GP Education Series: Immunotherapy

Wednesday, 22nd of February 2017

Key Points Summary

PDF Downloadable Version

  1. Recent Advancements in the Role of Immunotherapy for the Treatment of Cancer: Hype vs. Reality

Dr Jo Lundy MBBS, FRACP (Medical Oncologist)

Immunotherapy

  • Targets and harnesses the body’s own immune system to attack cancer cells
  • Encompasses a range of targets and types of treatments:

-Vaccines

-Oral agents

-Monoclonal antibodies

Milestones in Immunotherapy Development

  • 1893: William Coley uses live bacteria as immune stimulant to treat cancer
  • 1949: Sir Mac Burnet publishes theory of acquired immunological tolerance
  • 1957: discovery of tumour specific antigens in mice by George Klein
  • 1967: Burnet proposes theory of immunosurveillance
  • 1973: dendritic cells discovered by Ralph Steinman
  • 1991: discovery of molecularly defined tumour antigens recognized by human T cells
  • 1992: IL-2 approved as anti-cancer therapy
  • 1997: first approval of monoclonal antibody as anti-cancer therapy
  • 1998: first report of complete/partial regressions with therapeutic cancer vaccine
  • 2010: first approval of therapeutic cancer vaccine

Immunotherapy in Melanoma (CTLA-4 Inhibition)

(Original study results published in ‘The New England Journal of Medicine’, Vol. 363, No. 8)

Ipilimumab in Melanoma

  • Fully human monoclonal antibody (IgH1) that blocks CTLA-4
  • 676 pts, pre-treated melanoma
  • Median OS was 10 vs. 6.4 months (p<0.001)
  • Best overall response rate in ipilimumab arm 10.9%
  • 60% of responders maintained an objective response for >2 years
  • Approved by FDA in 2011
  • Listed on PBS for treatment of metastatic melanoma in 2013
  • Ongoing clinical trials evaluating activity of ipilimumab and other CTLA4 inhibitors (e.g. tremelimumab)

Ipilimumab Toxicity

  • Activation of T-cell immune response can be a powerful tool against tumour cells
  • Immune response is not tissue specific
  • Increased immune activity in normal tissues can lead to a diverse range of toxicities
  • Important to recognize and treat potentially serious toxicity

Toxicities

Dermatological

  • Pruritis
  • Rash (early, in 30-50%)
  • Vitiligo (late)
  • Stevens-Johnson syndrome/TEN (rare)

Gastrointestinal

  • Diarrhoea/colitis (after ~6 weeks)

Hepatotoxicity

  • Raised ALT/AST (~10%, with high grade hepatotoxicity in ~2% often slow to resolve)

Endocrinopathy

  • Hypophysitis (up to 10%), hypothyroidism (~10%)
  • Adrenal crisis rare but potentially life-threatening

Less-Frequent Toxicities

Respiratory

  • Pneumonia
  • Sarcoidosis
  • Pneumonitis

Ocular toxicity

  • Episcleritis
  • Conjunctivitis
  • Uveitis

Renal toxicity

  • Interstitial nephritis
  • Membranous nephropathy

Pancreatitis

Neurological syndromes

  • Posterior reversible encephalopathy
  • Aseptic meningitis
  • Guillain-Barre syndrome

Haematological syndromes

  • Red cell aplasia
  • Neutropaenia
  • Coagulopathies (all rare)

Immune-Mediated Adverse Reactions

Gastrointestinal

  • Diarrhoea
  • Abdominal pain
  • Blood or mucus in stool
  • Bowel perforation
  • Peritoneal signs
  • Ileus

Liver

  • Abdominal liver function tests (e.g. AST, ALT) or total bilirubin

Skin

  • Pruritus
  • Rash

Neurologic

  • Unilateral or bilateral weakness
  • Sensory alterations
  • Paresthesia

Endocrine

  • Fatigue
  • Headache
  • Mental status changes
  • Abdominal pain
  • Unusual bowel habits
  • Hypotension
  • Abnormal thyroid function tests and/or serum chemistries

Other adverse reactions (e.g. ocular manifestations)

Immunotherapy in Melanoma (PD1 Inhibition)

Nivolumab (PD1 Inhibitor)

Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer

(Original Article Published in ‘The New England Journal of Medicine’, Vol. 366, No. 26)

  • Objective responses induced by anti-PD-1 (nivolumab) are rapid and durable

-Sixty-five of 306 patients had ORs (CR+PR, 21%):

-30 of 65 (46%) responses were evident at first tumour evaluation (8 weeks)

-42 of 65 (65%) patients had responses lasting >1 year

-35 of 65 (54%) responses were ongoing at time of data analysis (March 2013)

-Responses persisted off-drug

Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab

(Original Report Published in the ‘Journal of Clinical Oncology’, Vol. 32, No. 10)

  • Confirmed activity of nivolumab (monoclonal antibody targeting PD1)
  • Phase II study
  • n=107
  • Heavily pre-treated (>1 and up to 5 lines)
  • Received up to 96 weeks of nivolumab
  • Median OS was 16.8 months
  • 1 year survival 62%
  • 2 year survival 43%

Nivolumab in Previously Untreated Melanoma without BRAF Mutation

(Original Article Published in ‘The New England Journal of Medicine)

  • Phase III study
  • 418 patients
  • Previously untreated melanoma
  • No BRAF mutation
  • Compared nivolumab (with dacarbazine matched placebo) with dacarbazine (with nivolumab matched placebo)

Pembrolizumab

Prembrolizumab versus Ipilimumab in Advanced Melanoma

(Original Article Published in ‘The New England Journal of Medicine)

  • Randomized controlled phase III study
  • 834 patients with advanced melanoma
  • Randomized 1:1:1 ratio to pembrolizumab (at a dose of 10mg per kilogram of body weight) every 2 weeks/every 3 weeks/4 doses of ipilimumab (at 3mg per kilogram) every 3 weeks
  • Primary outcome 6 month progression-free-survival:

-47.3% for pembrolizumab every 2 weeks

-46.4% for pembrolizumab every 3 weeks

-26.5% for ipilimumab

-Grade 3-5 toxicity lower in both pembrolizumab groups (13.3 and 10.1%) than in ipilimumab group (19.9%)

Drugs Blocking PD-1/PD-L1

  • Active against multiple cancer types
  • Drugs targeting a single molecular pathway have an unprecedented activity spectrum and provide a “common denominator” for cancer therapy
  • Durable objective tumour regressions in patients with:

-Melanoma (17-40% of patients responding)

-Lung cancer (10-30%)

-Kidney cancer (12-29%)

-Bladder cancer (25%)

-Ovarian cancer (6-23%)

-Head and neck cancer (14-20%)

-Hodgkins lymphoma (87%)

-Gastric cancer

-Breast cancer

-Mesothelioma

PD1 Inhibition in Lung Cancer

Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer

(Original Article Published in ‘The New England Journal of Medicine’)

Nivolumab:

  • N=135
  • Median OS = 9.2 (7.3-13.3)
  • 1 year OS = 42% of patients (34-50)
  • No. of deaths = 86
  • Patients with ongoing response = 63% (17 of 27 patients with response)

Docetaxel

  • N = 137
  • Median OS = 6.0 (5.1-7.3)
  • 1 year OS = 24% of patients (17-31)
  • No. of deaths = 113
  • Patients with ongoing response = 33% (4 of 12 patients with response)

PD1 Inhibition in Renal Cell Carcinoma

Nivolumab Versus Everolimus in Advanced Renal-Cell Carcinoma

(Original Article Published in ‘The New England Journal of Medicine’, Vol. 373, No. 19)

  • Randomized phase III study of 821 patients with previously treated advanced clear cell RCC
  • Randomized 1:1 to nivolumab or everolimus
  • Nivolumab median OS = 25.0 months (95% confidence interval [CI], 21.8 not estimable)
  • Everolimus median OS = 19.6 months (95% CI, 17.6 to 23.1)
  • HR for death with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002)
  • Less toxicity in nivolumab arm

Combination Therapy

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

(Original Article Published in ‘The New England Journal of Medicine’)

  • Phase III study of 945 patients with untreatable unresectable stage III or IV melanoma
  • Randomized 1:1:1 to combination therapy or ipilimumab/nivolumab as monotherapy
  • At median follow up of ~12 months: PFS significantly better in combination arm:

-11.5 months (combo) = 95% CI 8.9-16.7

-6.9 months (nivolumab) = 95% CI 4.3-9.5

-2.9 months (ipilimumab) = 95% CI 2.8-3.4

Challenges in Clinical Practice

Finding new ways to evaluate therapy

  • Immunotherapy works in a different way to standard chemotherapy
  • Clinical trials are needing to adapt to allow for differences (e.g. different endpoints, different radiological response criteria)

Who to give immunotherapy to?

  • While a wide range of tumours show some response, there are disappointing results in others (e.g. colorectal cancer)
  • Not all patients suitable:

-Any autoimmune condition can be unmasked/aggravated by immune checkpoint blockade

-Pivotal clinical trials have excluded any patient with a history of autoimmune disease or steroid requirement

Need for biomarkers/predictors of response

  • PDL1 expression on tumour cells has been demonstrated to be prognostic/predictive of response to anti-PD1 therapy in some studies, however have failed to show similar results in others

-To date, no reliable predictor of response identified

  • “Mutational load” of tumours may correlate with response to immunotherapy

Potential for combination therapy (other drugs/radiotherapy) to increase likelihood of tumour response (many studies ongoing)

Further Challenges

  • Cost and access:

-Nivolumab, pembrolizumab and ipilimumab approved by PBS listing for use in advanced melanoma

-Many clinical trials still underway and many more planned

-Cost of treatment course for individual patient may range up to tens or even hundreds of thousands of dollars

Conclusion

  • Immunotherapy has been the most exciting development in cancer treatment in the past decade, and has increased treatment options for many patients
  • As more patients gain access to these drugs, all clinicians should be aware of immunotherapy and its potential toxicity and early management
  • A number of patients from early immunotherapy studies remain disease free >5 years post treatment = much hope for a “cure’ in a small percentage of patients, but a long way to go in others


2. The Role of Radiotherapy Used in Conjunction with Immunotherapy for the Treatment of Cancer

Dr David Blakey MBBS, FRANZCR (Radiation Oncologist)

Clinical Trials of RT and Immunotherapy

  • Currently 91 active clinical trials in the US combining radiation and immunotherapy

Stereotactic Radiotherapy

  • Planning using all imaging modalities
  • Motion management (immobilisation devices, 4D CT)
  • On-treatment image guidance
  • Tight margins

GP Education Series: Breast Cancer

Wednesday, 16th of November 2016

Key Points Summary

PDF Downloadable Version

1) Screening, Diagnosis and Surgical Management of Breast Cancer

Dr Melanie Walker, MBBS, FRACS (Breast Surgeon)

Oncoplastic Breast Surgery

  • Combination of optimal cancer surgery with plastic surgical techniques to achieve the best oncological and aesthetic outcome after breast surgery
  • The aim: to improve women’s long term quality of life and body image after breast cancer treatment
  • Involves a range of simple through to complex rearrangements of breast volume (volume displacement)

– Includes therapeutic mammoplasty

  • Or breast volume replacement, where adjacent or remote tissues are used for various types of flap reconstructions to maintain breast shape

Types of Mastectomy

  • Radical
  • Simple
  • Skin sparing
  • Nipple sparing (total skin sparing)

– Prophylactic/risk reducing surgery

– Therapeutic

– Local recurrence after therapeutic NSM <5%

– <1% cancer in retained nipple after risk reducing NSM

– Partial necrosis up to 16%

– Full necrosis up to 8%

Breast Imaging

  • Women with breast symptoms should be referred for diagnostic imaging assessment, not to a breast screening service

Screening Mammography

  • Patient should be asymptomatic
  • Generally, the radiologist does not see films until the patient has left the radiology department

Diagnostic Mammography

  • Patients with breast signs or symptoms (palpable lump, pain, nipple discharge)
  • Patients with abnormality detected on screening mammogram
  • Performed under the supervision of a radiologist
  • Additional specialized mammographic views +/- US

Breast Density

  • Cannot be predicted based on physical exam

– Unrelated to breast size or consistency

  • More common in younger women during breast feeding, women using hormone replacement therapy
  • 60% of women under 50, 40% of women in their 50s and 25% of women in their 60s have radiographically dense breasts
  • Sensitivity and specificity reduced

– Sensitivity 33-81%

– False positives increased

  • Breast density is a significant independent risk factor for breast cancer

– 4-5x relative risk

Breast MRI

  • Very high sensitivity for the detection of breast cancer (>90%)
  • Vast majority of malignant lesions enhance
  • High NPV
  • Lower specificity

– ~30-60% PPV

  • Some benign lesions enhance
  • Normal breast parenchyma may enhance
  • Low PPV
  • 6 prospective non-randomized trials in high risk women (20-80% lifetime risk)
  • Sensitivity 71-100%

– vs. 16-40% with mammo or US

  • Specificity lower than mammo in all trials

– Call back 8-17%

– Biopsies 3-15%

  • No mortality/survival data
  • No RCTs

Limitations and Problems

  • Contra indications-METAL
  • Patient claustrophobia/noisy/obesity/prone position
  • Pregnancy – gadolinium contrast contra indicated
  • Breast feeding – cease for 24 hours
  • IV line
  • Time consuming – 25 minutes
  • Scheduling difficulties (day 6-16 menstrual cycle)
  • Expensive
  • Limited equipment
  • Limited trained technologists
  • Need expert, experienced interpretation
  • MR guided biopsy time consuming

Indications for Breast MRI

  • Screening for breast cancer in young high risk women
  • Assessment for women with a new breast cancer diagnosis for:

– Assessment of extent of disease (local staging) in women with a recent breast cancer diagnosis

– The role of MRI in this situation is controversial:

> It can estimate tumour size and diagnose unsuspected multifocality/multicentricity with a high sensitivity

> May lead to more extensive surgery without definite evidence of benefit

– Screening the contralateral breast for cancer in women with a recent (ipsilateral) breast cancer diagnosis (the role of MRI in this situation is also uncertain)

Other Uses of Breast MRI

  • Assessing the integrity of breast prosthesis
  • Assessment of the breast in occult primary breast cancer
  • Monitoring response to neo-adjuvant chemotherapy in women with breast cancer
  • Problem solving: e.g. scar vs. recurrence in treated breast, lesion characterization (multiple or indeterminate on US/mammo)

Digital vs. Film Mammography

  • Both use x-rays

Film

  • Image captured on film

Digital

  • Image captured electronically and stored digitally
  • Viewed directly on a computer, radiologist can alter contrast/brightness/magnify without additional x-rays
  • Digital more expensive
  • More accurate than film in those:

– Perimenopausal or premenopausal

– Dense breast tissue

Studies

  • 4 major prospective studies comparing clinical results of digital vs. film-screen in breast cancer detection
  • No study has shown statistically significant difference in breast cancer detection
  • No study has evaluated the effect of digital mammography on breast cancer mortality

Potential Advantages

  • Greater contrast resolution
  • Storage issues
  • Post-processing image enhancement

– Alter contrast

– Alter brightness

– Magnify

  • Reduced recall rate
  • Slightly lower average dose
  • More speed of image acquisition, display, retrieval
  • Added applications: PACS, teleradiology, CAD

Tomosynthesis

  • Uses modified digital mammography unit to create 3D images
  • 3D principle of operation

– X-ray tube moves in an arc across the breast

– A series of low dose images are acquired from different angles

– Total dose approx. the same as one 2D mammogram

– Projection images are reconstructed into 1mm slices

  • Prelim studies suggest tomo has the potential to decrease the no. of recalls & possible to improve cancer detection rates (improve sensitivity)
  • Increased reading time
  • Potential to reduce compression force
  • May improve cancer detection by mammography by enabling readers to detect lesions which are very difficult or impossible to visualize on conventional imaging due to overlying glandular tissue

– Major factor contributing to the limited performance of mammography: tissue superimposition that is created by the overlap of normal breast structures in a two-dimensional mammographic projection

– These overlapping structures can obscure a lesion making it more difficult to perceive or rendering it completely mammographically occult


2) Recent Developments in Radiation in Management of Breast Cancer

Dr David Blakey MBBS, FRANZCR (Radiation Oncologist)

Altered Fractionation

Hypofractionated RT

  • Started as an empirical practice in government-run health care systems of UK and Canada
  • Initially, a purely logistical exercise to reduce treatment duration & create machine space
  • Recently, 2 large trials, START-A and START-B, have validated that clinically as well, hypofractionated RT is safe and effective
  • In fact, even while delivering a lower BED, the hypofractionated regimens have shown a survival advantage over conventional fractionation

ASTRO 2008 Plenary

  • Canadian trial 1993-1996
  • N= 1234 women
  • 42.5Gy in 16# vs 50Gy in 25#
  • Median follow up – 12 years
  • Local recurrence at 10 years – 6%
  • Excellent cosmesis at 10 yrs – 70%
  • No difference between 16 and 25 fractions

START-A (1998-2002)

  • 1998-2002
  • N=2236
  • EBC (pT1-T3a, pN0-N1, M0)
  • BCS=1900 (85%) & MRM = 336 (15%)
  • Locoregional relapse rates were 3.6%, 3.5% and 5.2%, respectively
  • Late effects, based on photographs and patient assessments, were significantly lower with 39Gy as compared to 50Gy
  • 3 Arms:

– 50Gy/25#/5 weeks

– 41.6Gy/13#/5 weeks

– 39Gy/13#/5 weeks

– Median FU = 5.1 years

START-B (1992-2001)

  • N=2215
  • EBC (pT1-T3a, pN0-N1, M0)
  • BCS=2038 (92%) & MRM = 177 (8%)
  • Locoregional relapse rates were 3.3% and 2.2%, respectively
  • Absolute differences in locoregional relapse was =0.7% (95%CI-1.7% to 0.9%), meaning that with 40Gy the relapse rate would be at most 1% worse and at best 1.7% better

Partial Breast Irradiation

  • Conform RT to uniformly cover lumpectomy cavity plus 1-2cm margin
  • Minimal RT to normal uninvolved breast
  • Provide comparable tumouricidal RT dose as conventional whole breast irradiation
  • Deliver homogenous dose:

– Optimize cosmetic result

– Avoid fibrosis and fat necrosis

Rationale

  • Approximately 90% of tumour recurrence is local in the vicinity of lumpectomy cavity
  • Concentrates radiation on the most likely area for tumour recurrence
  • Recurrences away from tumour bed (elsewhere failures) appear unaffected by whole breast radiation therapy

Benefits

  • Accelerated radiation therapy decreasing treatment time from 6 weeks to 4-5 days
  • Consistent and reproducible dose distribution and delivery
  • Eliminates cardiac/pulmonary dose
  • Reduced skin reaction in large breasted patients

Advantages of Breast Brachytherapy vs. External Beam RT

Breast Brachytherapy

  • 5 days (10 fractions)
  • Dose is higher to tissue at greatest risk for sub-clinical malignant cells
  • Reduction in skin, cardiac and lung dose
  • Ideal for patients who live far from RT centre
  • Convenient
  • May increase number of women treated with BCT

External Beam RT

  • 6 weeks (30 fractions)
  • Homogeneous dose
  • Logistical problem for patients
  • Difficult for frail, elderly, or chronically ill patients
  • Interferes with schedule of working women
  • Some BCT candidates will opt for mastectomy

Disadvantages of PBI vs. EBRT

PBI

  • Invasive
  • Not useful for treatment of nodal basins
  • May miss tumour foci in other quadrants
  • Low, but definite risk of infection and/or fat necrosis
  • Requires special skills for performing; in placing catheters and dosimetry

EBRT

  • Non-invasive
  • Can cover nodal regions
  • Treats multi-centric carcinoma
  • Low complication rate
  • Linear accelerators widely available
  • Most radiation oncologists experienced

Respiratory Gating

  • Trilogy includes the RPM Gating System

– Infrared camera

– External marker block

– Gating workstation

  • Process

– Place block on patient’s abdomen

– Camera monitors block motion

– Respiratory waveform shows how the block moves

– User sets upper and lower thresholds; the beam is on

– Whenever the block moves outside the thresholds; the beam is off

– Free-breathing and breath hold protocols are supported, as are gating at inhalation or exhalation or at any other point in the respiratory cycle


3) Systemic Therapy of Breast Cancer, Including Recent Developments

Dr Min Ne Wu MBBS, FRACP (Medical Oncologist)

  • Population risk for breast cancer for Australian women: 12%
  • New diagnosis of breast cancer (2015): ~16000 cases
  • Breast cancer accounts for 12% of all cancer diagnosis in Australia each year
  • Breast cancer specific mortality (2015): ~3000 deaths

Systemic Therapy

Primary prevention

Tamoxifen

  • When taken preventively daily for 5 years, reduces risk of developing breast cancer in Australian women, who are at increased risk of breast cancer, by more than 30% over 20-year period
  • PBS listed for this indication recently

Neo-adjuvant therapy

Adjuvant therapy (secondary prevention)

Endocrine therapy

  • Pre-menopausal women with hormone receptor positive, HER 2 negative breast cancer
  • Exemestane plus ovarian function suppression vs. Tamoxifen alone

– 10-15% improvement in 5 year breast cancer free interval in high recurrence risk group

– At least 5% improvement in intermediate risk group

– Minimal improvement for low risk group

Extended endocrine therapy

  • After 5 years of Tamoxifen, additional 5 years of Tamoxifen or Aromatase Inhibitors (AI)

– Reduces distant recurrence, new primary breast cancer

– Improves disease free and overall survival

– Benefit particularly after year 10

  • After 5 years of AI, additional 5 years of AI

– Reduces the risk of recurrence and new contralateral breast cancer

– Improves disease free survival

– No difference in overall survival

  • No direct comparison using AI vs. Tamoxifen as extended endocrine therapy after 5 years of Tamoxifen
  • Toxicities:

– Extended Tamoxifen vs. Placebo

> Increased incidence of endometrial cancer and pulmonary embolus

> Reduced rate of ischaemic heart disease

– Extended AI vs. Placebo

> Increases risk of bone-related toxicity

Targeted therapy (Anti-HER 2 therapy)

Chemotherapy

Metastatic breast cancer

Endocrine therapy

Targeted therapy (Anti-HER 2 therapy)

  • Trastuzumab (Herceptin) – Monoclonal ab
  • Pertuzumab (Perjeta) – monoclonal ab
  • Lapatinib (Tykerb) – tyrosine kinase inhibitor

Chemotherapy

Immunotherapy

  • In clinical trial

GP Education Series: Lung Cancer

Wednesday, 24th of August 2016

Key Points Summary

PDF Downloadable Version

1) Historical Background Epidemiology and Screening

Dr Sameer Kaul MBBS, FRACP (Respiratory Physician)

Lung Cancer Today (Australia)

  • 4th most commonly diagnosed invasive cancer
  • No. 1 cause of cancer deaths in both male and female
  • No. 1 cause of burden of disease for males
  • Estimated 12,203 new cases in 2016
  • 9.4% of all new cancer cases
  • 5 year survival of 15%
  • 18.8% of all cancer deaths in 2016
  • Disproportionately effects the poor and elderly
  • Low risk patients: minimal or absent history of smoking and or other known risk factors
  • High risk patients: history of smoking or other known factors (e.g. first degree relative with lung cancer, or exposure to asbestos, radon, uranium)

Risk Factors

  • Tobacco smoking: 90% males and 65% females
  • Occupational exposures
  • Metals: arsenic, cadmium, nickel
  • Radon gas (less of an issue in Australia)

Smoking Cessation (Australia)

  • Biggest public health success story
  • 1991 – daily smoking rate 25%
  • 2014-15 – daily smoking rate 14.7%

Late Detection

  • 75% present in advanced stages of disease

Possible Reasons for Late Detection

  • Stigmatization of Lung Cancer
  • Perception of fatalism in patients and clinicians
  • Poorly coordinated care

Screening

Need for screening

  • Smoking cessation is not enough to decrease rising Lung Cancer rates
  • Long lag period between stopping smoking and development of smoking-related diseases

How to screen

  • CXR
  • Blood tests?
  • Sputum cytology
  • CT scan

Whom to screen

  • Smokers
  • Older patients
  • Family history
  • Previous cancers
  • Chronic lung disease patients

National Lung Screening Trial (NLST)

  • Population: 55-74, asymptomatic, USA, 30 pack year hx and smoked in last 15 years, n=53454
  • Arms: low dose CT scan, <2mSv,
  • Primary outcome: lung cancer mortality
  • Study terminated early at 6.5 years follow up owing to significant improvements in both:

– Lung cancer mortality: 356 deaths CT arm vs 443 CXR or relative mortality reduction of 20%

– 6.7% reduction in all cause mortality

What stages were picked better by low dose CT?

  • 292 cases picked by low dose CT vs 190 cy CXR
  • Mainly Stage 1A cancer 132 vs 46
  • No difference in Stage IIb to IV
  • Mainly adenocarcinomas and bronchioalveolar carcinomas

Conclusions

  • Unlikely to be a ‘one-hit wonder’ with over 50,000 people
  • Very low complication rates in trial
  • Similar trials over Europe, trials in Perth and Queensland
  • Queensland interim results similar to NLST
  • US preventative task force has already recommended routine annual CT scanning

Should There Be a Screening Program in Australia?

Potential advantages

  • Long preclinical phase making early diagnosis possible
  • Proven improved survival for patients diagnosed early:
  • Patients with Stage 1 disease have 5 year survival rates of up-to 60%
  • Patients with Stage 4 disease have 5 year survival rates of up-to 5%
  • Clear risk factor (smoking) making a target group easy
  • High prevalence likely to lead to higher detection rates, possibly making it cost-effective

Potential disadvantages

False Positivity

  • NLST had an extremely high false positive rate of 96.4%
  • In NLST, over 3 years, 25% of 53454 subjects had a significant lesion, 96.4% were benign
  • Potential for increased number of needless invasive procedures including biopsies which can substantially increase cost and additional harm and complications

Cost

  • Early estimates from Australian researchers suggest screening will be expensive
  • In the NLST: low dose CT screening was estimated to cost $81,000 per quality-adjusted life year (QALY) gained

Radiation Risk

  • Low dose CT scans have 10X higher radiation exposure vs CXR
  • Using NLST data: an estimated 1 cancer death per 2,500 people screened can be attributed to the radiation alone

Overdiagnosis

Fleischner Society Pulmonary Nodule Recommendations:

Solid Nodules

  • Nodule size: < 4mm
  • Low risk patients: no follow-up needed
  • High risk patients: follow-up at 12 months and if no change, no further imaging needed
  • Nodule size: 4-6mm
  • Low risk patients: follow-up at 12 months and if no change, no further imaging needed
  • High risk patients: initial follow-up CT at 6-12 months and then at 18-24 months if no change
  • Nodule size: >6-8mm
  • Low risk patients: initial follow-up CT at 6-12 months and then at 18-24 months if no change
  • High risk patients: initial follow-up CT at 3-6 months and then at 9-12 and 24 months if no change
  • Nodule size: >8mm
  • Either low or high risk patients
  • Follow-up CTs at around 3, 9 and 24 months
  • Dynamic contrast enhanced CT, PET, and/or biopsy

Sub Solid Nodules: Solitary

  • Solitary pure ground-glass nodules
  • Nodule size < 5mm
  • No CT follow up required
  • Nodule size > 5mm
  • Follow up CT at 3 months, then annual CT for at least 3 years
  • Solitary part-solid nodules
  • Initial follow-up CT at 3 months
  • If persistent and solid component <5mm
  • Annual CT for at least 3 years
  • If persistent and solid component > 5mm
  • Biopsy or surgical resection

Multiple Sub Solid Nodules

  • Pure ground glass nodules < 5mm
  • CT at 2 and 4 years
  • Pure ground glass nodules >5mm, without a dominant lesion (s)
  • Initial follow-up CT at 3 months, then annual CT for at least 3 years
  • Dominant nodule (s) with part-solid or solid component
  • Initial follow-up CT at 3 months
  • If persistent, biopsy or surgical resection (especially if has >5mm solid component)

Conclusion

  • Lung Cancer is No. 1 cancer killer in Australia
  • Numbers are on the rise despite smoking rates falling
  • Screening strategies not established yet
  • High index of suspicion and targeting high risk groups is key

 


2) Modern Surgical Techniques in Diagnosis and Management of Lung Cancer

Mr Adrian Pick MBBS, FRACS (Cardiothoracic Surgeon)

Modern Lobectomy

  • ‘Keyhole’ (minimal access)
  • Smaller incisions
  • No rib spreading
  • Muscle preservation
  • Via mini thoracotomy

Advantages

  • 5mm ports
  • No rib spreading
  • Earlier mobilization and rehabilitation

Other Indications for Keyhole Surgery

  • Facilitates diagnosis
  • Therapeutic
  • Palliative

Pulm Metastasectomy

  • Peripheral lesions
  • PET
  • +/- prior CT guided needle localization
  • Disadvantage: precludes digital palpation

Post-operative care

  • Analgesia
  • Fluid management
  • Respiratory physiotherapy

Post Thoracotomy Pain

  • Majority related to intercostal nerve injury
  • Second component ligamentous and muscular stretch: intercostal retraction
  • Third component: muscle division

Conclusion

  • Early detection
  • Early intervention
  • Modern surgical techniques
  • Rapid recuperation and enhanced survival

 


3) Current Practices in Radiation Oncology in the Management of Lung Cancer

Dr David Blakey MBBS, FRANZCR (Radiation Oncologist)

Radiotherapy and Lung Cancer

  • Palliation of symptomatic local or metastatic disease (20-30Gy in 5-10 fractions)
  • Curative treatment of stage IIIA/B disease (in combination with chemotherapy, 60Gy in 30#)
  • Post-operative treatment in setting of +ve surgical margins or +ve mediastinal nodes (50Gy in 25#)
  • Curative treatment of medically inoperable stage I/II disease (60Gy in 30#)
  • Curative treatment of OPERABLE early stage disease

What is SBRT/SABR

  • High dose
  • High precision
  • Few fractions
  • Extra-cranial sites

Features of lung SABR

  • Accounting for motion: 4D Planning
  • Many beam directions: 7-11 Beams/Arc Therapy
  • Accurate targeting: CBCT pre-RT
  • Small tumour volumes: small margins
  • Steep dose gradients: inhomogeneous target dose
  • High dose per fraction: short total treatment duration

Who is suitable for SBRT?

  • Biopsy-proven NSCLC
  • Stage 1 disease on basis of CT/PET/EBUS/mediastinoscopy findings
  • Tumour size <5cm
  • Lesion outside “no fly zone”

Side effects of SBRT

  • Pneumonitis
  • Chest wall pain
  • Oesophagitis
  • Rib fracture
  • Haemoptysis
  • Vascular injury
  • Spinal cord injury

Future Directions

  • Randomized comparison of surgery vs SABR for operable patients

– ACOSOG Z4099/RTOG 1021: Wedge vs SABR

– STARS Trial: Lobectomy vs SABR for Stage I

  • Can adjuvant systemic therapy improve outcomes for early stage inoperable patients?

– CALGB/RTOG – SABR +/- chemo for 2-5cm T1 tumours

Summary

  • SBRT is emerging as the new “standard of care” for medically inoperable early stage NSCLC patients
  • Early data suggests that it may also achieve high local control and survival rates in operable patients
  • SBRT is a promising treatment modality for patients with oligometastatic dz to the lung

 


4) Improvements in Systemic Therapy of Lung Cancer

Dr Muhammad Alamgeer MBBS, MRCP, FRACP (Medical Oncologist)

Current NSCLC Therapeutic Profile

Chemotherapy

  • Histologic subtyping for chemotherapy
  • Since 1940’s – initially lymphomas/leukemia
  • Solid tumours since 1960s
  • Gradual improvement in:

– Dosing methodologies

– Tumour selection

– Toxicity management

– Supportive care

  • Use of combination agents
  • Novel agents discoveries

Induction chemotherapy (4-6 cycles)

  • Platinum doublet
  • Cisplatin or carboplatin in combination with another agent (gemcitabine, paclitaxel, docetaxel, pemetrexed, vinorelbine)
  • Different toxicity profiles
  • Histological subtype matters

Maintenance chemotherapy

  • At least stable disease after induction therapy
  • Continue until disease progression
  • More useful in adenocarcinoma
  • Advantages:

– Maintains disease control

– Improves PFS

– Improves OS

– Maintains quality of life

– Opportunity to treat more patients

– Patients support maintenance therapy

  • Disadvantages

– Cumulative toxicity with Grade 3/4 AEs in 30% to 40% of patients

– Cost

– Lack of reliable predictive biomarkers

– Limited role in SCC

Treatment after progression on chemotherapy

  • Second line chemotherapies
  • Clinical trial
  • Immune therapies: rapidly evolving

Targeted therapy

  • Genomics-driven TKIs

– EGFR

– ALK

– ROS1

  • Therapeutic targeting of a specific genetic or epigenetic alteration either specific to the tumour or predominantly found/expressed in the tumour or its microenvironment
  • Since early 2000’s
  • Exemplified by:

– Imatinib (Gleevec) in CML & GIST

– Sunitinib (Sutent) in RCC

– Trastuzumab (Herceptin) in Breast Cancer

– Retuximab (Mabthera) in NHL

Selection for molecular testing in NSCLC

  • All patients with adenocarcinoma or NSCLC NOS
  • Pure SCC diagnosis is appropriate for EGFR mutation and ALK testing in some clinical settings

– Young, never/light smoker

– Small biopsy specimens

  • Novel technologies being used to detect broader array of mutations and gene arrangements

Therapies available

  • EGFR
  • ALK

Therapies available in clinical trials

  • cMET
  • BRAF
  • HER2
  • FGFR

Therapies not available

  • KRAS

– Common in adenocarcinoma

– Smokers

– Very poor prognosis

Pros

  • Rapid initial response
  • Usually oral
  • Better tolerated
  • Better QOL
  • May have survival advantage over chemo

Cons

  • Benefit not durable
  • Eventual resistance
  • Not entirely safe
  • Dependence on ‘positive test’
  • Access to novel drugs
  • Not very active in CNS

Immune Therapies

  • Common agents:

– Nivolumab (Opdivo)

– Pembrolizumab (Keytruda)

  • Improvement in survival after progression on first line chemotherapy in both SCC and ADC
  • Rapid development in almost any clinical situation

– First line or second line

– With or without chemotherapy/targeted therapies

– Small cell, brain metastasis

Pros

  • Durable response
  • May not need to treat until progression
  • Generally better tolerated than chemotherapies

Cons

  • Work in a subpopulation (20-30%)
  • No useful bio-marker discovered yet
  • Cost
  • Availability
  • Immune-related adverse effects (irAEs)

– All healthcare team members should be educated about potential AEs

– Rapid and timely diagnostic and therapeutic intervention is imperative for optimal control of irAEs

> Persistent grade 2 irAEs and grade 3/4 irAEs are treated with steroids

> Early discontinuation of steroids may predispose to relapse

– Re-initiation of treatment may be possible with optimal management

– Approximately 5% of pts experience evidence of enlarging tumour lesions prior to a response

> Pseudoprogression can be managed by continuing treatment and monitoring closely

The Future

  • Immune therapies

– Combination of immune agents

  • Evolution of molecular profiling
  • Technological developments

– Diagnostics

– Blood based tests

– Rapid results

– Less need to repeat biopsies

  • ?Cure a possibility – at least in some cases

Small Cell Lung Cancer

  • Limited disease (one hemithorax)

– Combination chemo + radiotherapy

  • Extensive disease

– Chemotherapy (Platinum Etoposide)

  • Almost always progression after initial excellent response
  • Prognosis is around 12 months in extensive stage
  • No change in therapy or prognosis over the last 20 years
  • Novel therapies – IO/PERP inhibitors look promising

GP Education Series – Colorectal Cancer

Wednesday, 1st of June 2016

Key Points Summary

PDF Downloadable Version

1) Screening for Colorectal Cancer

Dr Michael Merrett MBBS (Hons), FRACP (Gastroenterologist)

Colorectal Cancer: Who is at risk?

  • People aged 50 years and over

– Adenomatous colonic polyps are found in about 25 per cent of people by the age of 50; the prevalence continues to increase with increasing age

  • Family history of polyps and bowel cancer
  • Personal history of polyps and bowel cancer
  • Inflammatory bowel disease
  • Environmental risks
  • Others

 

Screening vs. Surveillance

Screening: Investigation of patients who have no symptoms or signs of disease

  • Average Risk Patients: Faecal Occult Blood Test (FOBT) vs. Colonoscopy
  • High Risk Patients: Focus on colonoscopy screening

National Bowel Cancer Screening Program

  • Faecal Immunochemical Test (FIT) vs. gFOBT
  • Immunoassay specific for faecal human haemoglobin – no need to avoid red meat etc.
  • Negative for upper GI bleeding – globin is digested in GI transit (e.g. ok to test on aspirin)
  • Equally accurate for R vs. L colon bleeding (i.e. globin is digested)

Surveillance: Refers to follow-up testing in patients who have a history of:

Colon Polyps

  • Once identified by screening, patients should be entered in a colonoscopy surveillance program
  • Modifiers:

– Patient factors (patient’s opinion/anxieties, listen to improve compliance)

– Number and morphology of polyps

– Extent of family history of CRC

– Quality of preparation and procedure

– Anti-platelet agents (Warfarin, NOAC)

Colorectal Cancer

  • Patients should have full visualization of the colon at the time of diagnosis or soon after surgery

Inflammatory Bowel Disease (IBD)

 

Chromoendoscopy

Clinical Applications

  • Esophagus

– Esophageal carcinoma

– Barret’s esophagus

  • Stomach

– Intestinal metaplasia

– Polyps

– Early gastric cancer

  • Duodenum

– Celiac disease

  • Colon

– Polyps and early colon cancer

– Ulcerative colitis

– Cancer surveillance in IBD

 

Magnification Chromoendoscopy and Narrow Band Imaging

  • Improves detection of small, flat and depressed neoplastic lesions and also results in the detection and removal of clinically insignificant non-adenomatous polyps
  • Differentiation between non-neoplastic and neoplastic tissue is frequently possible
  • Subject to operator-dependence
  • Training required for recognition of different mucosal patterns and flat or depressed lesions
  • A standard terminology has not been validated or universally adopted

 

Colonoscopy

Complications

  • Pre-procedure: issues with fasting, preparation fluids and changes to medications
  • Bloating and pain: negligible if CO2 insufflation and with use of water immersion/exchange
  • Anaesthetic risk: including aspiration
  • Bleeding requiring admission: 8/1000
  • Perforation: 0.6 – 2/100
  • Death (from any cause): 1/10000

Why Is Colonoscopy Not Perfect?

  • Poor bowel preparation
  • Inexperienced endoscopists
  • Rapid extubation
  • Failure to recognize small or flat neoplastic lesions

Colonoscopy for Colon Lesions Should Include:

  • Evaluation of macroscopic appearance
  • Evaluation of mucosal pattern

 

Colorectal Cancer

  • Screening programs are based on the adenoma-adenocarcinoma sequence
  • Colon cancers are believed to arise from elevated lesions that are visible with endoscopy
  • Some lesions in the colon are flat or depressed and may be missed during routine colonoscopy

Non-Protruding Colonic Lesions

  • Flat adenomas may represent up to 25% of colon adenomas
  • Flat adenomas are:

– More likely to have high-grade dysplasia and cancer despite their smaller size

– Harder to detect with conventional endoscopy

  • Narrow Band Imaging (NBI) or chromoendoscopy is necessary for detection of flat lesions

Aberrant Crypt Foci (ACF)

  • ACF may be the earliest identifiable neoplastic lesions in the colon
  • ACF may be identified by magnification chromoendoscopy in otherwise normal appearing mucosa
  • These lesions are oval or semicircular and slightly raised above the surrounding mucosa
  • The hyperplastic foci have a stellate or slit-like pit pattern
  • The neoplastic foci have a tubular pattern

Hereditary Non-Polyposis Colorectal Cancer

Clinical Features

  • Early but variable age at CRC diagnosis (age ~ 45 years)
  • Multiple primary cancers
  • Proximal colon distribution of CRC
  • Poorly differentiated, mucinous with lymphocytic infiltrate
  • Extracolonic cancers – endometrium, ovary, stomach, urinary tract, small intestine, bile ducts, sebaceous skin tumours

Identification – Revised Amsterdam Criteria by The International Collaborative Group on HNPCC

  • There should be at least three relatives with HNPCC-associated cancer (colorectal cancer, cancer of the endometrium, small bowel, ureter, or renal pelvis)
  • One should be a first degree relative of the other two
  • At least two successive generations should be affected
  • At least 1 should be diagnosed before age 50
  • Familial adenomatous polyposis should be excluded in the colorectal cancer case(s) if any
  • Tumours should be verified by pathological examination

Screening

  • Mismatch repair genes correct nucleotide base pairing and other errors
  • HNPCC – germline mutations so that cells accumulate DNA errors throughout their genome
  • Accumulation of abnormalities of short sequences of DNA called microsatellites
  • Microsatellite instability (MSI) with disturbance of growth regulatory genes

Familial Adenomatosis Polyposis

  • AD – germline mutations in the APC gene
  • 1 in 10000 to 30000 births
  • Multiple adenomas with ~100% risk of CRC
  • Extracolonic tumours – upper GI lesions, desmoid tumours, osteomas etc.

Hyperplastic Polyposis Syndrome (HPS)

  • At least 5 hyperplastic polyps proximal to the sigmoid colon with at least 2 being 10 mm diameter or,
  • Any number of hyperplastic polyps occurring proximal to the sigmoid colon in an individual with 1° relative with HPS, or
  • 30 or more hyperplastic polyps distributed through the colon
  • No germline mutation identified yet

Hyperplastic Polyps/Serrated Adenoma

  • 18% of ‘Hyperplastic polyps’ are SSA
  • Larger, proximal distribution, flat
  • Genetically stable until loss of MLHI gene with rapid progression to malignancy
  • SSA are the precursor for the 15% of sporadic CRC that are MSI-H but account for ‘interval’ CRC
  • Interval cancers are 3X more likely to be MSI-H and be proximally sited in the colon

 

Colon Cancer and Ulcerative Colitis

  • Colon cancer complicating chronic ulcerative colitis is believed to develop through a chronic inflammation-dysplasia-carcinoma sequence
  • Dysplasia and colitis associated-cancer can occur in macroscopically normal mucosa
  • The standard of care is to obtain random biopsies at 10-cm intervals throughout the colon during routine surveillance
  • Recent data suggest that narrow band imaging (NBI) and Chromoendoscopy improves detection of dysplasia and early colon cancer

 

Terminology

Endoscopic Image Enhancement

  • Image processing to improve the features of a given image

Image Analysis

  • Analysis of a stored image and extraction of characteristics in numerical parameters for subsequent reconstruction

Resolution

  • Ability to distinguish between two points that are close together
  • High resolution imaging improves ability to discriminate mucosal surface details
  • Resolution increases with the number of pixels in the CCD

Magnification Endoscopy

  • Ability to enlarge the image from 1.5x to 170x optical power using a moveable lens controlled by the endoscopist

Chromoendoscopy

  • Use of stains to delineate mucosal surface

Enhanced Magnification Endoscopy

  • Use of acetic acid to improve mucosal visualization

 

2) Latest Advances in Surgical Management Of Colorectal Cancer

Mr Tilan Beneragama MBBS, FRACS (General Surgeon)

What’s Different About Rectal Cancer?

Neoadjuvant Chemoradiotherapy

  • Long course

– Combined chemoradiotherapy over 5-6 weeks

– Surgery then delayed for 6 weeks

  • Short course

– Radiotherapy only over 5 days

– Surgery performed 2-4 days later

Who Gets Neoadjuvant Chemoradiotherapy?

  • Cancers less than 12cm from the anal verge

– T3 (through the rectal muscle wall)

– N1 evidence of lymph node involvement

  • Cancers of the lower third where by restorative resection is planned to downstage the primary
  • Risk factors for local recurrence:

– Size of local depth of invasion

– Involvement of CRM

– Short distance to anal verge

– Lymph node involvement

Local Treatment Options

  • Local excision

Option of No Surgical Treatment

  • Complete reliance on the chemo-radiotherapy alone 

 

Local Excision

  • Without neoadjuvant chemoradiotherapy

– High rates of local recurrence

– T3 cancers: 100% local recurrence

– T2: 50% local recurrence

– T1: 5-20% LR

  • There is role for local excisions of carefully selected T1 rectal cancers
  • The role of local excisions after neoadjuvant chemotherapy

– Still under investigations

 

Intersphincteric Dissections

  • Patients will all require long course neoadjuvant chemoradiotherapy
  • Involves standard abdominal approach
  • Per anal approach

– Transection at the dentate line

– Hand-sewn pull through anastomosis

  • Slightly worse functional outcomes but high overall patient satisfaction compared with APR

Outcomes

  • The functional outcome is assessed by:

– Number of stools: mean 5 per 24 hours

– The urgency for defecation: 20%

– Nocturnal defecation: 25%

– Use of hygiene pads: 20%

– Use of antidiarrheal medications: 30%

– Constipation due to stenosis

– Patient’s satisfaction with the outcome reaches 90%

  • The oncological outcome is assessed by:

– Local recurrence: 8%

– Distant metastases: 15%

– 3-year survival: 83%

– 5-year survival: 83%

– Disease-free survival at 3 years: 82%

– Disease-free survival at 5 years: 76%

– While in lower anterior resection, it has been estimated: 3-year survival of 89%, 5-year survival of 81%, disease-free survival at 3 years of 71% and at 5 years of 64%

 

Transanal Minimally Invasive Rectal Dissections

  • Laparoscopic instruments places transanally
  • Theoretically allow easier access to the lower mesorectal plane
  • Few case series
  • Discussion in meetings
  • No established role (yet)

 

Abdomino-Perineal Excision of the Rectum

  • Required when tumour extends to or is below the dentate line
  • Extra-levator abdomino-perineal excision rectum

– Huge defect which may need flap or mesh reconstruction

– Otherwise a perineal hernia will develop

  • If patient does not wish to have APR, there may be a role for:

– Local excision of smaller superficial cancers

– Watch and wait approach

 

Radical Peritonectomy + Heated Intraperitoneal Chemotherapy

  • Treatment of peritoneal carcinomatosis for colon cancer
  • Currently uncertain
  • Supported by enthusiasts
  • Primary surgical management of patients presenting with colon cancers with peritoneal metastasis
  • Second look laparotomy/laparoscopy in high risk patients after completion of chemotherapy
  • Uncertain how this radical protocol compares with modern chemotherapy
  • Available at Peter MacCallum Cancer Centre

 

Laparoscopic vs. Open Surgery (Colon Cancer)

  • Advantage with laparoscopic approach in terms of morbidity

 

Laparoscopic vs. Open Surgery (Rectal Cancer)

  • Advantage in the literature is less definite
  • The presence of permanent or temporary stoma negate the advantages of laparoscopic surgery

 

Laparoscopic vs. Robotic Surgery

  • Several technical advantages reported by surgeons who have access to the robot
  • No RCTs comparing laparoscopic vs. robotic surgery
  • Robotic surgery is far more expensive
  • Advantage is the potential to spare nerves
  • Nerves are only an issue in rectal cancer surgery

 

Conclusions

  • Lots of new developments in the surgical management of colon and rectal cancer, however they have not penetrated into mainstream practice
  • Importance of accurate preoperative assessment
  • Discussion and review of investigations in an MDT setting

 

3) Role of Radiation In Multidisciplinary Management of Colorectal Cancer

Dr Marcus Foo MBBS, BMedSci, FRANZCR (Radiation Oncologist)

Rectal Cancer Radiotherapy

  • Current neoadjuvant management approaches

– Short course in Scandinavia/Europe/UK

– Long course in US/Australia

  • More effective ‘tailoring’ of neoadjuvant therapy
  • RT (+- Stereotactic RT) For Metastatic Disease

What’s involved?

  • CT simulation (‘measurement’ session): 40-45 minutes
  • 1 week later: start treatment
  • Painless ‘high energy x-ray treatment’: 7-8mins/day (20-30mins/day in dept.)

Acute Toxicities

  • Generally well tolerated
  • Mild-moderate lethargy
  • Diarrhea (proctitis): Gastrostop/Lomotil etc.
  • Occasionally cystitis (usu. mild)
  • Sometime perianal/natal cleft skin reaction
  • Nausea uncommon
  • 5-FU/Capecitabine toxicities

– Temporary, worse at the end (for 7-10 days), then resolves over a few weeks

 

Low Tumours

  • Distal tumours: APR’s and higher rate of positive CRM
  • Long course preoperative CRT could provide sufficient down-staging, and possible avoid APR/permanent end colostomy

 

Older Patients

  • ?Local Excision
  • Unacceptable failure rates regional/nodal and distant
  • Poorer survival in T2 or higher

Can We Avoid Surgery Altogether?

  • Watch/wait approach
  • Long course pelvic chemo-radiotherapy (CRT)

– 10-15% pCR

– ?10-30% cCR

  • Some sustained cCR for >12 months, with no surgery
  • ~5-20% LR: all successfully salvaged
  • 0-7% distant metastases
  • 2-5 year OS 93-100%

 

Identifying CR

  • Difficult
  • Endoscopy
  • ?biopsy
  • MRI
  • PET

 

Distant Recurrences

  • LR recurrence rates reduced
  • DR rates still >20-40%
  • Interest in trying to incorporate systemic therapy in the mix early
  • Optimal timing and sequencing of neoadjuvant therapies
  • Preoperative chemotherapy and short course RT
  • Preoperative chemotherapy: risk-adapted selective pelciv CRT
  • ‘Sandwich’ CRT protocol

 

Metastatic Disease

  • Pattern of failure

– Peritoneal/Lung/Liver metastases

– Bone/Brain metastases

  • Palliation

– Primary pelvic disease

  • SBRT for aggressive Rx

– Lung mets.

– Liver mets.

– Brain mets.

  • Radiotherapy: well established role in palliating symptomatic disease

– Pelvic disease: rectal bleeding, pain (pre/sacral invasion) etc.

– Bone metastases

Oligo-Metastatic Disease

  • ‘Oligometastases’
  • Intermediary state between disseminated cancer and ‘localised’

Lung/Liver metastases

  • Systemic chemotherapy
  • Surgery: thoracic/liver/hepatobiliary
  • Other ‘local’ therapies:

– RFA

– Microwave ablation

– ?Stereotactic body radiotherapy (SBRT)


4) Recent Advances in Systemic Therapy of Colorectal Cancer

Dr Ben Markman MBBS (Hons), FRACP (Medical Oncologist)

Adjuvant Chemotherapy: Colon Cancer

  • Stage III: Yes
  • Stage I: No
  • Stage II: Maybe
  • Consider patient’s age and fitness
  • Benefit of ~10-15%
  • FOLFOX is standard
  • Single agent vs. doublet
  • No evidence for the use of biologicals
  • Survival benefit relatively small: 3.6%
  • No advantage to combination therapy over monotherapy

High Risk Features

  • Low number of lymph nodes examined (<12)
  • Poorly/undifferentiated histology
  • T4 disease
  • Obstruction/perforation
  • Lymphovascular invasion

Less Likely to Benefit

  • Age >70 years
  • MMR deficient

Mismatch Repair (MMR)

  • MMR is critical for maintenance of genomic stability

– One of the several mechanisms for DNA repair

  • In MMR deficiency, replication errors accumulate, resulting in a mutator phenotype, promoting cancer progression
  • Mainly affects small repeat segments (microsatellites) causing microsatellite instability (MSI)
  • Predicts for resistance to chemotherapy
  • Associated with better prognosis

 

Chemotherapy: Rectal Cancer

Chemoradiotherapy

  • For locally advanced disease

– T3/4, node positive

  • Combined chemoRT better than RT alone

– Improved OS

  • Pre-op chemoRT better than post-op

– No difference in distant failures or OS

– Fewer APRs, reduced toxicity, fewer local failures

  • Use single agent 5FU/capecitabine
  • No role for biologicals

Adjuvant Chemotherapy

  • Role less clear
  • Many results are an extrapolation from colon cancer studies
  • Often given for locally advanced disease

– Fluoropyrimidine monotherapy

– FOLFOX/XELOX

  • Various attempts to intensify chemotherapy to reduce distant failures

– During chemoRT

– Pre/post/peri chemoRT (prior to surgery)

  • No role for biologicals

Chemotherapy

Doublet

  • Cytotoxic doublet in most patients
  • Combines with biologicals
  • First and second line Rx

– FOLFOX/XELOX/FOLFIRI

Monotherapy

  • Fluoropyrimidine monotherapy +/- bevacizumab

– For those not needing or not fit for aggressive Rx

  • Irinotecan +/- cetuximab in later lines of Rx

Triplet

  • FOLFOXIRI

– Uncertain which patients

→ BRAF mutant patients +/- bevacizumab

→ Borderline resectable metastases +/- bevacizumab (especially in KRAS mutant patients)

 

Anti-Angiogenics

  • Well tolerated

– HT, proteinuria

– Arterial thrombosis, intestinal perforation, wound healing

  • More impact on PFS than OS
  • First line mCRC

– Combination chemo plus bevacizumab

– Fluoropyrimidine monotherapy plus bevacizumab

  • Second line mCRC

– Bevacizumab naïve

– Beyond progression in 1L bevacizumab

→Bevacizumab, aflibercept, ramucirumab

 

Biologicals

  • No role in the adjuvant setting
  • Both VEGF and EGFR inhibitors improve outcomes in mCRC
  • Indicated in 1L Rx for most, unless contraindications
  • Extended RAS testing as a predictor of resistance to anti-EGFR antibodies
  • No unequivocal evidence for superiority of one biological over another in 1L Rx

– Choice influenced by Rx strategy, safety, QoL, reimbursement, patient choice

 

BRAF mutations in CRC

  • Approx 5% of mCRC
  • Poor prognosis
  • Debatable efficacy of EGFR inhibitors
  • BRAF inhibitor monotherapy ineffective
  • Strategies

– Chemo intensification: FOLFOXIRI

– Combination biological therapy

→BRAF and EGFR inhibitors

→BRAF, EGFR and MEK inhibitors

 

Conclusions

  • No predictive biomarker for chemotherapy
  • Monotherapy for less fit / elderly patients
  • Doublets or triplets for a higher response rate
  • FOLFOX / XELOX and FOLFIRI similar efficacy
  • Only all-RAS wild type (50%) benefit from EGFR inhibition
  • No biomarker to select for anti-angiogenics
  • Treatment duration variable
  • Sequence of drugs less important than exposure to all drugs, including biologics

GP Education Series: Prostate Cancer (Case Discussions)

Wednesday, 6th of April 2016

Key Points Summary

PDF downloadable version

1) Screening, Early Diagnosis and Surgical Management of Prostate Cancer

Mr Alwin Tan (Urological Surgeon)

Diagnosis Consideration

  • Fhx, Ethnicity and Agent Orange exposure
  • DRE
  • PSA
  • Ultrasound
  • MRI: ?50% of patients before bx
  • Biopsy: transrectal vs transperineal
  • Once diagnosis confirm: CT, BS
  • ?PSMA Pet scan
  • MRI does not replace the finger: 1 in 6 prostate cancer diagnosed have low PSA but picked up as irregularity on DRE

Gleason Score – The Prognosis

  • Gleason score is from 1 – 5
  • Gleason Sum = major gleason score + 2nd major gleason score
  • +2 – 10 (majority 6 – 10)
  • Carries the prognostic factor

Staging the Cancer

  • Bone scan: esp. with symptom or PSA >10
  • CT scan: look for lymph nodes (diagnosis based on size)
  • MRI: soft tissue
  • Endo rectal MRI: not specific enough

PSMA Pet Scan

  • 1% false positive
  • PSA >0.2
  • Also picks up nodes and bone mets.

Victorian Prostate Cancer Registry: On Low Risk Prostate Cancer, Gleason 6

  • 42% of men are diagnosed in Victoria with low risk prostate cancer Gleason 6 is managed with active surveillance
  • A large proportion of the remaining have robotic surgery

Active Surveillance

  • Postpone immediate therapy
  • Definite treatment in place if progression
  • Not like the old watchful waiting (for symptomatic or metastatic)

Arguments for:

  • Prostate cancer not clinically significant yet
  • Reliable parameter: clinical + pathological + imaging to help distinguish that less chance of progression and spread
  • All treatments have some side effects
  • Time and surveillance will pick out those than need to reclassify as higher risk
  • ?psychological burden

Evidence

  • Autopsy studies
  • Epidemiological studies
  • Prostate Bx trials

Guidelines for selection not universal: NCNN

  • Fhx and ethnicity and agent orange exposure
  • T1c or T2a clinically
  • Gleason 6 – less than 3 cores +ve – less than 50% at core
  • PSA 6 or less & PSA density < 0.15ng/ml/g
  • MRI – small or not visible
  • Repeat bx in 6-12 months
  • Individual preferences
  • ?PSA pet scan individual cases

Surveillance strategy – still in progress

  • PSA change 3-6 monthly
  • Repeat bx under 1 year and after that 2 – 4 years
  • Up to 28% have higher grade missed

 6 Shades of Prostate Cancer Based on Criteria

  • Local therapy: new or relapse
  • Gleason score – 6 vs. 7 vs. 8-10
  • PSA <10, 10-20 vs. 20
  • Digital rectal normal vs. nodule vs. mass
  • % biopsy <50% vs. more at core
  • Imaging ECE, SV, nodes, bones
  • GOAL: get the best treatment for your stage

Shade 1 = low risk

  • No previous therapy
  • Small nodule or no nodule
  • Gleason 6 and PSA <10
  • Scan shows no ECE
  • Monitor because:
  • Higher grade missed
  • New cancer develop

Shade 2 – Intermediate Risk

  • No previous surgery
  • Grade 7
  • PSA 10-20
  • Unilateral node
  • Scan: no ECE

Shade 2 – 2 Groups

  • Low risk
  • Gleason 3+4 = 7
  • % bx <50%
  • Only one intermediate risk
  • Management
  • Active surveillance
  • Seed implant – Brachytherapy
  • IMRT
  • Focal therapy
  • Surgery
  • ?Hormone therapy

 Shade 2 – High Risk

  • High risk
  • Gleason 4+3 = 7
  • Over 50% cores %
  • 2 or more intermediate risk
  • Scan –ve
  • Options:
  • Surgery (but may get +ve margin)
  • IMRT
  • HDR

Shade 3: High Risk

  • No previous treatment
  • Gleason 8, 9, 10 or PSA >20
  • ECE, SVI or node mets
  • Options:
  • Surgery +/- consolidation XRT
  • IMRT -& anti androgen
  • ?Chemotherapy

Shade 4: Previous Local Treatment Rising PSA

  • Good marker of relapse
  • Find the location: now good imaging
  • Prostate region
  • Pelvic lymph node
  • Bones
  • PSA doubling time
  • Options:
  • Local: cryo? Hifu?
  • Radiotherapy
  • ?Add hormone

Shade 5 mets

  • Radical surgery or chemo XRT

Surgery vs. Seeds

  • Clinical Onc 29:362.2010
  • Seeds implants shows better:
  • Urinary function
  • Sexual function
  • Overall satisfaction
  • No difference in bowel function
  • At 12 years out: equivalent or better “cure rate”

Seeds & Brachytherapy

  • Now 13 years on the Mornington Peninsula

Advantage

  • Day procedure
  • High preservation of erection
  • High preservation in ability to climax
  • In cancer G6 and single core small Gleason 7: cancer free as good if not better than surgery
  • Incontinence rare
  • Back at work within 3 days
  • Radioactive for 63 days

Beware

  • No colonoscopy or Bx without contacting the radiation oncologist or the surgeon
  • Biopsy can lead to FISTULA formation
  • 1 patient out of 513 did not do that

Cancer Recurrance at 13 year follow up

  • 5 patients in 825 cases
  • 2% stricture
  • 1% bladder irritation

Surgery: Radical Prostatectomy

Principles

  • Save the nerve (neurovascular preservation)
  • Preserve the external sphincter
  • Preserve the bladder neck

 If considered organ confined (T1 – T2): radical prostatectomy a choice

  • Aim:
  • Preserve the nerves
  • Preserve the urethra
  • Preserve the bladder neck
  • Risk:
  • Impotence risk 30-60%
  • Incontinence: 1-3% still uses pad at the end of 12 months
  • Home with IDC for 1-2 weeks

Penile Rehabilitation

  • Start Viagra, Levitra or Cialis early
  • Start at low dose
  • Important to get patient to understand initially is micro vessels induction and erection may not happen till 6-12 months

Gel in Space & Gold

Advantage

  • Temporary separation between rectum and prostate
  • Day procedure
  • Single needle insertion during gold seeds insertion
  • Reduce radiation dose to rectum

Symptoms

  • Minimal but may get some rectal symptoms
  • Grade 1 at worst
  • Gel absorbed over 3-6 months: need to keep bowel loose with Metamucil etc.
  • Personal series of 30 with 15 completing 12 months follow up

Botox to Bladder

  • Via a cystoscope
  • Day procedure
  • Now covered by PBS from September 2015
  • Good for irritable bladder: mainly OAB (both neurogenic and non-neurogenic) and post radiation
  • Can go into retention (so must be able to ISC if cannot avoid)

Green Light Laser

Where do we use it?

  • Benign prostate for outlet obstruction
  • Prostate cancer patient with obstructive issues: pre-brachytherapy and pre-external beam radiotherapy
  • Post-radiotherapy: bladder neck stricture and radiation induced bleeding (beware of Xaroleta)

Advantages

  • No need to stop any anti coagulation
  • Small instrument compared to Gyrus or traditional TURP
  • Almost no bleeding
  • Most go home after one night (unless over 80yo)
  • Must take it easy for 4 weeks (reactionary bleed especially on blood anticoagulation)

2) Latest Improvements in Radiation Therapy for Prostate Cancer – Impact of New Technologies

Dr David Blakey (Radiation Oncologist)

CASE

  • 51yo male, no significant prior health issues
  • Screening PSA: 4.2
  • DRE T1c
  • Estimated prostate volume 19cc (renal tract US)
  • TRUS-guided prostate biopsy = Gleason 3+3=6 Ca in 1 of 12 cores
  • MRI: no abnormality detected (“active surveillance advised”)
  • Staging CT/bone scan: clear
  • Urinary flow rate: peak 28ml/sec, mean 16ml/sec, res volume 90ml

Options

  1. Active surveillance
  2. Surgical prostatectomy
  3. Prostatic IMRT with IG
  4. LDR brachytherapy

MBS LDR Brachy

Requirements

  • Prostate: radioactive seed implantation of, radiation oncology component, using transrectal ultrasound guidance, for localized prostatic malignancy at clinical stages T1 (clinically unapparent) or T2 (tumour confined within prostate)
  • Gleason score ≤ 7
  • PSA ≤ 10ng/ml (at the time of diagnosis)
  • Procedure must be performed at an approved site in association with a urologist

Indications

  • Histologically proven low to intermediate risk prostate cancer
  • Clinical stage T1c-T2NX or N0M0 (UICC 1997)
  • Pre-treatment PSA <10ng/ml
  • Gleason score ≤ 7
  • Ideally a prostate volume ≤ 50cc assuming no pubic arch interference
  • Fit for general or spinal anaesthetic
  • Life expectancy > 10 years
  • Urinary function is satisfactory (e.g. urinary flow > 15ml/sec, IPSS <10)

Contra-indications

  • Previous TURP (patients with minimal volume loss from previous TURP may still be considered if satisfactory dosimetry can be achieved)
  • Higher risk patients with PSA > 10ng/ml and Gleason score > 7 are not suitable for permanent seed brachytherapy alone
  • No contraindications on cystoscopy – no median lobe etc.

Brachy Process

  1. Volume study
  2. Implant (prescribed dose + 145Gy to PTV, using Iodine 125 seeds)
  3. Post-implant dosimetry (CT scan)

Side Effects

  • Short term: occur during or within a few weeks of finishing radiotherapy (usually temporary)
  • Perineal bruising and swelling
  • AUR
  • Urinary frequency/dysuria
  • Rectal urgency
  • Long term side effects: may be permanent
  • Urethral stricture
  • Obstructive urinary symptoms
  • Urinary incontinence
  • Impotence
  • Prostato-rectal fistulas (rare)
  • Rectal bleeding (rare)

PSA Response:

  • 12/13: 0.25
  • 3/14: 0.25
  • 9/14: 0.54
  • 3/15: 0.36
  • 9/15: 0.18
  • 3/16: 0.16

——————————————————————————————-

CASE

  • 64yo
  • PSA 17.4
  • TRUS prostate biopsy: Gleason 5+9 = 4 in every core
  • Staging CT/bone scan clear
  • Commenced GnRH agonist, continued for 2.5yrs
  • Prostatic IMRT July-Sept 2010 (78Gy in 29 fractions)

PSA Response

  • 03/11: 0.03
  • 04/12: <0.03
  • 03/13: <0.03
  • 04/14: 0.26
  • 01/15: 1.24
  • 07/15: 3.08
  • 04/16: 8.69

——————————————————————————————-

CASE

  • 65yo fit man
  • PSA 02/15: 6.2
  • TRUS prostate biopsy: Gleason 3+4=7 malignancy
  • 6.16 robotic prostatectomy
  • Path: multifocal Gleason 4+3=7 prostate cancer, with extra-prostatic extension/+ve surgical margin R apex. SV/bilat nodes –ve

PSA Response

  • 08/15: 0.03
  • 10/15: 0.05
  • 01/16: 0.08

Adjuvant Prostate Bed RT

  • Post radical prostatectomy for adenocarcinoma prostate
  • One of the following adverse pathological features:
  • Extraprostatic extension (pT3a, pT4)
  • Seminal vesicle invasion (pT3b)
  • Positive resection margins
  • No evidence of lymph node or distant metastases
  • Undetectable PSA
  • ECOG 0-2
  • Ideally within 4 months of radical prostatectomy

Salvage Prostate Bed RT

  • Previous radical prostatectomy for adenocarcinoma prostate
  • A persistently elevated PSA >6wks post radical prostatectomy (including elevations in the ultrasensitive range)
  • A rising PSA from previously undetectably level
  • Note: it is important to demonstrate a progression in the PSA from undetectable levels, particularly in the ultrasensitive range. PSA should be performed by the same laboratory)
  • No evidence of distant metastatic disease
  • ECOG 0-2

3) What’s New in Metastatic Prostate Cancer?

A/Prof Vinod Ganju (Medical Oncologist & Clinical Haematologist)

CASE

  • 66yo male
  • Presented to his GP with 2yr of LUTS
  • PR = large hard prostate, bilateral involvement
  • PSA 153
  • Ref to an urologist
  • CT and bone scan = large prostate, fatty change in the liver, no mets

Diagnosis & Staging

  • MRI pelvis = 100ml prostate vol.
  • Normal <30ml
  • PSMA PET = LAPC, involving both lobes and seminal vesical, no LN or distal mets
  • TRUS Bx: 8/8 cores positive for Gleason 9 adenoca
  • Stage T3b N0 M0 (stage 3)
  • LAPC locally advanced prostate ca

History

  • FHx: nil for cancer
  • PHx: morbid obesity (wt 151 kg, 161cm, BMI 55)
  • Abdo liposuction, complicated by infection, slow healing
  • NIDDM, HbA1c = 7.5%
  • HT
  • Hypercholesterolemia
  • Depression in the past
  • OA
  • SHx: divorced, lives alone, in contact with his daughter
  • IT consultant, self-employed, works part-time
  • Ref to Meridith Studdert prostate care RN for counselling and support

Management

  • TURP: major improvement in his LUTS
  • PSA 61
  • Considered for a clinical trial (ENZARAD) but found to be ineligible
  • 5/15: ADT (Zoladex and Cosudex)
  • 7/15: PSA nadir 16
  • 11/15: PSA 33 while on ADT
  • Chemotherapy (based on 2 trials)
  • STAMPEDE
  • GETUG 15
  • Docetaxel chemotherapy for 6 cycles
  • Dexamethasone premed given
  • Required insulin on day 1
  • Input from GP re. oral hypoglycemic and monitoring
  • Main side effect was lethargy
  • Completed chemotherapy 6 wks ago
  • Awaiting cystoscopy
  • Plan for radical radiotherapy to the prostate
  • IMRT
  • 70-78 Gy

Important side effects of Docetaxel chemotherapy

  • Febrile neutropenia, septicaemia
  • Lethargy
  • Diarrhoea or constipation
  • Nausea
  • Myalgia
  • Mouth ulcers
  • Hair loss

——————————————————————————————-

Prostate Cancer Systemic Therapies: Historical Overview

  • Orchiectomy alone
  • Lutenizing hormone-releasing hormone (LH-RH) agonists:
  • May be associated with tumor flare when used alone
  • Initial concomitant use of antiandrogens should be considered in the presence of:
  • Liver pain
  • Ureteral obstruction
  • Impending spinal cord compression
  • Leuprolide plus flutamide
  • The addition of antiandrogen to leuprolide has not been clearly shown in a meta-analysis to improve survival
  • Estrogens (diethylstilbestrol [DES], chlorotrianisene, ethinyl estradiol, conjugated estrogens-USP and DES-diphosphate).
  • DES is no longer commercially available
  • Immediate versus deferred hormonal therapy
  • LH-RH agonists or antiandrogens
  • Maximal androgen blockade (MAB)
  • Continuous versus intermittent hormonal therapy
  • Hormonal treatments added to external-beam radiation therapy (EBRT)
  • Chemotherapy for hormone-resistant prostate cancer
  • Bisphosphonates
  • Bisphosphonates and decreasing risk of bone metastases
  • Abiraterone acetate is an inhibitor of androgen biosynthesis that works by blocking cytochrome P450c17 (CYP17)
  • Enzalutamide: an androgen-receptor signaling inhibitor
  • Has been shown to increase OS and QOL in men with metastatic prostate cancer that has progressed despite ADT
  • Denosumab: a monoclonal antibody that inhibits osteoclast function
  • Radiopharmaceutical therapy
  • Immunotherapy

STAMPEDE

  • Large, randomized, multiarm, multistage trial
  • Ongoing since 2005
  • Standard of care: androgen deprivation therapy with or without external beam radiation therapy
  • Compares SOC vs SOC plus docetaxel vs SOC plus zoledronic acid vs SOC plus both agents
  • Men with high-risk locally advanced or metastatic prostate cancer who are hormone therapy naïve
  • Primary end point: OS
  • Secondary endpoints:
  • Failure-free survival (FFS)
  • Prostate-specific antigen (PSA)
  • Local lymph node failure
  • Distant metastases
  • Prostate cancer death
  • Toxicity
  • Quality of life
  • Cost-effectiveness

Conclusions

  • Cytotoxic Chemotherapy i.e. Docetaxel may benefit some patients be given earlier in the course of the disease
  • It may be useful additional treatment in some patients with aggressive locally advanced disease
  • Chemotherapy appears to confer greater benefit when given earlier rather than the previous approach of the “end of the line therapy”.

GP Education Series: Mesothelioma

Wednesday, 10th of February 2016

Key Points Summary

PDF downloadable version

1) Asbestos Lung Disease and Malignant Mesothelioma – Diagnostic Challenges

Dr Sameer Kaul (Respiratory Physician)

Asbestos

  • Naturally occurring fibres of hydrated magnesium silicates
  • Tensile strength and properties well suited for construction and insulation
  • Serpentine
  • Chrysotile
  • Amphibole
  • Crocidolite/amosite/tremolite

Asbestos exposure

  • Mining/milling of fibres
  • Textiles/cement/shipbuilding/insulation industries
  • Non-occupational exposure to airborne asbestos (regular exposure to soiled work clothes brought home by an asbestos worker, renovation or demolition, environmental exposure of industrial sources, natural environmental exposure to geological sources)
  • Environmental exposure – industrial emissions – low level – more likely in mesothelioma not asbestosis

Asbestos related diseases

  • Pleural diseases
  • Plaques
  • Pleural thickening
  • Benign effusions
  • Malignant effusions
  • Lung (asbestosis)
  • Malignancies
  • NSCLC
  • SCC
  • Mesothelioma

 History

  • Asymptomatic usually 20-30 years post-exposure
  • Latency period inverse to degree of exposure
  • Insidious onset of breathlessness with exertion
  • Progress despite no further asbestos exposure

Examination

  • Bibasal end inspiratory crackles – 32-64%
  • Clubbing – 32-42%
  • Cor Pulmonale in advanced disease

Tests

  • Lung function tests – early decrease in DLCO, later decreased FVC, SVC, TLC
  • No airflow obstruction FEV1/FVC>70
  • Chest XRAY – Lower zones with mid zone plaques, usually no lymphadenopathy
  • Gallium lung scan – still experimental
  • HRCT chest

Pathological diagnosis (rarely required)

  • Uncoated/coated asbestos fibres with interstitial fibrosis changes of UIP
  • Asbestos Bodies – asbestos fibres with coating of iron and protein
  • Open Lung Bx or BAL fluid

Pleural plaques

  • Hylanised collagen fibres in parietal pleura
  • 20+ years post asbestos exposure
  • Inflammation in response to asbestos fibres sent to pleural surface
  • Adjacent to ribs 6-9
  • Also diaphragmatic pleura
  • Less likely in visceral pleura, intercostal spaces and absent in region of costophrenic sulci and lung apices
  • Don’t have further disease potential
  • Marker for asbestos exposure
  • Considered independent risk factor for pleural mesothelioma

Diagnosis

  • CXR – 20%
  • CT Chest 50%
  • Path 80%
  • CT helps to distinguish from extrapleural fat and endothoracic fascia

 Benign pleural effusions

  • Early manifestation within 10 years of exposure
  • Typically small unilateral
  • Asymptomatic
  • Pain, fever, dyspnoea
  • Can happen after minimal exposure – no clear dose correlation
  • Usually resolve over months some recur

Diagnosis

  • History
  • Pleural tap – usually exudate, blood stained
  • Needs follow up to resolution or biopsy

 Diffuse pleural thickening

  • Starts as fibrosis or visceral pleura
  • Secondary thickening of Parietal pleura
  • Obliteration of costophrenic sulci

CT Scan

  • Smooth uninterrupted pleural opacity
  • At least 25% of chest wall
  • >8cm cranio caudal direction
  • >5cm of chest wall in cross section
  • Thickness>3mm

Rounded Atelectasis

  • Folded lung/Blesovsky’s syndrome
  • Subpleural mass out of which emanates a swirl of vessels and bronchi that curve like a comet tail as they connect the atelectatic lung parenchyma to the hilum
  • Lower lobes/lingual/right middle lobe
  • If characteristic comet tail is not identified biopsy recommended
  • Characteristic rounded atelectasis with all of the above-mentioned findings does not have to be biopsied
  • Rounded atelectasis can persist for years, can clear spontaneously, or, in rare cases, can grow
  • Approximately 70 percent of cases of rounded atelectasis are associated with previous asbestos exposure

CT Scan

  • Pleural thickening
  • Round, oval or triangular shaped mass adjacent to the pleura
  • Comet tail sign – vessels converge into the mass in a curvilinear fashion

 Mesothelioma

  • Neoplasm arising from mesothelial surfaces of the pleural and peritoneal cavities, the tunica vaginalis, or the pericardium
  • 80% pleural origin
  • 70 percent cases associated with documented asbestos exposure

Exposures – History

  • Occupational
  • Non-occupational
  • Radiation
  • Viral Oncogenes
  • Genetic factors

Diagnosis

  • History
  • Imaging
  • Tissue

History (non specific)

  • Gradual onset
  • Breathlessness
  • Chest pain
  • Loss of weight

Imaging

  • CT Chest – can detect invasion, chest wall and lymph node involvement
  • PET – uptake may help distinguish benign from malignant
  • MRI – useful to define local extent of disease
  • Blood tests – mesothelin, osteopontin, fibulin-3 – Non specific

Diagnosis

  • Pleural fluid cytology +26%
  • CT guided pleural biopsy +39%
  • Medical Pleuroscopy 98%
  • Surgical biopsy

Difficulties

  • History not helpful
  • CT not always confirmatory
  • Recurrent pleural effusions common, mesothelioma less common
  • Making diagnosis even with tissue not easy

Conclusions

  • Mesothelioma is difficult to diagnose
  • Keep high index of suspicion
  • History and timelines important
  • Recurrent pleural effusions are a red flag
  • Negative tissue does not mean negative for mesothelioma
  • More tissue is usually better
  • Thoracoscopy/surgery for best tissue

2) Therapeutic Advances and Treatment of Malignant Mesothelioma

Dr Muhammad Alamgeer (Medical Oncologist)

Mesothelioma in Australia

Number of new cases in 2014 was: 641

  • Deaths = 607
  • 518 (81%) were male
  • Male : Female = 4:1
  • >80% aged 65-84 (largest number in 70-74)

Asbestos Containing Materials (ACMs)

  • 95% of Mesothelioma cases are asbestos related
  • Only 7% of asbestos workers will develop the disease
  • 50% of non-occupational asbestos related MM are females
  • Non Asbestos causes:
  • Carbon Nanotubes
  • Radiation
  • ?Virus

Mesothelioma: Germline mutations and asbestos exposure

  • Mesothelioma relatively uncommon insidious and potentially lethal disease linked to asbestos, erionite exposure and, potentially, radiation
  • Cappadocia, Turkey: genetics influences risk of mesothelioma in persons exposed to erionite
  • BAP1 germline mutatations can predispose patients to familial and sporadic Mesothelioma and uveal melanoma
  • Tumour suppressor gene located on chromosome
  • Somatic mutations or 3p21.1 loss lead to BAP1 inactivation
  • In these individuals, asbestos exposure may predispose mesothelioma

Frontline systemic therapy for advanced mesothelioma

  • Mesothelioma was largely chemoresistant with response rate < 15%
  • Combination regimens improved response rate
  • Historically, the most efficacious agents incombination included: doxorubicin, epirubicin, mitomycin, cyclophosphamide, ifosfamide, and platinum agents

Current standard of care in Australia

  • Cisplatin 75mg/mg2 + pemetrexed 500mg/m2 every 3 weeks
  • Carboplatin + pemetrexed can be used in patients who cannot tolerate cisplatin

VEGF in Mesothelioma

  • Mesothelioma patients have highest VEGF levels
  • VEGF expression coorelated with microvascular density and poor survival
  • VEGF is a paracrine growth factor for mesothelioma cells
  • Thus VEGF may be an appropriate Target for Therapy in mesothelioma

MAPS: randomized trial of Cis/Pem + Bev in unresectable mesothelioma

  • Improvement in Median Survival (16.1 to 18.8 months, p=0.0167)
  • Higher adverse effects (grade 3/4)
  • High serum VEGF levels associated with worse prognosis
  • Not available in Australia yet

Nantadenib: An oral VEGF inhibitor

  • A small molecule Tyrosine Kinase inhibitor of VEGFR, pDGFR & FGFR
  • Double blind, multicentre, randomized phase II/III trial

Immunotherapy

CTLA4 – Tremilimumab

  • Phase II study
  • 29 patients
  • DCR 31%
  • Median survival 10.7 months
  • Phase II study
  • 29 patients
  • DCR 51%
  • Median survival 11.3 months

PD-1: Pembrolizumab

  • Single agent phase I/II study
  • Reported in abstract
  • 28/38 PDL-1 positive
  • 20% response rates
  • 72% disease control rates
  • Low toxicity
  • Some very long/durable responses
  • Randomized phase II study underway

Mesothelin-based approach

  • Mesothelin is a protein present on normal mesothelial cells and overexpressed in several human tumours, including mesothelioma
  • Adoptive immune therapy: T cells, subtypes of immune cells, are taken out and modified in a way that they target a specific protein on cancer cells, and then injected back in

Conclusions

  • Multiple challenges in the management of MPM
  • Recent improvement in survival seen in MPM
  • Areas being improved upon:
  • Diagnostic work-up
  • Accurate staging methodologies
  • Treatment response monitoring
  • Understanding of biology
  • Clinical trial design
  • Supportive/palliative care

3) Surgical Management of Malignant Mesothelioma

Mr Adrian Pick (Cardiothoracic Surgeon)

Surgery for Mesothelioma

  • Diagnostic
  • Palliative
  • Cytoreduction
  • ?Preventative

Pleurectomy vs. Extrapleural Pneumectomy (Pros and Cons)

Pleurectomy

  • Higher local recurrence (70-100%)
  • Less cytoreductive
  • Lower mortality
  • Lower morbidity
  • Adjuvant radiation difficult

Extrapleural Pneumonectomy

  • Lower local recurrence (13 – 30%)
  • More cytoreductive
  • Higher mortality
  • Higher morbidity
  • Adjuvant radiation easy

Multimodality Cytoreducation

Pleurectomy and decortication

  • Aim to fully expand lung
  • Aim to remove disease from chest wall
  • De-bulk tumour (Cytoreductive Surgery)

Diaphragm and pericardium rarely resected.

Radiotherapy to drain site

Pre and post-operative chemotherapy

Conclusions

  • Radical surgery can be performed safely with an acceptable mortality and morbidity
  • Patients appear to get symptom relief from the operation in terms of chest wall pain and shortness of breath
  • Disease free interval lengthened

4) Legal Perspectives for Asbestos Disease Sufferers

Margaret Kent (partner at Slater and Gordon)

What is a compensable asbestos-related condition?

  • Mesothelioma
  • Lung Cancer – dose related/competing causes/synergy
  • Asbestosis – once diagnosis established
  • Pleural plaques – usually not compensable
  • Other asbestos related diseases (for example, sometimes pleural thickening)

Types of compensation

  • Common Law negligence claims
  • Statutory schemes, including no fault – i.e Workers Compensation, Comcare
  • In Victoria, time limits apply to the bringing of a claim. It is important that people seek advice early, so that they can make informed decisions

Common law negligence claims

To bring a successful claim, the plaintiff must prove the following:

  • Duty of care
  • That a duty of care exists and is owed by a defendant to a plaintiff. Relationships that give rise to duty of care most often relevant to asbestos claims are those between an employer and employee, a manufacturer and a consumer and an occupier and a person who enters onto the property
  • Breach
  • That there was a breach of duty of care
  • That the defendant did something or failed to do something that resulted in a failure to meet the required standard of care
  • Causation
  • That in breaching its duty of care, the defendant’s act or omission was a cause or contributing factor to the plaintiff’s injury

In Common Law cases the plaintiff is entitled to claim damages (compensation) for the following:

  • Pain and suffering
  • Loss of expectation of life
  • Past and future medical expenses
  • Past and future economic loss
  • Voluntary care – compensation for the extra care that family or friends provide to the plaintiff
  • Repayments – General principle of an award of damages is to restore the plaintiff to the position that he or she would have been in had the injury not occurred. The plaintiff should recover damages generally no more or less than they actual loss. Accordingly where someone else has met a cost created by the injury, they must be repaid (for example, Private Health insurers, Medicare, Department of Veteran’s Affairs)

Common Law litigation process

  • Confirming diagnosis
  • Establishing the contribution of the asbestos related disease to symptoms (primarily non malignant asbestos related conditions)
  • Identifying the source of the exposure
  • Identifying the Defendans
  • Issuing Supreme Court proceedings in most cases
  • Speedy trial application if the condition is terminal
  • Interlocutory procedures
  • Application for a de bene esse hearing where necessary
  • Pre-trial conference – most cases resolve at around this stage
  • Trial

Survivorship – Estate Claims

  • A person with an asbestos related injury MUST issue proceedings in Court prior to their death, in order to protect their entitlements to damages for pain and siffering
  • Accordingly it is critical that people with asbestos related diseases receive timely legal advice so that those entitlements are not lost
  • One a claim is issued in court, should a person die before the conclusion of the legal proceedings the Executor of the estate can be substituted as the plaintiff and the claim may be continued after the person’s death

GP Education Series – Prostate Cancer

Thursday, 5th of November 2015

Key Points Summary

PDF downloadable version

1) Current Imaging of Prostate Cancer by MRI and Metases by PSMA PET

Dr Robert Dempster (Radiologist)

Screening Prostate Cancer

  • Reduces the number presenting with metastatic disease but has a far smaller impact on mortality
  • ERSPC & USPTF recommend against population based PSA screening

Over-diagnosis, Over-investigation, Over-Treatment: low grade “cancer”

  • Gleason Grade = most common + least common
  • Screening preferentially detects low grade G6 (Gleason 6) which is very common and should not have the label “cancer”. Reasons for this are:
  • G6 is metabolically indolent
  • Locally indolent
  • Has no metastatic potential

Relative vs. Absolute Risk Reduction

  • Trials: Benefit RRR vs. Harm ARR: “All trials publish benefits in relative terms and harms in absolute terms and downplay or ignore overall mortality effect”

High grade Prostate Cancer is highly lethal

  • Task: to find and treat the high risk disease but to NOT find the G6, otherwise the patient is stuck on the Treadmill

MRI Prostate

  • In the context of History/Examination/PSA/Biopsy
  • Non-invasive
  • Evaluates the whole gland
  • Reasonably accurate

PSMA PET

  • Very new
  • Improved accuracy: metastatic disease Pre Op-High Grade Cancers/Post Op-PSA Recurrence

Urology

  • Field leading the new paradigm of approach to cancer by establishing a clear distinction between clinically significant and non-significant cancer

2) Latest Developments In Diagnosis and Management of Early Prostate Cancer

Mr Alwin Tan (Urological Surgeon)

Diagnosis consideration

  • Fhx, Ethnicity & Agent orange exposure
  • DRE
  • PSA
  • Ultrasound
  • MRI: ?50% of patients before bx
  • Biopsy: transrectal vs. transperineal
  • Once diagnosis is confirmed: CT, BS
  • ?PSMA PET Scan

Active Surveillance

  • Postpone immediate therapy
  • Definite treatment in place if there is progression
  • Not like the old ‘watchful waiting’ (for symptomatic or metastatic)

Arguments for Active Surveillance:

  • Prostate cancer not clinical significant yet
  • Reliable parameter: clinical + pathological + imaging to help distinguish that less chance of progression and spread
  • All treatments have some side effects
  • Time and surveillance will pick out those than need to reclassify as higher risk
  • ?psychological burden

Surveillance Strategy: still in progress

Guidelines for selection not universal – NCCN

  • PSA change 3-6 monthly
  • Repeat bx under 1 years and after that 2-4 years
  • Up to 28% have higher grade missedVs. Surgery

Seeds

  • J. Clinical Onc 29:362.2010

Seeds implants shows better:

  • Urinary function
  • Sexual function
  • Overall satisfaction
  • No difference in bowel function
  • At 12 years out – equivalent or better “cure rate”

Advantages:

  • Day procedure
  • High preservation of erection
  • High preservation in ability to climax
  • In cancer G6 and single core small Gleason 7 – cancer free as good if not better than surgery
  • Incontinence rare
  • Back at work within 3 days
  • Radioactive for 63 daysAim

Radical prostatectomy (if considered Organ confined T1-T2)

  • Preserve the nerves
  • Preserve the urethra
  • Preserve the bladder neck

Risk:

  • Impotence risk 30-60%
  • Incontinence – 1-3% still uses pad at the end of 12 months
  • Home with IDC for 1-2 weeks

Botox to Bladder

  • Via a cystoscopy
  • Day procedure
  • Now covered by PBS (from September 2015)
  • Good for irritable bladder – mainly OAB (both neurogenic and non-neurogenic) and post radiation
  • Can go into retention (so must be able to ISC if cannot avoid)

Green Light Laser

Where is used:

  • Benign prostate for outlet obstruction
  • Prostate cancer patient with obstructive issues: Pre Brachytherapy & Pre External Beam Radiotherapy
  • Post Radiotherapy: bladder neck stricture and Radiation Induced bleeding (beware of Xareoleta)

Advantage:

  • No need to stop any anti coagulation
  • Small instrument compared to Gyrus or traditional TURP
  • Almost no bleeding
  • Most go home after one night (unless they’re over 80 years old)
  • Must take it easy for 4 weeks (reactionary bleed especially on blood anticoagulation)

3) Latest Improvements in Radiation Therapy for Prostate Cancer – Impact of Technologies

Dr Marcus Foo (Radiation Oncologist)

External Beam Radiotherapy

  • Painless
  • Mostly non-invasive
  • Every day, 5days/week
  • 7.5-8 weeks, daily treatment (37-39 treatments [or fraction])
  • 74-78 Gray/37-39 fractions
  • 5 minutes/day (30 mins/day)
  • Patients are NOT RADIOACTIVE

Dose-escalated imaged-guided intensity-modulated EBRT (IGRT-IMRT)

  • Insertion of Gold-fiducial markers
  • Antibiotics
  • TRUS-guided insertion of 3 gold seeds
  • Gold seeds are used to accurately target cancer with radiation.

Stereotactic Body Radiotherapy

  • High dose radiation

SBRT for Prostate Cancer

  • Predominantly for “oligo-metastatic” deposits, i.e. 3-6 mets only
  • Bone
  • Nodal
  • Trials
  • ?Prostate primary?

4) What’s New In Metastatic Prostate Cancer

Dr Sanjeev Sewak (Medical Oncologist)

Results of 3 randomized chemotherapy trials in hormone naïve prostate cancer

In fit patients presenting with advanced cancer, early introduction of chemotherapy with Docetaxel is associated with substantial improvement in overall survival. Careful selection of patients suitable for this treatment is required.