Prsentation PowerPoint

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Title
Abstract
Inclusion criteria
Treatment administration
Background
Treatment schedule
Results (1,2) Acute toxicity assessment
Patient characteristics
Results (3) Tolerance of Amifostine
Aims of the study
Conclusion
Study methods and design
C. Durdux et al. Abst. 1011, ASTRO 2005
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No protecting effect of Amifostine (A) on acute
toxicity of chemoradiation in head and neck
cancer .

• DURDUX C.1, DERRIEN G1., LEVITCHI M.1, THARIAT
  J1., BRASNU D2., HOUSSET M1.1 Radiotherapy
  Department 2Otorhinolaryngology Department
  Georges Pompidou Hospital, Paris, France.

C. Durdux et al. Abst 1011, ASTRO 2005
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Abstract 1011

• Purpose To evaluate the efficiency of A on
  acute mucositis and skin toxicity related to
  chemoradiation in head and neck cancer.
• Patients and methods Between 03/01 and
  03/05, 72 patients (pts) with local advanced head
  and neck cancer (squamous cell carcinoma, 64 pts
  undifferenciated, 5 pts, others, 3) received
  chemoradiation using classical fractionation.
  Tumor location was as followed nasopharynx, 5
  pts oropharynx 50 larynx, 9 hypopharynx, 7
  others, 3. Dose radiation exceeded 55 Gy in all
  pts but 2. Concomitant chemotherapy (weekly
  regimen) was cisplatin for 46 pts, carboplatin
  for 17, paclitaxel for 7 and other for 2. A was
  administered in a 3 minute I.V. infusion with
  saline hydratation and emesis prevention. Group 1
  (40 pts) received 200 mg/sqm of A before each
  fraction of radiotherapy (5 days per week). Group
  2 (32 pts) received 340 mg/sqm of A once a week
  (chemoradiation day) and 200mg/sqm the other days
  (4 days per week). No significant difference was
  observed in patient characteristics between
  groups 1 and 2.
• Results 83 of pts received 80 of
  theoretic dose of A (90 in group 1 and 75 in
  group 2). Treatment was stopped in 18 pts (25)
  because of hypotension (11 pts), vomiting (7) and
  other (2). Grade 2 and grade 3-4 acute mucositis
  were seen in 25 (62 ) and 9 (22) cases
  respectively in group 1. Grade 2 and grade 3-4
  acute mucositis were seen in 27 (84 ) and 2 (6)
  cases respectively in group 2 (p0.11). Grade 2
  radio-epithelitis was seen in 21 patients (52 )
  of group 1 and 17 patients (53). Grade 3
  epithelitis occurred in 3 cases (2 in group 1 and
  1 in group 2). Acute xerostomia was mild in both
  groups.
• Conclusion In this study, A did not appear as
  a radioprotector for mucositis and skin toxicity
  related to chemoradiation. The study is on going
  on a larger population.
•  

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Background

• Treatment of advanced head and neck cancers is
  based on radiotherapy with concomitant
  chemotherapy.
• Chemoradiation results in significant acute side
  effects such as mucositis and xerostomia.
• Amifostine is an aminothiol prodrug converted to
  the active free thiol by membrane-bound alkaline
  phosphatase, effective to prevent chronic
  xerostomia.
• Preclinical datas demonstrated a
  radiation-induced mucositis prevention by
  Amifostine 1
• Recent clinical studies demonstrated Amifostine
  could be useful in reducing acute mucositis and
  dysphagia resulting from chemoradiation in head
  and neck cancers 2,3.

•  

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Aims of the Study

• To explore the efficiency of 2 dose levels of
  amifostine on acute toxicity observed during
  chemoradiation in head and neck cancers
• Primary endpoint acute toxicity of
  chemoradiation
•     - mucositis
• - skin toxicity
• - acute xerostomia
• Secondary endpoint tolerance of Amifostine

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Study Methods and Design

• Phase II prospective monocentric study
• Between 03/01 and 03/05, 72 patients enrolled
• - with histologically proven carcinoma of
  oral cavity or pharyngo-larynx
• - with who performance status lt 2
• - with adequate haematological, hepatic, and
  renal function
• - without metastasis
• Chemoradiation in curative intent
• Major salivary glands included in irradiated
  volume (gt 55 Gy)
• Radioprotection by Amifostine according to 2
  dose levels
• - low dose group 1 from March 2001 to December
  2002
• - high dose group 2 from February 2004 to April
  2005
• Clinical assessment for acute toxicity every week
  from the start of therapy until 3 months after
  the end of RT using RTOG scales.

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Inclusion Criteria

• Patient selection according to the following
  criteria
• Histologically documented head and neck carcinoma
• WHO performance status (PS) lt 2
• Age gt 18 lt 70 years
• Adequate hematological parameters including
  neutrophils gt 1,500/mm3, platelets gt
  100,000/mm3, hemoglobin gt 8g/dl, serum creatinine
  and total bilirubin lt 1.5 times upper normal
  limit of testing laboratory, SGOT, SGPT ? 3 times
  upper normal limit of testing laboratory
• No prior radiotherapy
• Curative intent treatment

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Treatment Schedule

• Radiotherapy
• 3D radiotherapy with 6 18 MV photons beams and
  6-12 electrons beams
• Total dose gt 55 Gy on tumor site and/or cervical
  lymph nodes (areas II, III, IV, V)
• Fractionation 1,8 Gy per day, 5 days a week
• Weekly Chemotherapy
• Platine derivatives
• - cisplatine 20 mg/sqm
• - Carboplatine (carbo) AUC1
• Paclitaxel 50 mg/sqm
•  
• Protective agent Amifostine 2 groups of
  patients
• Group 1 Amifostine 200 mg/sqm before each
  fraction of radiotherapy 5 days per week
  (including days of concomitant chemotherapy)
• Group 2 Amifostine 340 mg/sqm once a week
  (chemoradiation day) and 200 mg/sqm the other
  days (4 days per week)
• Amifostine was administered in a 3 minute-IV
  infusion 30 minutes before radiotherapy.
• Hydratation and emesis prevention by setrons were
  systematically performed.

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Patient characteristics

• Group 1 Group 2 Total
• (40 patients) (32 patients)
  (72)
• Sex ratio (M/F) 31/9 26/6 57/15
• Mean age (year) 54 55
• WHO PS
• lt2 39 (98) 30 (94) 69 (96)
• Mean weight (kg) 72 70
• Histologic subtype
• UCNT 2 (5) 3 (9)
• squamous cell 35 (88) 29 (91 )
  64 (89)
• other 3 -
• Tumor sites
• oral cavity 5 -
• oropharynx 28 (70) 22 (69 ) 50
  (70)
• hypopharynx 5 2
• larynx 4 5
• nasopharynx 2 3
• others 3 -

NS
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Treatment administration

• Group 1 Group 2 Total
• (40 patients) (32
  patients) (72)
• Chemotherapy (N pts)
• cisplatin 29 17
  46 (64 )
• carboplatin 5 12 17
• paclitaxel 5
  2 7
• carbo paclitaxel -
  1 1
• cisplatin then carbo 1
  - 1
• Number of cycles (mean) 7.3 1.36
  7.2 1.21 NS
• Radiotherapy (mean dose, Gy)
• tumeur 62 2 67 7
• cervical nodes 65 12 56
  14
• Amifostine (mean dose, mg)
• days with RT alone 363 38 366
  41 NS
• days with RT CT - 622 70

NS
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Results (1)

• Amifostine dose-intensity
• Number of patients received gt 80 of theoric
  dose of Amifostine
• N patients Group 1 Group 2 Total
• (40 patients) (32 patients)
• 36 (90 ) 24 (75) 83
• p 0.59

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Results (2)

• Chemoradiation acute toxicity
• N patients Group 1 Group 2 Total
• (40 patients) (32 patients)
• Mucositis
• grade 1 4 3 7
• 2 25 (62) 27 (84 ) 52 (72 )
• 3 5 2 7
• 4 4 - 4
• Epithelitis
• grade 1 16 (40 ) 14 (44 ) 30
  (42 )
• 2 21 (52 ) 17 (53 ) 38 (53
  )
• 3 2 1
• 4 - -
• No statistical significant difference between
  groups 1 and 2

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15
22
p0.11
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Results (2)

• Chemoradiation acute toxicity
• N patients Group 1 Group 2 Total
• (40 patients) (32 patients)
• acute xerostomia
• grade 1 21 (52 ) 1 22 (30 )
• 2 15 (37 ) 30 (94 ) 45 (62
  )
• 3 2 - 2
• 4 - - 0
• dysgueusia
• grade 1 25 (62 ) 8 (25 ) 33
  (46 )
• 2 11 (27 ) 16 (50 ) 27 (37
  )
• 3 1 7 (22 ) 8 (11 )
• 4 - -

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Results (3)

• Tolerance of Amifostine
• N patients Group 1 Group 2 Total
• (40 patients) (32 patients)
• hypotension
• grade 1 - 7 (22 )
• 2 7 (17 ) 4 (13 ) 11
  (15 )
• 3 - - 0
• 4 - - 0
• nausea/vomiting
• grade 1 2 11 (34 ) 13
  (18 )
• 2 10 (25 ) 10 (31 ) 20 (28
  )
• 3 2 6 (19 ) 8 (11 )
• 4 - - 0

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Results (3)

• Tolerance of Amifostine
• Treatment was stopped before the end of
  radiotherapy in 18 patients (25 ) related to
• hypotension 11 patients
• vomiting 7
• sideration 1
• patient refusal 1
• No cutaneous rash

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Conclusions

• High dose administration of Amifostine (340
  mg/sqm once a week for 6 to 8 weeks) is feasible.
• Amifostine was well-tolerated with adequate
  hydratation and emesis prevention for standard
  administration (group 1) or high dose (group 2).
• Acute xerostomia related to radiotherapy was mild
  (grade 3 - 4, 2).
• With 15 grade III-IV mucositis and 39 grade
  II III epithelitis, Amifostine did not appear
  as a radioprotector to chemoradiation.
• Moreover, Grade III-IV mucositis rate could be
  lower with high dose Amifostine (group 1, 22
  group 2, 6) but statistical difference was not
  significant (p0.11).
• The study is on going on a larger population.

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References

• Cassatt DR, Fazenbaker CA, Bachy CM, Kifle G, Mc
  Carthy MP. Amifostine (Ethyol) protects rats from
  mucositis resulting from fractionated or
  hyperfractionated radiation exposure. Int J
  Radiat Oncol Biol Phys 2005 61(3) 901 7
• Antonadou D, Pepelassi M, Synodinou M, Puglisi M,
  Throuvalas N. Prophylactic use of amifostine to
  prevent radiochemotherapy-induced mucositis and
  xerostomia in head-and-neck cancer. Int J Radiat
  Oncol Biol Phys 2002 52(3) 739 47
• Suntharalingam M, Jaboin J, Taylor R, Wolf J,
  Banglore M, Van Echo D, Ord R. The evaluation of
  amifostine for mucosal protection in patients
  with advanced loco-regional squamous cell
  carcinomas of the head and neck (SCCHN) treated
  with concurrent weekly carboplatin, paclitaxel
  and daily radiotherapy (RT). Semin Oncol 2004
  331 (6 suppl 18) 2 7