Gilbert D.A. Padula

Normalization of serum testosterone levels in patients treated with neoadjuvant hormonal therapy and three-dimensional conformal radiotherapy for prostate cancer

PURPOSE To determine the expected time to serum testosterone normalization after short-course neoadjuvant androgen deprivation therapy (NAAD) and three-dimensional conformal radiotherapy for patients with localized prostate cancer and to identify pretreatment predictors that correlated with the time to testosterone normalization. METHODS Between 1993 and 1999, 88 patients with localized prostate cancer, treated with NAAD and external beam radiotherapy, were prospectively monitored after treatment with sequential testosterone levels. NAAD was administered before and during the entire course of radiotherapy and discontinued at the end of treatment. The median duration of NAAD was 6 months. The actuarial rate of serum testosterone normalization from the end of treatment was evaluated, and the presence or absence of androgen deprivation-related symptoms was correlated with serum testosterone levels. Symptoms assessed included weight gain, loss of libido, breast tenderness, breast enlargement, hot flashes, and fatigue. RESULTS Serum testosterone levels returned to the normal range in 57 (65%) of the 88 patients and failed to normalize in 31 patients (35%). The median time to normalization was 18.3 months. The actuarial rate of normalization at 3, 6, 12, and 24 months was 10%, 26%, 38%, and 59%, respectively. In a multivariate analysis, a pretreatment testosterone level in the lower range of normal was the only variable that predicted for delayed testosterone normalization after NAAD (p = 0.00047). Among 45 patients with information concerning androgen deprivation-related symptoms recorded 1 year after cessation of NAAD, 24 (53%) had normalized testosterone levels, but in 21 patients (47%), the levels had not yet returned to normal. At 1 year, only 1 (4%) of 24 patients whose testosterone level had returned to normal experienced NAAD-related symptoms compared with 14 (67%) of 21 patients who did not have normal testosterone levels (p <0.001). CONCLUSION Testosterone levels often remain depressed for extended periods after cessation of short-course NAAD. Lower baseline testosterone levels predict for a delay in testosterone normalization, and the persistence of symptoms related to androgen deprivation correlates with low testosterone levels.

Intensity-modulated radiotherapy with simultaneous integrated boost to dominant intraprostatic lesion: preliminary report on toxicity.

ObjectivesTo evaluate the feasibility of intensity-modulated radiotherapy with simultaneous integrated boost to the dominant intraprostatic lesion for definitive treatment of prostate cancer. Materials and MethodsPatients were deemed eligible for the study if they had histologically proven stage cT2-T3 N0M0 prostate adenocarcinoma. In addition <20% risk of lymph nodal involvement according to Roach formula, was required for enrollment. Patients were treated with intensity-modulated radiotherapy with simultaneous integrated boost technique to the dominant intraprostatic lesion defined by magnetic resonance imaging. The prescribed dose to the prostate and seminal vesicles was 72 Gy (1.8 Gy per fraction). The dose delivered to the intraprostatic lesion received was 80 Gy (2 Gy per fraction). Acute gastrointestinal (GI) and genitourinary (GU) toxicity was evaluated weekly during treatment, and at 1 and 3 months thereafter. Late GI and GU toxicity was evaluated by Kaplan Meier method. ResultsForty patients were deemed evaluable. Acute and late GI and GU toxicity were evaluated in all patients. Two patients (5%) developed acute grade 3 GI toxicity and 1 patient (2.5%) developed acute grade 3 GU toxicity. No grade 4 acute GI or GU toxicity occurred. With a median follow-up of 19 months (interquartile range, 15 to 26 mo), the 2-year actuarial cumulative incidence of grade ≥2 rectal toxicity was 9.5%. The 2-year actuarial cumulative incidence of grade ≥2 urinary toxicity was 13.3%. ConclusionsTreatment related acute toxicity was low in our cohort. Prolonged observation with a larger series of patients is necessary to evaluate late toxicity and local control.

Short-Course Accelerated Radiotherapy in Palliative Treatment of Advanced Pelvic Malignancies: A Phase I Study

PURPOSE To define the maximum tolerated dose of a conformal short-course accelerated radiotherapy in patients with symptomatic advanced pelvic cancer. METHODS AND MATERIALS A phase I trial in 3 dose-escalation steps was designed: 14 Gy (3.5-Gy fractions), 16 Gy (4-Gy fractions), and 18 Gy (4.5-Gy fractions). The eligibility criteria included locally advanced and/or metastatic pelvic cancer and Eastern Cooperative Oncology Group performance status of ≤ 3. Treatment was delivered in 2 days with twice-daily fractionation and at least an 8-hour interval. Patients were treated in cohorts of 6-12 to define the maximum tolerated dose. The dose-limiting toxicity was defined as any acute toxicity of grade 3 or greater, using the Radiation Therapy Oncology Group scale. Pain was recorded using a visual analog scale. The effect on quality of life was evaluated according to Cancer Linear Analog Scale (CLAS). RESULTS Of the 27 enrolled patients, 11 were male and 16 were female, with a median age of 72 years (range 47-86). The primary tumor sites were gynecologic (48%), colorectal (33.5%), and genitourinary (18.5%). The most frequent baseline symptoms were bleeding (48%) and pain (33%). Only grade 1-2 acute toxicities were recorded. No patients experienced dose-limiting toxicity. With a median follow-up time of 6 months (range 3-28), no late toxicities were observed. The overall (complete plus partial) symptom remission was 88.9% (95% confidence interval 66.0%-97.8%). Five patients (41.7%) had complete pain relief, and six (50%) showed >30% visual analog scale reduction. The overall response rate for pain was 91.67% (95% confidence interval 52.4%-99.9%). CONCLUSIONS Conformal short course radiotherapy in twice-daily fractions for 2 consecutive days was well tolerated up to a total dose of 18 Gy. A phase II study is ongoing to confirm the efficacy on symptom control and quality of life indexes.

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).

Clinical target volume delineation including elective nodal irradiation in preoperative and definitive radiotherapy of pancreatic cancer

BackgroundRadiotherapy (RT) is widely used in the treatment of pancreatic cancer. Currently, recommendation has been given for the delineation of the clinical target volume (CTV) in adjuvant RT. Based on recently reviewed pathologic data, the aim of this study is to propose criteria for the CTV definition and delineation including elective nodal irradiation (ENI) in the preoperative and definitive treatment of pancreatic cancer.MethodsThe anatomical structures of interest, as well as the abdominal vasculature were identified on intravenous contrast-enhanced CT scans of two different patients with pancreatic cancer of the head and the body. To delineate the lymph node area, a margin of 10 mm was added to the arteries.ResultsWe proposed a set of guidelines for elective treatment of high-risk nodal areas and CTV delineation. Reference CT images were provided.ConclusionsThe proposed guidelines could be used for preoperative or definitive RT for carcinoma of the head and body of the pancreas. Further clinical investigations are needed to validate the defined CTVs.

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.

Prolonged chemoradiation in locally advanced carcinoma of the uterine cervix: final results of a phase ii study (ester-1).

Introduction:The aim of this phase II study was to evaluate response and toxicity of a prolonged chemoradiation regimen in patients with locally advanced cervical cancer. Patients and Methods:Three cycles of concomitant chemotherapy were used with cisplatin (20 mg/m2, 2-hour intravenous infusion, days 1–4) and 5-fluorouracil (1000 mg/m2, 24-hour continuous intravenous infusion, days 1–4) administered at weeks 1, 5, and 9 of radiotherapy. In combination, radiotherapy was delivered to a planning target volume (PTV) defined as the CTV (clinical target volume) plus 8 mm. The CTV was defined as follows: gross tumor volume, upper half of the vagina (if not involved) or the whole vagina (if clinically involved), uterus, obturator nodes, external iliac nodes, internal iliac nodes, and the presacral nodes (cranial to S2). The prescribed dose to the PTV was 50 Gy, 2 Gy/fraction (ICRU 62) delivered in 25 fractions with a 2-week break at 20Gy and 40 Gy (split-course technique). Early and late toxicity was assessed according to the RTOG and RTOG/EORTC toxicity scales. Perioperative toxicity was evaluated according to the Chassagne classification of surgical complications. Results:A total of 25 patients were included in this study. Median age was 52 years (range, 28–69). Clinical stage was: IB2-II: 19 patients (76%), III–IVA: 6 patients (24%). All patients completed the prescribed dose of chemoradiation and were evaluated 4 weeks after the end of treatment. Complete and partial clinical local response was observed in 4 and 19 patients, respectively (totaling 92% of clinical responses). About 32% of patients experienced grade 3 to 4 toxicity, in particular, grade 3 or 4 hematological toxicity was observed in 7 patients and 1 patient developed grade 3 genitourinary toxicity. No patients developed grade 3 gastrointestinal toxicity or skin toxicity. Of total, 22 patients (88%) underwent radical hysterectomy. Seven patients (28%) showed a complete response (CR) to treatment, and 7 patients (28%) showed microscopic residual disease (&mgr;PR), totaling 14 patients (56%) complete/partial microscopic responses. Perioperative morbidity was higher than reported in historical controls especially in terms of tissue fibrosis (64%) and perioperative urinary toxicity (14%). Actuarial 2-year local control, disease-free survival, and overall survival were 65.5%, 61.8%, and 80.8%, respectively. Conclusion:A prolonged treatment with more chemotherapy courses does not improve tumor response and increases the risk of perioperative complication. This treatment regimen, considering the low incidence of acute gastrointestinal toxicity, might be tested in the adjuvant setting.

Neoadjuvant Accelerated Concomitant Boost Radiotherapy and Multidrug Chemotherapy in Locally Advanced Rectal Cancer: A Dose-Escalation Study

ObjectivesTo determine the maximal and safely dose of preoperative radiotherapy and concurrently intensified chemotherapy regimen (raltitrexed plus oxaliplatin) in locally advanced rectal cancer patients. MethodsPatients with cT3-T4 and/or cN≥1 or locally recurrent rectal cancer were sequentially assigned to 4 treatment schedules of chemoradiation: standard radiotherapy (50.4 Gy/5.5 wk) plus raltitrexed (cohort A), accelerated radiotherapy (55 Gy/5 wk) plus raltitrexed (cohort B), standard radiotherapy plus raltitrexed and oxaliplatin (cohort C), accelerated radiotherapy plus raltitrexed and oxaliplatin (cohort D). Patients were treated in cohorts of 6 to 12 per group. The maximal tolerated dose was exceeded if more than one-third of patients in a given cohort experienced dose-limiting toxicity (DLT). DLT was defined as any grade ≥3 toxicity according to the Radiation Therapy Oncology Group criteria. ResultsForty-six consecutive patients were enrolled. In cohort A, 6 patients received the planned treatment with no DLT. In cohort B, 1 of 8 patients experienced a DLT. In cohort C, a DLT occurred in 2 of 6 patients and therefore, a cohort expansion was required. Three of 16 patients treated at this dose level experienced a DLT. In addition, cohort D was expanded and DLT was found in 4 of 16 patients. Therefore, the maximal tolerated dose was not exceeded at any treatment level. ConclusionsAn intensified regimen of chemoradiotherapy delivering raltitrexed and oxaliplatin concurrently with concomitant boost radiotherapy (55 Gy/5 wk) can be safely administered in patients with locally advanced rectal cancer. On the basis of these results, this intensified regimen could be tested in a phase II study.

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.

Short-Course Radiotherapy in Elderly Patients with Early Stage Non-Melanoma Skin Cancer: A Phase II Study

Aim: To evaluate outcome of an accelerated radiotherapy (RT) regimen in elderly patients with an early stage non-melanoma skin cancer (NMSC). Methods: Total RT dose was 30 Gy in 5 Gy fractions in six consecutive days. Results: Thirty-one patients were enrolled. Fourteen were aged ≥80 years. Acute skin and observed late toxicity were exclusively of grade 1. Thirty patients showed a complete response (median follow-up 30 months). Two-year actuarial local control was 93.2%. The cosmetic result was mostly judged as good or excellent. Conclusions: Short-course RT in elderly NMSC patients produces >90% local control of disease.