Bone Density as a Marker of Response to Radiotherapy in Bone Metastatic Lesions: A Review of the Published Data.

Metastases to the bone are presenting in a great percentage of patients with cancer, causing a variety of symptoms, affecting the quality of life and survival of patients. A multidisciplinary approach from different health providers is required for treatment, including radiation oncologists, medical oncologists and surgeons. The role of radiotherapy in the management of bone metastases has long been established through multiple randomized trials. The estimation of response to the therapy is subjective and is based on the palliation of the symptoms that the patients report. However, a quantification of the tumor burden and response to the treatment with the use of an objective method to measure those parameters is a clinical expectation in oncology. The change in bone density in affected areas (mainly lytic) after local radiotherapy, representing the cellular changes that have occurred, is a promising marker of response to treatment.

Bilateral metastases to extraocular muscles from lobular breast carcinoma.

BACKGROUND: Metastastic carcinoma to extraocular muscles is extremely rare, but even more so is the case of a bilateral one. CASE REPORT: A 50-year-old woman with a history of mastectomy for a T4N1M0 right breast carcinoma was referred to us with diplopia due to bilateral extraocular muscle metastases, 5 years post mastectomy. Multiple metastases to the whole body were also present. A combination of high-dose irradiation, hormonotherapy and chemotherapy were performed. RESULTS: Despite the multidisciplinary treatment approach, the diplopia persisted. A literature review revealed only 4 cases of bilateral metastases to extraocular muscles. The present case is the second attributed to lobular carcinoma and the only one treated with a high dose of radiotherapy combined with systemic therapy. CONCLUSION: In a cancer patient, any orbital change must be examined for the possibility of an extraocular metastasis. Conclusions affecting the optimal treatment policy of extraocular muscle metastases are difficult to determine, due to the small number of reported cases.

Cytoprotective efficacy of amifostine against radiation- induced rectal toxicity: objective and subjective grading scales for radiomucositis.

Curative radiation therapy of pelvic malignancies, frequently results in dose limiting toxicities such as serous, mucoid, or more rarely, bloody diarrhea. Several studies have evaluated the cytoprotective effects of amifostine in preventing rectal mucositis associated with radiation treatment. We searched Medline for published comparative studies that evaluated the use of amifostine to reduce radiation-induced toxicity associated with pelvic irradiation. In ten studies there was an evidence-based cytoprotection (P less than 0.05)by amifostine. Although results are variable, current evidence suggests that amifostine may have a radioprotective effect in the rectal mucosa, particularly when administered intrarectally. Significant improvements were seen in both symptomatic and objective(rectosigmoidoscopy) end points. There is a need to conduct well-designed clinical trials with sufficient numbers of participants to confirm these findings together with a cost benefit study. Objective measurements using rectosigmoidoscopy are superior to subjective measures such as WHO or RTOG/EORTC toxicity grading scales.

Phase II multicenter randomized study of amifostine for prevention of acute radiation rectal toxicity: topical intrarectal versus subcutaneous application.

PURPOSE: To investigate the cytoprotective effect of subcutaneous vs. intrarectal administration of amifostine against acute radiation toxicity. METHODS AND MATERIALS: Patients were randomized to receive amifostine either intrarectally (Group A, n = 27) or a 500-mg flat dose subcutaneously (Group B, n = 26) before irradiation. Therapy was delivered using a four-field technique with three-dimensional conformal planning. In Group A, 1,500 mg of amifostine was administered intrarectally as an aqueous solution in 40 mL of enema. Two different toxicity scales were used: the European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group (RTOG) rectal and urologic toxicity criteria and the Subjective-RectoSigmoid scale based on the endoscopic terminology of the World Organization for Digestive Endoscopy. Objective measurements with rectosigmoidoscopy were performed at baseline and 1-2 days after radiotherapy completion. The area under the curve for the time course of mucositis (RTOG criteria) during irradiation represented the mucositis index. RESULTS: Intrarectal amifostine was feasible and well tolerated without any systemic or local side effects. According to the RTOG toxicity scale, Group A had superior results with a significantly lower incidence of Grades I-II rectal radiation morbidity (11% vs. 42%, p = 0.04) but inferior results concerning urinary toxicity (48% vs. 15%, p = 0.03). The mean rectal mucositis index and Subjective-RectoSigmoid score were significantly lower in Group A (0.44 vs. 2.45 [p = 0.015] and 3.9 vs. 6.0 [p = 0.01], respectively), and the mean urinary mucositis index was lower in Group B (2.39 vs. 0.34, p < 0.028). CONCLUSIONS: Intrarectal administration of amifostine (1,500 mg) seemed to have a cytoprotective efficacy in acute radiation rectal mucositis but was inferior to subcutaneous administration in terms of urinary toxicity. Additional randomized studies are needed for definitive decisions concerning the cytoprotection of pelvic irradiated areas.

Liposomal doxorubicin in conjunction with reirradiation and local hyperthermia treatment in recurrent breast cancer: a phase I/II trial.

PURPOSE: This is the first study to evaluate the tolerability and activity of liposomal doxorubicin (Caelyx; Schering-Plough Pharmaceuticals) < or =60 mg/km(2) in patients with locally recurrent breast cancer, when administered in conjunction with reirradiation and local hyperthermia treatment. EXPERIMENTAL DESIGN: Fifteen female patients, who had undergone a radical mastectomy and conventional radiotherapy (60 Gy) in the front chest wall, were entered on a multimodal protocol consisting of initial treatment with radiotherapy and a monthly infusion of liposomal doxorubicin < or =60 mg/m(2) in conjunction with local hyperthermia treatment. All patients received reirradiation up to a total dose of 30.6 Gy (1.8 Gy/fraction, 5 days a week). To evaluate the drug's safety, the first 5 patients initially received a dose of 40 mg/m(2) liposomal doxorubicin, which was then escalated to 60 mg/m(2). The other 10 patients received 60 mg/m(2) for all six cycles of chemotherapy. Hyperthermia (HT) was produced in the region of interest (ROI) using waveguides at a frequency of 433 MHz. The RSS was obtained from the curves representing the change in the ROI's surface with time for each patient, as fitted by linear regression. Linear regression analysis was used to study the relationship between the time interval from liposomal doxorubicin infusion to HT and the RSS. RESULTS: At doses of < or =60 mg/m(2), liposomal doxorubicin was well tolerated, with only mild hematological and nonhematological toxicity. All patients showed an objective measurable response, with 3 patients (20%) demonstrating a clinically complete response. There was a significant correlation between the duration of response and Avg Min T(90) > 44 degrees C (r(s) = 0.917, P < 0.0001) and the Mean[Tmin] (r(s) = 0.909, P < 0.0001). The RSS was significantly correlated with the interval between liposomal doxorubicin infusion and HT, as the smaller the time interval, the greater the clinical benefit (r = 0.76, P = 0.001). CONCLUSIONS: The multimodal treatment was effective and well tolerated, producing an objective measurable response in all patients. Local HT had a significant effect on patients' response to the drug. The relationship between thermal dose and liposomal action requires further investigation.

Prognostic Value of MRS Metabolites in Postoperative Irradiated High Grade Gliomas.

PURPOSE: We studied the prognostic significance of Magnetic Resonance Spectroscopy (MRS) in operated high grade gliomas. MATERIALS AND METHODS: Twelve patients were treated with radiotherapy and Temozolomide. The MRS data were taken four weeks after operation (before radiotherapy) and every six months after the completion of RT. The N-acetyl aspartate, choline, creatine, and myo-inositol parameters were quantified, analyzed, and correlated to recurrence-free survival (RFS). RESULTS: The median RFS was 26.06 months. RFS was significantly worse in elderly patients (P = 0.001) along with the higher choline/creatine ratios at either baseline (P = 0.003) or six months post Radiotherapy (P = 0.042). Median RFS was 23 months in high choline/creatine levels ≥ 2 at 6 months after radiotherapy and 11 months for those with < 2 choline/creatine levels. There was a significant correlation of maximum difference of choline/creatine ratio with RFS (rho = 0.64, P = 0.045). CONCLUSION: Age and choline/creatine ratio are strong independent prognostic factors in high grade gliomas.

Prognostic Significance of Serum Inflammatory Response Markers in Newly Diagnosed Non-Small Cell Lung Cancer before Chemoirradiation.

PURPOSE: To identify whether the serum's baseline C-reactive protein (CRP) and albumin (Alb) levels related to clinicopathological parameters and overall survival (OS) in non-small cell lung cancer (NSCLC). METHODS: In total, 100 consecutive patients (mean age = 68.38 ± 10.85 years) that underwent chemoradiotherapy were studied. Measurements of CRP and Alb were performed before any treatment. RESULTS: Serum CRP levels were significantly associated with histological grade (P < 0.001), TNM stage (P < 0.001), PS (P = 0.009), and Alb (P < 0.001). Additionally CRP and Alb levels were found significantly associated with overall survival in univariate analysis (log-rank test, P < 0.001 and P = 0.002, resp.) and CRP remained significant after controlling for age, alcohol, performance status, and TNM stage, whereas albumin showed a borderline effect on the hazard rate (P = 0.052). CONCLUSIONS: CRP and Alb are both promising biomarkers in identification of NSCLC patients with poor prognosis and form a possible target for intensifying their therapies.

Impact on cytoprotective efficacy of intermediate interval between amifostine administration and radiotherapy: a retrospective analysis.

PURPOSE: To evaluate the cytoprotective impact of the interval between amifostine administration and radiotherapy (RT). METHODS AND MATERIALS: In a nonrandomized study, we reviewed the records of 177 patients with tumors localized in the pelvis (prostate, bladder, or gynecologic cancer), upper abdomen (pancreas, stomach, kidney), thorax (lung and breast cancer), head and neck (nasopharynx), soft tissue (sarcomas), and central nervous system. The patient records were stratified according to whether the patients had undergone RT either 25-40 min (Group 1, 96 subjects) or 10-15 min (Group 2, 81 subjects) after i.v. amifostine administration. The mean toxicity score was the mean value of recorded acute radiation toxicity. The mean interruption time was the mean value of the recorded interruption time due to radiation toxicity. RESULTS: A significantly reduced severity of symptoms related to oral (p = 0.023), esophageal (p = 0.05) and rectal (p = 0.015) mucosa was noted in Group 2. A statistically significant reduction in the mean toxicity score (p <0.001) and mean interruption time (p = 0.001) was observed in Group 2 vs. Group 1. In terms of the incidence of radiation-induced dermatitis and alopecia, multivariate logistic analysis revealed only the total dose (p = 0.018) and the amifostine-RT interval (p = 0.002) as independent factors. CONCLUSION: A significantly better cytoprotective effect of amifostine against radiation-induced mucositis, dermatitis, and alopecia was noted if RT was administered no later than 15 min after i.v. amifostine infusion. The results presented here need additional investigation with randomized prospective trials.

Re-irradiation in conjunction with liposomal doxorubicin for the treatment of skin metastases of recurrent breast cancer: a radiobiological approach and 2 year of follow-up.

Thirty patients with local relapses after radical mastectomy and radiotherapy and undergoing infusion of liposomal doxorubicin (40 mg/m(2) monthly for 6 months) were randomized to receive re-irradiation. Radiotherapy was with either 17 fractions of 1.8 Gy, 5 days a week (N=15, group A) or 4 Gy plus two fractions of 3 Gy the 1st week and six fractions of 3 Gy given every second day (N=15, group B). Eight patients from group A (53.3%) and nine patients (60%) from group B demonstrating a clinically complete response (P=0.9). Grade I/II acute skin toxicity was monitored in 26.6% of patients in group A versus 73.3% in group B. The radiation schedule of group A seems superior for grade I/II acute (P=0.027) and late (P=0.015) skin toxicity. The linear quadratic model enabled the prediction of tumor response as well as normal skin reactions.

Duration of bisphosphonate treatment: results of a non-randomised study in patients previously treated with local irradiation for bone metastases from breast cancer.

PURPOSE: To assess whether disodium pamidronate (DP) once started should be given life-long in women with lytic bone metastases. PATIENTS AND METHODS: One hundred and three women with breast cancer who had at least one osteolytic lesion received 180 mg of DP as a 2-h intravenous infusion given every 4 weeks for a life-time, following local radiotherapy. After six cycles, 26 out of 103 patients (25%) refused to continue their bisphosphonate-treatment. Thus two groups were constituted: non-stop (group A) and premature discontinued (group B). The new skeletal complication free survival (NSCFS) was the primary endpoint verified during extramural review. Performance status, pain-score and biochemical markers were secondary endpoints. RESULTS: Generally DP was well tolerated. At 36 months, the proportion of patients having had any skeletal complication was 54.5 and 84.6% in group A and B, respectively. The median time of NSCFS was apparently longer for group A. In group A, the pain score and the ECOG status were significantly lower, while the overall survival appeared to be longer. Multivariate analysis revealed age, nodal status and interruption of treatment as prognostic factors to NSCFS, with relative risk 1.05, 2.3 and 1.5 respectively. CONCLUSION: Data concerning the suspension of new skeletal complications, as well as the apparent improvement of overall survival, pain score and ECOG status, suggest that the pamidronate-treatment should not be stopped once started. These results should be confirmed in a randomised trial.

Irradiation Toxicity and Inflammatory Bowel Diseases (IBD): Review.

BACKGROUND/AIM: The evaluation of radiotherapy toxicity in oncologic IBD patients. Defining the optimal patient and treatment factors that would be able to reduce the risk to organs. MATERIALS AND METHODS: A review of all published radiotherapy trials was performed to identify the clinical and treatment factors of inflammatory bowel disease's patients treated for different solid tumors. RESULTS: Overall, acute (Grade ≥ 3) gastrointestinal complications attributable to RT ranged between 20-21% of the treated patients. A late Grade ≥ 3 gastrointestinal toxicity was developed in a range between 8-29%. CONCLUSION: A special attention should be given to the description of IBD location, activity status, concurrent chemotherapy, irradiation dose and technique, in order to minimize post-irradiation morbidity. It is not easy to distinguish late morbidity attributable to radiotherapy due to the IBD itself.

The key role of bisphosphonates in the supportive care of cancer patients.

UNLABELLED: The present review aims at providing an assessment of the clinical significance of Biphosphonates (BPs) in the treatment of patients with cancer. MATERIALS AND METHODS: A systematic literature review was performed based on database search in PubMed/Medline and included articles up to August 2013. RESULTS: BPs can reduce, delay, and prevent complications related to bone metastases. They improve mobility, functionality, pain, and quality of life. They limit survival of any inactive cancer cells in the microenvironment of the bone marrow, contributing to their death from anti-neoplastic treatments. Moreover, they limit and delay bone morbidity due to osteoporosis related to hormonotherapy in breast and prostate cancer. Finally, benefits can be derived from the combination of BPs with radiotherapy in bone density, recalcification, opioid use, and patient's quality of life and performance status. CONCLUSION: The contribution of BPs in the course of certain neoplasms is preventive and synergistic to other treatments.

Amifostine: the first selective-target and broad-spectrum radioprotector.

After several decades of preclinical and clinical research, the first approved radioprotective drug, amifostine, is being used in clinical practice. Amifostine has been shown to specifically protect normal tissues from damage caused by radiation and chemotherapy. An inactive prodrug, amifostine is converted to an active thiol by dephosphorylation by alkaline phosphatase in the normal endothelium. The hypovascularity and acidity of the tumor environment and the differential expression of alkaline phosphatase in normal and neoplastic tissues contribute to its cytoprotective selectivity. The cytoprotective mechanism of amifostine is complicated, involving free-radical scavenging, DNA protection and repair acceleration, and induction of cellular hypoxia. The U.S. Food and Drug Administration has approved the i.v. use of amifostine to reduce the cumulative renal toxicity associated with repeated administration of cisplatin in patients with advanced ovarian cancer and to reduce the incidence of moderate to severe xerostomia in patients undergoing postoperative radiation treatment for head and neck cancer, where the radiation port includes a substantial portion of the parotid glands. Nonetheless, amifostine has potential applications in many other oncologic settings. Novel schedules and routes of administration are under investigation and may further simplify the use of amifostine, reduce any undesired effects, and considerably broaden its applications. This review summarizes the clinical experience with amifostine and provides insight into future clinical directions.

Phase II study of temozolomide and concomitant whole-brain radiotherapy in patients with brain metastases from solid tumors.

BACKGROUND: The aim of this study was to evaluate the effectiveness and possible toxicity of the combination of temozolomide (TMZ) with whole-brain irradiation (WBI) in the treatment of brain metastases from solid tumors. PATIENTS AND METHODS: 33 patients with brain metastases were included in the study and treated with TMZ 60 mg/m2/day (days 1-16) concomitantly with WBI (36 Gy/12 fractions given in 16 days). One month after the end of radiotherapy, 6 cycles of TMZ were administered as adjuvant treatment (200 mg/m2/day for 5 consecutive days every 28 days). RESULTS: Responses were assessed using computed tomography at the end of the 3rd and 6th cycle of chemotherapy. The objective response rate was 54.5% and 57.6% after the 3rd and the 6th cycle, respectively. The median overall survival was 12 months. In patients with metastases from lung cancer the objective response rate was 11/14 (78.6%) after both the 3rd and the 6th cycle of treatment. The most common side effects were anemia (24.2%), thrombocytopenia (18.2%), as well as nausea and vomiting (18.2%). The high incidence of hepatotoxicity (45.5%) might be related to concomitantly administered antiepileptic drugs and not to TMZ. CONCLUSION: WBI combined with TMZ as concomitant and adjuvant treatment is effective in treating brain metastases, with acceptable mild side effects.

Solitary brain metastasis from classic biphasic pulmonary blastoma: a case report and review of the literature.

BACKGROUND: Classic biphasic pulmonary blastoma (CBPB) is a rare and aggressive primary malignancy, brain metastases of this type of tumor are even rarer. CASE REPORT: A 51-year-old male patient with a solitary cerebral metastasis, diagnosed ten months after left pneumonectomy for a CBPB, was treated by surgery and accelerated hypofractionated radiotherapy. RESULTS: The patient died 15 months after partial removal of the brain metastasis. Literature review revealed only 4 cases of solitary brain metastases from this type of malignancy. The present case is the second one reported with a combined treatment of surgery and radiotherapy resulting in the longest survival. CONCLUSION: The best treatment for CBPB is difficult to determine because of the small number of cases, however, the combination of surgery with radiotherapy seems to be effective. The effectiveness of chemotherapy has not been ascertained.

Isolated talus metastasis from breast carcinoma: a case report and review of the literature.

BACKGROUND: Acrometastases are very rare and have been identified in only a few cases on the foot. At the onset, they might be misdiagnosed as arthritis. CASE REPORT: A 59-year-old woman with isolated metastasis to the talus, originating from breast carcinoma was treated by radiotherapy, letrazole, and intravenous bisphosphonates. RESULTS: The review of the literature revealed that this is the first case of an isolated metastasis to the bone of talus from a breast carcinoma, while there are a few cases originating from other organs. The differential diagnosis of acrometastases may be difficult. CONCLUSION: Pain in the foot or hand of a patient with a known history of malignancy should be considered as potential metastasis.

Use of image processing techniques to assess effect of disodium pamidronate in conjunction with radiotherapy in patients with bone metastases.

The aim of this study was radiographically to monitor the effect of disodium pamidronate on metastatic bone disease, using image-processing techniques. Eighteen patients with osteolytic metastases from breast cancer received an intravenous infusion of 180 mg disodium pamidronate every 4 weeks for a period of 6 months. The first session of intravenous infusions was given concurrently with external beam radiotherapy with a 6 MV linear accelerator (total dose 30 Gy in 10 fractions). Radiographs of osteolytic lesions were obtained at every session of the treatment, retaining the same settings for each modality. The analysis of the attributes of the images was based on measuring the first-order statistics of the gray-level histogram in terms of mean value (MVGLH) and energy (EGLH). The measurements showed significant differences for MVGLH and EGLH values (p < 0.05, Wilcoxon test). Analytically, there was an 11.08% (95% CI = 10.21, 11.93) mean reduction of EGLH and an 11.63% (95% CI = 10.96, 12.29) mean increase of MVGLH of the x-ray images, before and after the combined treatment protocol. The changes in the image-processing indices were also highly correlated with the reduction of the patient's pain score. These findings indicate an important increase in bone mass and bone formation, which the radiologists found difficult to identify visually.