Therapy Side Effects

Transcription

1 Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer Therapy Side Effects

2 Therapy Side Effects Versions : Albert / Bischoff / Costa / Friedrichs / Göhring / Jackisch/ Lisboa / Nitz / Schmidt / Souchon / Stickeler / Untch Version 2012: Stickeler / Müller

3 Toxicity Assessment Grade Acute Toxicity According to WHO 1 or NCI-CTC 2 Information required 0 none organs involved 1 mild type of toxicity 2 moderate time interval after treatment 3 severe effect on general health status 4 life threatening treatment required recovery achieved Long-Term Toxicity No general assessment scale 1 WHO Handbook for reporting results of cancer treatment, N0 48 (1979) (WHO offset Publications, Geneva) 2 National Cancer Institute, NHI,Bethesda, USA, Common Toxicity Criteria,

4 Cytotoxic Anti-Cancer Drugs Acute Toxicity I Haematol. Toxicity Nausea/ Vomit. Alopecia Mucositis/ Stomatits Cardiac Toxicity Renal Toxicity Cyclophosphamide Methotrexate Fluorouracil Carboplatin Cisplatin Capecitabine Gemcitabine Epi-/Doxorubicin Pegliposomal Doxorubicin Liposomal Doxorubicin (+) (+) Mitoxantrone Paclitaxel nab-paclitaxel Docetaxel Vinorelbine ++ (+) + Hepatic Toxicity + + +

5 Cytotoxic Anti-Cancer Drugs Acute Toxicity II Allergic Reaction Bladder Toxicity Skin Toxicity Cyclophosphamide Methotrexate Diarrhea Neuropathy Hand- Foot-S. 5-Fluorouracil Carboplatin Cisplatin +++ Capecitabine Gemcitabine Other Flue-like Synd., Oedema Epi-/Doxorubicin + Paravasates Liposomal Doxo. + + Pegliposomal Doxo Mitoxantrone ++ Paclitaxel nab-paclitaxel Myalgia Myalgia Docetaxel Myalgia, Fluid retention, nails! Vinorelbine ++ Thrombophlebi tis

6 Long-Term Toxicity Cardiotoxicity Equivalent cardiotoxicity of doxorubicin and epirubicin at recommended dose levels ( and mg/m² cum. dose, resp.) 2b B Liposome encapsulated anthracyclines (doxorubicin) induce less cardiotoxicity 1b B Anthracycline- or trastuzumab-associated cardiotoxicity may occur earlier/more frequently: 2b B Age > 65 yrs Obesity (> 27 kg/m²) Hypertension Hypercholesterolemia Pre-existing cardiac diseases (incl. borderline LVEF) Diabetes mellitus Oxford / AGO LoE / GR Monitoring of cardiac function before / during / after treatment: Echocardiography (LVEF or SF in %) 3b C +

7 Feasibility of Treatment Combinations Considering Toxicities Regarding cardiac toxicity Oxford / AGO LoE / GR Trastuzumab simultaneous to radiotherapy 2b B + Trastuzumab simultaneous to epirubicin 2b B +/- Trastuzumab simultaneous to doxorubicin 2b B - Anthracycline simultaneous to radiotherapy 2c C - Regarding breast fibrosis Tamoxifen simultaneous to radiotherapy 3 C + Chemotherapy simultaneous to radiotherapy 1b B -

8 Side Effects of Trastuzumab Algorithm in Case of Cardiac Toxicity Symptoms LVEF Trastuzumab LVEF Monitoring Therapy asymptomatic Slightly decreased Continue Check within 4 weeks Decreased below 45% Decreased below 30% Reconsider Continue if M1 Stop if M0 Interrrupt Check within 2 4 weeks Improved: further monitoring Not improved: stop Trastuzumab Check within 2 weeks Improved to > 45%: cont. Trastuzumab Not improved: stop Trastuzumab Consider b-blocker Consult cardiologist Consult cardiologist symptomatic Slightly decreased Continue Check within 4 weeks Exclude anemia Decreased below 45% Reconsider Continue if M1 Stop if M0 Check within 2 4 weeks Improved: further monitoring Not improved: stop Trastuzumab Consult cardiologist Decreased below 30% Stop Consult cardiologist Modified acc. to Keefe DL, Cancer 2002

9 Secondary Malignancies I With regard to solid tumours, chemotherapy induced secondary malignancies are rare events Alkylating agents increase the risk of secondary leukaemia dose-dependently to a total of 0,2 0,4 % within 10 to 15 years Anthracycline-containing regimens increase the risk of MDS and secondary leukaemia to 0,2 1,7 % within 8 to 10 years 2a Radiotherapy increases the risk of leukaemia by 0,2 0,4% in patients treated with anthracycline-containing chemotherapy Tamoxifen approximately doubles the risk for developing endometrial cancer Oxford LoE 2a 2a 2b 2b

10 Secondary Malignancies II (after Radiotherapy) The risk of developing secondary cancers is low if modern radiation techniques are applied and should not deter the use of radiotherapy when indicated Postmastectomy radiotherapy (PMRT) may moderately enhance the risk of ipsilateral lung cancer and angiosarcoma appearing 5 10 years after treatment Oxford LoE 2b 1a Enhanced risk especially among ever smokers 2b PMRT may moderately enhance the risk of esophageal cancer appearing after treatment with probable relationship to smoking, alcohol use and chronic inflammatory disease (not applicable to patients treated with current techniques) 2b a

11 Chemotherapy Related Amenorrhea (CRA) CRA may be permanent or temporary Depends on CTX regimen used Oxford LoE CRA is an (imperfect) surrogate for menopause and fertility Adjuvant endocrine therapy induces reversible amenorrhea, but delays conception to less fertile period Risk of CRA increases with age / treatment duration 2b Ovarian reserve of women who remain premenopausal after CTX is reduced CRA is associated with improved outcome (DFS/OS) 1b 2b Synonyma: Chemotherapy / Treatment induced Amenorrhea (TIA, CIA)

12 (Therapy Related) Fatigue Oxford / AGO LoE / GR Fatigue frequently present in breast cancer patients (30 60%) 2a B Psycho-social interventions specifically addressing fatigue are efficient in reducing fatigue 1a A ++ Physical exercise with ambiguous effects regarding fatigue 1b D + Methylphenidate might improve fatigue 1a D +

13 (Therapy Associated) Sleeping disturbance Sleep disturbances are a common problem of breast cancer patients during and after therapy (20 70%) 2a B Oxford / AGO LoE / GR Behavioral therapies have demonstrated efficacy in the treatment of insomnia and improve quality of life 1b A ++

14 (Therapy Associated) Depression Oxford / AGO LoE / GR Depression is an often reported adverse event in breast cancer patients (20 30%) 2a B Psychological interventions are effective to improve mood, but not survival in distressed and depressed patients 1b A Antidepressents have shown to improve depression in breast cancer patients 1b A Regular exercise participation can prevent depression among breast cancer survivors 2b B +

15 (Therapy Associated) Cognitive Impairment Oxford / AGO LoE / GR Therapy-related cognitive deficits (chemobrain frequently described (16 75%)) 2a B Cognitive-behavioral therapy is beneficial for cognitive function 2b B Methylphenidate might improve cognitive function in patients with cancer 3a C

16 Side-effects and Toxicity of Endocrine Agents I Visual Disturbances Osteoporosis Cerebro- Vascular Events * Fracture Cardiac risk Cognitive functions SERMs (+) + + AI 3rd Gen* (+) SERD + + GnRHa + + Arthralgia Myalgia Flush Dysfunctional Bleeding* Endometrial Changes Deep Venous Thrombosis Lipid Profile Impaired SERMs (+) (+) (+) AIs + (+) (+) Letrozole Anastrozole SERD Goserelin (+) +

17 Side-Effects and Toxicity Bisphosphonates (BP) and Denosumab (Db) Renal function deterioration due to IV-aminobisphosphonates Osteonecrosis of the jaw (ONJ) mostly under IV-BP and denosumab therapy (appr. 2%) Acute phase reaction (IV Amino-BPs, Db) 10 30% Gastrointestinal side effects (oral BPs) 2 10% In adjuvant bisphosphonate therapy, major side effects were observed rarely (except APR) Oxford LoE 1b 1b 1b 2b

18 Recommendations for Precautions to Prevent ONJ* Oxford LoE: 4 GR: C AGO: + During bisphosphonate treatment, avoid any elective dental procedures, which involve jaw bone manipulations if interventions are inevitable, prophylactic antibiotics are recommended (LoE 2b) Optimize dental status before start of bisphosphonate treatment, if feasible (LoE 2b) Inform patients about ONJ risk and educate about early symptom reporting In case of high risk for ONJ, use oral bisphosphonate In adjuvant bisphosphonate therapy, ONJ was extremely rare *Osteonecrosis of the jaw

19 Frequent Side Effects of Bisphosphonate Treatment Drug Acute Renal Upper Diar- ONJ Phase Tox. GI-SE rhea React. Clodronate 1500 i.v Clodronate 1600 p.o Non-A Ibandronate 50 mg p.o Amino Ibandronate 6 mg i.v Zoledronate 4 mg i.v Pamidronate 90 mg i.v Zoledronate 4 mg i.v. q6m

20 Key-Toxicities Small Molecules / Antibodies Oxford / AGO LoE / GR Cardiotoxicity (symptomatic) due to trastuzumab 1b A in the adjuvant setting (0,8 2,0%) Troponin I might identify trastuzumab-treated patients who are at risk for cardiotoxicity 2b B Bevacizumab (hypertonus, left ventricular dysfunction, bleeding, proteinuria) 1a A Lapatinib (diarrhea, skin rash, fatigue) 1b A