Radiation: Toxicities

Episode Notes

1. Types of toxicities from radiation

1. Deterministic: effects occur only above a certain threshold of exposure, and severity increases with increased dose

1. Usually predictable, reproducible

2. Most organ damage exhibits deterministic effects

2. Stochastic: no minimum threshold at which they begin to occur, doses of any magnitude can induce genetic changes leading to these effects

1. May occur many years later

2. Example: carcinogenesis

2. Timing of toxicities

1. Acute: definitions vary, but typically these are effects occurring within the first 120 days during and after radiation delivery (during the “inflammatory phase”)

2. Chronic: later effects, occurring in the “fibrotic phase”

1. Short term: less than 5 years from radiation

2. Long term: greater than 5 years from radiation

1. Less well documented, as many clinical trials stop collected data on patients after 5 years

3. GI toxicities: most frequent source of pelvic radiation side effects, most likely to impact QOL and daily activities

1. Acute: 

1. N/V: occurs early on

1. Management (Mgmt): antiemetics 

2. Diarrhea/abdominal cramping later (2-3 weeks into treatment)

1. Probiotics decrease reported diarrhea but have not been shown to decrease the amount of anti-diarrheal medication used

2. Supportive care for diarrhea: IV fluids, electrolyte repletion, fiber products (psyllium –after completing radiation), or low fiber diet (during radiation treatment), loperamide

3. Radiation proctitis: occurs in up to 20% of patients (usually grade 1-2). Diarrhea can be debilitating

1. Max total dose of 70-75Gy to the rectum recommended to prevent/reduce severity of radiation proctitis

2. Topical steroids or steroid enemas can help with radiation proctitis

4. Anorexia, malaise, rectal discomfort/bleeding, tenesmus

1. Colonoscopy/sigmoidoscopy with endoscopic fulguration of bleeding telangiectasias can help address bleeding sites

5. Small bowel obstruction:  increased risk with prior abdominal/pelvic surgery (due to adhesions); increased risk with >50Gy pelvic RT

1. Could be acute or chronic

6. In definitive treatment of Locally advanced cervical cancer (LACC), up to 20% of patients will experience grade 3+ AE

2. Chronic: due to mucosal atrophy, loss of mucin-producing goblet cells, fibrosis of the intestinal wall. 

1. Chronic malabsorption and diarrhea, vitamin deficiency (B12 due to damage to the vulnerable distal ileum)

1. Mgmt: multidisciplinary approach

2. Monitor vitamins especially B12, incorporate antidiarrheals

3. Bleeding: colonoscopy should be done to rule out malignancy

1. Medical therapy: sucralfate enemas, hyperbaric oxygen, endoscopic intervention (Described above)

2. Dysmotility/ileus, bowel obstruction 

1. Conservative treatment of bowel obstruction/ileus preferred

1. Risk of poor healing, malnutrition if surgical intervention

3. Emergency: bowel perforation: increased risk w/ diverticular disease, recurrent disease

1. Mgmt: surgical intervention w/ diversion; when reanastomosing, prioritization of healthy tissue is crucial

4. Emergency: Vascular fistula, GI bleed:

1. Mgmt: 

1. Stop all anticoagulation!

2. Rapid resuscitation: 2 large bore IVs, fluids, consider blood

3. Consult IR, vascular and/or trauma surgery

4. Massive transfusion protocol is often necessary and critical care may be needed

5. Prevention: come to radiation therapy with full bladder to displace bowel out of the field (bladder is more resilient than bowel)

1. QUANTEC study: limiting total radiation to the small bowel to 45Gy reduces the risk of acute grade 3+ toxicity

4. GU toxicities

1. Acute: up to 40% of patients will experience grade 1-2 acute urinary toxicity. Toxicity is dose dependent, and incidence varies significantly.

1. Doses <80Gy to the urinary system suggested to prevent grade III toxicity

2. Edema, perivascular fibrosis, replacement of smooth muscle with fibroblasts, increased collagen deposition, vascular ischemia of bladder wall > cystitis, incontinence, urgency/frequency.

1. Acute cystitis should resolve within 1-2 weeks of therapy

3. Prevention: come to radiation therapy with full bladder

4. Eval: urinalysis, urine culture

5. Treatment

1. NSAIDs for irritative voiding symptoms

2. Anticholinergics or antispasmodics for cystitis/bladder sparm

3. Phenazopyridine for dysuria

2. Chronic: due to epithelial and microvascular changes > collagen deposition, fibrosis, loss of tissue compliance

1. Hemorrhagic cystitis and hematuria, bladder ulcers: seen with higher total doses

1. Hemorrhagic cystitis is an emergency! Blood can lead to outlet obstruction > overdistension > autonomic instability and bladder rupture

1. Mgmt of hemorrhagic cystitis: 

1. Consult urology: continuous bladder irrigation with a 3-way foley

2. 2 large bore IVs for resuscitation

3. Monitor labs for anemia/consider transfusion

4. After stabilization: consider fulguration, hyperbaric oxygen, formalin (last effort)

2. Fistulization: can affect both the GI and GU systems. Reported in up to 7% of patients receiving radiation. Hx tobacco use or stage IVA disease increases risk.

1. Treatment: hyperbaric oxygen for symptom control, diversion for definitive treatment

3. Strictures of ureter/urethra: 2.5-5% of patients

3. Prevention: contouring of the urethra, IMRT, foley  placement and bladder distension

5. Vaginal Toxicities: up to 90% of patients receiving pelvic radiation will have some (29% have severe toxicity)

1. Atrophy, stenosis, loss of luication, fibrosis, dyspareunia, adhesions

2. Vaginal necrosis: rare, more common with previously used radiation sources for brachytherapy (like cesium), or if patients undergo re-irradiation

3. As with other organ sites, toxicities less severe with brachytherapy than with EBRT/combine treatment

4. Distal vagina most susceptible to stenosis

5. Mgmt: 

1. Vaginal dilators and/or other vaginal penetration with water-based lubricants: recommended ~3x/week for at least 1-2 years after radiation

1. This is crucial to perform surveillance exams; patients are often more willing to using dilators if they know why it’s necessary

2. Vaginal estrogen, vaginal moisturizers

3. Referral to sexual health clinic and pelvic floor PT

4. Partner/couples counseling

6. Ovarian Toxicities: ovaries are very sensitive, especially the oocytes (exposure to 2-4Gy can eliminate 50% of oocytes!!)

1. Young patients (<40): consider laparoscopic ovarian transposition at least 3cm from the planned field; reported success rate >80%, but there is a risk of ovarian failure with transposition itself

2. HRT is an option for many patients after treatment if they have experienced ovarian failure, depending on the tumor type and hormone responsiveness

7. Skin toxicities: skin is vulnerable since it has a quick turnover; vulvar radiation is large contributor to skin toxicity

1. Acute: occur 2-3 weeks into treatment: erythema, pain, pruritis, alopecia, dry and moist desquamation

1. Management: moisturizing creams (avoid dyes, fragrances, irritants), barrier ointments (helpful if there is dry desquamation), topical steroids (mometasone), silvadene (helpful for moist desquamation)

2. Sitz baths, medicated soaks

2. Chronic: fibrosis, collagen deposition, loss of elasticity, telangiectasias, hyperpigmentation, radiation necrosis, chronic pain

1. Mgmt: vitamin E, oral pentoxifylline can help manage

3. Prevention: keep the area clean and dry

8. Bone and bone marrow toxicities:

1. Bone: typically all chronic

1. Focal osteopenia: due to endothelial damage and intimal fibrosis, decreased osteoblast proliferation, decreased estrogen

2. Fracture: sacroiliac joints at particular risk 

2. Bone marrow: increased severity with chemoRT (50% chance of leukopenia/anemia)

1. Prevention: volume of bone marrow receiving 40+Gy is predictive of hematologic toxicity

9. Toxicities by modality: VBT creates less toxicities than EBRT modalities. Newer modalities like IMRT, VMAT are improving toxicity profiles of radiation

1. PORTEC-1 (EBRT vs. obs): EBRT patients with higher rates of incontinence, diarrhea, fecal leakage

2. PORTEC-2 (EBRT vs. VBT): VBT associated with improved symptoms for diarrhea, fecal leakage, and limitation in daily activities

3. Increased risk of toxicities and reduced QOL in patients requiring multiple therapeutic modalities: i.e. surgery and radiation. For this reason, surgery (example; cervical cancer) is often not recommended if the patient will need significant/definitive radiation afterwards

References

1.    Nout RA, Van De Poll-Franse L V., Lybeert MLM, et al. Long-term outcome and quality of life of patients with endometrial carcinoma treated with or without pelvic radiotherapy in the post operative radiation therapy in endometrial carcinoma 1 (PORTEC-1) trial. J Clin Oncol. 2011;29(13):1692-1700. doi:10.1200/JCO.2010.32.4590

2.    Nout RA, Putter H, Jürgenliemk-Schulz IM, et al. Quality of life after pelvic radiotherapy or vaginal brachytherapy for endometrial cancer: first results of the randomized PORTEC-2 trial. J Clin Oncol. 2009;27(21):3547-3556. doi:10.1200/JCO.2008.20.2424

3.    Kavanagh BD, Pan CC, Dawson LA, et al. Radiation dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl). doi:10.1016/J.IJROBP.2009.05.071

4.    Klopp AH, Yeung AR, Deshmukh S, et al. Patient-Reported Toxicity During Pelvic Intensity-Modulated Radiation Therapy: NRG Oncology-RTOG 1203. J Clin Oncol. 2018;36(24):2538-2544. doi:10.1200/JCO.2017.77.4273

5.    Yeung AR, Pugh SL, Klopp AH, et al. Improvement in Patient-Reported Outcomes With Intensity-Modulated Radiotherapy (RT) Compared With Standard RT: A Report From the NRG Oncology RTOG 1203 Study. J Clin Oncol. 2020;38(15):1685-1692. doi:10.1200/JCO.19.02381

6. Radiation Complications by Dr. Devin Miller, SGO ConnectEd Fellows Bootcamp