Chemotherapy

Role

  • Eradication of overt & micrometastatic disease
  • Permits less radical surgery
  • Useful in
    • Small blue cell – Ewings, rhabdomyosarcoma, etc
    • Osteosarcoma
    • MFH
  • Not good for
    • Chondrosarcoma (generally)
    • Fibrosarcoma
    • Liposarcoma
    • Leiomyosarcoma

General

  • Mode
    • Interferes with synthesis of
      • DNA
      • RNA
      • Protein
  • May be
    • Non specific (all cells)
    • Cell cycle specific (proliferating cells)
    • Cell phase specific (portion of proliferating cells)
  • Administration
    • IV
    • Intra-arterial
      • Theoretical advantages with intra-arterial
      • No improvement in long-term survival
  • Timing
    • Neoadjuvant (pre-op)
    • Adjuvant (post-op)
    • Standard is neoadjuvant
    • Allows assessment of response early in disease
      • Clinical
      • Radiological
      • Histological
    • Restage investigations after Neoadjuvant chemotherapy
  • Efficacy
    • Measured by extent of tumour necrosis
      • Good response is > 90% necrosis
      • Poor response is < 90% necrosis
    • Response is best prognostic factor
    • Osteosarcoma Huvos grading system
      • Grade I 0-50% tumour necrosis
      • Grade IV > 90% tumour necrosis

Chemotherapeutic agents

  • Belong to one of four categories
    • Alkylating agents
    • Antitumour antibiotics
    • Alkaloids
    • Antimetabolites
  • Alkylating Agents
    • Act by forming positively charged carbonium ions that then form covalent bonds on nucleic acids & proteins
    • Cross-linking of DNA & DNA breaks occur
    • Function independent of cell cycle
    • Not uniformly effective against same tumours
    • Include
      • Cyclophosphamide
      • Chlorambucil
      • Ifosamide*
      • Nitrosureas
  • Antitumour Antibiotics
    • Produced by species of Streptomyces
    • Intercalation between base pairs of DNA resulting in DNA breaks
    • Include
      • Adriamycin** (Doxorubicin)
      • Bleomycin
      • Mitomycin C
  • Plant Alkaloids
    • Derived from shrub Vinca Rosea
    • Bind to tubulin inhibiting microtubule assembly & disrupting mitotic process
    • Include
      • Vinca alkaloids
      • Vincristine
      • Vinblastine
  • Antimetabolites
    • Act as fraudulent substrates for biochemical reaction interfering with critical cellular function or replication
    • Act during S phase of replication & so primarily affect replicating cells
    • Include
      • Folate antagonists (Methotrexate***, Darcarbazine)
      • Purine antagonists
      • Pyrimadine antagonists (5 FU)
    • Ifosamide
      • Most active agent against sarcomas currently
      • Activated by hepatic P450 system
    • Adriamycin
      • Most active chemotherapeutic agent in treatment of sarcomas
      • Response rate of > 20% as single agent
      • Cardiotoxicity, Neutropenia, N & V, Alopecia, Stomatits occur
    • Methotrexate requires use of Leukovorin (folinic acid) rescue

Side effects

Proliferating tissues

  • Most common
    • Bone marrow
    • Oral/ Intestinal mucosa
  • Effects are
    • Myelosuppression
    • Stomatitis
    • Mucositis
    • Nausea
    • Vomiting
    • Anorexia

Non proliferating tissues

  • Less predictable
  • Transient toxicity
    • Pneumonitis (Bleomycin)
    • Haemorrhagic cystitis (Cyclophosphamide)
  • May cause chronic conditions
    • Pulmonary fibrosis (Bleomycin)
    • Nephrotoxicity (Methotrexate, Cisplatin)
    • Cardiotoxicity (Doxorubicin)
    • Neurotoxicity (Cisplatin, Vincristine)

Amelioration

  • Reduce toxic effects
  • Measures may be taken
    • Alkalinisation of urine & hydration for Methotrexate
    • Reversal “ rescues” such as Leucovorin (folinic acid) rescue for Methotrexate

Adverse effects on Surgery

  • Systemic
    • Neutropenia
    • Thrombocytopenia
    • Coagulopathy
  • Local
    • Cytotoxicity to tissue
    • Lead to
      • Wound complications
      • Delayed bone healing

Specific Tumours

Osteosarcoma

  • Improved 5 year survival from 20% » 80%
  • Improved limb salvage ability
  • Multiagent treatment
    • Rosen T10 protocol “MAC CAB” (now replaced by “MACI”)
      • Methotrexate
      • Adriamycin
      • Cyclophosphamide
      • Cisplatin
      • Actinomycin-D
      • Bleomycin
    • Preoperative
      • 2/12 treatment
      • 3 cycles 2 weeks apart
      • Disease restaged
      • Surgery if good response
    • Postoperative
      • Regimen continued for further 6-12/12

Ewings

  • Previously local treatment – surgery & radiotherapy
    • < 15% survival
  • Combination with chemotherapy
    • 50% 5 year disease-free
    • 70% 5 year overall survival
    • 30% 5 year survival if present with metastatic disease
    • Multiagent neoadjuvant therapy
  • 18/12 of treatment
  • 3 weeks of
    • Vincristine
    • Actinomycin D
    • Cyclophosphamide
    • Adriamycin
  • Alternating with 3 weeks of
    • Ifosphamide
    • VP-16
  • Surgery at time of maximal response – usually at 3-4/12

Malignant Fibrous Histiocytoma

  • Mainstay of treatment is resection
  • Multiagent neoadjuvant chemotherapy
    • Improves 5 year survival from 50% to 75%

Chondrosarcoma

  • Primary treatment is surgery as tumour resistant to chemotherapy
  • Occasionally used for palliation but effects unclear
  • Hormonal agents may be effective
    • E.g. HGH, somatomedin

Childhood Rhabdomyosarcoma

  • Improved survival from 20% to 60% 5 year
  • Much poorer for metastatic disease

Adult Soft Tissue Sarcomas

  • Treat as one disease
  • Controversial
  • No clear evidence of long-term efficacy with chemotherapy
    • Except MFH