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Journal Reading:

A comparison of weekly versus 3-weekly


cisplatin
during adjuvant radiotherapy for high-risk head
and neck cancer (HHNC)
Disusun Oleh:
Yeni Notanubun 102012435 UKRIDA
Fathinah Zuhudan R. 1102013107 YARSI
ABSTRAK
• To compare cumulative cisplatin dose & toxicity
• between patients who:
OBJEKTIF • received 3-weekly VS weekly cisplatin
• during adjuvant radiotherapy for high-risk head &
neck squamous cell carcinoma (HNSCC)

• HNSCC patients w/ involved resection margins


and/or extracapsular extension in 2 tertiary cancer
centers w/ different institutional practices
• Calculated cumulative cisplatin dose & Information
METODE on toxicity reviewed
• Compared between patients who received 3-weekly
VS weekly cisplatin
ABSTRAK

•270 high risk patients:


•60  3-weekly 100 mg/m2
•48  weekly 50 mg/m2 cisplatin during
adjuvant radiotherapy (60–66 Gy in 30–33
HASIL fractions).

•Mean cumulative cisplatin dose:


•199.4 mg/m2 (SE 5.4) in 3-weekly
•239.8 mg/m2 (SE 11.0, P = 0.001) in weekly
ABSTRAK

•Cumulative cisplatin >200 mg/m2 was given to:


•67.7% of patients in 3-weekly cohort
•85.2% (P = 0.039) in the weekly cohort.
HASIL
•The rate of feeding tube dependency 6 months
after treatment, osteoradionecrosis, neutropenic
fever, & persistent renal function decline were not
statistically different.
ABSTRAK

• Patients treated w/ weekly 50 mg/m2 cisplatin


received a higher cumulative dose w/ comparable
toxicity as patients who received 3-weekly 100
KESIMPULAN mg/m2 cisplatin.
• Efficacy & applicability to the frequently used
weekly 40 mg/m2 schedule remains to be evaluated
PENDAHULUAN

Patients HNSCC treated w/


primary surgery
have a very high risk of The combination of adjuvant
recurrence radiotherapy & high dose
IF resection margins (+) &/ cisplatin
IF there is extra-capsular induces significant acute &
extension of lymph node long term toxicity [1,2].
metastases.
3 studies demonstrated
that these patients derive
benefit from adding high
dose cisplatin [1–3].
PENDAHULUAN

However, weekly
and 3- weekly As an alternative, a weekly lower
cisplatin plus dose cisplatin schedule has been
radiotherapy have used, based on the assumption that
not been compared a weekly regimen is less toxic and
directly in a equally effective as 3-weekly high
randomized and dose cisplatin
adequately
powered study
TUJUAN

Aimed to compare:
1. Patient cohorts from 2 tertiary care centers
where one center routinely treats high-risk HNSCC patients postoperatively
with 3-weekly high dose cisplatin
and the other center routinely gives weekly cisplatin.

If weekly cisplatin is better tolerated than 3-weekly cisplatin,


this might be reflected by a higher cumulative cisplatin dose in patients
treated with a weekly schedule.
2. The cumulative cisplatin dose & toxicity between patients treated with a
weekly schedule & patients treated with the high dose 3-weekly schedule.
METODE

• Retrospective cohort study


• All consecutive patients w/ HNSCC who underwent
primary surgery & had (+) resection margins (<1mm)
Study design, &/ extra-capsular extension of lymph node
patients, & metastasis 
treatment
• stared adjuvant radiotherapy 01/03/2005 – 12/12/12
at PM & 15/12/2008 – 15/07/2013 at UMCG 
• institutional database & patient rec.
METODE

• PM  3 cycles of 3-weekly 100 mg/m2 cisplatin


• UMCG  7 weekly cycles cisplatin 50 mg/m2
• for both cisplatin schedules, patients were admitted
Study design, overnight for equivalent hydration regimens
patients, &
treatment
• PM postoperative IMRT
• UMCG  IMRT w/ simultaneous integrated boost
technique
METODE

• Patients received 66 Gy in 2Gy fractions on high risk


areas; 59,4 Gy in 1,8 Gy per fraction on intermediate
rsk areas; and 52,8 Gy on the elective nodal areas
Study design,
patients, &
treatment • All patients treated with 3-weekly high-dose
&weekly cisplatin (if the caloric intake by mouth was
insufficient) underwent prophylactic percutaneous
endoscopic gastrostomy (PEG)
METODE

• Primary endpoint: the cumulative cisplatin dose,


defined as the total dose in mg/m2 that a patient
received during the course of adjvant radiation
• Secondary endpoints: included:
• rate of tube feeding dependence at 6 months after
chemoradiotherapy;
Study endpoints
• the rate of osteoradionecrosis of the jaw after
& data analyses
treatment;
• the rate of neutropenic fever during treatment;
• the worst change of serum creatinine according to
the common terminology criteria for adverse
events version 4.0 (CTCAE 4.0);
• the change in body weight during treatment.
METODE

• Compared using
Study endpoints • two-sample t-tests
& data analyses • chi-squared test or Fisher’s exact
• Calculated using the binary logistic regression model
• analyses were performed with SPSS version 19
HASIL

Fourteen PM
patients were
excluded from the
cumulative dose
and toxicity
comparisons
because of
treatment with:
HASIL

The most
frequently
documented
reasons for
withholding
chemotherapy
during High dose 50 mg/m2
HASIL adjuvant
radiotherapy.

Chemo-
Radiotherapy
Comparison Cohort
HASIL
Chemo-
Radiotherapy
Comparison Cohort
HASIL  All patients were treated with
intensity modulated radiation
therapy (IMRT).
Chemo-  All patients except for one in the
Radiotherapy 3-weekly cohort completed
Comparison Cohort radiotherapy.

 Patients treated with 3-weekly


cisplatin received 60–72 Gy in 30–
36 fractions.
 All except one patient in the
weekly cisplatin cohort received
66 Gy in 33 fractions
HASIL  The mean cumulative cisplatin dose was
Cumulative higher in patients treated with weekly
Cisplatin cisplatin (239.8 mg/m2 , standard error
Dose (SE) 11.0)
 Also the percentage of patients who
received a cumulative cisplatin dose
>200 mg/m2 was higher in the weekly
cohort (85.2%)
 There was no significant interaction
between RT dose schedule, cisplatin
regimen, and the cumulative mean
cisplatin dose (p = 0.34)
Treatment The toxicity rates between patients
HASIL Morbidity
treated with the 3-weekly and
weekly regimens were similar

Of all weekly treated


patients, 40% completed
treatment without tube
feeding.

was low and not signifi-


cantly different between
treatment cohorts
Treatment The cumulative cisplatin dose
HASIL Morbidity
was similar in patients with and
patients without
osteoradionecrosis
• The baseline
creatinine value was
compared with the
highest creatinine
value between start &
6 weeks aft treatment
for each patient
• no grade 4, only 1
grade 3 renal toxicity
in both
• 6 weeks aftr
completion of
treatment, grade 1
present in 2 patients
3-weekly cohort & 3
patients weekly
• Only 1 patient 3-
weekly had
permanent grade 2
HASIL
Recurrance
Rate
DISKUSI

weekly regimen allowed for


more cisplatin to be
delivered during radiation, patients treated with the weekly
without evidence of added regimen had more frequent and
toxicity more severe mucositis This trial
used a weekly 40 mg/m2 cisplatin
dose
DISKUSI

lower rate of feeding tube


use during treatment, weight feeding tube insertion was
loss was less in patients performed in 90% of 3-weekly
treated with weekly cisplatin treated patients and 41% of
in our study. weekly treated patients, but in
contrast to our results more
weekly treated patients
experienced P10% weight loss
› A likely explanation is the higher rate of mandibulectomy in the weekly
compared to the 3-weekly cohort (32% versus 13%), which maybe an important
risk factor for development of osteoradionecrosis.
› Another independent risk factor is radiotherapy dose to the bone
› In the weekly cohort, more patients had involved margins (79% versus 45%)
and received 66 Gy to the area of the primary tumor.
› Several other studies showed higher percentage of severe mucositis in patients
treated with weekly cisplatin compared
to patients treated with 3-weekly cisplatin.
› weight loss and tube feeding dependence do not suggest
excess mucositis and acute dysphagia in the weekly cohort
› Age and performance status were the main reasons for patients not
receiving chemotherapy
› The high percentages of comorbidities and poor performance status
were likely related to the etiological risk factors tobacco and alcohol use
in HNSCC patient population.
› However, a better overall survival was demonstrated in patients who
received a cumulative cisplatin dose
P240 mg/m2 in a study with weekly and 3-weekly cisplatin combining
adjuvant and definitive chemoradiotherapy.
› dosis tinggi cisplatin sekali tiap 3 minggu dengan radiasi untuk HNSCC
beresiko tinggi yang telah direseksi tetap menjadi terapi standar yang
ditunjuang oleh bukti ilmiah level 1 (evidence based level 1).
KESIMPULAN

 This retrospective comparison has demonstrated that


around one half of high-risk HNSCC patients are not eligible
for cisplatin during postoperative radiotherapy.
 Weekly 50 mg/m2 cisplatin permits a higher cumulative
dose to be delivered with no evidence of excess toxicity
compared to 3-weekly 100 mg/m2 cisplatin during
postoperative radiotherapy.
 Efficacy remains to be determined and it is unclear if this
data is applicable to the 40 mg/m2 weekly cisplatin
schedule, which is a commonly used alternative to high
dose 3-weekly cisplatin.6
TERIMAKASIH
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