Abrahim Al-Mamgani

Update of Dutch multicenter dose-escalation trial of radiotherapy for localized prostate cancer.

PURPOSE To update the analysis of the Dutch dose-escalation trial of radiotherapy for prostate cancer. PATIENTS AND METHODS A total of 669 patients with localized prostate cancer were randomly assigned to receive 68 or 78 Gy. The patients were stratified by age, institution, use of neoadjuvant or adjuvant hormonal therapy, and treatment group. The primary endpoint was freedom from failure (FFF), with failure defined as clinical or biochemical failure. Two definitions of biochemical failure were used: the American Society for Therapeutic Radiology and Oncology definition (three consecutive increases in prostate-specific antigen level) and the Phoenix definition (nadir plus 2 microe secondary endpoints were freedom from clinical failure, overall survival, and genitourinary and gastrointestinal toxicity. RESULTS After a median follow-up of 70 months, the FFF using the American Society for Therapeutic Radiology and Oncology definition was significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 54% vs. 47%, respectively; p = 0.04). The FFF using the Phoenix definition was also significantly better in the 78-Gy arm than in the 68-Gy arm (7-year FFF rate, 56% vs. 45%, respectively; p = 0.03). However, no differences in freedom from clinical failure or overall survival were observed. The incidence of late Grade 2 or greater genitourinary toxicity was similar in both arms (40% and 41% at 7 years; p = 0.6). However, the cumulative incidence of late Grade 2 or greater gastrointestinal toxicity was increased in the 78-Gy arm compared with the 68-Gy arm (35% vs. 25% at 7 years; p = 0.04). CONCLUSION The results of our study have shown a statistically significant improvement in FFF in prostate cancer patients treated with 78 Gy but with a greater rate of late gastrointestinal toxicity.

Role of Intensity-Modulated Radiotherapy in Reducing Toxicity in Dose Escalation for Localized Prostate Cancer

PURPOSE To compare the acute and late gastrointestinal (GI) and genitourinary (GU) toxicity in prostate cancer patients treated to a total dose of 78 Gy with either a three-conformal radiotherapy technique with a sequential boost (SEQ) or a simultaneous integrated boost using intensity-modulated radiotherapy (SIB-IMRT). PATIENTS AND METHODS A total of 78 prostate cancer patients participating in the randomized Dutch trial comparing 68 Gy and 78 Gy were the subject of this analysis. They were all treated at the same institution to a total dose of 78 Gy. The median follow-up was 76 and 56 months for the SEQ and SIB-IMRT groups, respectively. The primary endpoints were acute and late GI and GU toxicity. RESULTS A significantly lower incidence of acute Grade 2 or greater GI toxicity occurred in patients treated with SIB-IMRT compared with SEQ (20% vs. 61%, p = 0.001). For acute GU toxicity and late GI and GU toxicity, the incidence was lower after SIB-IMRT, but these differences were not statistically significant. No statistically significant difference were found in the 5-year freedom from biochemical failure rate (Phoenix definition) between the two groups (70% for the SIB-IMRT group vs. 61% for the SEQ group, p = 0.3). The same was true for the 5-year freedom from clinical failure rate (90% vs. 72%, p = 0.07). CONCLUSION The results of our study have shown that SIB-IMRT reduced the toxicity without compromising the outcome in patients with localized prostate cancer treated to 78 Gy radiation.

Local Anatomic Changes in Parotid and Submandibular Glands During Radiotherapy for Oropharynx Cancer and Correlation With Dose, Studied in Detail With Nonrigid Registration

PURPOSE To quantify the anatomic changes caused by external beam radiotherapy in head-and-neck cancer patients in full three dimensions and to relate the local anatomic changes to the planned mean dose. METHODS AND MATERIALS A nonrigid registration method was adapted for RT image registration. The method was applied in 10 head-and-neck cancer patients, who each underwent a planning and a repeat computed tomography scan. Contoured structures (parotid, submandibular glands, and tumor) were registered in a nonrigid manner. The accuracy of the transformation was determined. The transformation results were used to summarize the anatomic changes on a local scale for the irradiated and spared glands. The volume reduction of the glands was related to the planned mean dose. RESULTS Transformation was accurate with a mean error of 0.6 +/- 0.5 mm. The volume of all glands and the primary tumor decreased. The lateral regions of the irradiated parotid glands moved inward (average, 3 mm), and the medial regions tended to remain in the same position. The irradiated submandibular glands shrank and moved upward. The spared glands showed only a small deformation ( approximately 1 mm in most regions). Overall, the primary tumors shrank. The volume loss of the parotid glands correlated significantly with the planned mean dose (p <0.001). CONCLUSION General shrinkage and deformation of irradiated glands was seen. The spared glands showed few changes. These changes were assessed by a nonrigid registration method, which effectively described the local changes occurring in the head-and-neck region after external beam radiotherapy.

Long-term results of the Dutch randomized prostate cancer trial: Impact of dose-escalation on local, biochemical, clinical failure, and survival

PURPOSE Nowadays, advanced irradiation techniques make it possible to escalate safely the dose in prostate cancer. We studied the effect of a higher dose on tumor control in a randomized trial with a median follow-up of 110 months. PATIENTS AND METHODS Patients with T1b-T4N0 prostate cancer (n=664) were randomized between 78 Gy and 68 Gy. Primary endpoint was biochemical and/or clinical failure (BCF) according to the American Society for Therapeutic Radiology and Oncology (ASTRO) guidelines (3 consecutive rises), and to Phoenix (nadir plus 2 μg/L). Secondary endpoints were clinical failure (CF), local failure (LF), prostate cancer death (PCD), and overall survival (OS). Explorative subgroup analyses were performed. RESULTS BCF rate (HR=0.8; 20% less events) and LF rate (HR=0.5; 50% less events) were significantly lower in the 78 Gy arm (p<0.05). CF, PCD and OS were similar in both arms. A significant heterogeneity of treatment effect was found for PSA cutoffs between 7 and 10 μg/L. CONCLUSION We observed significantly less BCF and LF in the high-dose arm. This suggests improvement of the therapeutic ratio. However, we observed similar rates of CF and PCD at the current update. More follow-up is needed to investigate which patients benefit in terms of prolonged OS.

Urinary Obstruction in Prostate Cancer Patients From the Dutch Trial (68 Gy vs. 78 Gy): Relationships With Local Dose, Acute Effects, and Baseline Characteristics

PURPOSE To investigate the relationship between late urinary obstruction and the details of the dose distribution of irradiated prostate cancer patients, taking into account their baseline symptoms and acute complaints. PATIENTS AND METHODS We selected patients from the Dutch multicenter trial randomized between 68 Gy and 78 Gy, for whom toxicity data and dose data were available (n = 557). The absolute dose surface parameters of the delineated bladder were calculated. Next, we constructed three-dimensional dose maps of the area around the prostate, providing an approximate identification of the corresponding anatomic locations. The dose difference maps were constructed by subtracting the mean dose maps of the patients with and without late urinary obstruction. Selected local dose points were analyzed using Cox regression analysis. RESULTS Urinary obstruction was scored for 40 patients, including 19 of 296 patients who received 68-72 Gy and 21 of 261 patients who received 76-78 Gy. A total of 19 events occurred within 2 years after irradiation and 21 events after 2 years. The bladder surface receiving >or=80 Gy predicted (p <.01) the occurrence of obstruction within 2 years. The dose difference map indicated highly significant differences in the bladder neck situated in the trigonal region (p < .001) that were especially predictive of obstruction after 2 years and of the diagnosis of bladder neck obstruction. Baseline complaints and transurethral resection of the prostate and acute complaints were mainly predictive for obstruction within 2 years. CONCLUSION Relatively early events of urinary obstruction were associated with urinary problems existing before RT, acute toxicity, previous transurethral resection of the prostate, and hotspots in the bladder. Events after 2 years were associated with the local dose in the trigonal area.

Fully automated volumetric modulated arc therapy plan generation for prostate cancer patients

PURPOSE To develop and evaluate fully automated volumetric modulated arc therapy (VMAT) treatment planning for prostate cancer patients, avoiding manual trial-and-error tweaking of plan parameters by dosimetrists. METHODS AND MATERIALS A system was developed for fully automated generation of VMAT plans with our commercial clinical treatment planning system (TPS), linked to the in-house developed Erasmus-iCycle multicriterial optimizer for preoptimization. For 30 randomly selected patients, automatically generated VMAT plans (VMATauto) were compared with VMAT plans generated manually by 1 expert dosimetrist in the absence of time pressure (VMATman). For all treatment plans, planning target volume (PTV) coverage and sparing of organs-at-risk were quantified. RESULTS All generated plans were clinically acceptable and had similar PTV coverage (V95% > 99%). For VMATauto and VMATman plans, the organ-at-risk sparing was similar as well, although only the former plans were generated without any planning workload. CONCLUSIONS Fully automated generation of high-quality VMAT plans for prostate cancer patients is feasible and has recently been implemented in our clinic.

Dose Uncertainties in IMPT for Oropharyngeal Cancer in the Presence of Anatomical, Range, and Setup Errors

PURPOSE Setup, range, and anatomical uncertainties influence the dose delivered with intensity modulated proton therapy (IMPT), but clinical quantification of these errors for oropharyngeal cancer is lacking. We quantified these factors and investigated treatment fidelity, that is, robustness, as influenced by adaptive planning and by applying more beam directions. METHODS AND MATERIALS We used an in-house treatment planning system with multicriteria optimization of pencil beam energies, directions, and weights to create treatment plans for 3-, 5-, and 7-beam directions for 10 oropharyngeal cancer patients. The dose prescription was a simultaneously integrated boost scheme, prescribing 66 Gy to primary tumor and positive neck levels (clinical target volume-66 Gy; CTV-66 Gy) and 54 Gy to elective neck levels (CTV-54 Gy). Doses were recalculated in 3700 simulations of setup, range, and anatomical uncertainties. Repeat computed tomography (CT) scans were used to evaluate an adaptive planning strategy using nonrigid registration for dose accumulation. RESULTS For the recalculated 3-beam plans including all treatment uncertainty sources, only 69% (CTV-66 Gy) and 88% (CTV-54 Gy) of the simulations had a dose received by 98% of the target volume (D98%) >95% of the prescription dose. Doses to organs at risk (OARs) showed considerable spread around planned values. Causes for major deviations were mixed. Adaptive planning based on repeat imaging positively affected dose delivery accuracy: in the presence of the other errors, percentages of treatments with D98% >95% increased to 96% (CTV-66 Gy) and 100% (CTV-54 Gy). Plans with more beam directions were not more robust. CONCLUSIONS For oropharyngeal cancer patients, treatment uncertainties can result in significant differences between planned and delivered IMPT doses. Given the mixed causes for major deviations, we advise repeat diagnostic CT scans during treatment, recalculation of the dose, and if required, adaptive planning to improve adequate IMPT dose delivery.

Hypofractionated radiotherapy denoted as the "Christie scheme": an effective means of palliating patients with head and neck cancers not suitable for curative treatment.

Objectives. A prospective study of the efficacy and toxicity profile of patients with squamous cell carcinoma of the head and neck (HNSCC) without curative treatment options treated consistently with hypofractionated radiotherapy schedule. Patients and methods. Between 1995 and 2006, 158 patients with HNSCC, unsuitable for curative treatment, were treated with a hypofractionated scheme of radiotherapy consisting of 16 fractions of 3.125 Gy. Endpoints of the study were response rates, loco-regional control, disease-free survival, overall survival, acute and late toxicity, and quality of life (QoL). Results. Seventy four percent of patients were male, 31% had oropharyngeal cancer and 81% stage IV disease. With 45% complete response and 28% partial response an overall response rate of 73% was achieved, 6% had stable disease, and 21% progressed during or directly after completion of treatment. Median survival time was 17 months and 62 patients (40%) survived ≥1 year after RT. The actuarial rates of loco-regional control, disease-free survival and overall survival were 62%, 32% and 40% at 1-year, respectively and 32%, 14% and 17% at 3-years, respectively. Acute grade ≥3 skin and mucosal toxicities were observed in 45% and 65% of patients, respectively. Severe late toxicity was reported in 4.5% of patients. Of patients surviving ≥1 year after RT, retrospective chart review showed that 50% gained weight, pain improved in 77%, performance status in 47% and only 29% of them was still feeding-tube dependent. Conclusions. Our hypofractionated radiotherapy scheme is an effective, well-tolerated and safe palliative schedule in HNSCC who are unsuitable for curative treatment options. Using 3.125 Gy per fraction (Christie scheme), excellent palliation was achieved resulting in acceptable response rates, excellent symptom control, acceptable toxicity profile, and good QoL of patients surviving ≥1 year after completion of treatment.

Subgroup analysis of patients with localized prostate cancer treated within the Dutch-randomized dose escalation trial.

PURPOSE To investigate the effect of dose escalation within prognostic risk groups in prostate cancer. PATIENTS AND METHODS Between 1997 and 2003, 664 patients with localized prostate cancer were randomly assigned to receive 68- or 78-Gy of radiotherapy. Two prognostic models were examined: a risk group model (low-, intermediate-, and high-risk) and PSA-level groupings. High-risk patients with hormonal therapy (HT) were analyzed separately. Outcome variable was freedom from failure (FFF) (clinical failure or PSA nadir+2 microg/L). RESULTS In relation to the advantage of high-dose radiotherapy, intermediate-risk patients benefited most from dose escalation. However no significant heterogeneity could be demonstrated between the risk groups. For two types of PSA-level groupings: PSA<10 and > or = 10 microg/L, and <8, 8-18 and >8 microg/L, the test for heterogeneity was significant (p=0.03 and 0.05, respectively). Patients with PSA 8-18 microg/L (n=297, HR=0.59) derived the greatest benefit from dose escalation. No heterogeneity could be demonstrated for high-risk patients with and without HT. CONCLUSION Intermediate-risk group derived the greatest benefit for dose escalation. However, from this trial no indication was found to exclude low-risk or high-risk patients from high-dose radiotherapy. Patients could be selected for high-dose radiotherapy based on PSA-level groupings: for patients with a PSA<8 microg/L high-dose radiotherapy is probably not indicated, but should be confirmed in other randomized studies.

The impact of treatment modality and radiation technique on outcomes and toxicity of patients with locally advanced oropharyngeal cancer

To investigate the impact of treatment modality and radiation technique on oncologic outcomes and toxicity of patients with locally advanced oropharyngeal cancer (OPC).