Thymidine phosphorylase to dihydropyrimidine dehydrogenase ratio as a predictive factor of response to preoperative chemoradiation with capecitabine in patients with advanced rectal cancer.

PURPOSE: To identify if thymidine phosphorylase (TP), dihydropyrimidine dehydrogenase (DPD), and ratio TP/DPD levels in tumor tissues are potential predictive factors for response to combined preoperative chemoradiation with capecitabine, in patients with locally advanced rectal cancer (LARC). METHODS AND PATIENTS: Between 2004 and 2006, 28 patients with LARC (cT2-T4, N0-N2) were treated with neoadjuvant chemoradiation. Total radiation dose was 50.4 Gy and daily dose was 1.8 Gy in 5.5 weeks. Capecitabine was administrated 1,650 mg/m(2)/day, 7 days/week. Preoperative staging was based on combined computer tomography and endorectal ultrasound. Tissue samples, both neoplastic and normal ones, were endoscopically taken before treatment for TP and DPD measurement with ELISA. Levels of total proteins were calculated by the Bradford method. RESULTS: Median TP, DPD, ratio TP/DPD levels in the primary tumors were 32.85 U/mg, 18.73 U/mg, and 1.64 respectively. Median ratio TP/DPD of patients with proven pathological "response" (downstaging of the disease) was higher than the "no response" group, 4.40 and 1.42, respectively (P = 0.0001). Levels of TP and DPD in tumor tissue did not reveal any statistically important difference between the two groups. CONCLUSIONS: TP/DPD ratio is a possible predictive factor for tumor response after concomitant preoperative chemoradiation with capecitabine in LARC.

Dosimetry in translation total body irradiation technique: a computer treatment planning approach and an experimental study concerning lung sparing.

PURPOSE: To describe and evaluate a method that uses a 3-dimensional (3D) treatment planning system (TPS) to determine the relative dose to the lung, and to study the beam filtration required for lung sparing in translation total body irradiation (TBI). Special dosimetric problems related to moving couch were also considered. MATERIALS AND METHODS: The irradiation technique employed in our hospital is that of patient translation. The patient is positioned on a moving couch passing under a stationary Co-60 beam so that his/her entire body is irradiated. Measurements of basic data at source-skin distance (SSD)=150 cm were used to implement the Co-60 TBI unit to TPS (THERAPLAN plus), which was then used in dose computations. Two stationary, opposed anterior-posterior (40 x 40 cm) fields were employed to irradiate the Alderson phantom. The midline dose to either lung was computed and correction factors (CFs) were obtained that depend on the anatomy and densities of the tissues involved. These factors give the midline lung dose increase relative to the midline dose at the level of the mediastinum. Once the required lung dose was decided, the computed CF was used to estimate the filtration required from the measured broad beam attenuation data. The shielded lung dose distribution could be obtained from the TPS using a transmission corresponding to narrow beam geometry. To verify the TPS computations, measurements using a dosimeter and a diode system were carried out, employing solid water phantoms and the Alderson phantom. RESULTS: For the TPS employed, the computed midline CFs were lower than those measured in simple geometry phantoms for lung densities of 0.2-0.35 g/cm(3), by no more than 2%. For the Alderson phantom studied (lung density of 0.32 g/cm(3)), the computed CF was 1.11, which was 2% higher than the measured value. CONCLUSION: The advantages of a 3D TPS (dose distribution inside the lung, lung dose volume histograms [DVH], accurate attenuator shape from patient's anatomy etc.) allowed to study the lung dose in the Alderson phantom and to estimate the beam filtration required for lung sparing in TBI. The accuracy in lung dose computations, excluding the soft-tissue/lung interface was < or = 5%, which is within the clinical dose requirements. This procedure has been applied to a number of patients prior to their irradiation. Computations and in vivo measurements were in good agreement.

Intraoperative electron beam radiotherapy followed by moderate doses of external beam radiotherapy in the treatment of resected soft tissue sarcomas of the extremities.

PURPOSE: Soft tissue sarcomas (STS) have a high incidence of local recurrence. In an effort to improve the local control rate and the survival in patients with STS, treatment strategies employing intraoperative electron beam radiotherapy (IOERT) in combination with external beam radiotherapy (EBRT) and extensive surgical resection have been explored. This study assesses the rate of overall survival (OS), local control and toxicity of this multimodal approach for primary and recurrent STS of the extremities. PATIENTS AND METHODS: From 1999 to 2004, 36 patients were treated at Agios Savvas Cancer Hospital for primary or recurrent extremity STS with IOERT as a component of their treatment. All patients underwent surgical resection, IOERT, and most of them received postoperative EBRT with a median dose of 45 Gy. Chemotherapy was given to patients with high grade tumors. Thirteen patients were treated for primary disease and 23 for isolated local recurrence.The locations of the tumors were as follows: upper limbs n=19, lower limbs n=17. Tumor size was >5 cm in 16 (44%) patients and high-grade histology (II-III) was present in 24 (67%) patients. Six (17%) patients had positive surgical margins. RESULTS: With a median follow up of 24 months (range 6-48) OS was 72% (84.5% for patients with low grade lesions compared to 65% for high grade lesions, p=0.127, and 90% for tumors <5 cm compared to 50% for tumors >5 cm, p=0.0136). Overall local tumor control rate was 89% (92% in primary disease group versus 87% in isolated local recurrence group, p=0.136, and 93% for patients with negative surgical margins versus 67% for those with positive margins, p=0.0013). Distant metastases occurred in 10 patients (1 of 13 (8%) with primary disease, and 9 of 23 (39%) with isolated local recurrence). All distant metastases were to the lungs. Twelve (33%) patients developed moderate neurotoxicity. CONCLUSION: In selected patients, IOERT results in excellent local control and OS with acceptable toxicity.

Clinical and experimental evidence of Bcl-2 involvement in the response to photodynamic therapy.

PURPOSE: The role of apoptosis related proteins in the response of human malignancies to photodynamic therapy (PDT) is under investigation. The aim of the study was to examine the role of p53 and of bcl-2 protein expression in the response to PDT. MATERIALS AND METHODS: Paraffin-embedded material from 37 patients with early esophageal cancer treated with PDT (argon dye laser after intravenous injection of hematoporphyrine derivative) was studied immunohistochemically for p53 protein nuclear accumulation and bcl-2 cytoplasmic expression. Patients with residual disease after two rounds of PDT received definitive radiotherapy. In a subsequent in vitro study, W138 human lung fibroblasts and W138-SV-40 virus transformed were assessed for their sensitivity to PDT. The constitutive bcl-2 overexpression of the transformed cells vs. normal cells (assessed with RT-PCR) was 16-fold. RESULTS: Positive bcl-2 and p53 expression was noted in 10 out of 36 (27%) and 14 out of 36 (39%) patients, respectively. Seven out of 11 tumors (63%) with bcl-2 expression responded completely to PDT vs. 6 out of 26 (23%) of cases with no bcl-2 expression (p = 0.02). No association of p53, T-stage and of histology grade with response to PDT or PDT/RT was noted. The sensitivity to PDT of transformed human fibroblasts compared to normal ones was 4 times more at a fluence of 4.3 J/cm2 (4% vs. 1% cell kill) as well as at a fluence of 5.4 J/cm2 (8% vs. 2% cell kill). CONCLUSION: Bcl-2 protein expression is associated with favorable response to PDT and can be used as a predictor of cancer response to PDT. This finding can be explained by experimental studies showing that PDT induces selective degradation of the bcl-2 protein, leading to apoptosis by decreasing the bcl-2/bax ratio. Studies on PDT combination with agents targeting bcl-2 (i.e. taxanes) are on going to eventually assess a super-additive effect.

Outcome of patients receiving photodynamic therapy for early esophageal cancer.

PURPOSE: Photodynamic therapy (PDT) has shown remarkable activity in a variety of human cancers. In the present study, we report the effects of PDT on inoperable early-stage esophageal cancer. METHODS AND MATERIALS: Sixty-two patients were treated with an argon dye laser (630 nm wavelength, 300-800 mW of power, energy dose of 200-300 J/cm) after intravenous injection of 5 mg/kg of hematoporphyrin derivative. Eighteen patients (29.5%) had in situ carcinoma (Tis), 30 (48.5%) had T1-stage cancer, 7 (11%) had T2-stage cancer, and 7 (11%) had recurrent disease in the anastomotic area after previous surgery without evidence of invasion outside the lumen. Patients with residual disease after two rounds of PDT received definitive radiotherapy. Patients were evaluated for response to therapy and survival. The follow-up time ranged from 3 to 90 months (median, 32 months). RESULTS: The complete response (CR) rate was 37% (23 of 62) in patients who received PDT alone and 82% (51 of 62) in those who also received radiotherapy. The CR rate after PDT alone was statistically higher (p = 0.04) for patients who had Tis/T1 lesions (21 of 48; 44%) than for those with T2-stage disease (2 of 7; 28%) or recurrent tumors (0 of 7; 0%). Fifty-two percent of patients who had CR following PDT alone did not suffer local tumor recurrence. The median local progression-free survival times after PDT and additional radiotherapy (in cases with incomplete response) was 49 months for Tis- and T1-stage lesions, 30 months for those with T2-stage disease, and 14 months for patients with locally recurrent disease. Patients who completely responded to PDT had a median overall survival (OS) of 50 months, which was significantly longer (p < 0.003) than that of patients not responding to PDT. Toxicity was minimal; we recorded three cases of esophageal stenosis (7%) and one case of tracheo-esophageal fistula (2.5%) after combined PDT and radiotherapy. CONCLUSION: PDT is an effective regimen for early esophageal cancer, giving a CR rate of about 40%, long-term local control and favorable overall survival. Additional radiotherapy in cases of incomplete response to PDT is effective and potentially curative in another 45% of cases.

Liposomal doxorubicin and conventionally fractionated radiotherapy in the treatment of locally advanced non-small-cell lung cancer and head and neck cancer.

PURPOSE: Stealth (ALZA Corporation, Palo Alto, CA) liposomal drug formulation allows a higher intratumoral accumulation and a prolonged plasma half-life of the encapsulated drugs. In the study presented here, we evaluated the feasibility of Stealth liposomal doxorubicin (Caelyx; ALZA Corporation) administered concurrently with conventionally fractionated radiotherapy in the treatment of non-small-cell lung cancer (NSCLC) and head and neck cancer (HNC). PATIENTS AND METHODS: Fifteen patients with NSCLC and 15 with squamous-cell HNC were recruited in two phase I dose-escalation trials. The starting dose of Caelyx was 10 mg/m(2) every 2 weeks (for three cycles during radiotherapy) and was increased by 5 mg/m(2) dose increments for every three patients. RESULTS: The maximum tolerated dose of Caelyx was 20 mg/m(2) for HNC and 25 mg/m(2) in NSCLC patients. Oral/pharyngeal mucositis was the dose-limiting toxicity for HNC patients. "In field" radiation skin toxicity was slightly increased. Hematologic toxicity was minimal. Single photon emission computed tomographic evaluation of Caelyx distribution, using technetium-99m-diethylenetriamine pentaacetic acid labeling, revealed a high intratumoral accumulation of the drug. The tumor to thoracic vessel area count ratio in the NSCLC cases ranged from 0.6 to 1.6 (mean +/- SD, 1.01 +/- 0.29), whereas this ratio was higher (0.8 to 1.85; mean +/- SD, 1.35 +/- 0.39) in HNC cases (P =.049). The complete response rate was 21% in the NSCLC cases and 75% in the HNC cases. NSCLC cases with higher Caelyx tumor accumulation responded better to the regimen. The tumor microvessel density assessed with the anti-CD31 monoclonal antibody directly correlated with the degree of the Caelyx accumulation (P =.007; r =. 92). CONCLUSION: We conclude that combination of radiotherapy with Stealth liposomal doxorubicin is feasible. The potential role of such a regimen in the treatment of highly angiogenic tumors requires further investigation.

Concurrent conventionally factionated radiotherapy and weekly docetaxel in the treatment of stage IIIb non-small-cell lung carcinoma.

Docetaxel has shown remarkable radiosensitizing in vitro properties. In a previous phase I/II dose escalation study in non-small-cell lung cancer (NSCLC) we observed a high response rate after concomitant boost radiotherapy and weekly docetaxel. The maximum tolerated dose was 30 mg m(-2) week(-1). In the present phase II study we evaluated whether weekly docetaxel and conventionally fractionated radiotherapy could be better tolerated and equally effective in the treatment of locally advanced NSCLC. Thirty-five patients with T3, T4/N2, T3/M0-staged disease were recruited. Docetaxel (30 mg m(-2)) was given as a 30 min infusion once a week. Asthenia and radiation-induced oesophagitis were the main side-effects of the regimen enforcing 2-week treatment delay in 6/35 (17%) patients and minor delay (3-7 days) in another 11/35 (31%) patients. Neutrophil, platelet and haemoglobin toxicity was minimal, but pronounced lymphocytopenia was observed. Complete response (CR) of the chest disease was observed in 12/35 (34%) patients and partial response in 16/35 (46%). Although not statistically significant (P=0.19), a higher CR rate (8/18; 44%) was observed in patients who accomplished their therapy within the scheduled treatment time (44-47 days) as compared to patients that interrupted their treatment for several days due to treatment-related toxicity (CR 4/17; 23%). The overall survival and the local progression-free survival at 1 year was 48% and 60% respectively. We conclude that docetaxel combination with radiotherapy is a promising approach for the management of locally advanced NSCLC that results in high CR rate. Further trials with docetaxel-based radiochemotherapy should integrate accelerated radiotherapy together with cytoprotection.

Concurrent hypofractionated radiotherapy and 5-Fluorouracil for advanced sarcomas of the bone.

Purpose. 5-Fluorouracil (5-FU) has shown radiosensitizing properties in vitro. This paper reports the effects of radiotherapy and concomitant intravenous 5-FU radiosensitization in the treatment of advanced bone sarcomas.Subjects/methods. Four patients with large inoperable bone sarcomas (three chondrosarcomas and one fibrosarcoma) were treated with hypofractionated radiotherapy and concomitant 5-FU bolus injection (300 mg m(-2)) before each fraction of radiotherapy. A radiation fraction of 5 Gy was given twice a week to a normalized total dose (alpha/beta=4 Gy) of 75 Gy.Results. The regimen was well tolerated, the main toxicity being grade I/II diarrhoea in two cases with pelvic irradiation. Treatment interruption for 1 week was necessary in two cases with pelvic disease but not in two patients treated for sarcoma of the extremities. A complete symptomatic relief was obtained in all cases immediately after the third to the fifth fraction and the median duration was 10 months. Computed tomography scan documented a partial response in 2/4 cases.Discussion. Hypofractionated radiotherapy combined with potential lethal damage inhibitors for bone sarcomas requires further investigation.

Hypofractionated radiotherapy with 5-fluorouracil radiosensitization for locally "far advanced" breast cancer.

Seventeen patients who had locally far-advanced breast cancer were treated with hypofractionated radiotherapy (4-5 Gy/fraction, twice a week) and concomitant 5-fluorouracil (5-FU 300 mg/m2 intravenously, 1 hour before every radiotherapy fraction). Fourteen of the seventeen patients had disease that was not responding to chemotherapy. Early toxicity was low and none developed grade III/IV toxicity. Two of the seventeen patients showed moist skin desquamation and four of seventeen had grade II anemia. Of eight patients who survived longer than 12 months, symptomatic breast fibrosis was observed in one (12%), asymptomatic pericarditis in one (12%) and symptomatic radiation pneumonitis in one (12%). Plexopathy and arm edema grade II were observed in one patient and two patients, respectively. Quality of life substantially improved. Complete response was documented in five of the seventeen patients (29%), with pathologic confirmation in three. Seven of the seventeen (41%) patients were considered to be partial responders, four (23%) had a minimal response, and one (6%) progressed during treatment. Local progression-free survival (1-24 months) was achieved in 12 of 17 patients. Four of the seventeen (23%) patients are alive, with no evidence of disease (local or distant) 8 to 24 months after radiotherapy. Hypofractionated chemoradiotherapy with 5-FU is an effective, convenient, and well-tolerated regimen for far-advanced breast tumors.

Cytogenetic comparisons of synchronous carcinomas and polyps in patients with colorectal cancer.

Thirty tumorous lesions from seven patients with colorectal cancer were short-term cultured and cytogenetically analysed: 16 non-adenomatous polyps, six adenomas, seven carcinomas, including one in polyp, and one lymph node metastasis. Clonal chromosome aberrations were found in 20 samples in 100% of the carcinomas, in 100% of the adenomas and in 37.5% of the non-adenomatous polyps, i.e. all ten lesions with a normal karyotype were histologically diagnosed as hyperplastic polyps. Although adenomas and carcinomas shared several karyotypic features, two chromosome aberrations, der(8;17)(q10;q10) and -14, were found in carcinomas but not in adenomas, indicating that they might be specifically associated with carcinoma development in the large bowel mucosa. The karyotypic similarity seen between the malignant and benign tumours in the same patient, and also sometimes among non-malignant polyps in the same case, indicates that these microscopically distinct lesions may be part of a single neoplastic clonal expansion.

Correlation between karyotypic pattern and clincopathologic features in 125 breast cancer cases.

A correlation analysis was performed on 125 cytogenetically characterized breast cancer cases to assess the relationship between the tumor karyotype and clinicopathologic features. The carcinomas of young women had a higher modal chromosome number than those of older women. The number of chromosomal aberrations and modal chromosome number were also found to correlate with the histologic type, grade and mitotic activity of the tumor. Whereas all lobular carcinomas were karyotypically normal or near-diploid, more than 3 aberrations and sometimes near-triploid or near-tetraploid karyotypes were common findings in ductal carcinomas, especially in grade-III tumors and in tumors showing high mitotic activity in vivo. Karyotypes with cytogenetically unregulated clones and unbalanced structural chromosomal rearrangements were more frequent in infiltrating than in in situ carcinomas but, at least as far as the second of these 2 characteristics is concerned, especially in infiltrating carcinomas that also had an in situ component. The presence of cytogenetic polyclonality correlated with tumor grade. Although recurrent chromosome aberrations were significantly more common in ductal than in lobular carcinomas, none of these breast cancer-associated anomalies seemed to be specific for any particular clinicopathologic parameter. The associations between modal chromosome number and mitotic activity and between cytogenetic polyclonality and tumor grade were found to be statistically significant in multivariate models. No correlations was seen between the karyotypic findings and tumor size or the presence of axillary-lymph-node metastases.