A.G. Morganti

Combined-modality therapy in locally advanced primary rectal cancer.

AbstractPURPOSE: Patients with unresectable, locally advanced rectal cancer are reported to have a dismal prognosis. The aim of this study was to analyze the effect of combined-modality therapy on clinical outcome. METHODS: From March 1990 to December 1997, 43 patients (28 males; median age, 62 years; median follow-up, 74 months) with locally advanced (T4 and/or N3) nonmetastatic rectal cancer received external-beam radiation (23.6 plus 23.6 Gy (split course), 8 patients; 45 Gy, 35 patients) plus 5-fluorouracil (96-hour continuous infusion, Days 1–4, at 1,000 mg/m2/day) and mitomycin C (10 mg/m2, intravenous bolus, Day 1). Concomitant chemotherapy was repeated at the beginning of the second course (split-course group) or in the last week of radiotherapy (continuous-course group). After 6 to 8 weeks, patients were evaluated for surgical resection and intraoperative radiation therapy (10 to 15 Gy). Thereafter, adjuvant chemotherapy (5-fluorouracil plus leucovorin, 6–9 courses) was prescribed. RESULTS: During chemoradiation, 5 patients (11.6 percent) developed Grade 3 to 4 hematologic toxicity. After chemoradiation, 29 patients (67.4 percent) had an objective clinical response (complete response, 2.3 percent; partial response, 65.1 percent). Thirty-eight patients underwent radical surgery (anterior resection, 24 patients; abdominoperineal resection, 14 patients; intraoperative radiation therapy boost on the tumor bed, 19 patients), and 2 patients had partial tumor resection. No perioperative deaths occurred in the patient group. Five-year survival and local control rates were 59.9 and 69.1 percent, respectively. Distant metastasis occurred in 44.2 percent of patients. Statistically significant relationships between intraoperative radiation therapy and local control (P = 0.0104), radical surgery and survival (P = 0.0120), and adjuvant chemotherapy and disease-free survival (P = 0.0112) were observed. CONCLUSIONS: Our data suggest that combined-modality therapy was relatively well tolerated and resulted in good local control and survival. With regard to the impact of surgical resection on survival, additional studies aimed at improving the local response rate are necessary, whereas the positive impact of intraoperative radiotherapy on local control appears to justify the inclusion of this therapeutic modality in prospective multi-institutional trials.

A PHASE I DOSE-ESCALATION STUDY (ISIDE-BT-1) OF ACCELERATED IMRT WITH TEMOZOLOMIDE IN PATIENTS WITH GLIOBLASTOMA

PURPOSE To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (IMRT) with temozolomide (TMZ) in patients with glioblastoma. METHODS AND MATERIALS A Phase I clinical trial was performed. Eligible patients had surgically resected or biopsy-proven glioblastoma. Patients started TMZ (75 mg/day) during IMRT and continued for 1 year (150-200 mg/day, Days 1-5 every 28 days) or until disease progression. Clinical target volume 1 (CTV1) was the tumor bed +/- enhancing lesion with a 10-mm margin; CTV2 was the area of perifocal edema with a 20-mm margin. Planning target volume 1 (PTV1) and PTV2 were defined as the corresponding CTV plus a 5-mm margin. IMRT was delivered in 25 fractions over 5 weeks. Only the dose for PTV1 was escalated (planned dose escalation: 60 Gy, 62.5 Gy, 65 Gy) while maintaining the dose for PTV2 (45 Gy, 1.8 Gy/fraction). Dose limiting toxicities (DLT) were defined as any treatment-related nonhematological adverse effects rated as Grade >or=3 or any hematological toxicity rated as >or=4 by Radiation Therapy Oncology Group (RTOG) criteria. RESULTS Nineteen consecutive glioblastoma were treated with step-and-shoot IMRT, planned with the inverse approach (dose to the PTV1: 7 patients, 60 Gy; 6 patients, 62.5 Gy; 6 patients, 65 Gy). Five coplanar beams were used to cover at least 95% of the target volume with the 95% isodose line. Median follow-up time was 23 months (range, 8-40 months). No patient experienced DLT. Grade 1-2 treatment-related neurologic and skin toxicity were common (11 and 19 patients, respectively). No Grade >2 late neurologic toxicities were noted. CONCLUSION Accelerated IMRT to a dose of 65 Gy in 25 fractions is well tolerated with TMZ at a daily dose of 75 mg.

Effect of whole pelvic radiotherapy for patients with locally advanced prostate cancer treated with radiotherapy and long-term androgen deprivation therapy

PURPOSE To evaluate the effect of whole pelvic radiotherapy (WPRT) in prostate cancer patients treated with RT and long-term (>1 year) androgen deprivation therapy (ADT). METHODS AND MATERIALS Prostate cancer patients with high-risk features (Stage T3-T4 and/or Gleason score≥7 and/or prostate-specific antigen level≥20 ng/mL) who had undergone RT and long-term ADT were included in the present analysis. Patients with bowel inflammatory disease, colon diverticula, and colon diverticulitis were excluded from WPRT and treated with prostate-only radiotherapy (PORT). Patients were grouped according to nodal risk involvement as assessed by the Roach formula using different cutoff levels (15%, 20%, 25%, and 30%). Biochemical disease-free survival (bDFS) was analyzed in each group according to the RT type (WPRT or PORT). RESULTS A total of 358 patients treated between 1994 and 2007 were included in the analysis (46.9% with WPRT and 53.1% with PORT). The median duration of ADT was 24 months (range, 12-38). With a median follow-up of 52 months (range, 20-150), the overall 4-year bDFS rate was 90.5%. The 4-year bDFS rate was similar between the patients who had undergone WPRT or PORT (90.4% vs. 90.5%; p=NS). However, in the group of patients with the greatest nodal risk (>30%), a significant bDFS improvement was recorded for the patients who had undergone WPRT (p=.03). No differences were seen in acute toxicity among the patients treated with WPRT or PORT. The late gastrointestinal toxicity was similar in patients treated with PORT or WPRT (p=NS). CONCLUSIONS Our analysis has supported the use of WPRT in association with long-term ADT for patients with high-risk nodal involvement (>30%), although a definitive recommendation should be confirmed by a randomized trial.

Concomitant boost radiotherapy and multidrug chemotherapy in the neoadjuvant treatment of locally advanced rectal cancer: Results of a phase II study

Abstract Background. An intensified multidrug chemotherapy regimen (raltitrexed plus oxaliplatin, Tom-Ox) plus concomitant boost radiotherapy, in the neoadjuvant treatment of locally advanced rectal cancer patients, was shown feasible in our previous study. The aim of this study was to evaluate the efficacy in terms of pathologic complete response to pre-operative therapy. Material and methods: A Phase II study was designed and clinical stage T3-T4 and/ or N ≥ 1 patients were treated with concomitant boost radiotherapy (55 Gy/5 weeks) plus concurrent chemotherapy (Tom-Ox). The primary endpoint was the assessment of efficacy in terms of clinical and pathologic response to pre-operative therapy. According to the Gehans design study, 25 patients were enrolled. Toxicity was assessed according to the RTOG-EORTC and CTCAE v.3.0 criteria. Results: Twenty-five consecutive patients were treated. Twenty-two of the 25 (88%) patients had a partial clinical response at the time of pre-operative magnetic resonance imaging (MRI). Only one patient showed progressive systemic disease at pre-surgical revaluation and was subjected only to biopsy to evaluate pathological response. Twenty-four patients (96%) underwent surgery. Overall, pathologic complete response was observed in eight patients (32%; CI 0.95:12–55%) and only microscopic tumor foci (pTmic) in two patients (pT0-mic: 40%; CI 0.95:18–63%). Nineteen patients (76%) showed tumor down-staging. Proctitis and/or diarrhea were the most frequent acute side effects experienced. Eighteen patients had grade 1–2 toxicity (77%); whereas two patients experienced grade 3 toxicity (8%). Two-year Local control and actuarial Disease Free Survival were 100% and 91%, respectively. Conclusion. An intensified regimen of concomitant boost radiotherapy plus concurrent raltitrexed and oxaliplatin, can be safely administered in patients with locally advanced rectal cancer. This regimen produces high rates of pathological complete response. Based on available data, this type of treatment could be offered to patients with more advanced tumors (T4 or local recurrence).

Comparison of measured and computed portal dose for IMRT treatment.

A new 2D array Seven 29™ model (PTW, Freiburg), equipped with 729 vented plane‐parallel ion chambers, projected for pretreatment verification of radiotherapy plans, was used as a detector for the transmitted or portal dose measurements below a Rando phantom. The dosimetric qualities of the 2D array make it attractive for measuring transmitted dose maps from step‐and‐shoot intensity‐modulated radiotherapy (IMRT). It is well known that for step‐and‐shoot IMRT beams that use a small number of monitor units (MUs) per sequence, the early and recent electronic portal imaging devices (EPIDs) present a different response at X‐ray start‐up that affects the accuracy of the measured transmitted dose. The comparison of portal doses measured to those calculated by a commercial treatment‐planning system (TPS) can verify correct dose delivery during treatment. This direct validation was tested by irradiating a simulated head tumor in a Rando anthropomorphic phantom by step‐and‐shoot IMRT beams. The absolute transmitted doses on a plane orthogonal to the beam central axis below the phantom were measured by the 2D array calibrated in terms of dose to water and compared with the computed portal dose extracted by custom software. In a previous paper, the comparison between the IMRT portal doses, computed by a commercial TPS and measured by a linear array that supplied a 1 mm spatial dose resolution, was carried out. The γ‐index analysis supplied an agreement of more than 95% of the dose point with acceptance criteria, in terms of dose difference, ΔDmax, and distance agreement, Δdmax, equal to 4% and 4 mm, respectively. In this paper, we verify the possible use of the PTW 2D array for measurements of the transmitted doses during several fractions of head and neck tumor radiotherapy. There are two advantages in the use of this 2D array as a portal dose device for the IMRT quality assurance program: first is the ability to perform absolute dose comparisons for hundreds of measurement positions to verify the correct dose delivery in several fractions of the therapy; second is the efficiency in time to detect these kinds of dose distributions within the field of view area of the CT scanner. PACS number: 87.53.Xd

Feasibility Study of Moderately Accelerated Intensity-Modulated Radiotherapy Plus Concurrent Weekly Cisplatin After Induction Chemotherapy in Locally Advanced Head-and Neck Cancer

PURPOSE To evaluate the feasibility and efficacy of moderately accelerated intensity-modulated radiation therapy (IMRT) along with weekly cisplatin, after induction chemotherapy, in patients with locally advanced unresectable head and neck cancer (HNC). METHODS AND MATERIALS Patients with Stage III or IV locally advanced HNC, without progressive disease after three courses of induction chemotherapy, received concurrent chemo-IMRT (weekly cisplatin 30 mg/m(2) plus simultaneous integrated boost IMRT). A total of 67.5 Gy in 30 fractions were delivered to primary tumor and involved nodes, 60 Gy in 30 fractions to high-risk nodal areas, and 55.5 Gy in 30 fractions to low-risk nodal areas. RESULTS In all, 36 patients (median age, 56 years) with International Union Against Cancer (UICC) Stage III (n = 5) and IV (n = 31) were included. Of the 36 patients, 17 had received CF (cisplatin and 5-fluorouracil (CF) and 19 had received docetaxel cisplatin and 5-fluorouracil (DCF). During concurrent chemoradiation, 11 of 36 patients (30.5%) experienced Grade III mucositis (CF, 47%; DCF, 15%; p < 0.04). Grade III pharyngeal-esophageal toxicity was observed in 5 of 19 patients (26.3%; CF, 0.0%; DCF, 26.3%; p = 0.02). Two patients died of complications (5.5%). After chemoradiation, the complete response rate was 63.8%. Two-year local control was 88.7%. Two-year progression free survival and overall survival were 74.5% and 60.9%, respectively. CONCLUSIONS In our experience, a moderately accelerated chemo-IMRT was feasible after induction chemotherapy. However, a noteworthy early death rate of 5.5% was observed. Intensive supportive care strategies should be defined to better manage radiation-induced toxic effects. Longer follow-up is required to determine the incidence of late radiation toxicities and tumor control rates.

3D-Conformal Versus Intensity-Modulated Postoperative Radiotherapy of Vaginal Vault: A Dosimetric Comparison

We evaluated a step-and-shoot IMRT plan in the postoperative irradiation of the vaginal vault compared with equispaced beam arrangements (3-5) 3D-radiotherapy (RT) optimized plans. Twelve patients were included in this analysis. Four plans for each patient were compared in terms of dose-volume histograms, homogeneity index (HI), and conformity index (CI): (1) 3 equispaced beam arrangement 3D-RT; (2) 4 equispaced beam arrangement 3D-RT; (3) 5 equispaced beam arrangement 3D-RT; (4) step-and-shoot IMRT technique. CI showed a good discrimination between the four plans. The mean scores of CI were 0.58 (range: 0.38-0.67) for the 3F-CRT plan, 0.58 (range: 0.41-0.66) for 4F-CRT, 0.62 (range: 0.43-0.68) for 5F-CRT and 0.69 (range: 0.58-0.78) for the IMRT plan. A significant improvement of the conformity was reached by the IMRT plan (p < 0.001 for all comparisons). As expected, the increment of 3D-CRT fields was associated with an improvement of target dose conformity and homogeneity; on the contrary, in the IMRT plans, a better conformity was associated to a worse target dose homogeneity. A significant reduction in terms of D(mean), V90%, V95%, V100% was recorded for rectal and bladder irradiation with the IMRT plan. Surprisingly, IMRT supplied a significant dose reduction also for rectum and bladder V30% and V50%. A significant dosimetric advantage of IMRT over 3D-RT in the adjuvant treatment of vaginal vault alone in terms of treatment conformity and rectum and bladder sparing is shown.

Concomitant boost dose escalation plus large-field preoperative chemoradiation in locally advanced carcinoma of the uterine cervix: Results of a phase I study (LARA-CC-1)

OBJECTIVE To determine the recommended preoperative dose of large-field chemoradiation along with concomitant boost dose escalation on the tumor in locally advanced cervical carcinoma (LACC). PATIENTS AND METHODS A radiation dose of 40Gy over four weeks, 2Gy per fraction, was delivered to the tumor and the lymphatic drainage (planning target volume, PTV2), which encompassed a volume larger than standard (upper field border: L3 vertebra), concurrently with chemotherapy (cisplatin and 5-fluorouracil). Radiation dose was escalated to the macroscopic tumor only (PTV1) with a concomitant boost strategy. Three dose levels were planned: levels 1 (no PTV1 boost), 2 (45/2.25Gy) and 3 (50/2.5Gy). Patients were treated in cohorts of six to twelve per group using a standard phase I study design. The recommended dose was exceeded if >2 of 6 patients in a cohort experienced dose-limiting toxicity (DLT). RESULTS 32 patients (median age: 50 years; FIGO stage IB2: 4, IIA: 3, IIB: 21, III-IVA: 4) were enrolled. Median follow-up was 18 months (3-49 months). The most common grade 3/4 toxicity was gastrointestinal (diarrhea). Since three DLTs (grade 3 diarrhea, n=2; grade 3 proctitis, n=1), were observed in 4 patients at level 3, the trial was closed and level 2 was judged as the recommended dose. CONCLUSION Based on the data from this phase I study, 45Gy/2.25Gy to macroscopic tumor and 40Gy/2Gy to lymphatic drainage may be considered the recommended doses.

Postoperative intensity modulated radiation therapy in high risk prostate cancer: a dosimetric comparison.

The aim of this study was to compare intensity-modulated radiation therapy (IMRT) with 3D conformal technique (3D-CRT), with respect to target coverage and irradiation of organs at risk for high dose postoperative radiotherapy (PORT) of the prostate fossa. 3D-CRT and IMRT treatment plans were compared with respect to dose to the rectum and bladder. The dosimetric comparison was carried out in 15 patients considering 2 different scenarios: (1) exclusive prostate fossa irradiation, and (2) pelvic node irradiation followed by a boost on the prostate fossa. In scenario (1), a 3D-CRT plan (box technique) and an IMRT plan were calculated and compared for each patient. In scenario (2), 3 treatment plans were calculated and compared for each patient: (a) 3D-CRT box technique for both pelvic (prophylactic nodal irradiation) and prostate fossa irradiation (3D-CRT only); (b) 3D-CRT box technique for pelvic irradiation followed by an IMRT boost to the prostatic fossa (hybrid 3D-CRT and IMRT); and (c) IMRT for both pelvic and prostate fossa irradiation (IMRT only). For exclusive prostate fossa irradiation, IMRT significantly reduced the dose to the rectum (lower Dmean, V50%, V75%, V90%, V100%, EUD, and NTCP) and the bladder (lower Dmean, V50%, V90%, EUD and NTCP). When prophylactic irradiation of the pelvis was also considered, plan C (IMRT only) performed better than plan B (hybrid 3D-CRT and IMRT) as respect to both rectum and bladder irradiation (reduction of Dmean, V50%, V75%, V90%, equivalent uniform dose [EUD], and normal tissue complication probability [NTCP]). Plan (b) (hybrid 3D-CRT and IMRT) performed better than plan (a) (3D-CRT only) with respect to dose to the rectum (lower Dmean, V75%, V90%, V100%, EUD, and NTCP) and the bladder (Dmean, EUD, and NTCP). Postoperative IMRT in prostate cancer significantly reduces rectum and bladder irradiation compared with 3D-CRT.

Integrated radiosurgical treatment of resectable pancreatic head carcinoma.

Thirty-six patients with pancreatic head carcinoma entered a protocol, but only 20 were suitable for resection and evaluation of long-term survival. They were nine males and 11 females, with a mean age of 64.3 years. Following surgical resection, 10 Gy was delivered to the tumor bed intraoperatively. Postoperative radiotherapy was performed 4-6 weeks after surgery: patients were treated with 50.4 Gy (1.8 Gy/day, 5 days/week) to the tumor and nodal bed. Since 1991, 10 patients have also received preoperative short-course radiotherapy (5 Gy) of the liver and pancreas. Postoperative morbidity was 25%; two postoperative deaths were observed in patients with locally advanced neoplasms, in whom a vascular resection was also performed. Only 14 patients started postoperative radiotherapy, which was interrupted in two cases. At present, 14 patients are dead and four are alive and disease free. The local recurrence rate was 11.1% and distant metastases were observed in 66.7% of cases. The median actuarial survival was 11.9 months, but it was 18.5 months in patients with disease-free resection margins. A significantly better survival was also observed in patients submitted to short-course preoperative radiotherapy. These preliminary results show that intraoperative and perioperative radiotherapy is feasible and may improve local control of disease. Unfortunately, these results are not matched by a significant improvement in survival due to the high incidence of intraabdominal metastases. Thus, new therapeutic modalities, including preoperative radiotherapy (with or without chemotherapy), should be tested.