Role of diffusion-weighted imaging, apparent diffusion coefficient and correlation with hepatobiliary phase findings in the differentiation of hepatocellular carcinoma from dysplastic nodules in cirrhotic liver.

OBJECTIVES: To investigate the utility of diffusion-weighted imaging (DWI), apparent diffusion coefficient (ADC) and the correlation with hepatobiliary phase (delayed phase imaging, DPI) findings in the differentiation of cirrhotic hepatocellular nodules. METHODS: Forty-three patients with 53 pathology-proven nodules (29 hepatocellular carcinomas (HCCs), 13 high-grade (HGDNs) and 11 low-grade dysplastic nodules (LGDNs); mean size 2.17 cm, range 1-4 cm), who underwent liver MRI with DWI and DPI sequences, were retrospectively reviewed. Lesions were classified as hypointense, isointense, or hyperintense relative to the adjacent liver parenchyma. ADC of each nodule, of the surrounding parenchyma, and lesion-to-liver ratio were calculated. RESULTS: Hyperintensity versus iso/hypointensity on DWI, hypointensity versus iso/hyperintensity on DPI, and the mean lesion-to-liver ratio showed a statistically significant difference both between HCCs versus DNs and between "HCCs + HGDNs" versus LGDNs (p < 0.05); sensitivity, specificity, and accuracy for the diagnosis of "HCCs + HGDNs" were 96.8 %, 100 %, 97.4 % respectively when combining hyperintensity on DWI and hypointensity on DPI, and 90.9 %, 81.0 %, 83.6 % respectively when lesion-to-liver ratio was <0.95. CONCLUSIONS: Hyperintensity on DWI, especially in association with hypointensity on DPI, and low lesion-to-liver ratios should raise the suspicion of HCC, or at least of HGDN, thus helping the characterization of atypically enhancing lesions. KEY POINTS: • Usefulness of DWI and ADC is shown in differential diagnosis of cirrhotic nodules. • Correlation of DWI with DPI improves differential diagnosis of cirrhotic nodules. • Characterization of atypically enhancing lesions becomes more confident.

Molecularly targeted therapy and radiotherapy in the management of localized gastrointestinal stromal tumor (GIST) of the rectum: a case report.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. The main treatment for localized gastrointestinal stromal tumors is surgical resection. These tumors respond poorly to conventional cytotoxic chemotherapy agents and to radiotherapy. Imatinib mesylate, a small-molecule kinase inhibitor, has proved useful in the treatment of recurrent or metastatic GISTs and is now being tested in the adjuvant and neoadjuvant setting. The role of radiotherapy in the management of patients with GIST is currently restricted to symptomatic palliation. We present the case of a 54-year-old man affected by rectal GIST extending to the anal canal, with constipation, hematochezia, and anal pain. He received imatinib, 400 mg orally per day, for a week before and during radiation therapy. Irradiation was delivered to the gross tumor volume by 3D conformal therapy. The planned total dose was 50.4 Gy in fractions of 1.8 Gy daily. We observed a partial clinical response 3 weeks after the end of combination treatment. The patient then underwent a sphincter-saving surgical procedure. There was no perioperative morbidity and a complete pathological response was obtained. At the present time, the role of radiotherapy in the management of patients with GIST is restricted to symptomatic palliation. The introduction of molecularly targeted therapy combined with radiation therapy could improve the outcomes for patients diagnosed with GIST.

Novel prognostic groups in thymic epithelial tumors: assessment of risk and therapeutic strategy selection.

PURPOSE: To assess the role of multimodality treatment on patients with thymic epithelial tumors (TETs) (i.e., thymomas and thymic squamous cell carcinoma) and to define the prognostic classes according to the Masaoka and World Health Organization histologic classification systems. METHODS AND MATERIALS: Primary surgery was the mainstay of therapy. Extended thymectomy was performed in all cases. The cases were primarily staged according to the Masaoka system. Adjuvant radiotherapy was given to patients diagnosed with Masaoka Stage II, III, and IVA TET. Adjuvant chemotherapy was administered in selected cases. RESULTS: We reviewed the records of 120 patients with TETs, with a mean follow-up of 13.8 years. Of the 120 patients, 98 (81.6%) received adjuvant radiotherapy. Of these 98 patients, Grade 1-2 pulmonary or esophageal toxicity was acute in 12 (12.2%) and late in 8 (8.2%). The median overall survival was 21.6 years. Of the 120 patients, 106 were rediagnosed and reclassified according to the World Health Organization system, and the survival rate was correlated with it. Three different prognostic classes were defined: favorable, Masaoka Stage I and histologic grade A, AB, B1, B2 or Masaoka Stage II and histologic grade A, AB, B1; unfavorable, Stage IV disease or histologic grade C or Stage III and histologic grade B3; intermediate, all other combinations. The 10- and 20-year survival rate was 95% and 81% for the favorable group, 90% and 65% for the intermediate group, and 50% and 0% for the unfavorable group, respectively. Local recurrence, distant recurrence, and tumor-related deaths were also evaluated. CONCLUSION: The analysis of our experience singled out three novel prognostic classes and the assessment of risk identified treatment selection criteria.

Role of induction therapy in esophageal cancer.

Esophageal cancer ranks sixth among the causes of death from cancer worldwide. Patients undergoing surgery have a median survival ranging from 13 to 19 months; 2-year survival rates range from 35 to 42 percent, and 5-year survival rates from 15 to 24 percent. In particular, the 3 year survival (= SVV) is about 26%, with a median survival of 17 months. An interesting point is that about 20-25% of the patients has only locoregional involvement as pattern of failure. At least two randomized studies reported about the combined use of radiotherapy and chemotherapy as sensibilization. They assessed that patients treated with chemoradiation had a longer median survival compared to patients receiving radiation therapy alone, both in early and advanced stages. Moreover radiochemotherapy seems able of achieving high rates of downstaging and of increasing overall and disease-free survival.

Dose and volume as predictive factors of pulmonary toxicity.

Dose and volume and their correlation with the development of pulmonary toxicity are among the most widely studied and validated factors in radiotherapy. Most common treatment planning systems allow prompt assessment of Vdose and Mean Lung Dose (MLD). The former represents the percentage of normal lung parenchyma receiving a dose equal to or higher than the established threshold dose; the latter corresponds to the mean dose delivered to the normal lung parenchyma. Most important studies reported on the subject and threhold values recommended for Vdose and MLD are analyzed. The monitoring system of late toxicity used by the authors is presented.

Dose fractionation and biological optimization in breast cancer.

Standard radiotherapy in breast cancer is performed at the dose of 1.8-2 Gy daily 5 fractions a week for a total dose between 45 and 60 Gy. However research is addressed to different fractionations. For total time reduction, the interest was focused on conventional brachytherapy which radiobiologically represents "continuous" accelerated hyperfractionation, as well as on conventional external beam radiotherapy with accelerated hyperfractionation. A phase I study was conducted to define and validate a radiotherapy schedule with non conventional fractionation. Nine patients with metastatic breast cancer were enrolled in the study. None of them had undergone breast surgery or lymph node dissection. They were sequentially divided into three different, progressively increasing dose levels administered with double daily fractionation. Each schedule of accelerated fractionation (AF) included the administration of 1.8 Gy in two daily fractions, at least six hours apart for 10, 11 and 12 days and a total dose of 36, 39.6 and 43.2 Gy, respectively. Results of dose escalation, acute toxicity and mathematical calculation of radiobiological equivalence led to consider the dose of 36 Gy in 20 fractions during 10 days the most suitable for cost/benefit ratio within a non conventional fractionation.

Lymphatic drainage, CTV and molecular imaging in non-small cell lung cancer.

Prognosis for non-small cell lung cancer (NSCLC) patients who have locally advanced unresectable disease is poor for persistent thoracic disease and development of distant metastasis. In view of the poor rate of local control following conventional radiation therapy, there is a great need for methods to improve its efficacy. Three-dimensional conformal radiation therapy (3DCRT) is a high precision radiotherapy able to deliver higher doses with smaller doses to the surrounding normal tissues. However, the real problem is: "what do I want to treat?" This question is addressed based on the clinical and biological target volume definition. Selection of the CTV is therefore basically the clinical compromise between the most radical possible CTV and the critical normal tissue tolerance. The clinical target volume includes the GTV plus a margin to encompass subclinical or microscopic malignant disease immediately adjacent to it. Standard radiation therapy consists of a dose of 40 Gy to the entire mediastinum, supraclavicular fossa, and ipsilateral hilum, even if there is no evidence of disease in these areas. Despite the high risk of nodal spread in lung cancer, the benefit of additional elective nodal irradiation (ENI) is not proven while it seems to significantly increase the rate of radiation morbidity. Several studies have been published where ENI was systematically omitted. The main arguments for omitting ENI and the principal clinical experiences, are discussed.

Dose fractionation and biological optimization in lung cancer.

The treatment of choice of patients with locally advanced non-small cell lung cancer is radiotherapy combined or not with chemotherapy. Only 30% of lung cancer patients are operable for cure at diagnosis. Consequently the knowledge of the radiobiological basis and of clinical outcomes achieved with radiation therapy is of the utmost importance. Total dose, fractionation, concomitant chemotherapy are the main factors to be examined. In order to improve local control several attempts are reported in the literature. They concern: changes in fractionation and total dose; the use of radiosensitizers and radioprotectors; combined chemoradiation and molecular therapies.

Neoadjuvant concurrent chemotherapy and radiotherapy in non-small cell lung cancer.

Abstract. Radiotherapy was the standard treatment for patients with locally advanced non-small cell lung cancer until the mid 1990s. Chemotherapy was added in order to improve outcome, and during the last decade sequential, concurrent or mixed modalities have been extensively explored and discussed. Goals of neoadjuvant chemoradiation are resecability and downstaging. Recent published experiences evidenced that neoadjuvant chemoradiotherapy is feasible if delivered with low total dose and limited volume; pathological downstaging to stage 0-I could be a reasonable surrogate end-point for overall and disease free survival and for distant metastasis.

Adding ipsilateral V20 and V30 to conventional dosimetric constraints predicts radiation pneumonitis in stage IIIA-B NSCLC treated with combined-modality therapy.

PURPOSE: To determine lung dosimetric constraints that correlate with radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional radiation therapy and concurrent chemotherapy. METHODS AND MATERIALS: Between June 2002 and December 2006, 97 patients with locally advanced non-small-cell lung cancer were treated with concomitant radiochemotherapy. All patients underwent complete three-dimensional treatment planning (including dose-volume histograms), and patients were treated only if the percentage of total lung volume exceeding 20 Gy (V(20)) and 30 Gy (V(30)), and mean lung dose (MLD) had not exceeded the constraints of 31%, 18%, and 20 Gy, respectively. The total and ipsilateral lung dose-volume histogram parameters, planning target volume, and total dose delivered were analyzed and correlated with pneumonitis incidence. RESULTS: If dose constraints to the total lung were respected, the most statistically significant factors predicting pneumonitis were the percentage of ipsilateral lung volume exceeding 20 Gy (V(20)ipsi), percentage of ipsilateral lung volume exceeding 30 Gy (V(30)ipsi), and planning target volume. These parameters divided the patients into low- and high-risk groups: if V(20)ipsi was 52% or lower, the risk of pneumonitis was 9%, and if V(20)ipsi was greater than 52%, the risk of pneumonitis was 46%; if V(30)ipsi was 39% or lower, the risk of pneumonitis was 8%, and if V(30)ipsi was greater than 39%, the risk of pneumonitis was 38%. Actuarial curves of the development of pneumonitis of Grade 2 or higher stratified by V(20)ipsi and V(30)ipsi were created. CONCLUSIONS: The correlation between pneumonitis and dosimetric constraints has been validated. Adding V(20)ipsi and V(30)ipsi to the classical total lung constraints could reduce pulmonary toxicity in concurrent chemoradiation treatment. V(20)ipsi and V(30)ipsi are important if the V(20) to the total lung, V(30) to the total lung, and mean lung dose have not exceeded the constraints of 31%, 18%, and 20 Gy, respectively.

Beams arrangement in non-small cell lung cancer (NSCLC) according to PTV and dosimetric parameters predictive of pneumonitis.

The aim of this study is to propose and validate an original new class of solutions for three-dimensional conformal radiation therapy (3DCRT) treatment planning for non-small cell lung cancer (NSCLC) according to the different patterns of disease presentation (on the basis of tumor location and volume) and to explore beams arrangement (planar or no-planar solutions) to respect dose constraints to the lung parenchyma. Benchmarks matched to validate the new approach are interuser reproducibility and saving on planning time. Tumor location was explored and specific categories created according to the tumor volume and location. Therefore, by applying planar and no-planar 3D plans, we searched for an optimization of the beams arrangement for each category. Dose-volume histograms (DVHs) were analyzed and a plan comparison performed. Results were then validated (class solution planning confirmation) by applying the same strategy to another group of patients. This has been realized at two dose levels (50.4 and 59.4 Gy). Fifty-nine patients were enrolled in this dosimetric study. In the first 27 patients ("exploratory sample") three main planning target volume location categories were identified according to the pattern of the disease presentation: (1) centrally located; (2) peripheral T and mediastinal N (P+N); and (3) superior sulcus. Original class solutions were proposed for each location category. On the next 32 patients ("validation sample"), the treatment planning started directly with the recommended approach. Mean V(20 Gy) value was 18.8% (SD +/- 7.25); mean V(30 Gy):12% (SD +/- 4.05); and mean lung dose: 11.6 Gy (SD +/- 5.77). No differences between the two total dose level groups were observed. These results suggest a simple and reproducible tool for treatment planning in NSCLC, allowing interuser reproducibility and cutting down on planning time.

Multimodality treatment of stage III non-small cell lung cancer: analysis of a phase II trial using preoperative cisplatin and gemcitabine with concurrent radiotherapy.

INTRODUCTION: We report the results of a phase II trial exploring the efficacy and the feasibility of combination of gemcitabine and cisplatin concurrent with radiotherapy followed by surgery in patients with stage III non-small cell lung cancer. METHODS: Patients with histocytologically confirmed non-small cell lung cancer were treated with cisplatin 80 mg/sqm/wk of 1 and 4 or 20 mg/sqm/d of weeks 1 and 4 and weekly gemcitabine at 300 to 350 mg/m2 plus involved field radiotherapy. A 3D-conformal radiotherapy was delivered up to 50.4 Gy, with daily fractionation of 1.8 Gy. After clinical, radiologic, and pneumological reassessment, patients who reentered criteria for resectability were operated. RESULTS: The stage at diagnosis was IIIA-N2 in 29 patients and IIIB-T4N0-2 for vascular direct infiltration for the remaining 21. Fifteen patients (30%) experienced acute grade 3 to 4 hematological toxicity, whereas acute grade 3 esophageal toxicity was recorded in three patients (6%). One patient developed a grade 4 pulmonary toxicity (2%). Clinical response was 40 (80%) partial response, one (2%) stable disease, and nine (18%) progressive disease. Thirty-six patients (72%) underwent surgery. Final pathology showed a downstaging to stage 0 to I in 25 cases (50%). Median overall survival for all patients was 21.8 months, with a 3-year survival of 40.2%. CONCLUSIONS: The results of this phase II trial confirm the feasibility and the efficacy of concurrent chemoradiotherapy followed by surgery.