Maurizio Amichetti

Radical radiation alone versus radical radiation plus microwave hyperthermia for N3 (TNM-UICC) neck nodes: a prospective randomized clinical trial☆

Between September 1985 and December 1986, 44 N3 (TNM-UICC) metastatic squamous cell cervical lymph-nodes were randomized to receive conventionally fractionated radical irradiation (RT) to a total dose of 64-70 Gy, or conventionally fractionated radical irradiation plus twice a week local microwave hyperthermia (Ht). The two major end points of this study were (a) local control rates evaluated at 3 months after the end of combined therapy and (b) incidence of acute local toxicity. Thirty-six nodes (82%) were evaluable as of December 1986, at which time there was a premature closure of this study due to ethical reasons. An interim analysis had revealed a statistically significant difference in complete response rates in favor of the combined arm (p = 0.0152). The complete response rates were 82.3% (14/17) for the combined treatment arm versus 36.8% (7/19) for the control irradiation arm, leading to an iso-dose thermal enhancement ratio (TER) value of 2.23. Both arms are comparable in average total RT dose delivered (RT: 67.05 Gy; RT + Ht: 67.85 Gy) and in average maximum node diameter (RT arm: 4.81 cm; RT + Ht: 4.88 cm). Acute local toxicities were similar in irradiated and heated plus irradiated neck regions; only one skin burn was observed. As possible treatment related death, one patient in the RT + Ht arm died 2 months after completion of therapy with a carotid rupture associated with extensive tumor necrosis. These results confirm previous non-randomized reports suggesting that hyperthermia in combination with full dose conventionally fractionated irradiation significantly enhances the chance of early local control of fixed N3 neck nodes without exhibiting an increase of acute local toxicity.

Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial.

PURPOSE To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. METHODS AND MATERIALS Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week). RESULTS No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. CONCLUSIONS The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.

Radiation therapy of carotid body tumors

Chemodectomas of carotid artery bifurcation are generally managed with surgery, irradiation being reserved for inoperable, bulky, and recurrent tumors. Probably due to this “pretreatment” selection of patients, chemodectomas are anedoctally considered radioresistant tumors, although this concept is not supported by the recent literature. From 1968 to 1987, 13 carotid body tumors in seven patients were treated with irradiation as sole treatment (10 lesions) or as postoperative modality (three lesions). Familial occurrence and bilateral presentation were observed in 3 of 7 and in 6 of 7 patients, respectively. Total dose of irradiation was of 46–60 Gy (median 50 Gy, mean 52.25 Gy) with dose per fraction of 1.8–2.5 Gy. Local control (subjective or objective) was obtained in all the patients. Clinical results following World Health Organization (WHO) criteria were: 3 of 13 complete response, 7 of 13 partial response and 3 of 13 no change. Follow-up range is 1–19 years. Acute side effects were minimal and mid- or long-term toxicity was absent.

Systematic evaluation of three different commercial software solutions for automatic segmentation for adaptive therapy in head-and-neck, prostate and pleural cancer

PurposeTo validate, in the context of adaptive radiotherapy, three commercial software solutions for atlas-based segmentation.Methods and materialsFifteen patients, five for each group, with cancer of the Head&Neck, pleura, and prostate were enrolled in the study. In addition to the treatment planning CT (pCT) images, one replanning CT (rCT) image set was acquired for each patient during the RT course. Three experienced physicians outlined on the pCT and rCT all the volumes of interest (VOIs). We used three software solutions (VelocityAI 2.6.2 (V), MIM 5.1.1 (M) by MIMVista and ABAS 2.0 (A) by CMS-Elekta) to generate the automatic contouring on the repeated CT. All the VOIs obtained with automatic contouring (AC) were successively corrected manually. We recorded the time needed for: 1) ex novo ROIs definition on rCT; 2) generation of AC by the three software solutions; 3) manual correction of AC.To compare the quality of the volumes obtained automatically by the software and manually corrected with those drawn from scratch on rCT, we used the following indexes: overlap coefficient (DICE), sensitivity, inclusiveness index, difference in volume, and displacement differences on three axes (x, y, z) from the isocenter.ResultsThe time saved by the three software solutions for all the sites, compared to the manual contouring from scratch, is statistically significant and similar for all the three software solutions. The time saved for each site are as follows: about an hour for Head&Neck, about 40 minutes for prostate, and about 20 minutes for mesothelioma. The best DICE similarity coefficient index was obtained with the manual correction for: A (contours for prostate), A and M (contours for H&N), and M (contours for mesothelioma).ConclusionsFrom a clinical point of view, the automated contouring workflow was shown to be significantly shorter than the manual contouring process, even though manual correction of the VOIs is always needed.

Cisplatin, hyperthermia, and radiation (trimodal therapy) in patients with locally advanced head and neck tumors: A phase I–II study

PURPOSE Hyperthermia is now being widely used to treat clinical malignancies especially combined with radiotherapy and more rarely with chemotherapy. The combination of heat, radiation, and chemotherapy (trimodality) can lead to potent interaction. The present Phase I-II study was conducted to evaluate the feasibility and acute toxicity of a combination of cisplatin, hyperthermia, and irradiation in the treatment of superficial cervical nodal metastases from head and neck cancer. METHODS AND MATERIALS Eighteen patients with measurable neck metastases from previously untreated squamous cell head and neck tumors were entered into the trial. Therapy consisted of a conventional irradiation (total dose 70 Gy, 2 Gy five times a week) combined with a weekly administration of 20 mg/m2 iv of cisplatin and a total of two sessions of local external microwave hyperthermia (desired temperature of 42.5 degrees C for 30 min). RESULTS Feasibility of the treatment was demonstrated. Acute local toxicity was mild; no thermal blisters or ulcerations were reported and only two patients experienced local pain during hyperthermia. Cutaneous toxicity appeared greater than in our previous studies with irradiation plus hyperthermia and irradiation plus cisplatin. Systemic toxicity was moderate with major toxic effects observed in three patients (World Health Organization (WHO) grade 3 anaemia). Even though it was not an aim of the study to evaluate the nodal response, we observed a complete response rate of 72.2% (95% confidence interval 51-93.4%), 16.6% of partial response and 11.1% of no change. CONCLUSION The study confirms the feasibility of the combination of cisplatin, heat, and radiation with an acceptable toxicity profile. The trimodal therapy deserves further evaluation as a way to enhance the efficacy of irradiation in the treatment of nodal metastases from head and neck tumors.

Intensity-modulated radiation therapy in newly diagnosed glioblastoma: a systematic review on clinical and technical issues.

BACKGROUND AND PURPOSE Intensity-modulated radiation therapy (IMRT) could represent a new tool to improve the therapeutic ratio in the treatment of glioblastoma. This systematic review investigates the evidence behind the application of IMRT to glioblastoma, assessing the potential benefits from both the clinical and dosimetrical perspective. MATERIALS AND METHODS Two independent researchers systematically identified all relevant articles available on PubMed and MEDLINE databases until December 2009. RESULTS Ultimately, seventeen studies were included in the analysis, for a total of 204 treated patients and 148 patient datasets used in planning studies. Most dosimetrical studies provided statistical analysis. Clinical series did not include any randomized controlled study, ultimately hindering a meta-analysis. From the dosimetrical point of view, conformal radiotherapy and IMRT provide similar results in terms of target coverage, while IMRT is better in terms of dose conformity, in reducing the maximum dose to the organs at risk and in healthy brain sparing. In clinical reports, a wide variability was recorded concerning dose per fraction, total dose, and chemotherapy administration. A comprehensive qualitative comparison with literature on similar non-IMRT clinical series showed that in most IMRT series excellent compliance and low rates of toxicity were recorded. Hypofractionated regimens in association with chemotherapy showed results that are even superior to the standard treatment. CONCLUSIONS According to the available data, the dosimetrical advantages of IMRT translate into the clinical capability of delivering higher dose levels in a shorter time. This approach in glioblastoma patients with good prognosis suggests the possibility of improving outcomes without an increase in toxicity.

Pain after Quadrantectomy and Radiotherapy for Early-Stage Breast Cancer: Incidence, Characteristics and Influence on Quality of Life

Purpose: Conservative breast surgery (CBS) is viewed as a surgical technique able to improve the psychophysical outcome of women who underwent surgery for breast cancer (BC). CBS has clearly improved the impact of local treatment on postoperative body image adjustment, but the effect on patients’ quality of life (QL) is similar to that observed after mastectomy. This insufficient adjustment may be related to the fact that sensorial alterations, mainly pain, may produce negative effects on patients’ QL. This retrospective study, based on self-completed questionnaires, reports the patients’ descriptions of pain and its relationships with QL adjustment after quadrantectomy and radiotherapy for BC. Patients and Methods: We mailed a questionnaire to a consecutive series of 481 patients treated with CBS and radiotherapy from March 1995 to March 1998. The questionnaire, listing 129 items, comprised: (1) a pain assessment module with the short form of the McGill Pain Questionnaire exploring the characteristics and the description of the pain; (2) a QL questionnaire including four subscales (physical well-being, psychological well-being, physical autonomy, and relationships). Results: Three hundred and forty-eight patients (72%) completed the questionnaire, but 24 were excluded from the analysis due to absence of axillary dissection. One hundred and forty-one patients reported pain as a consequence of treatment. It generally started within 3 months after the completion of therapy, was localized in the axillary region and was intermittent. The pain was mainly described as aching (59%), tender (51%) and cramping (43%). Compared to the patients who did not experience pain, those who suffered from pain had significantly worse scores in physical (p < 0.0001), psychological (p < 0.0001), autonomy (p < 0.05), and relational subscales (p < 0.0001). Conclusions: Our data support the hypothesis that pain is a frequent sequela of CBS and radiotherapy, and that such symptoms can cause postoperative psychosocial distress, thus limiting patient adaptation and reducing the beneficial effect of CBS on body image.

Concurrent adjuvant chemotherapy and immediate breast reconstruction with skin expanders after mastectomy for breast cancer

AbstractBackground. Immediate breast reconstruction (IBR) by means of skin expander is currently one of the most widely used methods of breast reconstruction in mastectomized patients. However, given that many breast cancer patients usually receive adjuvant chemotherapy, the adoption of IBR raises new questions concerning possible cumulative toxicity. The present study reports our experience in the use of concurrent adjuvant chemotherapy and immediate breast reconstruction with skin expander after mastectomy for breast cancer and the acute cumulative toxicity of the treatments. Methods. We evaluated a consecutive series of 52 breast cancer patients who have received IBR by skin expander after radical mastectomy and adjuvant chemotherapy concurrently during skin expansion between 1995 and 1998 (IBR/CT group). We identified two series of control patients treated during the same period: 51 consecutive patients undergoing radical mastectomy and IBR without adjuvant chemotherapy (IBR group) and 63 consecutive patients undergoing radical mastectomy and adjuvant chemotherapy without IBR (CT group). For each patient, we evaluated the incidence of surgical complications and chemotherapys side effects and dose intensity. Results. The interval between surgery and the start of expander inflation was similar in IBR/CT (range 0–19, median 5 days) and IBR groups (range 0–40, median 5 days) and the timing of inflation was not influenced by chemotherapy. The overall incidence of surgical complications in patients undergoing IBR was low: seroma in eight cases, infection in one, skin necrosis in one, expander rupture in two and erythema in three. There were no statistically significant differences in the distribution of complications between the IBR/CT and IBR groups. The dose intensity of chemotherapy was similar between IBR/CT and CT groups, with a median dose intensity of 96% and 95% of the projected dose, respectively. The only statistically significant difference in terms of chemotherapy side effects (p=0.03) was that stomatitis was more frequent and intense in the CT than in the IBR/CT group. Conclusions. Concurrent treatment with IBR and adjuvant chemotherapy appears feasible and safe, it does not increase acute surgical complications or chemotherapy side effects, and does not require any changes in dose intensity or the timing of inflation.

Long–Term Cosmetic Outcome and Toxicity in Patients Treated with Quadrantectomy and Radiation Therapy for Early-Stage Breast Cancer

Breast conservation treatment followed, if useful, by adjuvant therapy is the treatment of choice in early breast cancer. Late cosmetic outcome and toxicity are important in comparing conservative treatment to mastectomy. We reviewed the records of 225 patients treated from 1981 to 1988 with a median follow-up of 74 months (range 12-156 months). Cosmetic results, either reported by the physician (82.4%) or by the patients themselves (81.5%), were generally excellent or good, and tended to decline with time (69 and 75.5%, respectively). Toxicity was mild with arm edema (14.6%) being the most frequent symptom. No severe toxicities were observed. We conclude that overall cosmesis has been acceptable in this series and that a low rate of long-term toxicity can be expected with this conservative approach.

Proton therapy in lung cancer: Clinical outcomes and technical issues. A systematic review

BACKGROUND AND PURPOSE To determine whether, according to the currently available literature, proton therapy (PT) has a role in the treatment of non-small-cell lung cancer (NSCLC), to assess its safety and efficacy and to evaluate the main technical issues specifically related to this treatment technique. MATERIALS AND METHODS During March 2007, two independent researchers conducted a systematic review of the current data on the treatment of NSCLC with PT. RESULTS In total, 113 reports were retrieved, 17 of which were included in the analysis. There were no prospective trials (randomized or non-randomized). Nine uncontrolled single-arm studies were available from three PT centers, providing clinical outcomes for 214 patients in total. These reports were mainly related to stage I-II tumors, with results comparable to those obtained with surgery, without significant toxicity. In addition, two papers were found that compared photon and proton dose distributions, which showed a potential for dose escalation and/or a sparing of the organ at risk with PT. Finally, six studies analyzed dosimetric and technical issues related with PT, mainly underlining the difficulties in designing dose distributions that are representative of the dose actually delivered during treatment. CONCLUSIONS Although from a physical point of view PT is a good option for the treatment of NSCLC, limited data are available on its application in the clinical practice. Furthermore, the application of PT to lung cancer does present technical challenges. Because of the small number of institutions involved in the treatment of this disease, number of patients, and methodological weaknesses of the trials it is therefore not possible to draw definitive conclusions about the superiority of PT with respect to the photon techniques currently available for the treatment of NSCLC.