Recent developments in radiotherapy and management of bowel toxicity

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1 The Roy al Marsden Recent developments in radiotherapy and management of bowel toxicity Dr Alexandra Taylor

Principles of pelvic external beam radiotherapy (EBRT) and brachytherapy established

2 Radiotherapy for cervical cancer Historical perspective 1901 First use of radium for cervical cancer 1912 Better outcomes when pelvic nodes were also treated 1920s 1930s Principles of pelvic external beam radiotherapy (EBRT) and brachytherapy established Standard pelvic fields described From Kinmouth, J.B., The Lymphatics, Arnold, London, 1972

3 Indications for Radiotherapy Primary Treatment Adjuvant Treatment CERVICAL CANCER Chemo-RT standard treatment bulky disease locally advanced node positive ENDOMETRIAL CANCER Adjuvant radiotherapy G3 IB Stage II - III VAGINAL CANCER VULVAL CANCER RECURRENCE

Radiotherapy for Gynaecological Cancer Typical treatment comprises:

Brachytherapy to boost macroscopic disease Volumes are often very large

organs at risk Late toxicity has significant impact on quality of life

4 Radiotherapy for Gynaecological Cancer Typical treatment comprises: External beam RT to pelvis for 5 weeks Concurrent chemotherapy Brachytherapy to boost macroscopic disease Volumes are often very large and encompass large amounts of normal tissues Close proximity to mobile organs at risk Late toxicity has significant impact on quality of life Uncontrolled pelvic disease difficult to palliate so local control very important

5 Radiotherapy Principles Relationship between dose and tumour control Dose limited by risk of toxicity Incidence Tumour Control Complications Dose

6 Radiotherapy Principles Relationship between dose and tumour control Dose limited by risk of toxicity Increase curve separation Reduces toxicity Incidence Tumour Control Complications Dose

7 Radiotherapy Principles Relationship between dose and tumour control Dose limited by risk of toxicity Increase curve separation Reduces toxicity Enables dose escalation Incidence Tumour Control Complications Dose

8 Radiotherapy Principles Relationship between dose and tumour control Dose limited by risk of toxicity Increase curve separation Reduces toxicity Enables dose escalation Incidence Oxygen ChemoRT Tumour Control Complications Dose

9 Radiotherapy Principles Relationship between dose and tumour control Dose limited by risk of toxicity Increase curve separation Reduces toxicity Enables dose escalation Incidence Oxygen ChemoRT Tumour Control Complications Dose

10 Radiotherapy through the 20 th century Brachytherapy standardisation 1920s 1930s 1950s 1960s 1980s 1999 Combination of DXT and brachytherapy

11 Radiotherapy through the 20 th century Brachytherapy standardisation Megavoltage treatment 1920s 1930s 1950s 1960s 1980s 1999 Combination of DXT and brachytherapy

12 Radiotherapy through the 20 th century Brachytherapy standardisation Megavoltage treatment 1920s 1930s 1950s 1960s 1980s 1999 Combination of DXT and brachytherapy Oxygen effect + importance of total treatment time

13 Radiotherapy through the 20 th century Brachytherapy standardisation Megavoltage treatment No improvement in survival with neo-adjuvant or adjuvant chemotherapy 1920s 1930s 1950s 1960s 1980s 1999 Combination of DXT and brachytherapy Oxygen effect + importance of total treatment time

Radiotherapy through the 20 th century Brachytherapy standardisation Megavoltage treatment No improvement in survival with neo-adjuvant or adjuvant

14 Radiotherapy through the 20 th century Brachytherapy standardisation Megavoltage treatment No improvement in survival with neo-adjuvant or adjuvant chemotherapy 1920s 1930s 1950s 1960s 1980s 1999 Combination of DXT and brachytherapy Oxygen effect + importance of total treatment time Concurrent Chemo- Radiation

15 Conventional External Beam Radiotherapy

16 Conventional External Beam Radiotherapy Standard field borders based on bony landmarks Issues: No individualisation of volumes Large volumes of normal tissue Poor dosimetry Risk of a geographical miss NO LONGER AN ACCEPTABLE TECHNIQUE IN THE UK

17 21 st Century Radiotherapy IMRT Functional imaging Image Guided / Adaptive radiotherapy Systemic therapies Image Guided Brachytherapy Stereotactic Radiotherapy

18 Example: Cervical cancer 35 year old woman presents with three months of irregular vaginal bleeding On examination: 5 cm tumour extending to left parametrium and down the anterior vaginal wall to 5 cm from introitus Histology: squamous cell carcinoma

19 3D EBRT Planning Techniques Conformal RT IMRT

Sensitivity 53% Locally advanced Sensitivity 70-80% Alters radiation fields in 11-19%

20 Detection of lymph node metastases CT and MRI Nodal metastases identified based on size criteria and morphology Sensitivity 40-60% PET Imaging modality of choice Early stage Sensitivity 53% Locally advanced Sensitivity 70-80% Alters radiation fields in 11-19% cases Salem et al. Limited detection of metastases <5 mm so risk of under-treating para-aortic disease

21 Conformal RT IMRT Simultaneous integrated boost IMRT

22 Conventional Brachytherapy X X

23 Conventional Brachytherapy Image Guided Brachytherapy b * * r X vp X

26 Clinical outcomes Potter et al; Radiother Oncol (2): consecutive patients with optimised planning Group 1: Group 2: GEC ESTRO volumes with dose adaptation and escalation since 2001 Mean dose (D90) Pelvic control (2-5 cm) Overall survival (2-5 cm) Pelvic control (> 5 cm) Overall Survival (> 5 cm) Late toxicity Group 1 (n=73) 81 Gy Group 2 (n=72) 90 Gy P value <0.01

27 Clinical outcomes Potter et al; Radiother Oncol (2): consecutive patients with optimised planning Group 1: Group 2: GEC ESTRO volumes with dose adaptation and escalation since 2001 Group 1 (n=73) Group 2 (n=72) Mean dose (D90) Pelvic control (2-5 cm) Overall survival (2-5 cm) Pelvic control (> 5 cm) Overall Survival (> 5 cm) 81 Gy 100% 82% 71% 28% 90 Gy 96% 71% 90% 58% P value <0.01 NS NS 0.05 <0.01 Late toxicity

28 Clinical outcomes Potter et al; Radiother Oncol (2): consecutive patients with optimised planning Group 1: Group 2: GEC ESTRO volumes with dose adaptation and escalation since 2001 Group 1 (n=73) Group 2 (n=72) Mean dose (D90) Pelvic control (2-5 cm) Overall survival (2-5 cm) Pelvic control (> 5 cm) Overall Survival (> 5 cm) Late toxicity 81 Gy 100% 82% 71% 28% 10% 90 Gy 96% 71% 90% 58% 2% P value <0.01 NS NS 0.05 <0.01

29 Re-irradiation

dose distributions - tracking with real time imaging Reduces volume of

30 Stereotactic Body Radiotherapy (SBRT/SRS/SABR) Combines - optimal target volume definition and patient immobilisation - complex, highly conformal dose distributions - tracking with real time imaging Reduces volume of normal tissue within the target volume Typically large doses in a few fractions

Stereotactic radiotherapy Availability Commissioning through Evaluation programme NHS England from July 2015 Named centres for SBRT Approved

31 Stereotactic radiotherapy Availability Commissioning through Evaluation programme NHS England from July 2015 Named centres for SBRT Approved indications 1. Re-irradiation Solitary pelvic recurrence or positive surgical resection margin 2. Oligometastases e.g. Lymph node metastasis

32 32 The Roy al Marsden Change Presentation title and date in Footer dd.mm.yyyy Proton therapy Proton IMRT Berman et al, 2014

33 The Roy al Marsden Management of Gastro-Intestinal Toxicity

34 Radiation bowel toxicity Most common late effect following pelvic radiotherapy USA: 140,000 cancer survivors with bowel symptoms Even low grade toxicity can significantly impact on quality of life Under-reported in clinical studies Treatment often viewed as futile I can cope with it If you understand the mechanisms then intervening may make a difference Hauer-Jensen et al Nat Review Gastro;

35 The pathological model Cell death Inflammation Oedema Damage to blood vessels Ischaemia Radiotherapy Fibrosis, stem cell depletion, atrophy First 3 months After 3 months A wound which does not heal Slide courtesy of Jervoise Andreyev

36 The pathological model Cell death Inflammation Oedema Damage to blood vessels Ischaemia Radiotherapy Fibrosis, stem cell depletion, atrophy First 3 months After 3 months A wound which does not heal Slide courtesy of Jervoise Andreyev

37 Interventions to reduce acute GI toxicity A. Pharmacological Intervention Amifostine Outcome Not proven Sucralfate 5-ASA No benefit No benefit (May even exacerbate) R Stacey et al, Ther Adv Chron Disease: 2014 ;5:15-29

38 Interventions to reduce acute GI toxicity B. Nutritional Intervention Elemental Diet Low Fat Diet Low Lactose Diet Fibre (low/high) Diet Outcome Not tolerated No benefit Possible benefit Poor compliance No benefit Possible benefit Wedlake et al, Aliment Pharmacol Ther 2013;37:

39 Interventions to reduce acute GI toxicity B. Nutritional Intervention Elemental Diet Low Fat Diet Low Lactose Diet Fibre (low/high) Diet Probiotics Outcome Not tolerated No benefit Possible benefit Poor compliance No benefit Possible benefit Probable benefit 4/5 positive studies Lactobacillus sp. (VSL#3) Wedlake et al, Aliment Pharmacol Ther 2013;37:

40 LATE TOXICITY

41 GI Consequences of Treatment Clinic The RMH Team Ann Muls MacMillan Nurse Consultant Linda Wedlake Consultant Dietitian Jervoise Andreyev Consultant Gastroenterologist Endoscopy Team Lorraine Watson MacMillan Dietitian Dr Clare Shaw Consultant Dietitian

42 The physiological model Any insult Inflammatory changes Atrophy / loss of stem cells Cell death Oedema ischaemia fibrosis

43 The physiological model Any insult Inflammatory changes Atrophy / loss of stem cells Cell death Oedema ischaemia fibrosis Potentially alter specific GI physiological function(s) Unrelated factors medication side effects stress sepsis premorbid conditions Symptoms

44 secretion Upper GI tract 8.5 litres 2000 ml permeability Carbohydrate malabsorption Dysmotility promoting bacterial overgrowth Fat malabsorption Colon Vitamin and bile acid malabsorption Altered motility Altered sphincter function Visceral neuropathy 200 mls Slide courtesy of Jervoise Andreyev

45 Managing bowel toxicity is easy Identify each symptom accurately Arrange appropriate tests Identify the physiological deficits causing the symptoms ->obvious treatment options

46 One symptom. diarrhoea pain incontinence wind constipation bloating rectal bleeding

47 Weak pelvic floor muscles One symptom. many possible causes fissure anxiety diarrhoea too much fibre pain infection incontinence cancer wind diverticulitis coeliac disease constipation pancreatic insufficiency inflammatory bowel disease polyp bloating medications telangiectasia bile acid malabsorption rectal bleeding SIBO

48 Individual symptoms Bleeding Bloating Borborygmi Nausea Nocturnal need to defecate Pain - abdomen Change in bowel habit Pain - back (new onset) Constipation Diarrhoea / loose stool Pain perineal / anal / rectal Median 12 symptoms (range 4-16) Perianal pruritus Evacuation difficulty Steatorrhoea Flatulence (oral / rectal) Frequency of defaecation Incontinence / soiling / leakage Loss of rectal sensation Tenesmus Urgency Vomiting Weight loss Mucus excess Benton 2011, Muls 2013

49 Investigation of symptoms RMH algorithm For each symptom: defined list of tests defined sequence of treatments Lancet :

50 Andreyev et al, Lancet Oncology 2007

New patients seen in GI consequences clinic 2013-14 Total of 66 women

Chemotherapy alone 0% 15% Radiotherapy alone 5% Median time from

51 New patients seen in GI consequences clinic Total of 66 women with gynaecological cancer Median age: 58 years (range: 27-81) Chemotherapy alone 0% 15% Radiotherapy alone 5% Median time from diagnosis to referral: 3.9 years (range: ) 14% 32% Surgery alone 9% 24%

52 Symptom profile at first consultation (n = 66) sexual concerns urinary problems fatigue stool type 6-7 bowel frequency > 4 x/d nocturnal defaecation perianal pruritis rectal bleeding steatorrhoea mucus discharge faecal leakage tenesmus urgency vomiting nausea reduced appetite heartburn borborygmi belching flatulence bloating perianal pain abdominal pain 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Grade

53 Symptom profile at first consultation (n = 66) sexual concerns urinary problems fatigue stool type 6-7 bowel frequency > 4 x/d nocturnal defaecation perianal pruritis rectal bleeding steatorrhoea mucus discharge faecal leakage tenesmus urgency vomiting nausea reduced appetite heartburn borborygmi belching flatulence bloating perianal pain abdominal pain 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Grade

54 Symptom profile at first consultation (n = 66) sexual concerns urinary problems fatigue stool type 6-7 bowel frequency > 4 x/d nocturnal defaecation perianal pruritis rectal bleeding steatorrhoea mucus discharge faecal leakage tenesmus urgency vomiting nausea reduced appetite heartburn borborygmi belching flatulence bloating perianal pain abdominal pain 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Grade

55 Tests done Blood screen 97% Gastroscopy + D2 aspirate 74% Breath test 71% SeHCAT scan 70% Faecal elastase 62% Flexible sigmoidoscopy 56% Colonoscopy 20% Imaging 1.5%

56 Top 10 diagnoses made Small Intestine Bacterial Overgrowth 61% Vitamin D deficiency 58% Bile Acid Malabsorption 56% Gastritis 26% Vitamin B12 deficiency 24% Trace element deficiency 23% Weak pelvic floor musculature 14% Telangiectasia in rectal wall 12% Rectal Polyp 11% Oesophagitis 9% Median number of diagnoses: 4 (range 1-8) 68% women had >3 diagnoses

Initial management Take a good symptom history - Check use of PPI, beta-blockers - Check dietary fibre intake Trial loperamide liquid 0.

57 Initial management Take a good symptom history - Check use of PPI, beta-blockers - Check dietary fibre intake Trial loperamide liquid mg Trial a regular stool bulking agent (Normacol) Pelvic floor exercises Guidance on self-management For complex management Refer to specialist multi-disciplinary team

58 GUT 2012 Critical questions to identify patients in need of specialist assessment Are they woken from sleep to defaecate? Do they have troublesome urgency of defaecation and /or faecal leakage? Do they have any GI symptoms preventing them from living a full life?

59 ORBIT trial: Randomised trial of algorithm-based management of GI symptoms Andreyev et al. Lancet 2013; 382: New GI symptoms after pelvic radiotherapy MacMillan Cancer Support late effects booklet Gastroenterologist Nurse After 6 months At any time Outcomes Significant improvement in symptoms after 6 months which is maintained at 12 months (p<0.001) No difference between gastroenterologist and nurse-led arms

60 Conclusions With increasing numbers of cancer survivors it is important to monitor the long term effects from treatment We need to assess the impact of changes in practice on toxicity SIB-IMRT Image guided brachytherapy Re-irradiation Immunotherapy Bowel toxicity can be significantly improved by using a systematic approach

Late effects of treatment for colorectal cancer. Claire Taylor Macmillan Nurse Consultant St Mark s Hospital

Late effects of treatment for colorectal cancer Claire Taylor Macmillan Nurse Consultant St Mark s Hospital The number of people living with cancer is set to double from 2m to 4m by 2030 Source: Maddams