Marco Lupattelli

Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: long-term analysis of 566 ypCR patients.

PURPOSE In the literature, a favorable prognosis was observed for complete pathologic response after preoperative therapy (ypCR) in patients with locally advanced rectal cancer. The aim of this study is to verify whether ypCR predicts a favorable outcome in a large series of patients. METHODS AND MATERIALS The Gastro-Intestinal Working Group of the Italian Association of Radiation Oncology collected clinical data for 566 patients with ypCR (ypT0N0) after neoadjuvant therapy. Eligibility criteria included locally advanced rectal cancer with no evidence of metastases at the time of diagnosis, evidence of ypCR after preoperative radiotherapy +/- chemotherapy (CT). RESULTS Median radiation dose was 50 Gy. A total of 527 patients (93%) received one of 12 different neoadjuvant CT schedules. Sphincter preservation, anteroposterior resection, and endoscopic surgery were performed in 73%, 22%, and 5% of patients, respectively. Adjuvant CT was administered to 22% of patients. Median follow-up was 46.4 months. Locoregional recurrence occurred in 7 patients (1.6%). Distant metastases occurred in 49 patients (8.9%). Overall, 5-year rates of disease-free survival, overall survival, and cancer-specific survival were 85%, 90%, and 94%, respectively. In multivariate analysis, only age and clinical stage statistically correlated with survival outcome. Adjuvant CT was still of borderline significance (worse for adjuvant CT). No relation was found between survival and neoadjuvant CT schedules. CONCLUSION A ypCR after neoadjuvant therapy identified a favorable group of patients, even in this large series of 566 patients collected in 61 centers. Locoregional recurrence occurred only in 1.6% patients.

Short-Course Versus Split-Course Radiotherapy in Metastatic Spinal Cord Compression: Results of a Phase III, Randomized, Multicenter Trial

PURPOSE Hypofractionated radiotherapy (RT) is often used in the treatment of metastatic spinal cord compression (MSCC). This randomized trial was planned to assess the clinical outcome and toxicity of two different hypofractionated RT regimens in MSCC. PATIENTS AND METHODS Three hundred patients with MSCC were randomly assigned to a short-course RT (8 Gy x 2 days) or to a split-course RT (5 Gy x 3; 3 Gy x 5). Only patients with a short life expectancy entered the protocol. Median follow-up was 33 months (range, 4 to 61 months). RESULTS A total of 276 (92%) patients were assessable; 142 (51%) treated with the short-course and 134 (49%) treated with the split-course RT regimen. There was no significant difference in response, duration of response, survival, or toxicity found between the two arms. When short- versus split-course regimens were compared, after RT 56% and 59% patients had back pain relief, 68% and 71% were able to walk, and 90% and 89% had good bladder function, respectively. Median survival was 4 months and median duration of improvement was 3.5 months for both arms. Toxicity was equally distributed between the two arms: grade 3 esophagitis or pharyngitis was registered in four patients (1.5%), grade 3 diarrhea occurred in four patients (1.5%), and grade 3 vomiting or nausea occurred in 10 patients (6%). Late toxicity was never recorded. CONCLUSION Both hypofractionated RT schedules adopted were effective and had acceptable toxicity. However, considering the advantages of the short-course regimen in terms of patient convenience and machine time, it could become the RT regimen of choice in the clinical practice for MSCC patients.

8 Gy single-dose radiotherapy is effective in metastatic spinal cord compression: Results of a phase III randomized multicentre Italian trial

BACKGROUND AND PURPOSE In a previous randomized trial we showed that the short-course radiotherapy (RT) regimen of 8 Gy x 2 was feasible in patients with metastatic spinal cord compression (MSCC) and short life expectancy. This phase III trial was planned to determine whether in the same category of patients 8 Gy single-dose is as effective as 8 Gy x 2. MATERIALS AND METHODS Three hundred and twenty-seven patients with MSCC and short life expectancy were randomly assigned to a short-course of 8 Gy x 2 or to 8 Gy single-dose RT. Median follow-up was 31 months (range, 4-58). RESULTS A total of 303 (93%) patients are assessable, 150 treated with the short-course and 153 with the single-dose RT. No difference in response was found between the two RT schedules adopted. Median duration of response was 5 and 4.5 months for short-course and single-dose RT (p=0.4), respectively. The median overall survival was 4 months for all cases. Light acute toxicity was registered in a minority of cases. Late toxicity was never recorded. CONCLUSIONS Both RT schedules adopted were effective. As already shown in several trials evaluating RT regimens in uncomplicated painful bone metastases, also MSCC patients may achieve palliation with minimal toxicity and inconvenience with a single-dose of 8 Gy.

Radiotherapy without steroids in selected metastatic spinal cord compression patients. A phase II trial.

A phase II trial was planned to investigate the feasibility of radiotherapy (RT) without steroids in 20 consecutive patients with metastatic spinal cord compression (MSCC), no neurologic deficits, or only radiculopathy, and no massive invasion of the spine at magnetic resonance imaging (MRI) or computed tomography (CT). Aiming at an early diagnosis, MRI or CT was prescribed for all cancer patients with back pain and osteolysis, even when there were no signs of neurologic spinal compression. All patients were given 30 Gy in 10 fractions over 2 weeks with no steroids. Back pain and motor capacity were the parameters adopted to verify response to RT. Sixteen of 20 patients (80%) were able to walk without support, and 14 (70%) had no radiculopathy. Seventeen of 20 cases (85%) achieved relief from back pain. Regarding motor function, all patients (100%) responded to RT because the 16 patients able to walk without support at diagnosis did not deteriorate and the other 4, who needed support, became ambulatory without motor impairment. Median survival time was 14 months. Eight of 20 (40%) treated patients are still alive (14 to 36 months after end of RT), fully ambulatory, and free from relapse in the treated spine. Acute side effects were documented in only 2 patients (10%) and were managed without steroids. The results of this study suggest that RT without steroids is a feasible regimen for MSCC patients with good motor function. Elimination of steroids from the standard treatment for MSCC avoids cortisone side effects above all in those patients with diabetes, hypertension, peptic ulcer, and other steroid-sensitive medical problems.

No benefit of adjuvant Fluorouracil Leucovorin chemotherapy after neoadjuvant chemoradiotherapy in locally advanced cancer of the rectum (LARC): Long term results of a randomized trial (I-CNR-RT).

BACKGROUND AND PURPOSE To evaluate the effect of adjuvant chemotherapy (ACT) in locally advanced rectal cancer (LARC) after neoadjuvant chemoradiation (NACT-RT). The study was funded by the Italian National Research Council (CNR). METHODS From September 1992 to January 2001, 655 patients with LARC (clinically T3-4, any N) treated with NACT-RT and surgery, were randomized in two arms: follow-up (Arm A) or 6 cycles of ACT with 5 fluorouracil (5FU)-Folinic Acid (Arm B). NACT-RT consisted of 45Gy/28/ff concurrent with 5FU (350mg/sqm) and Folinic Acid (20mg/sqm) on days 1-5 and 29-33; surgery was performed after 4-6weeks. Median follow up was 63·7months. Primary end point was overall survival (OS). RESULTS 634/655 patients were evaluable (Arm A 310, Arm B 324); 92·5% of Arm A and 91% of Arm B patients received the preoperative treatment as in the protocol; 294 patients of Arm A (94·8%) and 296 of Arm B (91·3%) underwent a radical resection; complete pathologic response and overall downstaging rates did not show any significant difference in the two arms. 83/297 (28%) patients in Arm B, never started ACT. Five year OS and DFS did not show any significant difference in the two treatment arms. Distant metastases occurred in 62 patients (21%) in Arm A and in 58 (19·6%) in Arm B. CONCLUSIONS In patients with LARC treated with NACT-RT, the addition of ACT did not improve 5year OS and DFS and had no impact on the distant metastasis rate.

Short-course radiotherapy (8 Gy × 2) in metastatic spinal cord compression: An effective and feasible treatment

PURPOSE To evaluate the clinical outcome and toxicity of a short-course regimen of radiotherapy (RT) in selected metastatic spinal cord compression (MSCC) patients. METHODS AND MATERIALS Between 1993 and 1995, 53 consecutive patients with MSCC from low radio-responsive primary tumors (non small cell lung, kidney, head and neck and gastrointestinal carcinomas, melanoma and sarcomas), or more radio-responsive ones (breast and prostate carcinomas, myeloma and lymphomas) with paresis, plegia, low performance status (PS ECOG > or = 2), and/or short life expectation, underwent short-course RT; a single fraction of 8 Gy repeated after 1 week in responders or stable patients, for a total dose of 16 Gy. Of 49 (92%) evaluable cases, 4 (8%) underwent surgery plus RT and the other 45 RT alone. Medium doses of parenteral dexamethasone (8 mg x 2/d) were given in all cases and precautional anti-emetics to those treated with fields covering the upper abdomen (20 of 49 cases). Median follow up was 25 months (range, 6-34). Response was assessed according to back pain, and motor and bladder capacity before and after RT. RESULTS Pain relief was achieved in 67% of patients and motor function response rate reached 63%. Early diagnosis and therapy were very important in predicting response to RT; all but two (91%) pretreatment walking patients and all but one (98%) with good bladder function preserved these capacities. On the contrary, when diagnosis was late, only 38% of nonambulatory patients and 44% of those with bladder retention improved. Median survival was 5 months, with a 30% probability of survival for 1 year. Length of survival was significantly longer for patients able to walk before and/or after RT. Good agreement between survival and duration of response was found with no evidence of relapse in the irradiated spine. Sickness appeared only in a few cases. Slight esophagitis was more frequent: dysphagia for solid foods in one-third of patients irradiated on the thoracic spine. Late toxicity was never recorded. CONCLUSION The short-course RT adopted gave a clinical outcome comparable with that resulting from more protracted regimens with only slight side effects. The use of a few large treatment fractions could be explored considering the associated advantages for patients and radiotherapy centers often overloaded by long patient waiting lists.

Comparison of two Different Radiotherapy Schedules for Spinal Cord Compression in Prostate Cancer

Aims and background To assess the clinical outcome and toxicity of two different radiotherapy (RT) schedules for the management of metastatic spinal cord compression from prostate cancer, we performed a prospective analysis of 44 patients with the complication. Methods Two different RT schedules were adopted, a split-course regimen of 5 Gy x 3, 4 days rest, and then 3 Gy x 5, and a short-course regimen of 8 Gy, 7 days rest, and then 8 Gy. The split-course RT was adopted for all prostate cancer patients referred to our center between 1986 and 1992. Starting in 1993, the short-course RT was added for patients with a poor prognosis (i.e., paresis or paraplegia, low performance status, and/or short life expectation), whereas others still underwent the split-course regimen. So, 27 (61%) patients were treated with the split-course and the other 17 (39%) with the short-course regimen. Medium follow-up was 48 months (range, 6 to 123). Results Back pain total response rate was 82%. Effectiveness of RT on motor and bladder capacity was conditioned by pretreatment status of patients. All 20 (100%) walking cases maintained the function, whereas 11 of 24 (46%) with motor impairment regained the ability. The difference in response rate was statistically significant (P<0.001). All 36 (100%) patients, able to void at presentation preserved the capacity, whereas 3 of 8 (38%) with sphincter dysfunction no longer needed an indwelling catheter. Posttreatment neurologic status was the only factor found to affect survival. Median survival, 9 months for the whole group, was 10 and 2 months for posttreatment walking and nonwalking patients, respectively (10 vs 2 months, P<0.001). Neither presence of other metastases nor RT regimen used (split vs short-course) conditioned response rate, duration of response or survival. Acute or late, severe toxicity was never recorded. No patient complained of spinal cord morbidity. Conclusions Both split-course and short-course RT schedules were effective and without complications. Early diagnosis was the most important prognostic factor, but there was also recovery of function in about half of the patients unable to walk, and about one-third of patients with bladder dysfunction before treatment. Since length of the course of therapy is a factor with an important impact on the patients quality of life, the short-course RT regimen adopted in the trial merits further investigation.

Patterns of care and survival in a retrospective analysis of 1059 patients with glioblastoma multiforme treated between 2002 and 2007: a multicenter study by the Central Nervous System Study Group of Airo (italian Association of Radiation Oncology).

OBJECTIVETo investigate the pattern of care and outcomes for newly diagnosed glioblastoma in Italy and compare our results with the previous Italian Patterns of Care study to determine whether significant changes occurred in clinical practice during the past 10 years. METHODSClinical, pathological, therapeutic, and survival data regarding 1059 patients treated in 18 radiotherapy centers between 2002 and 2007 were collected and retrospectively reviewed. RESULTSMost patients underwent both computed tomography and magnetic resonance imaging either preoperatively (62.7%) or postoperatively (35.5%). Only 123 patients (11.6%) underwent a biopsy. Radiochemotherapy with temozolomide was the most frequent adjuvant treatment (70.7%). Most patients (88.2%) received 3-dimensional conformal radiotherapy. Median survival was 9.5 months. Two- and 5-year survival rates were 24.8% and 3.9%, respectively. Multivariate analysis showed the statistical significance of age, postoperative Karnofsky Performance Status scale score, surgical extent, use of 3-dimensional conformal radiotherapy, and use of chemotherapy. Use of a more aggressive approach was associated with longer survival in elderly patients. Comparing our results with those of the subgroup of patients included in our previous study who were treated between 1997 and 2001, relevant differences were found: more frequent use of magnetic resonance imaging, surgical removal more common than biopsy, and widespread use of 3-dimensional conformal radiotherapy + temozolomide. Furthermore, a significant improvement in terms of survival was noted (P < .001). CONCLUSIONChanges in the care of glioblastoma over the past few years are documented. Prognosis of glioblastoma patients has slightly but significantly improved with a small but noteworthy number of relatively long-term survivors.

Infusional 5-fluorouracil and ZD1839 (Gefitinib-Iressa) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: a phase I and II Trial (1839IL/0092)

PURPOSE To report the final data of a Phase I and II study (1839IL/0092) on the combination of an anti-epidermal growth factor receptor drug (gefitinib), infusional 5-fluorouracil, and preoperative radiotherapy in locally advanced, resectable rectal cancer. METHODS AND MATERIALS Patients received 45 Gy in the posterior pelvis plus a boost of 5.4 Gy on the tumor and corresponding mesorectum. Infusional 5-fluorouracil (5-FU) and gefitinib (250 and 500 mg/day) were delivered during all radiotherapy course. An IORT boost of 10 Gy was allowed. The main endpoints of the study were to establish dose-limiting toxicity (DLT) and to evaluate the rate of pathologic response according to the tumor regression grade (TRG) Mandard score. RESULTS A total of 41 patients were enrolled. The DLT was not reached in the 6 patients enrolled in the dose-escalation part of the study. Of the 33 patients in the Phase II, TRG 1 was recorded in 10 patients (30.3%) and TRG 2 in 7 patients (21.2 %); overall 17 of 33 patients (51.5%) had a favorable endpoint. Overall, Grade 3+ toxicity was recorded in 16 patients (41%); these included Grade 3+ gastrointestinal toxicity in 8 patients (20.5%), Grade 3+ skin toxicity in 6 (15.3%), and Grade 3+ genitourinary toxicity in 4 (10.2%). A dose reduction of gefitinib was necessary in 24 patients (61.5%). CONCLUSIONS Gefitinib can be associated with 5-FU-based preoperative chemoradiation at the dose of 500 mg without any life-threatening toxicity and with a high pCR (30.3%). The relevant rate of Grade 3 gastrointestinal toxicity suggests that 250 mg would be more tolerable dose in a neaoadjuvant approach with radiotherapy and infusional 5-FU.

Radiation-induced myelopathy in long-term surviving metastatic spinal cord compression patients after hypofractionated radiotherapy: a clinical and magnetic resonance imaging analysis

BACKGROUND AND PURPOSE Hypofractionated radiotherapy is often administered in metastatic spinal cord compression (MSCC), but no studies have been published on the incidence of radiation-induced myelopathy (RIM) in long-term surviving patients. Our report addresses this topic. PATIENTS AND METHODS Of 465 consecutive MSCC patients submitted to radiotherapy between 1988 and 1997, 13 live patients (seven females, six males, median age 69 years, median follow-up 69 months) surviving for 2 years or more were retrospectively reviewed to evaluate RIM. All patients underwent radiotherapy. Eight patients underwent a short-course regimen of 8 Gy, with 7 days rest, and then another 8 Gy. Five patients underwent a split-course regimen of 5 Gy x 3, 4 days rest, and then 3 Gy x 5. Only one patient also underwent laminectomy. Full neurological examination and magnetic resonance imaging (MRI) were performed. RESULTS Of 12 patients submitted to radiotherapy alone, 11 were ambulant (eight without support and three with support) with good bladder function. In nine of these 11 patients, MRI was negative; in one case MRI evidenced an in-field relapse 30 months after the end of radiotherapy, and in the other, two new MSCC foci outside the irradiated spine. In the remaining patient RIM was suspected at 18 months after radiotherapy when the patient became paraplegic and cystoplegic, and magnetic resonance images evidenced an ischemic injury in the irradiated area. The only patient treated with surgery plus postoperative radiotherapy worsened and remained paraparetic. Magnetic resonance images showed cord atrophy at the surgical level, explained as an ischemic necrosis due to surgery injury. CONCLUSIONS On the grounds of our data regarding RIM in long-term surviving MSCC patients, we believe that a hypofractionated radiotherapy regimen can be used for the majority of patients. For a minority of patients, more protracted radiation regimens could be considered.