-stage                      Dose    ...
Bonner JA,et al. N Engl J Med 2006;354:567-578   .424 Patients        RT                 RT + CMabOS                  45  ...
Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma:   three meta-analyses of updated i...
Underperformance in Radiotherapy arm?                Brizel DM et al.N Engl J Med 1998;338:1798-1804122 patients          ...
Randomized trial of radiation therapy versus concomitant  chemotherapy and radiation therapy for advanced-stage           ...
Final results of the 94-01 French Head and Neck Oncology andRadiotherapy Group randomized trial comparing radiotherapy alo...
A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and  two variants of ac...
2 Yearendpoint            CFRT            70Gy/35#                       HFRT                              .              ...
Intensified hyperfractionated accelerated radiotherapy limitsthe additional benefit of simultaneous chemotherapy: resultso...
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers
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Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers

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  • The alternative strategy of accelerated treatment involves an approximately conventional total dose with a conventional fraction number, but since two fractions are given, the overall time is approximately halved. In practice, it is never possible to quite achieve this, since the early effects become limiting. It is usually necessary either to interpose a rest period in the middle of the treatment or to slightly reduce the dose with early effects as the limiting factor. The intent of this strategy is to reduce repopulation in rapidly proliferating tumours.
  • The basic aim of hyperfractionation is to further separate the early and late effects. The overall treatment time remains conventional at 6-8 wks, but since two fractions are used per day, the number of fractions are doubled to 60-80. The number of fractions must be increased because the dose per fraction has been decreased. The intent is to further reduce late effects while achieving the same or better tumour control and the same or slightly increased early effects.
  • H&amp;P should elicit weight, height, dysphagia h/o, anorexia, n/v, and identify anatomic reasons for malnutrition (mass/immobile tongue, dental caries, aspiration) Lab values include albumin, prealbumen, transferritin, retinol-binding protein) % of baseline weight loss = malnutrition = 10%--needs preop nutrition University of Pennsylvania nutritionists devised Prognostic Nutritional Index (PNI) which measures albumin, skin fold thickness, transferrin, skin testing—Goodwin and Torres showed that PNI &gt;25 needed aggressive nutritional restoration, PNI above 40 delay t/t until reconstituted
  • Anorexia: Megestrol (80-160mg qid), THC
  • Anorexia: Megestrol (80-160mg qid), THC
  • Anorexia: Megestrol (80-160mg qid), THC
  • Anorexia: Megestrol (80-160mg qid), THC
  • impact of mucositis and mucositis-related pain on a number of critical functions, including swallowing, talking, and eating
  • goal of which is to detail patterns of care and treatment outcomes for the general head and neck cancer population in the academic and community settings.
  • goal of which is to detail patterns of care and treatment outcomes for the general head and neck cancer population in the academic and community settings.
  • goal of which is to detail patterns of care and treatment outcomes for the general head and neck cancer population in the academic and community settings.
  • Precautions and challenges in delivering intense radiotherapy protocols with/without chemotherapy in head and neck cancers

    1. 1. IS
    2. 2. Naso-pharynx Oro-pharynx Oral CavityLarynx
    3. 3. Nasopharynx:Oral Cavity:1. Ant 2/3 Tongue2. Lip3. Floor of mouth4. Buccal mucosa5. Retromolar trigone6. Gum.Oro-pharynx: Hypo-pharynx:1. Post 1/3 Tongue 1. Pyriform sinus2. Post. Pharyngeal wall 2. Post. Pharyngeal wall3. Tonsil. 3. Post. Cricoid area
    4. 4. Larynx:I) Supra-Glottic: 1. Supra-hyoid epiglottis 2. Laryngeal aspect of AE Fold 3. Arytenoid 4. Infra-hyoid epiglottis 5. Ventricular bandsII) Glottic: 1. Vocal cord 2. Ant. Commissure 3. Post. CommissureIII) Sub-Glottis :
    5. 5. HEAD AND NECK
    6. 6. WHY RT IMPORTANT• Usually localized disease at presentation.• Remains localized for long even after diagnosis.• Curable with local form of treatment.• Only 5-10% distant metastasis without local recurrence.• Local control improves OS & DFS• Organ Preservation possible.
    7. 7. PRESENT STATUS HEAD AND NECK
    8. 8. PRESENT STATUS HEAD AND NECK• In developing countries most of the pt present in stage IIIB – IV A• So we need intensive treatment to improve LC by 10- 20 %
    9. 9. Which are the intensive regimens ? – Altered fraction • Hyperfractionatin/ Accelerated Fractionation/ CHART – CT+RT • Cisplatin/ 5FU/ Taxanes/ Gemcitabine/Combinations – Targeted therapies + RT • Trantuzumab/ cituximab / Monotuzumab – Altered fractionation + CTRT
    10. 10. NEED ? Toxicities Local control• We need to device regimens which give increase LC, Survival without increasing toxicities
    11. 11. Toxicities depends uponPatient Related Treatment Related Tumor Related Physician RelatedKPS Ports used Site CompetenceNutrition Energy selection Stage ConvenienceHydration Dose Location costSkin care Beam modifying Nodal Status Facilities devicesOral Hygiene Fractionation Depth of invasionDental Hygiene Setup Errors Quality Assurance
    12. 12. CONVENTIONAL RT• Conventional regimens • 1.8 - 2 Gy/ #, 1 #/day & 5 days/week • Weekly Dose accumulation of 9 -10 Gy
    13. 13. Altered fractionationsConventional fractionation:70Gy/35 F/ 7 W  HYPER FRACTIONATION –Any schedule employing a dose per fraction of lessHyperfractionation:81.6 Gy / 68 F / 6.8 W than 1.8 Gy  ACCELERATED – a schedule in which theAccelerated: 67.2 Gy / 42 F / 6w rate of dose- accumulation exceeds 10 Gy/week Accelerated: concomitant boost72 Gy / 42 F / 6 W
    14. 14. ALTERED FRACTIONATIONHYPERFRACTIONATION ACCELERATED FRACTIONATION PURE HYBRID CHART SPLIT COURSE CONCOMITANT BOOST
    15. 15. Accelerated fractionation• Reduction in overall treatment time reduces the chance of accelerated tumor cell repopulation• Greater probability of tumor regression for a given total radiation dose.• No increase in late normal tissue reactions-if dose per fraction is not increased and adequate interval is allowed between 2 fractions.• Increase in acute reactions -reduction in overall treatment time.
    16. 16. ACCELERATED TREATMENT Pure accelerated Hybrid accelerated fractionation• conventional total • ↓ overall treatment time with dose changes in fraction size, total dose,• conventional fraction and time distribution. number • Type A - shortened OTT with ↓ in• overall time is approx. the total dose (CHART) • Types B and C-duration modestly halved (2#/ day) shortened but the total dose is• Intent- to reduce same repopulation in rapidly • split-course (type B) proliferating tumours. • concomitant boost (type C)
    17. 17. Pure accelerated regimenRef #/day # Dose Results /wee kJackson 2(2.0) 10 66.0 CR 35%vs 29% (p=0.18)(Vancouver) 1(2.0) 5 66.0 no diff in relapse free survival Acute toxicity- 27%vs 8 % (p=.00006)Skaldowski 1(1.6-2) 7 70.0 3 yr LC 82%vs 37% (p<0.0001)CAIR (Polish) 1(1.6-2) 5 70.0 3yrOS 78% vs32% (p<0.0001) Acute toxicity-1·5 weeks earlier(66%vs 26%)Overgaard 1 (2.0 ) 6 66.0 5 yr LRC 66%vs 57% (p=0.01)DAHANCA 1(2) 5 66.0 5 yr DFS 72%vs 65% (p=0.004)Hliniak 1-2(2 ) 6 66.0 5yrLRC 52%vs47%(p 0.3) 1(2) 5 66.0 5yrDFS 41%vs 35% (p=0. 3)
    18. 18. DAHANCA 6&7 January, 1992 and December, 1999 726 stage I-IV 750Conventional Accelerated 66-68Gy/33-35# 66-68Gy/33-35#Wk 1 ♦ ♦ ♦ ♦ ♦ Wk 1 ♦ ♦ ♦ ♦ ♦ ♣Wk 2 ♦ ♦ ♦ ♦ ♦ Wk 2 ♦ ♦ ♦ ♦ ♦ ♣Wk3 ♦ ♦ ♦ ♦ ♦ Wk3 ♦ ♦ ♦ ♦ ♦ ♣Wk4 ♦ ♦ ♦ ♦ ♦ Wk4 ♦ ♦ ♦ ♦ ♦ ♣Wk5 ♦ ♦ ♦ ♦ ♦ Wk5 ♦ ♦ ♦ ♦ ♦ ♣Wk6 ♦ ♦ ♦ ♦ ♦ Wk6 ♦ ♦ ♦ ♦ ♦Wk7 ♦ ♦ ♦ ♦ ♦ Overgaard, Lancet 2003; 362: 933–40
    19. 19. DAHANCA 6&7For the first time showed improved• 5 yr locoregional control (66% vs 57%). [p=0.005].• 5 yr disease free survival ( 72% vs 65%). [p=0.01].• Improved voice preservation (80% vs 68%) [p=0.007] Overgaard, Lancet 2003; 362: 933–40
    20. 20. DAHANCA 6 and 7 trialsMucositis Late Morbidity53% VS 33% P<0.0001 Overgaard, Lancet 2003; 362: 933–40
    21. 21. ACCELERATION TYPE A Fraction Total dose Tumour response Complications per day (Gy)Dische 3 (1.5) 54.0(2wk No difference in More acute mucositis, lessCHART 1 (2.0) 66.0(6.5wks LRC,DFS &OS epidermal telangiectasia, and ) oedema with AFPoulsen 2 (1.8) 59.4(3.5wks 5 yr LRC- Severe acute MucositisTTROG 1 (2) ) 52%vs47%(p=0.35 yr (p=0.0006),lower frequency of 70(7wks) DFS 41%vs 35% grade >2 late side effects (p=0.32) (p<0.05)with AFBourhis 2 (2) 63.0(3.3wks 2 yr LRC Early stopping due to higherGORTEC ) treatment related deaths. 2(1) 58%vs 34%(p<0.01) 70.0(7wks) no diff in OS Lancet Oncology vol3 Nov 2002
    22. 22. CHART - unique form of hybrid fractionation.• 36 fractions over 12 consecutive days using 3 fractions per day,1.5Gy/fraction.• Total dose - 54Gy.(dose reduction by19%).• Acceleration of treatment time by 4.5 wks. Radiother Oncol. 44:123–36 (1997).
    23. 23. CHART Regime• MRC Trial-918 patients.• Mostly Laryngeal cancers.• Non-significant improvement in disease free survival.• Strong trend for improved benefit in patients with advanced disease(p=0.065).• Lesser late effects(mucosal ulceration, necrosis and telangiectasia).• Acute mucositis more severe 73% VS 43% (occurring in 3rd week). Radiother Oncol. 44:123–36 (1997).
    24. 24. Accelerated radiotherapy with delayed concomitant boost• Initial target volume- conventional daily fractions• Boost - second daily fraction in last 2 weeks• Total dose -63 Gy/35 days Grade 3 mucositis -50% DFS- 56% OAS -76% MACKENZIE I JROBP( 45, No. 3) 589–595, 1999
    25. 25. HYPERFRACTIONATION• To further separate the early and late effects• overall treatment time 6-8 wks• two fractions / per day• number of fractions are doubled to 60-80• dose per fraction - decreased• Intent - further reduce late effects while achieving the same or better tumour control and the same or slightly increased early effects.
    26. 26. TRIALS OF HYPERFRACTIONATION # per dose Tumour response Complications day 2 (1.2) 81.6 LRC-higher with HF and CBMarcial 1-2(1.6) 72.0 (p=0.045 & .06) More acute MucositisRTOG 2(1.6) 67.2 DFS trend favours HF; no no difference in late complications 1 (2.0) 70.0 difference in OS 5 yr LRC – More acute mucositis with NoHoriot 2 (1.15) 80.5 56%vs38%(p=0.02), difference with late complicationsEORTC 1 (2.0) 70.0 rate 5 yr LRCCummings 2(1.4) 58.0 More acute mucositis with 45% vs. 37% (p=0.01)PMH 1 (2.5) 51.0 Late Toxicity-8%vs.14% (p= 0.31) 5 yr OS 40%vs30%(p=0.01) (Lancet Oncology vol3 Nov 2002)
    27. 27. Effect of time interval between two fractions Usually > 6 hrs of gap between two fractions
    28. 28. Phase III Randomized Trial of Very Accelerated Radiation Therapy Compared With Conventional Radiation Therapy in Squamous Cell Head and Neck Cancer: A GORTEC Trial Conventional -70 Gy/ 35 # of 2 Gy over 49 days very accelerated RT-62 - 64 Gy/ 31-32 # over 22 to 23 days (2 Gy/fraction bid). J Clin Oncol. 2006 Jun 20;24(18):2873-8.
    29. 29. Phase III Randomized Trial of Very Accelerated Radiation Therapy Compared With Conventional Radiation Therapyin Squamous Cell Head and Neck Cancer: A GORTEC Trial J Clin Oncol. 2006 Jun 20;24(18):2873-8.
    30. 30. RTOG 9003 TRIAL (1073 PATIENTS)ARMS Dose/#; Dose Rx time LRC DFS OS Grade Late No. of # III/IV Toxicitie reactions sStandard 2Gy/#; 35 70Gy 7 week 46% 31.7% 46% 35% 9%fractionation #Accelerated 1.6Gy/#; 67.2Gy 6 week 47.5% 33.2% 46.2% 51% 8%fractionation 42 #with splitHyperfraction 1.2Gy/#; 81.6Gy 7 week 54% 37.6% 54.5% 55% 9%ation 68#Accelerated 1.8Gy/#; 50.4Gy 6 week 54.5% 39.3% 50.9% 59% 9%fractionation 30+12# + 8 Gywith CB Int J Radiat Oncol Biol Phys. 48:7-16 (2000).
    31. 31. Conclusion – Altered Fractionation• Local control and overall survival better at the cost of increased toxicities.
    32. 32. CHEMORADIOTHERAPY (MACH-NC Update)• 24 new trials,87 in total( 50 concurrent), 16,000 patients• Absolute benefit (overall) 5% at 5yrs• Concurrent RT, HR - 0.81(p=0.0001)• Absolute benefit (concurrent) 8% at 5 yrs•No difference between mono chemo (0.84) and poly chemo(0.77)• Magnitude of benefit higher for platinum based chemo (0.75)than for other chemo (0.86) [p=0.01]. JCO vol 22, No 14S (July 15 Supplement:5505(2004).
    33. 33. A Three-arm Randomized Trial TMH Experience Interim Analysis (Apr 2000 - Dec 2004, n= 150) Conventional Radiotherapy versusConcurrent Chemotherapy and Radiotherapy versus Accelerated Radiotherapy Advanced (Stage III & IV) Non- Nasopharyngeal Squamous Cell Carcinoma Of The Head and Neck
    34. 34. CONCLUSION (TMH Experience Interim Analysis (Apr 2000 - Dec 2004, n= 150)• Accelerated fractionation and Concomitant chemo radiotherapy is feasible in our setup• Acceptable Increased Acute Toxicity with chemoradiotherapy (reflected as increased hospitalisation)
    35. 35. Combination of altered fractionation and chemotherapy Several trials evaluated altered fractionation with chemotherapy. Showed some improvement in locoregional control and improved survival. 100% patients developed severe and early mucositis. Combination should only be used in a trial setting.
    36. 36. Randomized study -concurrent twice-a-day RT andchemotherapy (BIRCF) : results at 2 years (FNCLCC- GORTEC)Hyper fractionation(1.2 • Treatment complianceGy/# ,Twice-daily 80.4 was quite satisfactoryGy/46 day • Mucositis grade 3–4 -69.5% /82.6%Chemotherapy (arm B): • OS: 20.1% /37.8%(p<Cisplatin 100 mg/m2 0.038)5FU750 mg/m2/day • DFS: 48.2% vs. 25.2%cycle 1 (p < 0.002) IJROBP 64(4) 983–994, 2006
    37. 37. Hyper fractionated accelerated radiotherapy alone and with concomitant chemotherapy • 4 yr OAS - 18% /33%, (p = Arm A- 77.2 Gy (16 Gy as 0.25 ) 2Gy /#→rest as 1.4 Gy /# • 4-year DFS- 36%/ 41% (p = twice daily) Arm B- RT 70.6 Gy(30 Gy 0.5) as 2Gy /#→rest as 1.4 • Mucositis III/IV occurred in Gy /# twice daily) 27% in chemotherapy arm +MMC+5FU HEHR R&O July 2006,
    38. 38. INTENSIVE RADIOTHERAPY ± CHEMOTHERAPY PROTOCOLS• Leads to ↑ LRC and OS• Allow for Organ Preservation• By minimizing Sx, ↓potential cosmetic Sequelae• ↓functional impairment• Impose severe acute toxicities• Some degree of chronic impairment
    39. 39. INTENSIVE RADIOTHERAPY ± CHEMOTHERAPY PROTOCOLS• While on t/t performance and functional status decline dramatically• Corresponding increase in symptoms• Improvement in most domains by 12 mths• 1/3 continue to report difficulty in speech, swallowing and pain• Similar pretreatment magnitude.
    40. 40. INTENSIVE RADIOTHERAPY ± CHEMOTHERAPY PROTOCOLS• The most salient persistent difficulties : – Dry mouth – Taste – Sticky saliva – Comfort in eating/socializing with others – Ability to eat a full range of solid foods• Associated with QOL
    41. 41. TOXICITIES• Not unique with intensive protocols• Also seen in XRT or Sx+RT• In general, comparison across studies is difficult• Many reports include both early and late-stage patients at various times after treatment• Data are presented in terms of mean scores on a variety of measures
    42. 42. TOXICITIES
    43. 43. TOXICITIES• Unfortunately Late effects also• Just now being studied• Validated tools• Objective measures• Profound impact on pts. Physical, functional & emotional well being.
    44. 44. Patient Selection for Aggressive Treatment Regimens• Careful Selection of pts• Who are capable of withstanding added toxicity burden• Careful medical, psychological, and social history• Spend quality time with pt. for councelling• History of smoking or alcoholism: related comorbidities• Social support network and financial condition
    45. 45. Patient Selection for Aggressive Treatment Regimens• Age• Performance score ( KPS)• Education/ Literacy• Stage and Histology• Pretreatment nutritional assessment Thus most of Aggressive treatment regimens/ trials tend to skew more younger, healthier, educated pts.
    46. 46. Patient Selection for Aggressive Treatment RegimensTreatment Benefit Decreases With Increasing Age  2 meta-analyses Meta-Analyses of Radiotherapy in HeadAge Alt-RT vs standard RT Concomitant CT+RT vs and Neck Cancer; Bourhis J, ASTRO 2002 & RT ASCO 2004 # HR P Trend # HR P Trend Patients Test Patients Test Patients aged 71 years or older had< 50 1311 0.78 .007 2584 0.76 .003 lower performance status lower stage at presentation51-60 2300 0.95 3306 0.78 higher rate of laryngeal primaries higher percentage were women61-70 2346 0.92 2698 0.88 proportion of deaths due to causes other71+ 1085 1.08 692 0.97 than head and neck cancer increased with age Bourhis J Sr., Abstract 5501, Journal of Clinical Oncology, 24, 280s
    47. 47. Patient Selection for Aggressive Treatment Regimens "How do we generalize clinical trial results to the broader head and neck population, which is plagued with medical, social, and financial problems?"
    48. 48. NUTRITION• Significant proportion of pts. are malnourished at presentation• Malnutrition has significant impact on morbidity, mortality and QOL• Causes – ↓Nutrient intake – ↑ demand – Tx induced Derangements
    49. 49. NUTRITION• ↓ intake may be due to – Alcohol & Tobacco – Poor dentition – Partial or complete obstruction of aerodigestive tract – Trismus – Post-surgical functional and anatomic impairments of chewing and swallowing – Post-XRT mucositis, odynophagia, dysphagia, xerostomia – Chemotherapy-induced nausea, vomiting• ↑ nutrient loss: Vomiting
    50. 50. NUTRITION• ↑ Demand due to acute metabolic stress.• Stage III/IV head & neck cancer treated with multiple modalities—the strongest independent predictor of survival was pretreatment weight loss (Mick, et al).• Head & neck cancer patients shown to have a significant decrease in survival at 2 years if malnourished (57.5% vs. 7.5%) (Brookes, et al).
    51. 51. NUTRITION• Impact: – Immunocompetence – Inability to tolerate antineoplastic treatments – Toxicities more severe—treatment delays, higher costs• Assessment: – History & physical exam – Anthropomorphic measurements – Skin testing – Laboratory values – Weight loss as percentage of baseline weight – Dietitian referral
    52. 52. NUTRITION• Symptomatic treatment – Mucositis : Oral hygiene – Dental care – Nausea Vomiting: Ondensetron/ Graniseteron – Odynophagia• Nutritional counseling – Who tolerate PO – High calorie ,High protein Diet – Plenty of fluids – Diet modification: Bland, not very hot/cold, Soft consistency – Maintain Diet book
    53. 53. NUTRITION• Oral Supplementation: Commercially available : Costly• Enteral nutrition – Nasogastric tube feeding : • weight loss >5% • Need replacement when narrow lumen clogs/ discolouration/ hygiene • Pt. tolerance • Reflux – Gastrostomy/Jejunostomy feeding tube: • Open, endoscopic, flouroscopic
    54. 54. NUTRITION• Gastrostomy/Jejunostomy feeding tube: – Appropriate for patients who will need longer-term enteral feeds (at least 2 weeks) – Can be easily maintained and used in outpatient setting, less cosmetic impact – Fewer but severe complications – Complications: leak, infection, skin excoriation,dysfunction, pain – Isolated case reports of metastatic deposits
    55. 55. NUTRITION
    56. 56. NUTRITION• Impact of nutritional support:• Scolapio, et al showed that PEG placement before XRT resulted in prevention of weight loss, treatment interruption, and hospitalization for hydration.• Shaleen kumar et al. showed that PEG placement can improve compliance in delivering intensive chemoradiation.
    57. 57. Does the Use of a Percutaneous Endoscopic Gastrostomy (Peg) Improve Complianceto Intensive Chemo-Radiotherapy (Crt) Protocols in Advanced Head-Neck Cancers? Shaleen Kumar et al, SGPGI, UICC World Cancer Congress 2006• Stage III and IV SCC of Head and Neck region• 68 patients ( Aug 2003-Oct 2005)• 6 fraction-a-week radiotherapy protocol (70Gy/35fx/6 weeks) concurrent with weekly cisplatin 35mg/m2 The two groups were balanced for patient, disease and CRT interventions.
    58. 58. Resultsintensive CRT protocols are feasible provided there is a doable and effective nutritionsupportive system (i.e. PEG) in place. This measure limits treatment related mortality whichotherwise would negate any potential benefits of intensification
    59. 59. Patterns of change over timeLikert Scale
    60. 60. MUCOSITIS• Most devastating Acute toxicity• Physical manifestation of tissue damage• Incidence (Gr 3-4) ↑ – 30-40%( RT alone) to 60-100%( CMR)• No proven agent to prevent or treat till date• Current recommendation: supportive care – Pain control – Oral Hygiene – Nutritional counseling
    61. 61. MUCOSITIS• Grading requires visual examination• Predominantly based on presence of erythema and ulceration• Only visualized in oral cavity and oropharynx• Difficult to assess in nasopharynx, hypopharynx, larynx• Greatly underrepresent the extent and impact
    62. 62. MUCOSITIS• Underlying inflammation has many profound physiologic, functional, and symptom control implications• Not captured by assessment of mucosal integrity only• Inflammation results in – Edema – Pain – Dysphagia – Odynophagia – Altered diatery intake – Systemic manifestations
    63. 63. MUCOSITIS• Pt. self administered tool by Epstein and colleagues – Oral Mucositis Weekly Questionnaire -- Head and Neck (OMWQ-HN)• Self report that measures impact of mucositis• Used along with – Performance Status Scale for Head and Neck Cancer (PSS-HN) – Functional Assessment of Cancer Therapy (FACT-HN)• Found valid and reliable*• ↑oral pain was associated with decreasing oral functionEpstein JB, Beaumont JL, Gwede CK, et al. Preliminary results of the validation of a patient (pt) self-administered questionnaire (Oral MucositisWeekly Questionnaire-Head and Neck [OMWQ-HN]) to assess the impact of OM on pain and functioning in head and neck cancer (HNC). ProcAm Soc Clin Oncol. 2006;24:292s
    64. 64. MUCOSITIS• Used prospectively in 75 pts undergoing CCR – ↑Oral pain from baseline to week 6 – 76% by the end of week 6 : severe pain due to mouth and throat soarness – High % of patients were on opoids : Pain remained problamatic – Oral pain associated with ↓in swallowing and vocal function – Results in costly utilization of resources • Feeding tube placement • Unanticipated visits • HospitalizationIsitt J, Murphy BA, Beaumont JL, et al. Oral mucositis (OM) related morbidity and resource utilization in a prospective study of head and neckcancer (HNC) patients. Proc Am Soc Clin Oncol. 2006;24:289s
    65. 65. MUCOSITIS• No proven agents available to treat• Oral hygeine and pain is the dominant factor• Salt and soda gargles: cost effective• Micronized sucralfate suspension• Newer agents, such as palifermin (recombinant human keratinocyte growth factor-1) showed some benefit• Saforis (an oral glutamine suspension) may also promote recovery from mucosal damage• Wobe-Mugos (proteolytic enzymes)
    66. 66. MUCOSITIS• Wobe-Mugos comprised papain 100 mg, trypsin 40 mg, and chymotrypsin 40 mg• Efficacy of Wobe-Mugos((R)) E for Reduction of Oral Mucositis after Radiotherapy : Results of a Prospective, Randomized, Placebo-Controlled, Triple-Blind Phase III Multicenter Study• Result: tolerated well but no promising results
    67. 67. MUCOSITIS• GM-CSF:phase III study by RTOG 9901• Aim: reduce the severity and duration of mucositis• SC injection of GM-CSF 250 µg/m2 3 times a week• Result : no significant effect• New formulation : RK 0202(N-acetyl-L-cysteine ) – 6 times a day as oral rinse – Chambers et al showed some promising results. – Less mucositis(by 19 – 29% for 60Gy- 50 Gy),less FT and opoids
    68. 68. MUCOSITISHow To Control and reduce the severity and duration of mucositis?
    69. 69. SKIN REACTIONS
    70. 70. SKIN REACTIONS•Prophylactic : Pt. education and self care instructions•Avoid tight clothes: Friction•Oral intake of fluids: 3 – 4 lit/day•Avoid Shaving, soaps, cosmetics: irritation & dryness•Protection from temperature, Sun, Ice pack, Heating pads
    71. 71. SKIN REACTIONS• Dry desquamation: Flaky peeling of epidermis• Cracks and fissures are common• Sense of pain and pruritus• Effect of dose, friction• Can progress to moist desqumation• bacterial/ fungal infection
    72. 72. SKIN REACTIONS• Moist desq: Maintain hygiene – Prevent secondary infection – Promote reepithelization• Ulceration/necrosis – Use of Amniotic membrane: Available at tissue bank – May require tissue graft
    73. 73. SKIN REACTIONS
    74. 74. SKIN REACTIONS• Dini and colleagues: mixture of staeric acid, propylene glycol, glycerol & polysaturated alcohols• Hydrophilic+ Hydrophobic in a foam emultion• Form protective barrier without rubbing.• Complete dissaperance of symptoms in 58% – 50 % reduction in 38 %• Steroidal preparations : Betnovate-N ™
    75. 75. SKIN REACTIONSTo delay the occurrence and reduces the grade of acute skinreactions.
    76. 76. DENTAL CARE• Radiation induced decay, necrosis and subsequent need for dental extraction• Prophylactic care reduces incidence by 1/3rd• Already decayed teeth: pretreatment extraction• FGA : protection against acidic degradation• Damage to periodontal membrane: tooth decay• Decreased salivation
    77. 77. DENTAL CARE• Normal salivation acts as buffer• Prevention of salivary function may be useful• Use of Fluoride toothpaste
    78. 78. LORHAN• Prospective development of Longitudinal Oncology Registry of Head and Neck Carcinoma – document the outcome (tumor control, survival) – determine the incidence and severity of major dose- limiting and other important treatment toxicities such as • mucositis/stomatitis • skin reactions • infusion reactions • allergic reactions/hypersensitivity
    79. 79. LORHAN– identify supportive care received • for managing nutrition • Pain • Nausea • other complications such as feeding or tracheotomy tube use • opioid analgesic use • antiemetic use • use of other selected supportive care agents
    80. 80. LORHAN – Approximately 25,000 patients will be enrolled on the registry over the next 10 years – FU for at least 2 years and up to 10 years – If successful, the LORHAN database may provide invaluable insight into treatment outcomes in various head and neck patient populationsCurran W, Chen A, Harari P, et al. Longitudinal Oncology Registry of Head and Neck Carcinoma(LORHAN), a new national cancer registry. Proc Am Soc Clin Oncol. 2006;24:300s
    81. 81. Patients forget acute toxicities when they are cured ANDDoctors forget late toxicities when they are treating
    82. 82. Pre-treatment and treatment related risk factors for severe latetoxicity after chemo-RT for head and neck cancer: an RTOG analysis. Machtay M, Moughan J, Trotti A, et al Proc Am Soc Clin Oncol. 2006;24:280s • 3 CCR protocols (RTOG 91-11, 97-03, 99-14)
    83. 83. Pre-treatment and treatment related risk factors for severe latetoxicity after chemo-RT for head and neck cancer: an RTOG analysis. Machtay M, Moughan J, Trotti A, et al Proc Am Soc Clin Oncol. 2006;24:280s• 25 patients had a feeding tube at least 2 years after completion of therapy• Overall % of late effect = 43%• Predictors OR p Value – Age 1.05 .01 – Stage 3.08 .004 – Tumor Size 4.41 .03 – Neck dissection 2.55 .011
    84. 84. Pre-treatment and treatment related risk factors for severe latetoxicity after chemo-RT for head and neck cancer: an RTOG analysis. Machtay M, Moughan J, Trotti A, et al Proc Am Soc Clin Oncol. 2006;24:280s• % of late effects is high as compared to reported by Large RCTs• ↑Awareness and efforts to capture late effects
    85. 85. OTHER CHALLENGES• Normal tissue complication probability – Eg. cord tolerance – Due to addition of chemo• Second malignancies• Hypoxia• No surrogate markers• Strict QA
    86. 86. But,Activity does notalways meanprogress 89
    87. 87. norProgress is anhypothesis…. 90
    88. 88. Thank youProgress is definitegain in knowledgefor the future…. 91
    89. 89. Purpose: safety and efficacy of CBRT and concurrent Cisplat in Advanced H&N cancers Feb 2000 to June 2001, n= 95CBRT : ph I—44 Gy/22fx/4.5 weeks, ph IIa—16 Gy/8fx/1.5 weeks Ph IIb—10 Gy/8fx (delivered as a second daily fraction after a gap of 6 h along with phase IIa)CT: cisplatin 35 mg/m2 weekly usually preceding CBRT by an hour
    90. 90. ConclusionOn present evidence, in the settings of a developingcountry, CBRT with concurrent cisplatin cannot berecommended as primary therapy in advancedhead and neck cancers without formal comparisonwith other treatment modalities.
    91. 91. Some other useful data
    92. 92. Author No. of patients T-stage Dose Local Control(Institute) (Year)Cellai.E 205 (Early Glottic Ca)(Univ. of Florence) (1970-1985) T1a: 45 61-64Gy 43(96%) T1b: 110 97(88%) T2 : 50 38(76%)Chang 74 (Pharyngeal Ca)(Univ. of Oregon) (1971-1991) T1:6 60-70Gy 100% T2:27 59-72Gy 55% T3:32 59-74Gy 31% T4:9 60-70Gy 29%Overgaard 478 T1larynx(Danish Cancer Soc.) (1963-1985) Glottic:358 81% Supra: 117 55% Sub: 3Dinshaw 568 (1990 - 1996) All sites (except nasophx) 60 - 70 Gy 53%(Clinical oncology 2006 All stages
    93. 93. Bonner JA,et al. N Engl J Med 2006;354:567-578 .424 Patients RT RT + CMabOS 45 553 YearsLRC 34 473 YearsGr ¾ Mucositis 52 56
    94. 94. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta- Analysis of Chemotherapy on Head and Neck Cancer PignonJP et al.Lancet 2000;355:949-955 • Meta-analysis of 63 trials (10,741 patients) • Absolute survival benefit of 4% at 2 and 5 years in favour of chemotherapy • Chemotherapy given concomitantly to radiotherapy gave significant benefits.
    95. 95. Underperformance in Radiotherapy arm? Brizel DM et al.N Engl J Med 1998;338:1798-1804122 patients HF RT HF CTRT 7500cGY/30#/ 125 7000cGY/28#/ 125 cGy bid cGy bidOS 34 553 YearsLRC 44 703 YearsGr3 Mucositis 75 77
    96. 96. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. Calais G et al.J Natl Cancer Inst 1999;91:2081-2086 .226 patients RT CT RT 7000Cgy/35# 7000Cgy/35#OS 31 553 YearsLRC 42 663 YearsGr ¾ Mucositis 39 71
    97. 97. Final results of the 94-01 French Head and Neck Oncology andRadiotherapy Group randomized trial comparing radiotherapy alonewith concomitant radiochemotherapy in advanced-stage oropharynx carcinoma Denis F et al J Clin Oncol 2004;22:69-76226 patients RT CT RT 7000Cgy/35# 7000Cgy/35#OS 16 225 YearsLRC 25 485 YearsGr ¾ Mucositis 30 56
    98. 98. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standardfractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003. FU KK et al.Int J Radiat Oncol Biol Phys 2000;48:7-16 • .
    99. 99. 2 Yearendpoint CFRT 70Gy/35# HFRT . 81.6 Gy/68# AccSpRT 67.2 Gy/42# AccCon BoostRT 7 weeks 7 weeks 6 weeks 72 Gy/42# 6 weeksOS 46 54.5 46.2 50.9LRC 46 54 47.5 54.5Gr3 25 41 40 41Mucositis
    100. 100. Intensified hyperfractionated accelerated radiotherapy limitsthe additional benefit of simultaneous chemotherapy: resultsof a multicentric randomized German trial in advanced head- and-neck cancer. StaarS et al.Int J Radiat Oncol Biol Phys 2001;50:1161-1171• With accelerated radiotherapy, the efficiency of simultaneously given chemotherapy may be not as high as expected when compared to standard fractionated RT.

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