Late and Long-Term Effects of Treatment

Oxaliplatin-Induced Peripheral Neuropathy

Recent studies of long-term CRC survivors have begun to address the late and long-term effects of newer treatment regimens (Table 3). Oxaliplatin-induced peripheral neuropathy has become a common and occasionally dose-limiting toxicity in the CRC survivor population, usually manifesting as sensory impairment of the peripheral nerves in a stocking-glove distribution. Symptoms of numbness, pain, paresthesias, dysesthesias, and changes in proprioception may affect fine motor skills, such as writing, holding objects, buttoning shirts, picking up coins, and walking. Rarely, urinary retention and Lhermitte's sign (electric-shock sensation shooting down spine with neck flexion) can occur.^[42-44] Symptoms most commonly appear after cumulative doses of oxaliplatin exceeding 780 mg/m^[2], and are most likely caused by oxaliplatin accumulation in the dorsal root ganglia, with interference of calcium-dependent voltage-gated sodium channels by oxalate, a metabolite of oxaliplatin.^{[42,43,45-48]}

In the adjuvant setting, up to 92% of survivors treated with oxaliplatin and infusional 5-FU (FOLFOX) or bolus 5-FU (FLOX) developed some degree of sensory neuropathy, with 8% to 12% developing severe neuropathy interfering with function (grade 3) and 22% requiring premature discontinuation of oxaliplatin for severe neuropathy.^[49,50] Although most survivors have improvement or recovery of nerve function within 1 month of discontinuation of treatment, the median time to resolution of symptoms was approximately 9 months.^[51] Furthermore, 20% of survivors may have experienced a worsening of their symptoms after treatment discontinuation and up to 12% had persistent symptoms 4 years after completion of adjuvant treatment.^[7,51] Therefore, persistent numbness, tingling, and cold-induced pain may be a long-term problem in a small subset of survivors.^[52]

Measures to prevent or treat oxaliplatin-induced neuropathy are needed. In the metastatic setting, limited evidence shows that glutamine, reduced glutathione, alpha-lipoic acid, and oxcarbazepine may reduce the incidence and severity of sensory neuropathy, whereas gabapentin and carbamazepine have not been shown to be effective.^[53-58] A retrospective evaluation of calcium and magnesium infusions before and after oxaliplatin infusion suggested a reduction in chronic neuropathy without compromising chemotherapy efficacy, although this has not been confirmed in randomized prospective studies.^[59,60] In the adjuvant setting, the use of intravenous calcium gluconate and magnesium sulfate pre- and post-oxaliplatin infusion decreased the incidence of grade 2 neurotoxicity compared with placebo (28% vs. 58%; P = .01),^[61] although the study was stopped prematurely because of initial concerns regarding lower tumor response with the same intervention in the metastatic setting.^[62] Nonsteroidal anti-inflammatory medications, opioids, and referral to neurology or pain management for persistent symptoms may be useful, although their efficacy is unknown.^[44]

Bowel Dysfunction

Chronic diarrhea is reported by 13% to 50% of patients up to 10 years after treatment, with rectal cancer patients more likely than colon cancer patients to report diarrhea (24% vs. 10%; P = .04).^[18,32,63] Diarrhea has been associated with limitations in activity and can negatively affect QOL.^[18,32] Survivors who underwent an anterior resection reported a median of 3 bowel movements per day, frequency, urgency, evacuatory difficulties, and inability to differentiate stool and gas. These symptoms were most problematic during the first year after resection and were associated with fear, poor body image, and low self-confidence.^[38,64]

Both pre- and postoperative radiation for rectal cancer increases the risk for long-term bowel dysfunction. Preoperative short-course radiation (5 Gy in 5 fractions) has been associated with a 2.5-fold higher rate of small bowel obstruction and 2-fold higher incidence of abdominal pain compared with those not treated in this manner, and increased bowel frequency and limitations in activities of daily living and social activities up to 5 years after treatment.^[41,65,66] Postoperative radiation also results in frequent bowel movements, similar to survivors who undergo preoperative radiation, and is associated, up to 5 years after treatment, with clustering of bowel movements (42%), increase in nighttime bowel movements (46%), incontinence (39%), pad wearing (41%), and inability to defer defecation (78%).^[67,68] Long-term anorectal dysfunction after radiation, including reduced reservoir capacity, can persist at 10 years.^[69]

Treatment for bowel problems after CRC treatment typically includes antidiarrheal medications, bulk-forming agents, use of undergarment pads, and diet manipulation.^[64] Elimination of specific foods (e.g., fats and oils, meat, milk products, raw vegetables, fibrous foods) and the use of probiotic supplements have had limited benefit.^[63,70] Attention to this issue is imperative because survivors may assume abnormal bowel symptoms are an inevitable consequence of treatment and may not address persistent symptoms at follow-up appointments.^[63,71]

Pelvic Insufficiency Fractures After Radiation

Bone damage and risk for fractures may be increased after radiotherapy for rectal cancer. A large retrospective study of older women diagnosed with anal, cervical, or rectal cancer showed that survivors of rectal cancer experienced a 65% increase in the cumulative incidence of pelvic fractures after radiation compared with those who were not irradiated (11.2% vs. 8.7%; P < .001), resulting in a possible increase in the absolute lifetime risk for fracture from 17% to 27%. The effect of radiation remained significant after controlling for other risk factors.^[72]

The use of combined modality therapy may heighten the effect of radiation on bone density; medications and estrogen deficiency may further contribute to the risk for osteoporosis.^[73] Therefore, survivors who have received prior pelvic radiation should undergo long-term monitoring of bone density, appropriate medical treatment of osteopenia and osteoporosis, and careful evaluation if symptoms suggesting fractures develop.

Urogenital Dysfunction

Urinary and sexual dysfunction are known complications of rectal cancer treatment, reported in at least 30% of patients undergoing definitive treatment.^[41,74-77] In studies of short-course radiation followed by total mesorectal excision (TME) versus TME alone, symptoms at 5 years included urinary incontinence (38%), difficulties in bladder emptying (31%), need to void within 2 hours of voiding (70%), and need for protective pads (57%).^[41,74] Risk factors for postoperative incontinence included preoperative incontinence, female gender, perioperative blood loss, preoperative bladder emptying difficulties, autonomic nerve damage, and presence of a permanent stoma.^[40,41,74] Severity of urinary incontinence increased with time, from 18% at 3 months to 31% at 5 years, and contributed to a lower overall perception of health status.^[41,74]

Although preservation of autonomic nerves during TME has been shown to minimize permanent sexual dysfunction, abdominoperineal resection has been associated with lower sexual function at 5 years compared with anterior resection (26% vs. 48%; P = .001).^[38,78] Men enrolled in a TME trial reported generalized sexual dysfunction (76.4%), erectile dysfunction (79.8%), and ejaculatory problems (72.2%) after surgery. Risk factors included preoperative radiation, presence of a stoma, perioperative blood loss, anastomotic leak, and autonomic nerve damage. Women reported an increase in generalized sexual dysfunction (62%), dyspareunia (59%), and vaginal dryness (56.6%) after treatment. Risk factors included preoperative radiation and the presence of a stoma.^[75] Vaginal stenosis can also occur after pelvic radiation and contribute to dyspareunia.^[79]

Few intervention trials have targeted urogenital dysfunction in rectal cancer survivors. A study of 32 men undergoing rectal resection for cancer or inflammatory bowel disease showed that 79% of those receiving sildenafil reported reversal or satisfactory improvement in erectile dysfunction versus 13% receiving placebo (P = .0009).^[80] The use of vaginal dilators by women undergoing vaginal brachytherapy for cervical cancer has shown benefit in maintaining vaginal patency, and dilators have been used empirically in rectal cancer survivors.^[79,81]