Long term Consequences of Cancer Treatment in Adults

1
Long term Consequences of Cancer Treatment in
Adults

• Shaun Costello

2
Learning Objectives

• To understand the range of long term consequences
  of cancer treatment
• To understand the mechanisms by which treatment
  may induce side effects at distant points post
  treatment
• To understand how long terms side effects can be
  mitigated

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Consequences

• Direct toxicity of drugs / radiation
• Idiopathic reactions to drugs / radiation
• Collateral damage due to radiation
• Genetic susceptibilities
• Psychological consequences (Breast cancer)
• Second tumours
• Surgical alterations

4
Consequences

• The long term effects of cancer treatment often
  take many years to become evident
• Children and young adults are increasingly being
  treated successfully for malignancy
• Clinicians managing the complications of
  treatment are usually not those clinicians
  responsible for the initial therapy

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Frequency of Complications

• Largely unknown
• Several longitudinal studies of Breast Cancer
  and Hodgkin's disease 0.1 4 depending on
  modalities and drugs used
• Chemotherapy distant organ damage and second
  tumours often haematological
• Radiotherapy local organ damage second tumours
  often solid
• Effects of radiotherapy can be additive or
  synergistic with chemotherapy Breast cancer vs.
  lymphoma (Stanford experience)
• Multiple courses of radiotherapy are additive as
  regards risk of second malignancy non stochastic
  effect
• The effect of multiple courses of chemotherapy is
  unknown

6
Psychological consequences

• Change in body image
• Visual changes
• Changes in sexuality
• Post traumatic stress
• Loss of function

7
Mechanisms of Damage

• Surgical resection
• Failure or effect of prosthetics
• Free radicals radiotherapy, chemotherapy
• Arteritis obliterans, osteoradionecrosis
• Genetic lack of specific repair enzymes
• Genetic lack of specific enzymes involved in drug
  metabolism
• Immune balance changes

8
Central Nervous System

• Central nervous system can be subject to a number
  of drug toxicities commonly causing dementing
  syndromes and ataxia. Methotrxate and Vinca
  alkloids. Acute confusional states can also occur
• Often there is a synergistic effect with
  radiotherapy
• Commonly the long term effects of radiation are
  seen in clinical practice.

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Central Nervous System Radiation effects

• Global dementing syndromes are uncommon,
  radiation related injury tends to be specific to
  the area treated.
• Patients treated with whole brain radiation can
  develop global injury but this is much less
  common than was thought. Usually large fraction
  sizes are responsible leading to a relative
  overdose.
• Common clinical scenario is re presentation of a
  patient some years after treatment with a space
  occupying mass which is contrast enhancing on MRI
  scan. Frequently diagnosed as recurrent tumour.
  Symptoms are often progressive. and treated with
  palliative intent or further surgery.

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Central Nervous System Radiation effects

• MRI spectroscopy and PET scan reveal diagnosis
• Treatment corticosteroids or surgery.
• Development of cateracts is common but not often
  symptomatic and degeneration of the optic tracts
  is rare but well recognised.
• Cranial nerve damage to II, IV, V, VII, VIII can
  occur up to two years post XRT

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Hormonal side effects

• Early menopause secondary to chemotherapy or
  radiotherapy is common and well understood
• Late ovarian failure is less well recognised
• Late pituitary and thyroid dysfunction is
  systematically overlooked, esp in radiotherapy
  for head and neck cancer lead time of 10 years av
  
• Anti androgens and anti oestrogen's increasingly
  used lead to osteoporosis

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Oral Pain

• Dental
• - root exposure
• - caries
• - dentures
• - orthodontic appliances
• Soft tissue
• -chronic mucositis and sub mucous
  fibrosis
• Bone
• - osteomyelitis
• - osteoradionecrosis

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Oral Complications

• Xerostomia - radiotherapy
• Damage to the salivary glands leading to loss of
  acinar cells and loss of reflex stimulation due
  to lack of wetting agents causing lack reflex
  secretion from the salivary glands
• Prevention Amifostine / IMRT / fluoride trays/
  dental care
• Complications anorexia, weight loss, dental
  caries, sub mucosal fibrosis, osteo-radionecrosis

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Osteoradionecrosis

• Osteo-radionecrosis - radiotherapy
• non healing acellular avascular bone. Often
  present for years before leading to the
  development of complications.
• Presents as a minor area of infection, typically
  a small erythematous ulcer. Minimal to moderate
  pain and dental mobility. Progresses to extra
  oral and intra oral fistulas through which
  sequestrae of bone are extruded.

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Osteo-radionecrosis Therapy
                                  View "The
Adjunctive role of HBOT in the treatment of lower
extremity wounds in patients with diabetes" Diab
Spect 10(2) 1997118-23   Go To scientific
abstracts supporting the use of HBOT in selected
wounds   
Conditons commonly treated with HBOT
OsteoradionecrosisSoft tissue radionecrosisDiabe
tic UlcerationOsteomyelitisPreservation of skin
grafts and flaps Osteoradionecrosis
View the following information validating HBOT
Visit the UHMS indications site   Download
British Medical Journal (BMJ) review of HBOT 1998
Vol 137 p1140-3      Visit our Carbon Monoxide
Resource Page
Before and after 20 consecutive treatments with
HBOT at 2 ata. The mandable is now ready for the
plate to be removed and a rotation flap
constructed.   GO TO scientific abstracts
supporting the use of HBOT in Osteoradionecrosis S
oft tissue radionecrosis
Radiotherapy post surgical resection of an
ethmoid tumor has resulted in wound dehiscence.
20 treatments of HBOT at 2ata has allowed a
rotation flap to take. Selected problem wounds
including diabetic ulceration

• Osteo-radionecrosis is progressive. Treatment
  involves resection of involved bone and
  hyperbaric oxygen therapy.

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Pulmonary Complications - radiotherapy

• Mechanism radiation Damage to type I
  pneumocytes and capillary endothelium.
• Replacement takes place by re-differentiation of
  type II pneumocytes and endothelial repopulation.
• Loss of clonogenicity leads to areas of leaking
  capillaries and reduced compliance and gas
  transfer. This can occur after several weeks and
  some months after radiation. If it becomes
  chronic fibrosis and respiratory failure can
  occur
• At least 10 of the lung needs to be irradiated
  above 20Gy. Formulae vs Clinical testing

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Radiation Pneumonitis

• Clinical picture radiation pnemonitis,
  dyspnoea, cough, pyrexia (uncommon)
• Ground glass opacification, haziness in the
  irradiated area progressing to consolidation and
  fibrosis. Confined to the radiation portal
• 2-3 months post XRT
• Precipitating factors concomitant chemotherapy,
  previous radiation, and withdrawal of steroids
• Treatment Pnemonitis corticosteroids, fibrosis
  supportive measures
• Radiation induced BOOP, occurs with low doses
  outside the radiation portal and can occur on the
  contra lateral side. Responds rapidly to
  steroids. Idiosyncratic effect of radiation.

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Pulmonary Complications - chemotherapy

• Mechanisms are largely with the exception of
  bleomycin unknown.
• Production of reactive oxygen metabolites,
  including superoxide anion, hydrogen peroxide,
  and hydroxyl radicals, primarily from activated
  neutrophils.
• Bleomycin induces reactive oxygen radicals by
  forming a complex with Fe3
• Chemotherapeutic drugs can affect the balance of
  the local immune system
• Bleomycin and cyclophosphamide produce substances
  that can inactivate the antiprotease system,
  enhancing the effects of proteolytic enzymes on
  the lung.
• Bleomycin also causes profound effects on the
  fibrinolytic system, altering the
• balance between fibrin deposition and
  fibrinolysis on the alveolar surface, leading to
  fibrin deposition
• One of the potential determinants of bleomycin
  toxicity is the cytoplasmic cysteine proteinase
  bleomycin hydrolase, which is the major enzyme
  responsible for metabolizing bleomycin to a non
  toxic molecule. Genetic deficiencies of this
  enzyme are responsible for the idiosyncratic
  responses sometimes seen

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Pulmonary complications chemotherapy

• Clinical picture is very similar to that of
  radiation pnemonitis reflecting a common pathway
  with similar pathological findings
• Rarely acute bronchospasm can occur with the
  administration of vinca alkaloids and taxanes
• Progression to fibrosis can take many years
  especially in the case of cyclophosphamide and
  carmustine
• Chest x-ray often shows a diffuse
  reticulo-nodular pattern, in the case of
  bleomycin toxicity these nodules can grow and
  progress to cavitation with hypersensitivity
  reactions hilar shadowing can occur and in the
  case of methotrexate and procarbazine hilar
  lymphadenopathy can be seen.

20
Pulmonary complications chemotherapy

• In some cases even those with pathological
  conformation of fibrosis the chest x ray can be
  normal and a high resolution CT is required to
  make the diagnosis
• Management avoidance occasional reports of
  corticosteroids being effective

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Cardiac Complications

• Chemotherapeutic agents can cause a number of
  cardiac abnormalities, majority are acute
  arrhythmia or decompensation. Doxorubicin can
  cause late cardiac decompensation which is
  resistant to therapy occurs many years after
  completion of treatment. Presenting a insidious
  progressive cardiomyopathy cardiac failure and
  sudden death. This mechanism is thought to be
  mediated by free radical production within the
  myocardium.
• Amifostine can be used as a cardio protector
• Radiation was for many years thought to be benign
  as regards cardiac toxicity. However a range of
  trials show excess late cardiac deaths in those
  women treated for left sided breast cancer.
  Pathology shows fibrosis and atrophy of myocytes.
  However the most striking finding is accelerated
  coronary heart disease. With significant stenoses
  occurring 1 2 years after the completion of
  treatment.
• This complication has all but been eliminated by
  modern planning and treatment methods

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Gonadal Dysfunction

• Not in it self a late complication of treatment.
• Oocytes are exquisitely sensitive to the effects
  of chemotherapy and radiation.
• Treatment can cause a premature menopause in many
  women
• Some patients achieve the menopause apparently
  after treatment has finished as the depleted
  stores of immature oocytes run out.
• The menopause carries with it its own issues
  however often overlooked is the loss of
  reproductive capacity in young adults.
• Egg harvesting and in vitro fertilisation can be
  used to overcome this problem.
• Male gonadal dysfunction is unusual as is
  permanent infertility, most apparently infertile
  men will regain fertility after a lag time of up
  to 2 years. Late sterility and testosterone
  depletion can occur 5 10 years after therapy to
  the testes. Often seen in seminoma patients.
  Characterised by loss of secondary sexual
  characteristics and impotence. Treatment is by
  hormone replacement to restore potency and avoid
  osteoporosis.

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Carcinogenesis

• Most of the data to assess the relative risk of
  treatments derives from clinical trial data bases
  or cancer registries maintained by the larger
  cancer treatment centres
• Often despite the increased relative risk of
  development of a cancer due to treatment the
  absolute risk remains small as may of the cancers
  that are likely to be induced are uncommon within
  the population

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Carcinogenesis - radiotherapy

• Much of the evidence comes from Bomb data from
  Japan, Workplace accidents, therapeutic and
  diagnostic exposures
• Most cancers with the exception of CLL have been
  described after exposure
• The thyroid , female breast and bone marrow
  appear to be the most likely targets
• The risk of haematological malignancy occurs
  after a few years post treatment and peaks some 5
  9 years post treatment
• For solid tumours a lag phase of 5 10 years is
  required for tumour induction, peaking at around
  30 years and falling off there after.
• Risk of second primary tumour follows a bell
  shaped curve
• Risk factors for the development of a
  haematological tumour include total dose, dose
  rate and volume of marrow exposed
• Risk factors for solid tumours include young age
  of exposure, dose to threshold, site irradiated
  (thyroid and breast)
• Radiation acts synergistically with chemotherapy
  and smoking to cause second malignancy
• Patients with DNA repair deficiency syndrome ATA
  and RB are at increased risk

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Carcinogenesis - Chemotherapy

• Haematological malignancies AML CML and ALL not
  CLL
• AML gt ALL gt CML
• Much more potent than XRT in inducing
  haematological malignancy
• Many drugs which are carcinogenic in vitro have
  not been shown to be so in vivo
• Two classes of drugs are recognised as having
  significant potential
• Alkylating agents (1- 2 years peaks 5 10
  years).
• Topoisomerase II inhibitors (epipodophylotoxins,
  doxorubicin) (peak at 2-3 years)
• The relative risks of different compounds is not
  clear. Alkylating agent carry the most risk but
  the relative risks of the remainder is not clear.
  
• The risk of the development of solid tumours is
  not known. The lead time to induction may be
  longer than the current periods of observation
  seen in most databases. Exception is
  cyclophosphamide which is known to cause bladder
  cancer

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Second cancers Hodgkin's disease

• 62 excess malignancies per 10,000 person years
  observation
• Treatment induced leukaemia's
• The risk after radiotherapy is small
• Most of the risk is conferred by the use of
  chemotherapy especially alkylating agents
• Move to use of ABVD
• 10 fold increase in the risk of leukaemia (95
  fold AML)
• 3 fold risk of solid tumours (Non Hodgkin's
  lymphoma)
• Combined treatment with radiation lung,
  melanoma, stomach, bone and connective tissue.
  Lung cancers related to smoking
• Increased risk of thyroid and breast cancer
  especially in those treated with radiation before
  age 30 (12 and 4 fold respectively)

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Relative Risk post HD 9618 pts / 3 studies
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Relative Risk vs Age post HD 1253 pts
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Second cancers Non Hodgkin's Lymphoma

• Much less well studied than Hodgkin's disease
• Association of excess cases of AML and bladder
  cancer probably related to cyclophosphamide use
• Solid tumours related to TBI
• As for Hodgkin's disease the time lag for solid
  tumours can be 10 15 years and 2 5 years for
  leukaemia's

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Second cancers - Breast Cancer

• Large numbers of women surviving breast cancer
  have received chemotherapy
• Alkylating agents cyclophosphamide and
  doxorubicin are common agents.
• Alkylating agents increase the risk of leukaemia
  10 fold
• Splenectomy further increases the risk 2 fold
• Radiation increases the risk 2 fold
• Radiation plus chemotherapy 17 fold increase
• 5 per 10,000 cases treated at 10 years
• Risk is almost entirely in the pre-menopausal
  group

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Second cancers - Breast Cancer

• Risk is reduced by a move away from regional
  radiotherapy and towards doxorubicin containing
  regimens rather than alkylating agents. Reducing
  the dose of alkylating agent when used
• However it must be remembered that the most
  common solid second tumour after treatment for
  breast cancer is a contra lateral breast cancer
  (1 3 patients) very small numbers of these
  tumours can be attributed to treatment.
• Risk of contra lateral breast cancer reduced by
  tamoxifen 40, risk reduction with aromatase
  inhibitors 70
• Radiotherapy small risk of lung cancer smokers,
  most common tumour is angiosarcoma latent period
  20 years risk increased 9.5 fold

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Tamoxifen - risk
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Second cancers Testicular cancer

• 95 of germ cell cancers are cured in young men
• Teratomas Cisplatin containing therapies
• Seminoma Cisplatin or low dose radiotherapy
• Significant excess morbidity from second cancer.
• Leukaemia's secondary to chemotherapy and solid
  tumours from organs involved in the radiation
  field.
• Actuarial risks of developing any second cancer,
  excluding contralateral testicular tumours, were
  15.7 and 22.6
• Time lag 20 30 years

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Ovarian Cancer
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Paediatric cancers

• May successful treatments for paediatric cancer
  are performed.
• These children are at increased risk of a variety
  of malignancies 15 fold (75 in RB)
• Treatment related and genetic often with a long
  lead time.
• No consistent policy exists in NZ for long term
  follow up

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Radiotherapy and Retinoblastoma
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Miscellaneous organ damage

• Related to specific organ damage
• Can be induced by either chemotherapy or
  radiotherapy
• Nephrotoxicity Cisplatin /Radiation
• Hepatotoxicity Methotrxate / Radiation
• Gastrointestinal damage Radiation achlorhydria,
  pancreatic insufficiency, small and large bowel
  damage, strictures of hollow organs

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Conclusion

• Long term side effects of cancer treatment are
  becoming more common in general medical practice
• The lead time to side effects of radiation and
  chemotherapy extends far beyond the usual follow
  up period for the primary malignancy
• Side effects are often misdiagnosed or not
  anticipated
• Haematological malignancies are more common than
  solid tumours
• Haematological tumours are more common after
  treatment with alkylating agents
• Solid tumours are more common after treatment
  with ionising radiation
• The lead time for haematological tumours can be
  as short as two years and as long as ten, for
  solid tumours the lead time tends to be ten to
  thirty years
• Patients should were possible be enrolled in
  screening programmes
• Screening and follow up is not performed in a
  systematic way and patients are excluded from
  existing screening programmes