קווים מנחים לטיפול בגורמי צמיחה של השורה הלבנה

‫טיפול בגורמי צמיחה של השורה‬
‫הלבנה‪ :‬קווים מנחים בספרות‬
‫ונתונים לביסוסם‬
‫המצגת עוסקת בעיקר בהיבטים הקליניים הקשורים לטיפול‪ .‬השקפים‬
‫הקשורים באופן ישיר להמלצות המחלקתיות נמצאים בחלק השלישי של‬
‫המצגת‪ -"Guidelines for the use of CSFs” -‬ומסומנים עם רקע בצבע‬
‫תכלת‪.‬‬
‫ערך‪ :‬פרופ' נסים חיים‬
‫)עודכן‪ -‬יולי ‪(2014‬‬
Therapeutic benefits of GCSFs
Definition of neutropenia
and fever
Neutropenia: ANC < 500/mm3 or < 1000/mm3 and a
predicted decline to < 500/mm3 over the next 48 hrs.
Fever: >38.3 orally or >38.0 over 1 hr.
a rise in axillary temperature to >38.5 for a duration of
> 1 hr while having an ANC of < 500/mm3.
Therapeutic benefits of CSFs
Reduces the risk of febrile neutropenia?
- Yes
Reduced risk of febrile neutropenia
“Administration of CSFs result in a ~ 50% risk
reduction of developing febrile neutropenia”
Chemotherapy Induced Neutropenia
Planned DI + G-CSF
Primary prophylaxis
Crawford J. et al. N Engl J Med 1991;325:164-170.
Patients and methods:
211 SCLC patients participated a doubleblind, randomized, placebo-controlled
trial of G-CSF support to 6 cycles of
Cyclophosphamide, Doxorubicin, and
Etoposide.
Proportion Free of Fever
with Neutropenia
Purpose:
Testing the hypothesis and clinical implications of chemotherapy-related neutropenia
reduction in patients with cancer.
1.0
0.8
G-CSF
0.6
0.4
Placebo
0.2
P < 0.001
0.0
0
1
2
3
4
Cycles of Chemotherapy
5
6
Risk of febrile neutropenia with and without GCSFresults of a meta-analysis
Kuderer NM et al. J Clin Oncol 25: 3158-67, 2007(a meta-analysis of
15 controlled trials (n=3182 pts) using GCSF before the onset
of fever or neutropenia following systemic chemotherapy for
solid tumors or lymphomas):
Mean risk
for FN
39.5%
22.4%
RR=0.54---P<,0001
Control
GCSF
Therapeutic benefit of CSFs
Shortens the length of neutropenia and
febrile neutropenic episode, and
reduces the period of hospitalization
and IV antibiotics?
-Yes
Placebo
G-CSF
Neutrophils X 109/L
100
10
1
0.1
0.01
0
3
6
9
12 15 18 21
Day of Treatment
(CDE – Cyclophosphamide, Doxorubicin,
Etoposide)
Trillet-Lenoir V. et al. Eur J
Cancer 1993;29A(3):319-324..
Neupogen reduces the duration of
hospitalization
and i.v. antibiotic use in patients with AML
Median duration (days)
30
p=0.0001
25
20
p=0.0001
20
18.5
15
10
0
Hospitalisation
Neupogen
i.v. antibiotics
Placebo
Adapted from Heil G et al. Blood 1997
Therapeutic benefit of CSFs
Reduces the risk of documented
infection?
-Yes
Risk of documented infection-results of a
meta-analysis
Lyman GH et al. Am J Med 112: 406-11, 2002(a meta-analysis of 8 controlled trials
(n=1144 pts)…7 trials reported information on the documented infection…
mean risk of
documented
infection
17%
10%
control
Odds ratio= 0.51 (p= 0.001)
GCSF
Therapeutic benefit of CSFs
Reduces the risk of documented
infection-related mortality?
-Yes
Yes, it reduces the risk of documented infection-related
mortality. See:
Kuderer NM et al. J Clin Oncol. 2007, 25(21):3158-67:
Impact of primary prophylaxis with granulocyte
colony-stimulating factor on febrile neutropenia and
mortality in adult cancer patients receiving
chemotherapy: a systematic review.
‹#›
Risk of documented infection-related
mortality- results of a meta-analysis
Kuderer NM et al. J Clin Oncol 25: 3158-67, 2007: (a meta-analysis of 12 controlled
trials (n=3122 pts) using GCSF before the onset of fever or neutropenia following
systemic chemotherapy for solid tumors or lymphomas):
2.8%
1.5%
Control
GCSF
(RR=0.55; P=0.018)
*reduction in infection-related mortality was significant among studies of filgrastim but
did not reach statistical significance with lenograstim or pegfilgrastim.
Therapeutic benefit of CSFs
Reduces the need for dose reductions
and treatment delays (& reduced doseintensity)?
-Yes
Relative Dose Intensity (RDI)
Kuderer NM et al. J Clin Oncol 25: 3158-67, 2007(a meta-analysis of 10
controlled trials using GCSF before the onset of fever or neutropenia
following systemic chemotherapy for solid tumors or lymphomas):
Mean RDI
95.1%
86.7%
Controls
P = 0.001
GCSF
Therapeutic benefit of CSFs
Enables full-dose following a prior
cycle with febrile neutropenia?
-Yes
Full-dose chemotherapy following a
prior cycle with febrile neutropenia

Metastatic small cell lung cancer treated with a combination
of cyclophosphamide, doxorubicin, and etoposide
 Patients who developed neutropenic fever during the first
cycle received the second cycle with full dose+ G-CSF
 Only 23% of these patients developed neutropenic fever
during the second cycle.
(Crawford J et al. N Engl J Med 1991; 325: 164-170)
Full-dose chemotherapy with GCS-F support*
following a prior cycle with febrile neutropeniaDept Oncology, Rambam Medical Center experience
(Haim N, Shulman K, Goldberg H, Tsalic M. Med Oncol 22: 229-32, 2005)
* filgrastim (neupogen)300 or 480 mcg/day for ~10 days
Since September 1995, a standard policy in patients treated
with an intent for cure or for durable complete remission.
Eligibility criteria:
 Neutropenic fever was not associated with life-threatening
infection.
 There were no other dose-limiting toxicities.
 Age 75 or less; performance status (WHO) 0-2
…..contd
Next cycle (n+1) (full dose with GCSF support in all pts):
 Number of pts…………………………51
 Neutropenic fever:……………………..8/51(16%)
 Days of IV antibiotics:………………....4.5 (median),(3-7)
 Evidence of bacterial infection:………..none
Next cycle (n+2) (full dose with GCSF support in all pts):
 Number of pts…………………………41
 Neutropenic fever:……………………..4/41 (10%)
 There was no drug-related death associated with either cycle.
Conclusion:
A policy of full-dose chemotherapy with secondary G-CSF support in pts
who develop febrile neutropenia following moderately myelotoxic
chemotherapy is relatively safe and feasible.
Haim N, Shulman K, Goldberg H, Tsalic M. Med Oncol 22: 229-32, 2005
Therapeutic benefit of CSFs
Enables administration of dose-dense
therapy?
-Yes
Dose-intensity & Dose-density
90 mg/m2 every 3 wks
vs.
30 mg/m2/week:

Both regimens have the same dose intensity.
 30 mg/m2/week gives a greater dose
density than the 3-weekly administration.
Tolerability of dose-dense chemotherapy with
GCSF-breast cancer
Citron ML et al. J Clin Oncol 21: 1431-39, 2003
 AC (doxorubicin 60 mg/m2 & cyclophosphamide 600
mg/m2):
q 3 wks or q 2 weeks +filgrastim days 3-10 at 5 mcg/kg
rounded to either 300 or 480 mcg.
 Treatment was well tolerated. Severe neutropenia was
less frequent in patients who received the dose-dense
regimens (6% vs. 33%).
Dose-dense CHOP (CHOP-14)
•
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Cyclophosphamide 750 mg/m2 IV, day 1
Adriamycin 50 mg/m2 IV , day 1
Vincristine 1.4 mg/ m2 IV , day 1
Dexamethasone 20 mg IV, day 1
Prednisone 100 mg PO, days 2-5
Cycles are repeated every 2 weeks.
GCSF is given on days 4-13.
• Pfreundschuh M et al. Blood 104: 626-33, 2004 (young pts)
• Pfreundschuh M et al. Blood 104: 634-41, 2004 (elderly pts)
Therapeutic benefit of CSFs
Enables administration of “high-dose”
chemotherapy (without peripheral
blood stem cell support)?
-Yes
CHOP & Mega CHOP in aggressive non
Hodgkin`s lymphomas
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•
•
CHOP:
Cyclophosphamide 750 mg/m2 IV, day 1
Adriamycin 50 mg/m2 IV , day 1
Vincristine 1.4 mg/ m2 IV , day 1
Prednisone 100 mg PO, days 1-5
(cycles repeated every 3 weeks)
“Mega” CHOP:
Cyclophosphamide 1500mg/m2 IV (1hr), days
1 and 2
Mesna 200 mg/m2 X 4, IV, day 1; 200 mg/m2 X 8,IV day 2
Adriamycin 50 mg/m2 IV , day 1
Vincristine 1.4mg/m2 (max. 2mg) IV, day 1
Prednisone 100 mg PO , days 1-5
(cycles repeated every 3 weeks)
Therapeutic benefit of CSFs
Improves the outcome of febrile
neutropenia when started at the time of
established neutropenia?
+ : a marginal effect
CSFs for chemotherapy-induced febrile neutropenia: a meta-analysis
(Clark OA et al. J Clin Oncol 23: 4198-4214, 2005)
(13 trials with a total of 1,518 pts)
 Significantly reduces the length of hospitalization (HR=0.63;P=0.006)
 Significantly reduces the time to neutrophil recovery (HR=0.32;P<0.0001).
 A marginally significant result was obtained for the use of CSF in reducing
infection-related mortality (3.1% VS. 5.7%; HR=0.51; p=0.05).
Therapeutic benefit of CSFs
Improves treatment outcome?
?? Probably…
CSFs in lymphoma-meta-analysis
Bohlius J et al. Cochrane Database Syst Rev. 3: CD003189, 2004
(12 eligible randomized controlled trials with 1823 pts)
 -----reduced the risk of neutropenia, febrile neutropenia and
infection.
 However, there is no evidence that CSFs provide a
significant advantage in terms of CR, freedom from
treatment failure or overall survival.
But probably improves survival by decreasing mortality from
infection……see next….
Lyman GH et al: J Clin Oncol 28: 2914-24, 2010: Acute Myeloid Leukemia or
Myelodysplastic Syndrome in Randomized Controlled Clinical Trials of Cancer
Chemotherapy With Granulocyte Colony-Stimulating Factor: A Systematic
Review
(A meta-analysis showing that GCSFs improved survival in spite of increasing
the incidence of AML….probably the increased incidence of AML was due
higher chemo dose….).
‹#›
Therapeutic benefit of CSFs
Enables stem cell mobilization ?
- yes
Side effects of GCSFs
Side effects of GCSFs
Adverse Events –“Bone pain”
 In bone marrow bearing locations
 Usually of mild/moderate severity ~(15%)*
 Transient - controlled with oral analgesics
* Med Oncol 22: 229-32, 2005 : 20/51(=39%);severe in 8
(=16%)
Prevention of pegfilgrastim-induced bone pain
by naproxen
•
•
•
•
•
•
•
•
•
•
•
•
•
•
J Clin Oncol. 2012 Jun 1;30(16):1974-9. Epub 2012 Apr 16.
Prevention of pegfilgrastim-induced bone pain: a phase III double-blind placebo-controlled randomized clinical trial of the
university of rochester cancer center clinical community oncology program research base.
Kirshner JJ, Heckler CE, Janelsins MC, Dakhil SR, Hopkins JO, Coles C, Morrow GR.
Source
Hematology/Oncology Associates of Central New York, Community Clinical Oncology Program, East Syracuse, NY, USA.
[email protected]
Abstract
PURPOSE:
Pegfilgrastim-induced bone pain is a significant clinical problem that may result in discontinuation of pegfilgrastim and lead to less
effective chemotherapy dosing. Interventions for pegfilgrastim-induced bone pain are needed.
PATIENTS AND METHODS:
The University of Rochester Cancer Center Clinical Community Oncology Program Research Base randomly assigned 510 patients at 17
sites to receive either naproxen (500 mg two times per day) or placebo on the day of pegfilgrastim administration, continuing for 5 to 8
days after pegfilgrastim. Patients recorded pain severity (using a scale of 0 to 10) and duration in daily diaries. The primary outcome
measure was the area under the curve (AUC) for pain for days 1 through 5. Secondary outcome measures included the identification of
risk factors for the development of pain and response to naproxen.
RESULTS:
Patients' mean age was 55.6 years and 86% were female. Sixty-eight percent of patients had breast cancer and 10% had lung cancer.
Pain reached its peak at 3 days for both groups. The mean AUC for pain was 7.71 for the placebo group and 6.04 for the naproxen group
(P = .037). Naproxen reduced maximum pain from 3.40 to 2.59 (P = .005). Naproxen also reduced overall pain incidence from 71.3% to
61.1% (P = .020) and duration from 2.40 to 1.92 days (P = .009). The reduction in severe pain (> 5 on a scale of 1 to 10) from 27.0% to
19.2% was also significant (P = .048). Risk factors could not be identified to predict incidence, severity, or ability to prevent pegfilgrastiminduced bone pain.
CONCLUSION:
Our phase III randomized placebo-controlled clinical trial demonstrated that naproxen at a dose of 500 mg twice per day is effective in
reducing the incidence and severity of pegfilgrastim-induced bone pain.
Adverse Events – Transient elevations in LDH, uric
acid, and alkaline phosphatase (and in WBC/ANC
counts)
 In LDH, and uric acid: attributed to the proliferative effects of
G-CSF on neutrophil precursors in the bone marrow, with
increased cell turnover
 In alkaline phosphatase: potentially secondary effects on
bone.
 In WBC & ANC counts……
GCSF and lung toxicity
Pulmonary complications of GCSF are very rare and
include cough, dyspnea, and interstitial or alveolar
pulmonary edema. Few cases of acute respiratory
distress syndrome have been reported.
‹42›
A possible interaction between
bleomycin and GCSF
Martin WG et al. J Clin Oncol 23: 7614-20, 2005 :
GCSF was associated with increased lung toxicity in Hodgkin`s
disease patients treated with bleomycin containing drug
combinations).
(GCSF may enhance bleomycin-induced lung toxicity by a
mechanism that probably involved neutrophils).
On the other hand:
Saxman SB et al. Chest 111: 657-60, 1997 :
There is no increase in pulmonary toxicity with coadministration of G-CSF and bleomycin compared to
bleomycin alone in pts with advanced germ cell tumors.
GCSF: effect on spleen
 Spleen enlargement (Picardi M et al. Haematologica 88: 794, 2003),
 Splenic rupture (Falzetti F et al. Lancet 353: 555, 1999;
Dincer AP et al. J Pediatr Hematol Oncol 26: 761, 2004).
Allergic reactions; Cutaneous vasculitis (Amgen
March 2013)
GCSF & leukemia/MDSA meta- analysis
Lyman GH et al. J Clin Oncol 28: 2914-24, 2010 (meta-analysis):
“Delivered chemotherapy dose-intensity and risk of AML/MDS are
increased but all-cause mortality is decreased in patients receiving
chemotherapy with G-CSF support. Greater reductions in mortality
were observed with greater chemotherapy dose-intensity”.
“…. It remains impossible to distinguish any leukemia risk that
may be associated with G-CSF from the recognized dosedependent leukemogenic effects of many myelosuppressive
chemotherapeutic agents. The greater risk of AML/MDS observed
may be primarily related to the consistently increased dose of
chemotherapeutic agents with knownleukemogenic potential.
However, an enhanced leukemogenic effect of chemotherapy drugs
by G-CSF cannot be ruled in or out based on this analysis.
ESMO Recommendations: Crawford J et al. Ann Oncol 21 (suppl 5): v
248 v251,2010: ”There is a possible risk of subsequent acute myeloid
leukaemia (AML) or myelodysplastic syndrome (MDS) in women receiving
adjuvant chemotherapy for breast cancer and hGFs. However, this is
confounded by the higher doses of chemotherapy received by patients
receiving hGFs compared with those receiving standard dose reductions.
Long-term follow-up of dose-dense adjuvant chemotherapy where total dose
is the same has not demonstrated any difference in leukaemic risk. If an
increased risk is confirmed in some settings, the absolute risk is low (1.8%
compared with 0.7% within 48 months of breast cancer diagnosis) and,
therefore, the benefits of hGFs still outweigh the risk.
Guidelines for the
use of CSFs*
* “…guidelines cannot always account for individual variations
among patients. They are not intended to supplant physician
judgement with respect to to particular patients or special
clinical situations….”(ASCO guidelines-2006)
Types of CSFs, Dosage &
Administration
‫מינון וצורת מתן של של ‪Filgrastim & Pegfilgrastim‬‬
‫ככלל‪ ,‬מקובלות במחלקתנו המלצות ‪....NCCN‬‬
‫על פי המלצות מחלקתנו‪ :‬כאשר משך הסדרה הוא ארוך )‪ 4-5‬ימים( רצוי לתת‬
‫‪ GCSFs‬ביום שלאחר סיום המחזור‪ ,‬ולא מאוחר יותר‪.‬‬
‫‪‬כפי שמצוין‪ :‬המנה היומית המומלצת של פילגרסטים )נויפוגן או‬
‫טבגרסטים(היא ‪ 5‬מיקרוגרם‪/‬ק"ג‪ ,‬אך יש לעגל למנה הקרובה יותר לאמפולה‬
‫של ‪ 300‬או של ‪ 480‬מיקרוגרם‪....‬לכן‪ ,‬אם החולה שוקל < ‪ 78‬ק"ג‪ ,‬המנה‬
‫היומית המומלצת היא ‪ 480‬מיקרוגרם‪.‬‬
‫‪ 2‬תכשירים אחרים שכן נמצאים בארץ‪:‬‬
‫‪Lenograstim (Granocyte): Glycosylated G-CSF; produced in culture by‬‬
‫‪mammalian cells; identical to the natural molecule.‬‬
‫‪Recommended dose: 1 Amp = 263 mcg/day.‬‬
‫‪Tevagrastim (300 & 480 mcg): = Biosimilar of filgrastim‬‬
‫באיזה פרוטוקולים ניתן לתת ‪?Neulastim‬‬
‫כאשר משך הסדרה ‪ 2‬שבועות או יותר‪.‬‬
‫קיימת הוראה לא לתת ‪ GCSFs‬ביחד עם כימותרפיה או תוך‬
‫פחות מ‪ 24-‬שעות לאחר כימותרפיה‪ :‬ההסבר התיאורטי לכך‪ :‬תאי‬
‫השורה הלבנה מתחלקים במהירות )כתוצאה ממתן גורמי הצמיחה(‪ ,‬ולכן‬
‫רגישותם לכימותרפיה תהיה גבוהה‪....‬ראה המלצות היצרן‬
‫‪Amgen March 2013‬‬
‫מתי להתחיל במתן ‪ GCSFs‬ועד מתי להמשיך?‬
‫‪ ‬להתחיל ‪ 24‬עד ‪ 72‬שעות מסיום הכימותרפיה‪......‬‬
‫‪ ‬כאשר נותנים ‪ ,Filgrasim‬להמשיך עד שספירת‬
‫הנויטרופילים מגיעה ל‪/1500 <-‬ממ"ק‪ ,‬וזאת‪-‬לאחר‬
‫השפל‪/‬לאחרהשפל הצפוי‪..‬‬
‫‪..‬ראה גם בהמשך‪...‬‬
‫האם סביר להתחיל במתן ‪ GSSFs‬כטיפול מונע לאחר יותר מ‪ 72-‬שעות מסיום הטיפול?‪...‬ראה שוב‬
‫המלצות ‪ NCCN‬המעודכנות מ‪ .....: 2014-‬סביר לתת עד ‪ 3-4‬ימים אחרי הכימותרפיה‪.....‬המלצות‬
‫מחלקתנו‪ :‬א‪ .‬לתת עד ‪ 72‬שעות מסיום הכימותרפיה‪ ,‬ב‪ .‬כאשר הטיפול הכימותרפי נמשך מספר ימים‪,‬‬
‫רצוי לתת קרוב ל‪ 24-‬שעות מסיום הכימותרפיה ‪ ,‬ג‪ .‬לגבי נוילסטים‪ :‬רצוי לתת ביום שלאחר סיום‬
‫הכימותרפיה‪.‬‬
‫›‪‹#‬‬
Zwik C et al. Ann Oncol 22: 1872-7, 2012. Randomized comparison of
pegfilgrastim day 4 versus day 2 for the prevention of chemotherapyinduced leukocytopenia
'‫ שמס‬,‫ דחיית מתן התרופה לזמן‬:4 ‫הרציונל של מתן ביום‬
‫ יהיה כרוך בפינוי איטי יותר של‬,‫הכדוריות הלבנות מתחיל לרדת‬
.‫ צורת מתן זאת אינה מקובלת כשגרה‬.‫התרופה‬
‫‪Primary prophylaxis, Secondary prophylaxis, and‬‬
‫‪use in established neutropenic fever (without‬‬
‫)‪prophylactic use‬‬
‫‪Primary prophylaxis:‬‬
‫מדובר בטיפול מונע בחולה‪ ,‬שלא קבל עד כה ‪ GCSF‬באותו קו טיפולי‪.‬‬
‫‪Secondary prophylaxis:‬‬
‫חולה שלא קבל טיפול מונע בסדרה הקודמת‪ .‬הגיע לסדרה הבאה לאחר שפתח בסדרה‬
‫קודמת נויטרופניה וחום או אירוע אחר של נויטרופניה‪ ,‬שעשוייה להגביל את מינון‬
‫הכימותרפיה‪.‬‬
‫‪Use in established neutropenic fever (without prophylactic use):‬‬
‫החולה לא קבל טיפול מונע‪ .‬הגיע במצב של נויטרופניה וחום‪.‬‬
‫בהמשך התייחסות למצבים הנ"ל עם דגש על המלצות ה‪ ,NCCN-‬אך‬
‫יש לציין‪ ,‬כי העקרונות ב‪ guidelines-‬האחרים שהוזכרו דומים אחד‬
‫לשני‪.‬‬
‫‪.‬‬
‫‪Primary prophylaxis‬‬
‫בעיקרון‪:‬‬
‫יש לבצע הערכת סיכון לפני כל סדרה טיפולית ולחלק את החולים ל‪ 3-‬קבוצות עיקריות‪:‬‬
‫‪ .1‬סיכון גבוה )=סיכוי לנויטרופניה וחום < ‪ :(20%‬יש לתת טיפול מונע לכל החולים‪.‬‬
‫‪ .2‬סיכון בינוני )=סיכוי לנויטרופניה וחום ‪ :(10-20%‬יש לתת בהתאם לשיקול אינדיבידואלי‪,‬‬
‫המתייחס לגורמי הסיכון שקשורים בחולה ובטיפול שמקבל ובמטרת הטיפול )האם‬
‫קורטיבי‪/‬מאריך חיים(‪.‬‬
‫‪ .3‬סיכון נמוך )=סיכוי לנויטרופניה וחום > ‪ :(10%‬לא מקובל לתת ‪.GCSFs‬‬
‫‪ ‬ראה בהמשך "עץ החלטות" על פי ‪) NCCN‬אשר דומה בשאר ה‪ guidelines-‬שצוטטו(‬
‫)השקף הבא( ורשימת גורמי סיכון לתוצאות של נויטרופניה וחום )השקף שאחריו(‪.‬‬
‫‪ ‬ב‪ guidelines-‬שהוזכרו )ואשר ניתן להיכנס אליהם דרך האתר עם קישור( נמצאות‬
‫רשימות פרוטוקולים כימותרפיים בהתאם לסיכוי שלהם לגרום לנויטרופניה וחום‪.‬‬
‫‪Secondary prophylaxis‬‬
‫ראה עץ החלטות על פי ‪ :NCCN‬כאשר בסדרה קודמת הייתה נויטרופניה וחום או נויטרופניה‬
‫ממושכת‪ ,‬שבגללה התעכב מועד הסדרה הבאה‪.‬‬
Dose-dense ‫ בפרוטוקולים‬GCSFs ‫מתן‬
Use for mobilization of PBSCs
‫‪Use in established neutropenic fever (without‬‬
‫)‪prophylactic use‬‬
‫ככלל‪ :‬לא מקובל לתת באופן שגרתי טיפול בגורמי צמיחה של‬
‫השורה הלבנה בזמן נויטרופניה וחום )וכאשר החולה לא קבל‬
‫טיפול מונע(‪ .‬מתן ‪ GCSFs‬במצב כזה ייעשה על פי שיקול‬
‫אינדיבידואלי‪ .‬ראה בהמשך הגדרת מצבים‪ ,‬שעשויים להצדיק‬
‫מתן ‪ GCSFs‬במצב כזה‪.‬‬
‫הערה‪ :‬על פי הנחיות אלה אין צורך לתת פילגרסטים לחולה‬
‫שמגיע עם חום ונויטרופניה‪ ,‬לאחר שקבל טיפול מונע ראשוני‬
‫עם נוילסטים‪.‬‬
‫גורמי סיכון שיש להביא בחשבון בשיקול אינדיבידואלי אם לתת‬
‫גורמי צמיחה של השורה הלבנה במצב של נויטרופניה וחום )וללא‬
:(‫טיפול מונע קודם‬
‫ההחלטה תעשה‬
‫על פי שיקול‬
.....‫אינדיבידואלי‬
‘‘Treatment with G-CSF for patients with solid tumours and
malignant lymphoma and ongoing FN is indicated only in
special situations. These are limited to those patients who
are not responding to appropriate antibiotic management
and who are developing life-threatening infectious complications
(such as severe sepsis or septic shock).’’ Recommendation
grade: B.
‫ אינו מוצדק‬:‫ בחולה עם נויטרופניה ללא חום‬GCSFs ‫מתן‬
!‫כטיפול שגרתי‬
Therapy of patients with afebrile neutropenia
• 2005 recommendation. CSFs should not be routinely used for
patients with neutropenia who are afebrile.
• 2005 update. There are no new published data since the 2000
ASCO guideline that pertain to the use of CSF in patients who are
afebrile and neutropenic.
‫‪GCSFs during‬‬
‫‪concurrent/simultaneous/concomitant‬‬
‫‪chemo and radiotherapy‬‬
‫• הנתונים בספרות מאוד מוגבלים‪.......‬ההמלצות הפורמאליות הן לא‬
‫לתת ‪ GCSFs‬לחולים‪ ,‬שמקבלים טיפול משולב כימו ‪ +‬קרינתי‪,‬‬
‫במיוחד‪-‬טיפול משולב למיצר‪.‬‬
‫• ראה בהמשך המלצות‪:‬‬
‫‪ Amgen‬‬
‫‪ NCCN‬‬
‫‪ ASCO‬‬
GCSFs during concurrent/simultaneous/concomitant
chemotherapy and radiotherapy
Product information:
Simultaneous use of NEUPOGEN® with
chemotherapy and radiation therapy should
be avoided. AMGEN: Revised: 09/2013
‹#›
‫ על פיו מומלץ שלא לתת גורמי צמיחה של השורה הלבנה בשילוב עם‬,‫המחקר‬
‫טיפול‬
:‫ קרינה למיצר‬+ ‫כימו‬
•
•
•
•
•
•
‹#›
Bunn PA Jr ET AL. J Clin Oncol. 1995 Jul;13(7):1632-41. Chemoradiotherapy with or without granulocytemacrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: a
prospective phase III randomized study of the Southwest Oncology Group.
This phase III randomized trial was designed to determine if granulocyte-macrophage colony-stimulating factor
(GM-CSF) reduces the hematologic toxicity and morbidity induced by chemoradiotherapy in limited-stage smallcell lung cancer (SCLC)………
RESULTS:
There was a statistically significant increase in the frequency and duration of life-threatening thrombocytopenia (P
< .001) in patients randomized to GM-CSF. GM-CSF patients had significantly more toxic deaths (P < .01), more
nonhematologic toxicities, more days in hospital, a higher incidence of intravenous (IV) antibiotic usage, and more
transfusions. Patients randomized to GM-CSF had higher WBC and neutrophil nadirs (P < .01), but no significant
difference in the frequency of grade 4 leukopenia or neutropenia. Patients randomized to GM-CSF had a lower
complete response rate (36% v 44%), but the differences were not significant (P = .29). There were no significant
differences in survival (median, 14 months on GM-CSF and 17 months on no GM-CSF; P = .15).
CONCLUSION:
GM-CSF, as delivered in this study, should not be included with concurrent chemoradiotherapy treatment
programs for limited-stage SCLC. The simultaneous use of hematopoietic colony-stimulating factors (CSFs) and
chemoradiotherapy should be performed only in experimental settings. Chemoradiotherapy programs with cisplatin
and etoposide ([VP-16] PE) and simultaneous chest RT produce grade 4 neutropenia and thrombocytopenia in a
small-enough proportion of patients that prophylactic hematopoietic growth factors are clinically unnecessary.
‫מחקר שתומך במתן גורמי צמיחה של השורה הלבנה‬:‫ולעומת זאת‬
•
Sheikh H . Lung Cancer. 2011 Oct;74(1):75-9. Epub 2011 Feb 26. Use of G-CSF
during concurrent chemotherapy and thoracic radiotherapy in patients with
limited-stage small-cell lung cancer safety data from a phase II trial.
•
•
Abstract
There is paucity of data in the literature regarding the safety of combining granulocyte colony stimulating factor (GCSF) during chemo-radiotherapy (CTRT) in lung cancer patients. The ASCO 2006 recommendations advise
against use of CSFs during concomitant mediastinal CTRT. The only randomised study evaluating CSFs in this
context showed significant increase in grade 3/4 thrombocytopenia and an excess of pulmonary toxic deaths. In
the context of a phase II trial, 38 patients with limited-stage small cell lung cancer were randomised to receive
once-daily (66 Gy in 33 fractions) or twice-daily (45 Gy in 30 fractions) radiotherapy. Radiotherapy (RT) was given
concurrently with cisplatin and etoposide. G-CSF was given as primary or secondary prophylaxis or as a
therapeutic measure during an episode of febrile neutropenia according to local protocols. Common terminology
criteria for adverse events (CTCAE) v3.0 was used to record toxicity. Thirteen (34%) of 38 patients received GCSF concurrently with RT. With a median follow-up of 16.9 months, there were no treatment related deaths
reported. Seven (54%) patients experienced grade 3/4 thrombocytopenia and 5 (38%) experienced grade 3/4
anaemia. Thirty-one percent required platelet transfusions. No episodes of bleeding were observed. There were
no cases of grade 3/4 acute pneumonitis. These data suggests that with modern three-dimensional (3D) conformal
RT, G-CSF administration concurrently with CTRT does not result in the increase risk of pulmonary toxicity, but
does increase the risk of thrombocytopenia. Whether the risks of thrombocytopenia are outweighed by the
outcome of timely early concurrent CTRT is being evaluated prospectively in the ongoing phase III CONVERT trial
(NCT00433563) in which G-CSF is permitted during thoracic irradiation.
‫המלצות מחלקתיות למתן גורמי צמיחה של השורה‬
‫הלבנה במהלך טיפול קרינתי ו‪/‬או טיפול משולב של קרינה‬
‫וכימותרפיה‬
‫• רצוי להימנע ממתן ‪ GCSFs‬במהלך טיפול קרינתי‪ ,‬הניתן‬
‫לשדה גדול )מבחינת מח העצם שהוא כולל(‪.‬‬
‫• רצוי להימנע ממתן ‪ GCSFs‬במהלך טיפול קרינתי‪,‬‬
‫המשולב עם כימותרפיה‪ ,‬במיוחד עם הקרינה ניתנת‬
‫למיצר )למשל‪ ,‬בחולים עם סרטן ריאה מסוג תאים‬
‫קטנים(‪ .‬ניתן לשקול מתן גורמי צמיחה בחולים אלה‬
‫בהתאם לשיקול אינדיבידואלי‪...‬רצוי‪-‬בצורה מוגבלת(‪.‬‬
End