1. General principles of cancer chemotherapy
Silvio Monfardini,MD
Geriatric Oncology Program
Istituto Palazzolo, Fondazione Don Gnocchi, Milano

2. No conflict of interests
Disclosure
No conflict of interests
Giotto. Evil exorcism in Arezzo

3. WHY GERIATRICIANS SHOULD BE INFORMED ON (SIDE EFFECTS OF) CANCER CHEMOTHERAPY?

4. Why Geriatricians should receive some information on cancer chemotherapy
1) Follow up of patients receiving chemotherapy
2) Preexistent comorbidity and possible effect on that organ (example cardiac insufficiency and cardiac toxicity)
3) Limits to chemotherapy administration (example anemia,ipoalbuminemia)
4) Balance on advantages/disadvantges

5. The goal of chemotherapy in patients with advanced cancer
Chemotherapy objective response rates (CR,PR)
are leading to an increase in survival
And generally to an improvement in the quality of life

6. Tumors in which cure by chemoterapy is possible in advanced-stage disease
Gestional choriocarcinoma
Testicular cancer
Hodgkin’s lymphoma
Aggressive non-Hodgkin’s lymphoma
ALL, AML

7. Tumors in which useful responses by chemoterapy are possible in advanced-stage disease
Breast Carcinoma
Lung Carcinoma
Colorectal Carcinoma
Ovarian Carcinoma
Prostate Carcinoma

8. Objective responses in advanced solid tumors have usually a limited duration
Development of Cancer chemotherapy resistance : ability of cancer cells to evade the effects of chemotherapeutics

9. From L Balducci Mediterranean J 2010

10. In the last 50 years
Empirical drug screening of cytotoxic agents against uncharacterized tumor models
Target-oriented drug screening of agents with defined mechanisms of action.

12. Catharanthus roseus (Madagascar Periwinkle)
Vinca alkaloids: viblastine,vincristine

14. : etoposide, teniposide
Podophyllum peltatum
: etoposide, teniposide

16. Camptotheca acuminata
Topotecan

18. Taxus brevifolia
: Taxol

19. Vinblastin, vincristin Fluorouracile, actinomycinaD Melphalan
1945
Mechloretamin
Methotrexate
6-mercaptopurin
Busulfan
Clorambucil
Ciclophophamide
Vinblastin, vincristin
Fluorouracile, actinomycinaD
Melphalan
Procarbazin, 6-thioguanin
Cytosin arabinoside
Adriamicyn
1950
1955
1960
1965
VAMP e POMP in acute leukemias
First adj chemother with actinomycin D in Wilms Tumor
MOPP for Hodgkin’s disease
1970

20. Etoposide, mitoxantrone
Bleomycin, dacarbazin
CCNU, BCNU, cisplatin
Epirubicin
Etoposide, mitoxantrone
Ifosfamide + mesna
Carboplatin
Vinorelbin
Paclitaxel
Docetaxel
Camptotecin
TARGETED THERAPY
1970
1975
ABVD in Hodgkin’s disease
adjuvante CMF in breast. Ca.
adjuvante therapy forosteosarcoma
Bone marrow transplantation
PVB in testicular tumors
1980
Initial neoadjuvant chemother in various non resectable tumors
1985
Autologous bone marrow transplant with GM-CSF
1990
1995
Combination of chemotherapeutic drugs with specific molecular targets (Herceptin, Iressa)

21. Drug development Timeline

23. COMBINATION CHEMOTHERAPY : a strategy to increase response and tolerability and to decrease resistance
1) use drugs with non overlapping
toxicities so that each drug can be administered at near-maximal dose;
2) combine agents with different mechanisms of action
to inhibit the emergence of broad spectrum drug resistance

24. How many regimens in a pocket?

25. Example on the memento on dose and schedule

26. Chemotherapy complications are more common in the elderly
Myelosuppression1:neutropenia, thrombocytopenia, anemia
Mucositis2: oropharyngo-esophagitis, enterocolitis
Cardiomyopathy3
Peripheral neuropathy1
Central neurotoxicity4: cognitive decline, delirium, cerebellar dysfunction
There is controversy about whether myelodepression is more common in elderly patients. Retrospective studies of patients receiving CMF for metastatic breast cancer (Gelman 1984; Christman 1992) and Phase II studies in patients with various tumors (Giovanazzi-Bannon 1994) have not demonstrated increases in the incidence or severity of myelodepression in older patients. However, prospective studies in patients with large-cell lymphoma that specifically examined myelosuppression in patients older than 60 years who were receiving CHOP, CTVP (French version of CHOP), VMP, and other regimens showed that the risk of neutropenic complications and death from neutropenic infections is increased for older patients receiving moderately toxic CT, which is greater after age 70. (Balducci 2000)
Risk of mucositis is increased in older patients and may lead to lethal fluid depletion. (Stein 1995) Increased risk of mucositis may be due to decreased concentration of mucosal stem cells, increased destruction of rapidly proliferating mucosal cells, and decreased intracellular catabolism of fluoropyrimidine in the elderly. (Balducci 2000)
The risk of anthracycline cardiomyopathy increases with age (Von Hoff 1979) but the risk is limited to elevated total doses of the drugs (equivalent to doses of doxorubicin >450 mg/m2 of body surface area).
Cerebellar toxicity is typical of high doses of cytarabine, and may occur when a patient has a decreased GFR. (Gottlieb 1987). Cerebellar toxicity appears to be due to the accumulation of arauridine in the cerebellum (Rubin 1992); arauridine is a product of the catabolism of cytarabin and is excreted from the kidneys. When the GFR is reduced, arauridine accumulates in the plasma and tissues.
Christman K, Muss HB, Case D, et al. Chemotherapy of metastatic breast cancer in the elderly. JAMA 1992;268:57-62.
Gelman RS, Taylor SG. Cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: the elimination of age trends in toxicity by using doses based on creatinine clearance. J Clin Oncol 1984;2:
Giovanazzi-Bannon, Rademaker A, Lai G, et al. Treatment tolerance of elderly cancer patients entered into phase II clinical trials. An Illinois cancer center study. J Clin Oncol 1994;12:
Gottlieb D, Bradstock K, Koutts J, et al. The neurotoxicity of high-dose cytosine arabinoside is age-related. Cancer 1987;60:
Rubin EH, Andersen JW, Berg DT, et al. risk factors for high dose cytarabine neurotoxicity: an analysis of a cancer and leukemia group B trials in patients with acute myeloid leukemia. J Clin Oncol 1992;10:
Stein BN, Petrelli NJ, Douglass HO, et al. Age and sex are independent predictors of 5-fluorouracil toxicity. Cancer 1995;75:11-17.
Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin induced congestive heart failure. Ann Intern Med 1979;91:
Balducci The Oncologist 2000;
Stein Cancer 1995
Von Hoff Ann Intern Med 1979;
Gottlieb Cancer 1987

27. Clinical trials and drug toxicity in the elderly
Clinical trials and drug toxicity in the elderly. The experience of the ECOG Group. Cancer, 1983.

28. Leukopenia, infection Anemia Mucositis Cardiac toxicity
Main toxicities after chemotherapy possibly requiring therapy in patients followed by Geriatricians
Leukopenia, infection
Anemia
Mucositis
Cardiac toxicity

29. The type of side effects of chemotherapy
Geriatricians following also cancer patients should know
The type of side effects of chemotherapy

30. Side effects of chemotherapy
Immediate
- Anaphylactic shock
- Cardiac arrhythmia
- Pain at the site of injection

31. Side effects of chemotherapy
2. Early
- Nausea, vomiting
- Fever
- Hypersensitivity reactions
- Flu-like syndrome
- Cystitis

32. Side effects of chemotherapy
Intermediate (within days)
a) Bone-marrow depression
- after 1-3 weeks (majority of immunodepressive drugs)- after 4-6 weeks (nitrosoureas)
b) Stomatitis
c) Diarrhoea
d) Alopecia
e) Peripheral neuropathy, loss of reflexes
f) Paralytic ileus
g) Renal toxicity
h) Immunosuppression

33. Side effects of chemotherapy
4. Late (within months)
Injury to vital organs or system (heart-adriamycin; lung-bleomycin and busulfan; liver-methotrexate)
Effects on reproductive capacity (amenorrea, decreased sperm concentration)
Carcinogenic effects

34. Cancer chemotherapy administration
in older patients
Medical Oncologists: Specific knowledge and experience of the side effects and toxicities of the various cytostatic drugs
Geriatricians know more: changes with aging associated with possible increased chemotherapy toxicity: reduced functional reserve (liver, kidney, heart),greater anemia, ipoalbuminemia

35. Geriatricians should know which drugs may cause problems in case of:
Renal excretion: Cisplatin, Carbo, MTX, CTX, Capecitabine
Liver metabolism: antracyclines, taxanes, CTX, MTX,5-FU
Anemia/ipoalbuminemia: antracyclines,taxanes
Cardiomyopathty / cardiac function: antracyclines, Trastuzumab 5-FU, Taxol

36. Excretion of drugs
A decline in glomerular filtration rate (GFR) is one of the most predictable changes associated with age
Additional effect of comorbid conditions on renal function
Creatinine clearance should be evaluated in every elderly cancer patient.

37. Drugs requiring dose modification in renal dysfuction
(Cancer care in the older population, ASCO curriculum)
% dose reduction based on Crcl(ml/min)
30-60
10-30
<10
cisplatin
50%
Omit
carboplatin
20%
30%
cyclophosphamide 0%
bleomycin
25%
methotrexate
Nitrosoureas
Capecitabine
75%

38. Changes in hepatic metabolism in older patients leading to possible increased toxicity
Reduced Blood Flow
Reduced liver dimensions
Changements in the microsomial Cytocrom P450 (age after 70)
- Inductors P450: sex steroids , Fenobarbital
- Inhibitors P450: omeprazol,erithromycin
Polypharmacy

39. % dose reduction for hepatic dysfuction
DRUGS AFFECTED BY CHANGES IN HEPATIC METABOLISM (Cancer care in the older population, ASCO curriculum)
% dose reduction for hepatic dysfuction
Mild
(bili* ;SGOT**60-180)
Moderate
(bili* ;SGOT**>180)
Severe
(bili*>5.0)
Anthracyclines
Andriamycin
daunorubicin
50%
25%
75%
Omit
Taxanes
Vinca Alkaloids
Epipodophyllotoxins
Methotrexate 0%
Cyclophosphamide 5%
5-fluorouracil

40. Why Anemia and Hypoalbuminemia may lead to increased toxicity
Several circulating antitumor drugs (antracyclins, epipodofillotoxines, taxanes,camptotecins) are bound to red cells and to albumin.
If there is a decrease of red cells as well as of albumine, the unbound drug concentration increases
A low hemoglobin concentration is therefore an independent risk factor for toxicity.
And the same for albumin

41. Cardiotoxicity / Cardiomiopathy
Risk Factors
previous RT to the chest wall
preexisting cardiac disease
age > 65 years
Other dugs potentially cardiotoxic:
5-fuorouracil, Taxanes, Trastuzumab, Pertuzumab

42. Conventional doxorubicin-related CHF was
Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper Doxorubicin-induced cardiotoxicity is related with cumulative dose
Conventional doxorubicin-related CHF was
5% at a cumulative dose of 400 mg/m2,
16% at a dose of 500 mg/m2
26% at a dose of 550 mg/m2
Age was a risk factor,
hazard ratio (HR) of 2.25 in patients older than 65 years compared with those aged 65 years or younger.

43. Bone marrow Tolerance to Chemotherapy Lessens With Age
With age comes increased risk of
- neutropenia and its complications
Key point
The incidence and severity of the toxic effects of chemotherapy are greater in elderly patients.
Background
Decreased tolerance is related to the presence of comorbidities and the loss of functional reserve in the elderly; the impact of age itself is less clear.
Myelosuppression:
Elderly patients often have decreased hematopoietic reserves2,3:
May be related more to comorbidities than to age itself
Does not affect the basal state; mainly affects the response to stress or stimuli that normally trigger rapid hematopoiesis (eg, neutrophilic response to infection)
Increased risk of death due to infection is secondary to neutropenia in the elderly.9
Nonneutropenic forms of myelosuppression also occur:
Decreased erythrocyte count, causing anemia, which may lead to fatigue, and possibly impact mortality
Decreased thrombocyte count (and fragile vessels), causing increased bleeding
Mucositis is generally more severe in the elderly because their intestinal mucosal cells are more vulnerable to the cytotoxic effects of chemotherapy. Other factors may include decreased concentration of mucosal stem cells, increased destruction of rapidly proliferating mucosal cells, and decreased catabolism of certain agents in the elderly.
Susceptibility to cardiotoxicity is increased by the presence of cardiomyopathy due to chronic hypertension or ischemia, which are more common in elderly patients.
Neurotoxicity:
Peripheral nervous system: paresthesias (decreases in deep-tendon reflexes and touch sensitivity, and weakness)
Central nervous system: cognitive loss, cerebellar symptoms, especially in older patients with preexisting age-related cognitive deficits
Chemotherapy-induced anemia may cause deterioration in functional status.9
Potential loss of independence9:
Many elderly patients are at least partially dependent on help in routine daily activities.
Toxic effects of chemotherapy may cause further loss of independence, which has been linked to an overall poorer prognosis.

44. Central and peripheral nervous system possible toxicity of chemotherapeutic agents
Peripheral nervous system (distal peripheral neuropathy): cisplatin, vincristine, taxanes, and thalidomide
CNS (encephalopathy of various severities): methotrexate, vincristine, ifosfamide, fludarabine, cytarabine, 5-fluorouracil, cisplatin ,cyclosporine and the interferons

45. Toxicity of adjuvant chemotherapy for breast cancer increases with age
Postmenopausal women, “classic” CMF q28d  3 20 15 10 5
<65 years (n = 223)
>65 years (n = 76)
Patients (%)
Grade 3 toxicity
any type
Grade 3 hematologic toxicity
Grade 3 mucositis
Crivellari D, et al. J Clin Oncol. 2000;18:

46. Chemotherapy complications are more common in the elderly But: some drugs are elderly friendly
Some drugs are better candidates for elderly:
Vinorelbine,
Gemcitabine,
Carboplatin,
Caelix