Supportive Care Select Topics Updated May 2017 by Dr. Charles Lim (PGY-5 Medical Oncology Resident, University of Toronto)

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1 Supportive Care Select Topics Updated May 2017 by Dr. Charles Lim (PGY-5 Medical Oncology Resident, University of Toronto) Reviewed by Dr. Warr (Staff Medical Oncologist, University of Toronto) DISCLAIMER: The following are study notes compiled by the above PGY-5 medical oncology residents and reviewed by a staff medical oncologist. They reflect what we feel is relevant knowledge for graduating medical oncology residents preparing for their final examination. The information has not been surveyed or ratified by the Royal College. 1) Chemotherapy Induced Nausea and Vomiting (CINV) PATHOPHYSIOLOGY: Interplay between peripheral and central mechanisms, neurotransmitters and receptors Specific areas responsible for nausea and vomiting chemoreceptor zone, vomiting centre in the brain, vagal afferent pathway, enterochromograffin cells in the GI tract Enterochromograffin cells secrete substance P, cholecystokinin and 5-HT3 in response to chemotherapy These in turn bind to 5-HT3 receptors and NK-1 receptors on the end of vagal afferent nerves CNS processes the emetic stimuli and sends signals to various organs resulting in vomiting Other neurotransmitters including dopamine, GABA and cannabinoids also likely play a role in CINV RISK FACTORS: Female Younger age Vomiting during pregnancy Motion sickness CLASSIFICATION OF CINV: a) Acute CINV occurs minutes to hours after chemotherapy, maximal intensity at 5-6 hrs, usually resolves within 24 hours b) Delayed CINV occurs greater than 24 hours after chemotherapy, maximal intensity between 48 and 72 hours c) Anticipatory CINV precedes drug administration. Associated with a previous negative vomiting experience with chemotherapy. CLASSIFICATION OF CHEMOTHERAPY BY EMOTOGENIC POTENTIAL: Highly emotogenic (>90% of patients experience CINV): Anthracycline + Cyclophosphomide (Breast Cancer) Cisplatin Cyclophosphamide (if >1.5g/m2) Carmustine Dacarbazine Mechlorethamine Streptozocin

2 Moderately emotogenic (30-90% of patients experience CINV): Carboplatin Oxaliplatin Cyclophosphamide (<1.5g/m2) Ifosfamide Irinotecan Doxorubicin Epirubicin Low/ minimal emotogenic (<10-30% of patients experience CINV) Methotrexate Vinorelbine Recommended Anti-Emetic Regimens by Emetogenic Potential Risk Day of Chemo Subsequent Days High (>90%) Cisplatin and other single agents NK1R 5HT3 Dexamethasone Olanzapine NK1R (for aprepitant, Days 2-3) Dexamethasone (Days 2-4) Olanzapine (Days 2-4) High (>90%) Anthracycline + Cyclophosphamide for breast cancer Moderate (30-90%) Low (10-30%) NK1R 5HT3 Dexamethasone Olanzapine 5-HT3 Dexamethasone Dexamethasone NK1R (for aprepitant, Days 2-3) Olanzapine (Days 2-4) Dexamethasone (Days 2-3) Legend: NK1R = Neurokinin-1 receptor antagonist (eg. aprepitant, fosaprepitant) 5HT3 = 5-hydroxytryptamine receptor antagonist (eg. ondansetron, granisetron, palonesetron) [Note: aprepitant dosing is 125 mg Day 1, 80 mg on Day 2 and Day 3. For other NK1R antagonists, dosing is on Day 1 only] Evidence for different classes of anti-emetics: 1 st generation 5-HT3 Antagonists (i.e. ondansetron, granisetron) 1) A meta-analysis comparing the efficacy of four 5-HT3-receptor antagonists for acute chemotherapy-induced emesis.jordan K, Hinke A, Grothey A, et al.support Care Cancer 2007;15: Comparison of 1 st generation 5-HT3 receptor antagonists for prevention of acute CINV Included 44 randomized trials using granistron, ondansetron, tropisetron, or dolasetron Most 5-HT3 antagonists were equivalent with the exception of ondansetron vs. topisetron (ondasetron was better)

3 Possible advantage to higher dose of ondansetron (32 mg vs 24 mg) for cisplatin based regimens (however, FDA has considered 32mg high risk for QTc prolongation. No single dose higher than 16mg is recommended) 2 nd generation 5-HT3 antagonists (i.e. palonosetron) 1) A systematic review and meta-analysis of intravenous palonosetron in the prevention of chemotherapy-induced nausea and vomiting in adults.likun Z, Xiang J, Yi B, et al. Oncologist 2011;16: Comparison of palonosetron versus 1 st generation 5-HT3 antagonists for CINV Included 8 randomized control trials with a total of 3,592 patients There were statistically significant improvements in outcome of acute, delayed and overall phase (0-120 hours after chemotherapy) of CINV with palonosetron vs. 1 st generation 5-HT3 antagonists Subgroup analysis showed no difference in effectiveness between 0.25 and 0.75 mg doses of palonosetron, however the 0.75 mg dose appeared to cause more constipation compared to 1 st generation 5-HT3 antagonists Subgroup analysis showed that palonosetron was more effective in both highly emetic and moderately emetic chemotherapy regimens, and in combination with dexamethasone compared to 1 st generation 5-HT3 antagonists. Addition of aprepitant, however, was not evaluated in these trials Palonestron also has the advantage that is does not prolong the QTc interval NK-1 receptor antagonists (i.e. aprepitant, fosaprepitant) 1) Neurokinin-1 Receptor Antagonists for Chemotherapy-Induced Nausea and Vomiting: A Systematic Review. Dos Santos LV, Souza FH, Brunetto AT et al. JNCI 2012;104(17): Comparison of NK1R antagonists + standard therapy vs. standard therapy alone Included 17 randomized control trials with a total of 8,740 patients Pooled analysis demonstrated statistically significant improvement in acute, delayed and overall phase (0-120 hours after chemotherapy) of CINV in favour of NK1R antagonist containing regimens Secondary analysis demonstrated improved outcomes (rate of emesis, absence of nausea) in favour of NK1R antagonist containing regimens Subgroup analysis showed benefit for NK1R antagonists in both highly emetogenic and moderately emetogenic chemotherapy regimens Subgroup analysis showed no differences in efficacy for aprepitant/fosaprepitant vs. casoprepitant, and no differences in efficacy for IV vs. PO NK1R antagonist administration

4 The oral neurokinin-1 antagonist aprepitant for the prevention of chemotherapy-induced nausea and vomiting: a multinational, randomized, double-blind, placebo-controlled trial in patients receiving high -dose cisplatin the Aprepitant Protocol 052 Study Group. Hesketh PJ, Grunberg SM, Gralla RJ et al. J Clin Oncol 2003;21: Regimen Mechanism of Action of Experimental Drug Patients receiving cisplatin > or = 70 mg/m2 for the first time were given either standard therapy (ondansetron and dexamethasone on day 1; dexamethasone on days 2 to 4) or an aprepitant regimen (aprepitant plus ondansetron and dexamethasone on day 1, aprepitant and dexamethasone on days 2 to 3; dexamethasone on day 4) NK-1 antagonists centrally at NK-1 receptors in vomiting centers within the central nervous system to block their activation by substance P released as an unwanted consequence of chemotherapy Primary Endpoint Complete Response (no emesis and no rescue therapy) on days 1-5 post cisplatin Inclusion/Exclusion Only patients receiving cisplatin chemotherapy (>=70mg/m2) were Criteria eligible Size (N) 520 Results 72.7% complete response with aprepitant regiment vs. 52.3% with standard regiment (p<0.001) Toxicity Not reported Conclusion Addition of aprepitant was generally well tolerated and provided consistently superior protection against CINV inpatients receiving highly emetogenic cisplatin-based chemotherapy

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6 Efficacy and tolerability of aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients with breast cancer after moderately emetogenic chemotherapy. Warr DG et al. J Clin Oncol. 2005; 23(12): Regimen Aprepitant regimen (day 1, APR 125 mg, ondansetron (OND) 8 mg, and dexamethasone 12 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, APR 80 qd) or a control regimen (day 1, OND 8 mg and dexamethasone 20 mg before chemotherapy and OND 8 mg 8 hours later; days 2 through 3, OND 8 mg bid) Mechanism of NK-1 antagonists centrally at NK-1 receptors in vomiting centers Action of within the central nervous system to block their activation by Experimental Drug substance P released as an unwanted consequence of chemotherapy Primary Endpoint Primary endpoint: complete response, defined as no vomiting and no use of rescue therapy, during 120 hours after initiation of chemotherapy in cycle 1. Secondary end point: the proportion of patients with an average item score higher than 6 of 7 on the Functional Living Index Emesis questionnaire. Inclusion/Exclusion Inclusion: Criteria Breast cancer patients Treated with moderately emetogenic chemotherapy including cyclophosphomide Predicted life expectancy >= 4 months Karnofsky score >=60 Exclusion: Symptomatic brain metastases Received radiation to abdomen/pelvis in week before treatment Size (N) 866 patients Results Complete Response:50.8%v42.5%;P=.015 with aprepitant group compared to control group More patients in the aprepitant group reported minimal or no impact of CINV on daily life (63.5%v55.6%;P=.019) Toxicity Higher rate of constipation in the control group (18.0%v12.3%) and slightly more dyspepsia in the aprepitant group (8.4%v4.9%). Conclusion The aprepitant regimen was more effective than the control regimen for prevention of CINV in patients receiving both an anthracycline and cyclophosphamide Other Comments The absolute difference in no vomiting was 15-17% but there was minimal effect on nausea Corticosteroids 1) Contribution of dexamethasone to control of chemotherapy-induced nausea and vomiting: a meta-analysis of randomized evidence. Ioannidis JP, Hesketh PJ, Lau J. J Clin Oncol 2000;18: studies with 5613 patients were included Any study comparing dexamethasone to no treatment, placebo or other anti-emetic in patients on highly or moderately emetogenic chemotherapy For acute emesis, dexamethasone was superior to placebo or no treatment OR= 2.22; 95% CI For delayed emesis, dexamathesone was also better than placebo or no treatment OR 2.04, 95% CI

7 The pooled risk difference for complete protection from emesis was 16% for both the acute and delayed phases (95% CI, 13% to 19% and 11% to 20%, respectively) Olanzapine 1) Olanzapine for chemotherapy-induced nausea and vomiting: a systematic review. Hawking, CM and Kichendasse, G. Support Care Cancer (2014) 22: trials of CINV prophylaxis (488 patients) and 3 trials of breakthrough CINV (323 patients) Included patients on highly emetogenic and moderately emetogenic chemotherapy For CINV prophylaxis, improved CR was seen with olanzapine but was not statistically significant for the primary outcome of CR. Secondary endpoints were improved in one study (including no delayed nausea and no overall nausea). For breakthough CINV, olanzapine showed statistically higher rates of no emesis in the 72h following initiation of study treatment or complete response (no emesis and no use of additional antiemetics in all 3 studies The major limitation of this review was that three of the included trials were available only as conference abstracts and lacking full details of methodology, patient population and toxicity In addition, lack of blinding of several studies also created potential bias Taking these limitations into account, olanzapine is effective in preventing CINV and is effective as breakthrough for CINV 2) Olanzapine for the prevention of chemotherapy-induced nausea and vomiting (CINV). Navari R, Qin R, Ruddy J, et al: NEJM 2016; 375 (2): A randomized, double-blind, phase III trial was performed in 380 chemotherapy-naive patients receiving cisplatin ( 70 mg/m 2 ), or cyclophosphamide (600 mg/m 2 ) plus an anthracycline (60 mg/m 2 ), Patients received either 10 mg of oral olanzapine or matching placebo, plus 125 mg of aprepitant, a 5-HT3 agent, and 12 mg of oral dexamethasone prior to chemotherapy on day 1, followed by 10 mg/d of oral olanzapine or matching placebo and 8 mg of dexamethasone on days 2 to 4 post chemotherapy, plus 80 mg of aprepitant on days 2 and 3 post chemotherapy Primary endpoint was no nausea; secondary endpoint was complete response (no emesis, no rescue) The proportion of patients who had no nausea was significantly greater for the olanzapine arm compared with the placebo arm for the acute period (74% vs 45%,P<.0001), delayed period (42% vs 25%,P=.0008), and overall period (37% vs 22%,P=.0015) Complete response was also significantly improved for olanzapine recipients compared to placebo recipients for all three phases: acute (86% vs 65%,P<.0001), delayed (67% vs 52%, P=.0073), and overall (64% vs 41%,P<.0001 Transient sedation was observed in the olanzapine arm on day 2, but this sedation resolved despite continued use of olanzapine on days 3 and 4. No difference in appetite was observed in either arm on days 2 to 6 Conclusion - olanzapine in combination with a 5-HT3 receptor antagonist, aprepitant, and dexamethasone significantly improves the control of nausea and emesis in the acute, delayed, and overall phases for patients receiving highly emetogenic chemotherapy

8 Guidelines: ASCO - NCCN - MASCC/ ESMO - Review articles: Navari, R. and Aapro, M. Antiemetic prophylaxis for chemotherapy induced nausea and vomiting. N Eng J Med ; ) Hormone therapy associated vasomotor symptoms Hot flashes, the most common side effect of tamoxifen, occur in up to 80% of women receiving tamoxifen,and the occurrence of hot flashes can result in patient noncompliance Although hormone replacement therapy is the most effective treatment for reducing hot flashes, its use in women with a history of breast cancer is generally not recommended because of a concern that pharmacologic doses of hormones could promote growth of subclinical breast cancer metastases Both venlafaxine and gabapentin have been studied in the management of vasomotor symptoms associated with hormonal therapy for breast cancer or prostate cancer

9 Venlafaxine is superior to clonidine as treatment of hot flashes in breast cancer patients a double-blind, randomized study Loibl et al. Ann Oncol 2007; 18(4): Regimen Mechanism of Action of Experimental Drug mg clonidine bid or venlafaxine 37.5 mg bid x 4 weeks It has been demonstrated in several trials that venlafaxine and other SNRI or selective serotonin-reuptake inhibitors (SSRI) such as fluoxetine or paroxetine are effective in reducing hot flashes in cancer patients by at least 50% However, tamoxifen is recommended not to be combined with strong CYP2D inhibitors such as fluoxetine and paroxetine Primary Endpoint Inclusion/Exclusion Criteria Primary endpoint: hot flash frequency (number of hot flashes reported per week) in both treatment groups after 4 weeks of treatment. Secondary end point: hot flash severity score, incidence of toxic effects Inclusion: Bothersome hot flashes at least 14 times a week or must have been seeking help for hot flashes. The hot flashes had to be present for at least 4 weeks before study entry On treatment with Tamoxifen, gonadotropine-releasing agonists or aromatase inhibitors or no endocrine therapy ECOG 0-1 Exclusion: Metastatic disease Received radiation to abdomen/pelvis in week before treatment Size (N) 64 Results Venlafaxine decreased the frequency of hot flashes significantly compared with baseline (100%) by 57% [standard error (SE) 7.4]. Clonidine decreased the frequency by 37% (SE 4.7) The median hot flash frequency dropped by 7.6 hot flashes per day for patients receiving venlafaxine and 4.85 hot flashes per day for those receiving clonidine A 75% drop in hot flash frequency was reported by 29% (n=9) of the patients in the venlafaxine group compared with 12% (n=4) in the clonidine group Toxicity In both therapy groups the most common toxic effects were mouth dryness, tiredness, and restless sleep Nausea was significantly more frequently reported in the venlafaxine group compared with the clonidine group (P=0.05) Conclusion Venlafaxine is significantly more effective in reducing the frequency of hot flashes in breast cancer patients than clonidine

10 Gabapentin for hot flashes in 420 women with breast cancer: a randomised double-blind placebo-controlled trial Pandya et al. Lancet 2005; 366(9488): Regimen Placebo vs. gabapentin 300mg/day vs gabapentin 900 mg/day x 8 weeks Mechanism of Gabapentin is a GABA analogue used in the treatment of epilepsy, Action of neurogenic pain, restless-leg syndrome, essential tremor, bipolar Experimental Drug disorder, and migraine prophylaxis; it was first reported for its effects on hot flashes in five women and one man Primary Endpoint % reduction in hot flashes score from baseline Inclusion/Exclusion Inclusion: Criteria Patients aged >=18 with breast cancer having 2 or more hot flashes per day Exclusion: Patients receiving chemotherapy Patients taking venlafaxine, clonidine or anticonvulsants Size (N) 420 Results % change in in hot flash frequency vs placebo: 12% reduction with gabapentin 300mg (p=0.04) and 26% with 900 mg (p<0.0001) % change in hot flash severity vs placebo: 13% with 300mg dose (p=0.09) and 30% with 900mg dose (p<0.0001) At 8 weeks, 900mg dose was associated with a 46% reduction in hot flash severity Toxicity Somnolence or fatigue was the most common cause for discontinuing gabapentin 300mg or 900mg Conclusion Other Comments Gabapentin (up to 900mg) is an effective agent for the control of hot flashes in women with breast cancer Side effects and efficacy beyond 8 weeks were not examined, therefore the long term effects of this treatment remain unknown Other potentially active agents for vasomotor symptoms (without phase III evidence): - acupuncture - cognitive behavioural therapy - black cohosh (conflicting evidence) - relaxation therapy 3) Febrile Neutropenia Prophylaxis Febrile neutropenia is defined as an absolute neutrophil count (ANC) of < /L, or < /L predicted to fall below /L within 48 h, with fever or clinical signs of sepsis It is suggested that therapy be initiated if a temperature of >38.0 C is present for at least 1 hour or a reading of >38.3 C is obtained on a single occasion Febrile neutropenia and infection, are major toxicities associated with myelosuppressive systemic chemotherapy These complications require immediate assessment and often treatment with empiric antibiotics. Some patients may also require hospitalization

11 Risk factors for FN: Type and number of myelosuppressive chemotherapy agents used Type of cancer Age Comorbidities MASCC validated risk index score can identify patients at low risk (score >=21) for serious compliations of febrile neutropenia: Source: Granulocyte Colony Stimulating Factors (G-CSF) Several meta-analyses and systematic reviews confirm that the use of G-CSF in primary prophylaxis reduces the risk of FN and infection, allowing the maintenance of full-dose chemotherapy on schedule and of dose-dense chemotherapy regimens Guidelines: Guidelines from Europe (EORTC, ESMO) and the US (ASCO, NCCN) recommend G-CSF primary prophylaxis when the rate of febrile neutropenia is >20% Primary prophylaxis is also recommended in ASCO guidelines for elderly patients receiving curative intent treatment for aggressive lymphoma, and for patients receiving dose-dense regimens Individual assessment based on patient factors (i.e. age > 65, comorbidities) is suggested for regimens with an intermediate risk (10-20%) of febrile neutropenia No prophylaxis is recommended when rate of febrile neutropenia is <10% For palliative chemotherapy, dose reductions are favoured over the use of G-CSF Adverse effects: G-CSF generally well tolerated but mild to moderate bone pain can occur in 20-30% of patients Bone pain seems to be similar between daily filgrastrim and one time injection of pegfilgastrim Pain is generally well managed by use of NSAIDs Rare reports of AML, MDS, and splenic rupture

12 a) Filgastrim (Neupogen ) Reduction by Granulocyte Colony-Stimulating Factor of Fever and Neutropenia Induced by Chemotherapy in Patients with Small-Cell Lung Cancer Crawford et al. N Eng J Med 1991; 325: Regimen G-CSF (Filgastrim) 230 mcg SC once daily starting on day 4 vs placebo in patients receiving cyclophosphomide, doxorubicin and etoposide for SCLC Filgastrim continued until day 17 unless post-nadir neutrophil count 9 was > than 1.0 x 10/L after day 12. Mechanism of Human G-CSF is a hematopoietic growth factor that promotes the Action of proliferation and differentiation of neutrophils, both in vitro and in vivo. Experimental Drug The presumed target cells of this regulator molecule include a late precursor committed to the neutrophil lineage and the mature neutrophil. G-CSF also enhances the functional properties of mature cells by increasing phagocytic activity, antimicrobial killing, and antibody-dependent cell-mediated cytotoxicity Primary Endpoint Primary endpoint: effect of G-CSF on incidence of infection as manifested by fever with neutropenia after administration of cyclophosphamide, doxorubicin and etoposide. Secondary end point: reduction in duration and severity of neutropenia Inclusion/Exclusion Inclusion: Criteria Newly diagnosed small cell lung cancer (limited or extensive stage) ECOG 0-2 Size (N) 211 Results 50% reduction in rate of febrile neutropenia with G-CSF in cycle 1 28% vs. 57%, RR = 2.01, 95% CI ) Across all cycles, febrile neutropenia rate of 40% vs 77% with G-CSF, RR 1.9, 95% CI ) Median duration of grade IV neutropenia 1 day with G-CSF vs 6 days with placebo Toxicity Mild to moderate skeletal pain in 20% of patients receiving G-CSF Conclusion Other Comments G-CSF is effective at reducing rates of febrile neutropenia in patients receiving chemotherapy for SCLC. Incidence, duration and severity of grade IV neutropenia is also improved with G-CSF treatment. Treatment duration of G-CSF was between 9-12 days

13 b) Pegfilgrastrim (Neulasta ) A randomized double-blind multicenter phase III study of fixed-dose single-administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy Green et al. Ann Oncol 2003; 14(1): Regimen 6mg SC of pegfilgastrim x 1 vs 5mcg/kg/day SC of filgastrim for up to 14 days in patients 4 cycles of doxorubicin and docetaxel chemotherapy Mechanism of PEG-modification of filgrastim results in a new molecule called Action of pegfilgrastim, which in both experimental animals and healthy human Experimental Drug volunteers has decreased renal clearance and increased plasma half-life compared with filgrastim, thus sustaining the duration of the pharmacological effect Results of preclinical studies suggest that the biological activity of pegfilgrastim and filgrastim are similar, but with pegfilgrastim only requiring a single injection per chemotherapy cycle to achieve the same effect as multiple daily injections of filgrastim Primary Endpoint Primary endpoint: duration of grade IV neutropenia in cycle 1 Secondary end point: duration of grade IV neutropenia in cycle 2-4, incidence of febrile neutropenia, time to neutrophil recovery Inclusion/Exclusion Inclusion: Criteria High risk stage II or stage III/IV breast cancer ECOG <=2 Chemo naïve or adjuvant therapy only or only 1 chemotherapy regimen for metastatic disease Size (N) 157 Results Mean duration of grade IV neutropenia 1.8 days with pegfilgastrim vs 1.6 days with filgastrim mean difference of 0.23 days, 95% CI The incidence of febrile neutropenia was not statistically different between pegfilgrastim and filgrastim, with a 95% CI for the observed 7% difference of 19% to 5% Toxicity Conclusion Other Comments Bone pain (37% pegfilgrastim; 42% filgrastim) 1% and 8% of patients reporting severe bone pain in the pegfilgrastim and filgrastim groups, respectively A single fixed dose of pegfilgrastim administered once per cycle of chemotherapy was comparable to multiple daily injections of filgrastim in safely providing neutrophil support during myelosuppressive chemotherapy This was a non-inferiority study design

14 Blinded, randomized, multicenterstudy to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer Holmes et al. J Clin Oncol 2002; 20(3): Regimen Pegfilgastrim 100mcg/kg SC on day 2 vs filgastrim 5mcg/kg daily in patients receiving doxorubicin and docetaxel chemotherapy Mechanism of Action of PEG-modification of filgrastim results in a new molecule Experimental Drug called pegfilgrastim, which in both experimental animals and healthy human volunteers has decreased renal clearance and increased plasma half-life compared with filgrastim, thus sustaining the duration of the pharmacological effect Results of preclinical studies suggest that the biological activity of pegfilgrastim and filgrastim are similar, but with pegfilgrastim only requiring a single injection per chemotherapy cycle to achieve the same effect as multiple daily injections of filgrastim Primary Endpoint Primary endpoint: duration of grade IV neutropenia in cycle 1 Secondary end point: incidence of febrile neutropenia, time to neutrophil recovery Inclusion/Exclusion Criteria Inclusion: High risk stage II or stage III/IV breast cancer ECOG <=2 Size (N) 310 Results Mean duration of grade IV neutropenia 1.7 days with pegfilgastrim vs 1.8 days with filgastrim The incidence of febrile neutropenia was 9% with pegfilgrastrim vs 19% with filgrastrim (p<0.005) Toxicity No significant differences in adverse events between pegfilgastrim and filgastrim Conclusion Asingle injection of pegfilgrastim 100 microg/kgper cycle was as safe and effective as daily injections of filgrastim 5microg/kg/d in reducing neutropenia and its complications inpatients who received four cycles of doxorubicin and docetaxel Impact on Survival with G-CSF: Studies have shown controversial results as to whether the use of G-CSF has an impact on survival 2008 Cochrane review of 13 RCTs in patients with lymphoma showed reduced rates of febrile neutropenia and infection but no impact on overall survival Meta-analysis by Clark et al in 2005 concluded that G-CSF combined with empiric antibiotics can modestly reduce duration of neutropenia, fever and hospitalizations but mortality was not affected

15 Conversely, A systematic review of 25 RCTs by Lyman et al. in 2010 concluded that chemotherapy with G-CSF reduces all-cause mortality (estimated absolute decrease of 3.4 %) and that the reduction was greater with higher chemotherapy dose intensity - Lyman GH, Dale DC, Wolff DA et al (2010) Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: a systematic review. J Clin Oncol 28: Another review of 61 RCTs by Lyman et al. in 2013 associated primary G-CSF support of chemotherapy with significantly greater reductions in the relative and absolute risk of all-cause mortality Fluroquinolone prophylaxis Antibacterial Prophylaxis after Chemotherapy for Solid Tumors and Lymphomas Cullen et al. N Eng J Med ; Regimen Levfloxacin 500mg PO daily vs placebo x 7 days Mechanism of Levofloxacin It is active against a wide range of gram-negative Action of pathogens, as well as some gram-positive bacteria and organisms Experimental Drug causing atypical pneumonias Primary Endpoint Primary endpoint: incidence of clinically documented febrile episodes (temp >38C) attributable to infection. Secondary end point: incidence of all probable infections, severe infections and hospitalizations Inclusion/Exclusion Inclusion: Criteria Solid tumors (breast, lung, testicular) and lymphomas with chemotherapy regimens known to cause chemotherapy induced nausea and vomiting but not routinely given G-CSF or stem cell support Exclusion: Active infection, current antibacterial therapy, planned use of G-CSF, a history of adverse reactions to fluoroquinolones, epilepsy, a creatinine clearance below 40 ml per minute, pregnancy, and breast-feeding Size (N) 1565 Results Incidence of febrile episode 10.8% with levofloxacin vs 15.2% with placebo (p<0.001) Probable infection: 34.2% vs. 41.5% (p=0.005) Severe infection: 1.0% vs.. 2.0% (p=0.15) Hospitalization rates: 15.7% vs. 21.6% Toxicity Slightly higher rates of adverse events in the levofloxacin group due to GI toxicity and rash Conclusion Among patients receiving chemotherapy for solid tumors or lymphoma, the prophylactic use of levofloxacin reduces the incidence of fever, probable infection, and hospitalization Other Comments

16 Guidelines ASCO guidelines - ESMO guidelines - Neutropaenia Review Articles 1. Cortes de Miguel, S, Calleja Hernandez, MA, Menjon-Beltran, S, Vallejo-Rodriguez, I. Granulocyte colony-stimulating factors as prophylaxis against febrile neutropenia. Supportive Care Cancer 2015; 23: Lyman GH, Dale DC, Culakova E et al (2013) The impact of the granulocyte colony-stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials. Ann Oncol 2013; 24: