Acute and late adverse events

2.5.1. Acute and late adverse events of conventional EBRT

EBRT delivered with conventional techniques is fairly well tolerated, although grade 2 or higher acute rectal morbidity (discomfort, tenesmus, diarrhea) or urinary symptoms (frequency, nocturia, urgency, dysuria) requiring medication occur in approximately 60% of patients. Symptoms usually appear during the third week of treatment and resolve within days to weeks after treatment is completed. The incidence of late complications that develop > or = 6 months after completion of treatment is significantly lower, whereas serious complications that require corrective surgical intervention are rare. An analysis of 1,020 patients treated in two large Radiation Therapy Oncology Group (RTOG) trials 7506 and 7706 demonstrated an incidence of chronic urinary sequelae, such as cystitis, hematuria, urethral stricture, or bladder contracture, requiring hospitalization in 7.7% of cases, but the incidence of urinary toxicities requiring major surgical interventions such as laparotomy, cystectomy, or prolonged hospitalization was only 0.5% [20]. More than half of chronic urinary complications were urethral strictures, occurring mostly in patients who had undergone a previous transurethral resection of the prostate (TURP). The incidence of chronic intestinal sequelae, such as chronic diarrhea, proctitis, rectal and anal stricture, rectal bleeding or ulcer, requiring hospitalization for diagnosis and minor intervention was 3.3%, with 0.6% of patients experiencing bowel obstruction or perforation. Fatal complications were rare (0.2%). Most complications attributed to radiation therapy are observed within the first 3 to 4 years after treatment, and the likelihood of complications developing after 5 years in low. The risk of complications is increased when radiation doses exceed 70 Gy. The risk of rectal toxicity has been correlated with the volume of the anterior wall exposed to the higher doses of irradiation

2.5.2. Acute and late adverse events of CRT

Michalski et al. reported the toxicity outcomes of Stages T1-T2 prostate cancer in RTOG 9406, a phase I-II dose escalation study [21]. Two hundred twenty five patients were treated to 78 Gy (2 Gy fractions). The median follow-up was 2.2 years. Only 3% of patients had grade 3 acute toxicity. No grade 4 or 5 acute toxicity was reported. The late grade 2 and 3 bowel toxicity rates were 18% and 2%, respectively. 2 had grade 4 bowel toxicity. The late grade 2 and 3 bladder toxicity rates were 17% and 4%, respectively. No grade 4 or 5 late bladder toxicity was reported.

Zietman et al. reported acute and late genitourinary (GU) and gastrointestinal (GI) toxicity among patients treated on a randomized controlled trial [22]. The median follow-up was 5.5 years. The acute GU grade 3 toxicity for both the 70.2 Gy (1.8 Gy fractions) and 79.2 Gy dose arms in 2 Gy per fraction were 1%. The acute GI grade 3 toxicity for the 70.2 Gy and 79.2 Gy dose arms were 1% and 0%, respectively. The late GU grade 2 and 3 toxicity were 18% and 2%, respectively, for the 70.2 Gy dose arm, and 20% and 1%, respectively, for the 79.2 Gy dose arm (difference not significant between two arms). The late GI grade 2 for the 70.2 Gy and 79.2 Gy arms were 8% and 17%, respectively (p = 0.005). The late GI grade 3 toxicity, however, was 1% for both arms.

Zelefsky et al. reported the long-term tolerance of high-dose 3D-CRT at MSKCC [23]. The 5-year actuarial rate of grade 2 rectal toxicity for patients receiving 64.8 to 70.2 Gy was 7%, compared with 16% for those treated to 75.6 Gy and 15% for those who treated to 81 Gy (70.2 vs. 75.6 or 81 Gy, p <0.001). The 5-year actuarial rate of grade 3 or higher rectal toxicity was 0.85%, and no correlation between dose and the development of grade 3 complications was found within the range of 64.8 to 81 Gy. Multivariable analysis demonstrated the following variables as predictors of late grade 2 or higher GI toxicity: prescription doses >75.6 Gy (p < 0.001), history of diabetes mellitus (p = 0.01), and the presence of acute GI symptoms during treatment (p = 0.02). The 5-year actuarial likelihood of Grade 2 or higher late GU toxicity for patients who receiving 75.6 to 81 Gy was 15%, compared with 8% for those treated to 64.8 to 70.2 Gy (p = 0.008). The 5-year actuarial likelihood of the development of a urethral stricture (Grade 3 toxicity) for patients who had a prior TURP was 4%, compared with 1% for those who did not have a prior TURP (p = 0.03). No correlation was observed between higher radiation doses and the development of a urethral stricture. Multivariable analysis demonstrated the following variables as predictors of late Grade 2 or higher GU toxicity: prescription doses >75.6 Gy (p = 0.008) and the presence of acute GU symptoms during treatment (p <0.001).

Peeters et al. reported on the incidence of acute and late complications in a multicenter randomized trial comparing 68 Gy to 78 Gy 3D-CRT [24]. The median follow-up was 31 months. For acute toxicity, no significant differences were seen between the two arms. GI toxicity Grade 2 and 3 was reported as the maximum acute toxicity in 44% and 5%, respectively. For acute GU toxicity, these figures were 41% and 13%. The 3-year in incidence of grade 2 and higher GI and GU toxicities for the 68 Gy dose arm was 23.2% and 28.5%, respectively. The 3-year incidence of grade 2 and higher GI and GU toxicities for the 78 Gy dose arm was 26.5% and 30.2%, respectively. The differences were not significant. However, the authors did note a significant increase in grade 3 rectal bleeding at 3 years was 10% for the 78 Gy arm, compared to 2% for the 68 Gy arm (p = 0.007), and in nocturia (p = 0.05). The factors related to acute GI toxicity were hormone therapy (HT) (p < 0.001), a higher dose-volume group (p = 0.01), and pretreatment GI symptoms (p = 0.04). For acute GU toxicity, prognostic factors were: pretreat-ment GU symptoms (p < 0.001), ADT (p = 0.003), and prior TURP (p = 0.02). The following variables were found to be predictive of late GI toxicity: a history of abdominal surgery (p <0.001), and the presence of pretreatment GI symptoms (p = 0.001). The following variables were predictive of late GU toxicity: pretreatment urinary symptoms (p <0.001), the use of neoadjuvant ADT (p <0.001), and prior TURP (p = 0.006).

Sabdhu et al. reported that urethral strictures for 1,100 patients treated with 3D-CRT [25]. The 5-year actuarial likelihood of developing urethral stricture was 4% for 120 patients with a prior history or TURP compared to 1% for 980 patients with no history of TURP (p = 0.01). Other late urinary toxicities were not observed among patients with a prior history of a TURP. Lee et al. observed a 2% incontinence rate among patients with a prior history of TURP who were treated with EBRT compared with a 0.2% rate in patients without a prior TURP[26].

2.5.3. Acute and late adverse events of IMRT

In an attempt to improve further the conformality of the high-dose therapy plans and decrease the rate of grade 2 and higher toxicity, an IMRT approach was introduced for the treatment of clinically localized disease.

Zelefsky et al. reported their experience in 1571 patients treated with 3D-CRT or IMRT with dose raging from 66 to 81 Gy [27]. The median follow-up was 10 years. In this experience, IMRT significantly reduced the risk of grade 2 and higher late GI toxicities compared with conventional 3D-CRT (5% vs. 13%, p < 0.001), although IMRT delivered higher dose than 3D-CRT. However, IMRT increased the risk of acute and late grade 2 and higher GU toxicities and acute grade 2 and higher GI toxicities compared with conventional 3D-CRT (37% vs. 22%, p = 0.001, 20% vs. 12%, p = 0.01, and 3% vs. 1%, p = 0.04, respectively).

According to the latest report from MSKCC, actuarial 7-year grade 2 or higher late GI and GU toxicities with the use of IMRT to 86.4 Gy were 4.4% and 21.1%, respectively. Late grade 3 GI and GU toxicities were 0.7% and 2.2%, respectively [13].

Mamgani et al. compared the toxicity of 41 prostate cancer patients treated with IMRT to 78 Gy with that of 37 patients treated with the 3D-CRT approach at the same dose level within the Dutch dose-escalation trial [28]. They reported that IMRT significantly reduced the incidence of acute grade 2 or higher GI toxicity compared with 3D-CRT (20% vs. 61%, p = 0.001). For acute GU toxicity and late GI and GU toxicities, the incidence was lower after IMRT, although these differences were not statistically significant (53% vs. 69%, p = 0.3, 21% vs. 37%, p = 0.16, and 43% vs. 45%, p = 1.0, respectively).

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