Daniela Smaniotto

Neoadjuvant Chemotherapy and Radical Surgery Versus Exclusive Radiotherapy in Locally Advanced Squamous Cell Cervical Cancer: Results From the Italian Multicenter Randomized Study

PURPOSE Neoadjuvant chemotherapy (NACT) and radical surgery (RS) have emerged as a possible alternative to conventional radiation therapy (RT) in locally advanced cervical carcinoma. In 1990, a phase III trial was undertaken to verify such a hypothesis in terms of survival and treatment-related morbidity. PATIENTS AND METHODS Patients with squamous cell, International Federation of Gynecology and Obstetrics stage IB2 to III cervical cancer were eligible for the study. They received cisplatin-based NACT followed by RS (type III to V radical hysterectomy plus systematic pelvic lymphadenectomy) (arm A) or external-beam RT (45 to 50 Gy) followed by brachyradiotherapy (20 to 30 Gy) (arm B). RESULTS Of 441 patients randomly assigned to NACT+RS or RT, eligibility was confirmed in 210 and 199 patients, respectively. Treatment was administered according to protocol in 76% of arm A patients and 72% of arm B patients. Adjuvant treatment was delivered in 48 operated patients (29%). There was no evidence for any significant excess of severe morbidity in one of the two arms. The 5-year overall survival (OS) and progression-free survival (PFS) rates were 58.9% and 55.4% for arm A and 44.5% and 41.3% for arm B (P =.007 and P =.02), respectively. Subgroup survival analysis shows OS and PFS rates of 64.7% and 59.7% (stage IB2-IIB, NACT+RS), 46.4% and 46.7% (stage IB2-IIB, RT) (P =.005 andP =.02), 41.6% and 41.9% (stage III, NCAT+RS), 36.7% and 36.4% (stage III, RT) (P =.36 and P =.29), respectively. Treatment had a significant impact on OS and PFS. CONCLUSION Although significant only for the stage IB2 to IIB group, a survival benefit seems to be associated with the NACT+RS compared with conventional RT.

Analysis of intraprostatic failures in patients treated with hormonal therapy and radiotherapy: implications for conformal therapy planning

PURPOSE Conformal therapy of prostate cancer is based on high-dose irradiation to the entire prostate gland. The aim of this study was to analyze the pattern of intraprostatic recurrence in patients undergoing external beam radiotherapy (EBRT) at a dose of 65-70 Gy to evaluate whether conventional radiotherapy doses are adequate to control microscopic disease outside the primary tumor and therefore whether high-dose irradiation can be exclusively focused on the macroscopic disease. METHODS AND MATERIALS The clinical and radiologic reports of 118 patients with prostate cancer undergoing EBRT (64.8-70.2 Gy) combined with hormonal therapy were evaluated. In all patients, before and after therapy, the size and site of the primary neoplasm within the prostate were assessed by clinical examination and imaging studies. RESULTS With a median follow-up of 45 months (range 14-119), the 5-year actuarial local control rate was 83.9%. Twelve patients had an intraprostatic recurrence, with the appearance of a new nodule (in 5 patients with a complete response after therapy) or increased nodular size compared with the minimal size (in the 7 other patients). In all patients, on the basis of a semiquantitative evaluation of the site of recurrence, this was shown to originate within the initial tumor volume. CONCLUSION The results of this analysis seem to confirm some histologic findings observed in patients undergoing prostatectomy for local recurrence after radiotherapy that suggest that local recurrence usually originates in the primary tumor rather than in focal prostatic intraepithelial neoplasia. This observation might justify the application of conformal therapy procedures aimed at identifying the gross tumor volume, in the phase of boost, exclusively with the primary tumor.

Long-term analysis of clinical outcome and complications in locally advanced cervical cancer patients administered concomitant chemoradiation followed by radical surgery

OBJECTIVE Preoperative chemoradiation (CT/RT) has been shown to achieve encouraging results in terms of clinical outcome in locally advanced cervical cancer (LACC). The study aims at analyzing the long-term results of this multimodal approach in a single institution series of 184 cases. METHODS Patients underwent whole pelvic irradiation combined with cisplatin and 5-fluorouracil. After evaluation of clinical response, patients were triaged to surgery. Surgical morbidity was classified according to Chassagne grading system. Univariate and multivariate analyses were used to assess the prognostic and predictive role of clinicopathological parameters. RESULTS Clinical response was observed in 96.1% of cases. A total of 174 cases were submitted to radical surgery: 124 patients (71.3%) showed complete/microscopic pathological response. In multivariate analysis, clinical response, stage of disease, and histotype predicted response to CT/RT. With a median follow-up of 58 months, recurrence and death of disease were observed in 42 and 40 patients, respectively. The 5-year DFS was 75.5%, while the 5-year OS was 77.4%. Patients with no residual disease showed a significant longer DFS than patients with microscopic (p value = 0.0128), and macroscopic (p value = 0.0001) residual tumor after treatment. In multivariate analysis, residual tumor and stage of disease were the two most relevant prognostic factors for DFS and OS. As far as long-term toxicity is concerned, 8 out of 22 complications were grade 3/4. CONCLUSION Preoperative CT/RT is worth further investigation in LACC patients, providing encouraging survival outcomes and a favourable long-term toxicity profile.

COMBINED MODALITY TREATMENT IN UNRESECTABLE EXTRAHEPATIC BILIARY CARCINOMA

PURPOSE Cancers of the extrahepatic biliary tract are rare. Surgical resection is considered the standard treatment, but is rarely feasible. Several reports of combined modality therapy, including external beam radiation, often combined with chemotherapy and intraluminal brachytherapy, have been published. The purpose of this study was to evaluate the effect of chemoradiation plus intraluminal brachytherapy on response, local control, survival, and symptom relief in patients with unresectable or residual extrahepatic biliary carcinoma. METHODS AND MATERIALS From February 1991 to December 1997, 20 patients (14 male, 6 female; mean age 61 +/- 12 years; median follow-up 71 months) with unresectable (16 patients) or residual (4 patients), nonmetastatic extrahepatic bile tumors (common bile duct, 8; gallbladder, 1; Klatskin, 11) received external beam radiation (39.6-50.4 Gy); in 19 patients, 5-fluorouracil (96-h continuous infusion, days 1-4 at 1,000 mg/m(2)/day) was also administered. Twelve patients received a boost by intraluminal brachytherapy using (192)Ir wires of 30-50 Gy, prescribed 1 cm from the source axis. RESULTS During external beam radiotherapy, 8 patients (40%) developed grade 1-2 gastrointestinal toxicity. Four patients treated with external-beam plus intraluminal brachytherapy had a clinical response (2 partial, 2 complete) after treatment. For the total patient group, the median survival and time to local progression was 21.2 and 33.1 months, respectively. Distant metastasis occurred in 10 (50%) patients. Two patients who received external beam radiation plus intraluminal brachytherapy developed late duodenal ulceration. Two patients with unresectable disease survived more than 5 years. CONCLUSION Our data suggest that chemoradiation plus intraluminal brachytherapy was relatively well-tolerated, and resulted in reasonable local control and median survival. Further follow-up and additional research is needed to determine the ultimate efficacy of this regimen. New chemoradiation combinations and/or new treatment strategies (neoadjuvant chemoradiation) may contribute, in the future, to improve these results.

Concomitant Radiochemotherapy plus Surgery in Locally Advanced Cervical Cancer: Update of Clinical Outcome and Cyclooxygenase-2 as Predictor of Treatment Susceptibility

Objective: We have updated our findings on the efficacy of concomitant radiochemotherapy plus radical surgery in a larger series of patients (n = 54) with locally advanced cervical cancer (LACC). We also investigated the role of cyclooxygenase-2 (COX-2) in this clinical setting. Methods: Radiotherapy was administered to the whole pelvic region (1.8 Gy/day, totaling 39.6 Gy) in combination with cisplatin (20 mg/m2) and 5-fluorouracil (1,000 mg/m2) (both on days 1–4 and 27–30). Radical surgery was performed 5–6 weeks after the end of treatment. Results: A clinical complete or partial response was observed in all 53 evaluable patients (75.5 and 24.5%, respectively). At pathological examination, 23 of 51 patients (45.1%) undergoing radical surgery showed complete response to treatment, 18 patients (35.3%) only had microscopic residual disease, 6 patients (11.7%) had a partial response and 4 (7.8%) had no change in their disease. When logistic regression was applied, the FIGO stage (χ2 = 5.28, p = 0.021) and tumor to stroma COX-2 ratio (χ2 = 4.72, p = 0.029) retained an independent role in the prediction of the pathologic response to treatment. The 3-year disease-free survival (DFS) was 75.2%, with local relapse-free survival of 86.2% and metastasis-free interval of 89.9% at 3 years. Cases with a high COX-2 ratio showed a shorter DFS than cases with a low COX-2 ratio (p = 0.016). A direct association was shown between COX-2 ratio values and risk of recurrence, as assessed by Cox analysis using COX-2 ratio values as a continuous covariate (χ2 = 3.94, p = 0.047). Conclusion: This study confirms the possibility of achieving a very high rate of pathological responses in LACC patients administered chemoradiation plus surgery (3-year DFS 75.2%). Moreover, COX-2 status may play a role in the prognostic characterization and prediction of tumor response.

Cyclooxygenase-2 (COX-2) expression in locally advanced cervical cancer patients undergoing chemoradiation plus surgery

PURPOSE To investigate whether cyclooxygenase-2 (COX-2) could be a marker of clinical outcome in cervical cancer patients undergoing concomitant chemoradiation plus surgery. METHODS AND MATERIALS The study included 33 locally advanced cervical cancer patients; all underwent neoadjuvant chemoradiation, and responsive patients underwent radical surgery. Immunohistochemistry was performed with rabbit antiserum against COX-2. RESULTS COX-2 integrated density values (IDVs) in the tumor component ranged from 1.4 to 72.3 (median 15.0); in stromal inflammatory cells, COX-2 IDVs ranged from 1.4 to 96.0 (median 16.0). A statistically significant inverse relation was found between the COX-2 IDVs of the tumor vs. the stromal inflammatory component (r = -0.52, p = 0.0017). When the ratio between COX-2 IDV in the tumor vs. the stromal compartment was <or=1, it was considered to indicate cervical tumor with COX-2 expression in the tumor component lower or equivalent to COX-2 expression in the stroma. According to the chosen cutoff value, 17 (51.5%) of 33 were scored as having a high (>1) tumor/stroma COX-2 IDV ratio. Patients with a high tumor/stroma COX-2 IDV ratio had a shorter disease-free survival than did those with a low tumor/stroma COX-2 IDV ratio (p = 0.030). Similarly, those with a high tumor/stroma COX-2 IDV ratio had a shorter overall survival (p = 0.033). CONCLUSION The assessment of COX-2 status in both the tumor and the stromal compartment could provide additional information in the prognostic characterization of cervical cancer patients administered concomitant chemoradiation plus surgery.

Neoadjuvant chemoradiation followed by radical hysterectomy in FIGO Stage IIIB cervical cancer: feasibility, complications, and clinical outcome.

Objective: To demonstrate the efficacy and feasibility of preoperative chemoradiation followed by radical surgery in a consecutive series of patients with stage IIIB cervical cancer. Methods: Between October 1997 and July 2007, 39 patients with International Federation of Gynecology and Obstetrics stage IIIB cervical cancer were consecutively staged and treated at the Catholic University of Rome and Campobasso and at the National Cancer Institute of Milan. Radical surgery was performed 5 to 6 weeks after the end of the cisplatinum-based neoadjuvant chemoradiation. Results: Clinical responses were observed in 35 patients (92.1%): 6 (15.8%) complete and 29 (76.3.8%) partial. Radical surgery was performed in 35 patients (89.7%). According to Chassagne classification, we observed 7 (20.0%) grade 3, 17 (48.6%) grade 2, and 28 (80%) grade 1 surgical complications. At pathological examination, 12 patients (34.3%) showed complete response, 7 patients (20.0%) had only a microscopic disease, 8 patients (22.8%) had a partial response, and the last 8 patients (22.8%) had no change in disease. We registered 11 (31.4%) operative and 4 (11.4%) early postoperative complications. Median follow-up was 33 months (range, 3-80 months). The percentages of 3-year disease-free survival and overall survival were 67.6% and 70.0%, respectively. Patients with complete response and microscopic disease showed better prognosis than patients with partial response and no change (3-year disease-free survival, 100% vs 31%; and 3-year overall survival, 100% vs 39%). Conclusions: Chemoradiation followed by radical hysterectomy could be administered in patients with stage IIIB cervical cancer with an acceptable rate of complications and with a survival outcome similar to that of chemoradiotherapy, allowing the assessment of pathological response with its implication on clinical outcomes.

Interstitial brachytherapy for pancreatic cancer: Report of seven cases treated with 125I and a review of the literature

Since 1975, seven groups of investigators have reported clinical results of interstitial brachytherapy (IBT) for pancreatic cancer. The reports are comprised of data from 254 patients, 21 of whom died in the postoperative period for an overall operative mortality rate of 8.7%. Operative mortality rate range from 0% to 32% in individual reports. Most patients have been treated with 125I, although 25 patients were treated with 198Au seeds. Most investigators report combining IBT with external beam radiation therapy (EBRT) +/- adjuvant chemotherapy. In general, IBT has been associated with considerable morbidity. Median patient survival time has not exceeded 15 months. This report describes an additional seven patients with locally unresectable pancreatic cancer, without distant metastases, treated primarily with 60 to 100 Gy matched peripheral dose (MPD) by 125I IBT. One patient died postoperatively of a pulmonary embolus. Four of the remaining six patients were also treated with modest doses (10.5 to 30 Gy) of EBRT late in the course of the disease for local tumor progression. One developed a pancreaticocutaneous fistula, and one developed exacerbation of pre-existing diabetes mellitus. The median patient survival time from the date of IBT was 7 months (range: 0 to 21 months). One patient is alive without clinical evidence of cancer 9 months after IBT.

Chemoradiation with concomitant boost followed by radical surgery in locally advanced cervical cancer: a dose-escalation study.

Objective:Aim of this study is to evaluate the feasibility of an accelerated fractionation radiotherapy by concomitant boost in locally advanced cervical cancer patients, to explore the maximum tolerated dose (MTD) of radiation through a dose-escalation scheme, and to verify if increasing the radiation dose would result in a higher rate of pathologic complete response. Methods:During the first and the last week of treatment, a combination of cisplatin (20 mg/mq/d, IV, days 1–4) and 5-fluorouracil (1 g/mq/d, continuous venous infusion, days 1–4) was administered. The dose escalation of external radiotherapy was delivered on the primary tumor, using the concomitant boost technique (CB, 90 cGy per fraction), delivering 3 different dose levels: (1) 1 weekly boost for a total dose of 4320 cGy; (2) 2 weekly boosts, total dose 4680 cGy; (3) 3 weekly boosts, total dose of 5040 cGy. Results:Eighteen patients were submitted to a radiochemotherapeutic schedule of 3960 cGy in 22 fractions on pelvic lymph nodal stations. The MTD of radiation was not reached, being the only toxicities registered neutropenia G3 (n = 4), thrombocytopenia G3 (n = 1), stomatitis G3 (n = 1), diarrhea G3 (n = 2) easily managed. Six weeks after the end of radiochemotherapy, 17 patients were submitted to radical surgery, and are therefore evaluable for pathologic response. Among them, 15 complete remissions (88.2%, including 3 microscopical partial response), 1 partial response (5.9%), and 1 progression (5.9%) have been observed. Conclusions:These results demonstrate, even if in a small study, that this regimen of concurrent chemoradiation followed by radical surgery is well tolerated.

Concurrent 5-fluorouracil, mitomycin C and radiation, with or without brachytherapy, in recurrent endometrial cancer: a scoring system to predict clinical response and outcome.

AIMS AND BACKGROUND This prospective, phase II study aimed to test the efficacy of concurrent 5-fluorouracil, mitomycin C and radiation, with or without brachytherapy, on the clinical outcome of a series of recurrent endometrial cancer patients and to determine the prognostic impact of a subset of factors. METHODS Thirty patients with locally recurrent, nonmetastatic endometrial cancer received external beam radiation (4-week split course: 23.4 + 23.4 Gy) plus two courses of concomitant chemotherapy (5-fluorouracil, 96-h continous infusion, days 1-4; 1 g/m2/day; mitomycin C, 10 mg/m2, bolus iv, day 1). Nineteen patients (63.3%) underwent endocavitary, low-dose brachytherapy boost (20-25 Gy); eight patients (26.7%) received external beam radiation boost (14-20 Gy). RESULTS Eleven complete responses (36.7%), 11 partial responses (36.7%), 6 disease stabilizations (20.0%) and 2 progressions (6.6%) were observed. After a median follow-up of 27 months (range, 1-108), overall actuarial 3-year survival, progression-free survival and local progression-free survival were 46.8%, 35.2% and 41.2%, respectively. Two patients (6.7%) experienced hematological grade 3 toxicity. Two patients (6.7%) had grade 3 intestinal toxicity. Severe late toxicity was infrequent, only 3 patients showing severe vaginal stenosis (10.0%). A clinical score of 0 to 1 was assigned to each patient on the basis of the absence (score = 0) or presence (score = 1) of any of the following prognostic factors: time between surgery and recurrence shorter than 12 months, pelvic wall site of recurrence, positive lymph nodes, hemoglobin < 11 g/dL. With this device, it was clear that patients with a low score had a significantly better outcome (clinical remission: 77.2% of patients with a score < 2 vs 25.0% of patients with a score > or = 2, P = 0.009), better local control of the disease (50.2% vs. 0 at 3 years, P = 0.014,) and better overall survival (65.8% vs 0 at 3 years, P = 0.003). CONCLUSIONS Our data suggest that this combined modality therapy was relatively well tolerated and resulted in reasonable local control and survival. The scoring system proved to be helpful in identifying patients with the best chance of benefiting from the treatment.