Lesson 4 Surgery and Radiotherapy

• In 1895, Wilhelm Conrad Roentgen discovered x-rays
• Much of the early documented cancer surgery was for breast cancer (remember: most common cancer diagnosis)

  
• 3000BC: breast cancer patient reportedly treated by "cauterisation with a fire drill"
• Researchers observed that x-rays damaged skin
• Lorensius Heister's mastectomy tools (1748)
• By 1800: surgical resection of breast tumours commonly employed, +/- removal of surrounding breast, muscle, ribs and/or lymph nodes. Complete removal of the breast ("mastectomy") frequently performed.

  
• Researchers started to treat cancer patients with x-rays, as they thought radiation could destroy tumours if aimed at them

  
• Radiation causes DNA damage in proliferating cells, which provokes apoptotic cell death

  
• Goal of cancer surgery

  Remove all of the cancer cells

  
• Cancer was initially thought to radiate out from the primary tumour → removing some tissue surrounding the primary tumour was deemed desirable…but how much was enough?

  
• Surgeons assumed (without data) that "more is better" – trend towards increasingly extensive, disfiguring surgery
• Two main approaches to radiotherapy

  • Internal radiotherapy
  • External radiotherapy
• 1867: Charles Moore admonished surgeons recoiling from the "prevailing horror of such Amazonian surgery", urging them to perform more extensive resections
• 1894: William Halsted and Willy Meyer developed "radical" mastectomy procedures. Removal of breast, regional lymphatics, pectoralis muscles: cure rate reported as 40%

  
• Gradually, understanding of the way that cancer progresses improved. Rather than simply radiating, cells typically migrate via lymph system to distant organs.

  
• If cancer cells had already spread to distant sites, no amount of local resection would help. However, if cells had not yet metastasised to distant organs, minimal resection ("lumpectomy"), +/- removal of a few lymph nodes, would presumably be curative.

  
• External radiotherapy using ionising radiation (x-rays, gamma rays)


  • The part of the body containing the tumour is exposed to high-energy x-rays
  • X-rays can penetrate tissue but dose decreases with depth
  • Higher energy x-rays can penetrate deeper

  
• Particle beam therapy (protons)

  • Highly energetic protons are fired at the tumour
  • Protons tend to mostly affect cells at the end of their path, so cause less damage to tissue they travel through than x-rays
  • Emerging technique, expected to become more widely used due to its more specific targeting

  
• The first facility for particle beam therapy in Australia will open soon in Adelaide
• In the 1950s-1960s these ideas, and comparisons of outcomes (survival and quality of life) of patients after radical versus conservative surgery, led some surgeons to question the benefit of radical mastectomies

  
• Aim of radiotherapy


  • Maximise the radiation dose to the tumour
  • Minimise exposure of normal tissue to reduce killing and mutation of normal cells

  
• Stereotactic radiotherapy


  • Most often used for treating brain tumours
  • A frame is fitted to the patient's head, in place during imaging and radiotherapy, so radiation can be directed to the exact tumour site
• These comparisons were problematic, however… Maybe some hospitals or surgeons tended to see patients with more advanced cancer: their patients would have worse outcomes because their disease was more advanced, rather than because the surgical technique was suboptimal. Surgery requires technical expertise and practice - individual surgeons have their preferred approaches. Difficult to tell whether differences in outcome relate to approach or skill. And difficult to convince surgeons to compare approaches

  
• Maximising specificity of radiotherapy

  1. Multiple radiation beams that intersect at the tumour can increase specificity towards tumour

  2. "Gamma knife": numerous low intensity beams from different angles converge at brain tumours

  
• Answering this question required a side-by-side comparison: randomised controlled trial. Considerable resistance! But they convinced many patients to participate. Patients were randomised to treatment arms
• Total Body Irradiation


  • For patients with unresponsive leukaemia
  • Kills their entire blood system including the leukaemic cells
  • Lung and other organs are sometimes protected by lead shields
  • Serious side effects often occur nevertheless, due to killing normal cells
  • Subsequent stem cell transplant (bone marrow or cord blood) provides donated immune system
• No statistical difference in outcomes: removing muscle, many lymph nodes was unnecessary. Radical surgery created massive suffering for no survival benefit. Gut feelings about optimal treatments can be very wrong! Objective data is required
• Brachytherapy


  • Radioactive sources are introduced into the tumour or nearby
• Tissues, including tumours, drain fluid (possibly containing cancerous cells) into lymph vessels, which connect to lymph nodes. "Sentinel" nodes are those that receive fluid directly from the tumour – these are the most likely sites for initial cancer spread.

  
• Intraoperative radiation therapy


  • Intensive radiation treatment administered during surgery
  • Example: low dose prostate cancer brachytherapy - radioactive seeds injected into the prostate gland, give off radiation at a low dose rate over several weeks or months, seeds remain permanently
• Radioactive and/or coloured substance is injected into the primary tumour: nodes that become radioactive and/or coloured are resected and checked for cancer cells. Now: often, only the tumour (lumpectomy) plus sentinel nodes are surgically removed

  
• Surgical outcome (eg positive or negative margins)


  Can influence whether chemotherapy and/or radiotherapy is/are warranted
• Radioactive liquid therapy for thyroid cancer

  • Radioactive iodine is drunk, concentrates in the thyroid and destroys the whole organ (kills both cancerous and non-cancerous cells)
  • Patient must take replacement thyroid hormones

  
• Surgery can be used as a preventative measure when cancer risk is extremely high (eg familial cancer). Angelina Jolie inherited BRCA1 mutation: predisposes to breast and ovarian cancer. Mother, grandmother and great-grandmother died from ovarian cancer. Cousin, aunt and great aunt died of breast cancer. Jolie had prophylactic mastectomy and oophorectomy to reduce her risk

  
• Extracorporeal radiotherapy


  • Cancerous bones can be removed, irradiated, then replaced
  • Over time, living bone fuses with irradiated part, forming strong union, so metal supports can be removed
• Biopsy


  Small tumour piece removed, analysed by pathologist, to diagnose and plan treatment

  
• Adverse effects of radiotherapy

  • Acute (during or shortly after therapy): Treatment site, Premature menopause, Infertility, Heart damage, Lung damage
  • Late effects (years after therapy): Premature halt to growth, Tooth development defects, Cognitive defects, Second cancers
• Can use punch, needle, or tools attached to instruments. Can be performed by eye/touch or guided by ultrasound/CT
• Most adverse effects arise due to killing of non-cancerous cells, and second cancers are caused by damage to DNA of non-cancerous cells

  
• When surgeons have to remove non-cancerous tissue, reconstructions are sometimes possible. Breast implants (fat + muscle or saline/silicone). Bone cancer often arises in the growth plates of legs in patients who are still growing. Huge improvements in management: Initially (pre-1980: Amputation, ~1980-2000: Prostheses replaced as patient grows (lots of surgery), ~2000-2010: Invasive expandable prostheses (screw to expand), ~2010-now: Non-invasive expandable prostheses