Combined chemoradiotherapy with local microwave hyperthermia for treatment of T3N0 laryngeal carcinoma: a retrospective study with long-term follow-up.

The purpose of our study was to test the efficacy and toxicity of hyperthermia in conjunction with chemoradiotherapy for T3N0 laryngeal cancer. From 1997-2006, 25 patients diagnosed with T3N0 laryngeal carcinoma who denied laryngectomy were selected for this retrospective study. Patients received a total dose of 70 Gy (2 Gy per fraction, 5 days per week) in combination with 6 weekly sessions of hyperthermia, in addition to weekly cisplatin chemotherapy. The hyperthermia device was operated as a 433 MHz microwave heating with water loaded and water-cooled waveguides. The temperature was monitored subcutaneously in the skin under the aperture of the waveguide. The median follow-up was 60 months, while 23 of 25 patients (92%) presented complete response to treatment. The two patients that did not respond to thermoradiotherapy underwent total laryngectomy, and during follow-up were alive and free of disease. According to EORTC/RTOG criteria, toxicity was mild: three patients (12%) presented grade III, eight (32%) presented grade II and 14 (56%) presented grade I acute skin toxicity. Grade III laryngeal late toxicity (vocal cord malfunction due to severe oedema) was noted in two patients (8%) at 6-8 months post-thermo-chemoradiotherapy. Tmin was correlated (Spearman rho, p < 0.05) with response to treatment as well as with acute skin toxicity and laryngeal function. When a patient with T3N0 laryngeal carcinoma denies laryngectomy, an alternative treatment is combined thermo-chemoradiotherapy which seems to be effective and generally tolerable with radiation-induced skin toxicity and/or late side effects. A larger patient cohort is needed to confirm these results.

Tumour budding is a strong and independent prognostic factor in pancreatic cancer.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer that escapes detection and resists treatment. Tumour budding, defined as the presence of de-differentiated single tumour cells or small cell clusters at the invasive front of gastrointestinal carcinomas like colorectal, oesophageal, gastric and ampullary, is linked to adverse prognosis. Tumour budding has not yet been reported in PDAC. AIM: To assess the frequency and prognostic impact of tumour budding in PDAC. METHODS: Whole-tissue sections of 117 PDACs with full clinico-pathological and follow-up information, including postoperative therapy, were stained using a pancytokeratin marker. Tumour budding was assessed in 10 high-power fields (HPFs) by two pathologists. High-grade budding was defined as an average of >10buds across 10HPFs. Measurements were correlated to patient and tumour characteristics. The study was performed according to the REMARK guidelines. RESULTS: Inter-observer agreement was considered strong (ICC=0.72). Low-grade budding was observed in 29.7% and high-grade budding in 70.3% cases. High-grade budding was linked to advanced pT classification (p=0.0463), lymphatic invasion (p=0.0192) and decreased disease-free (p=0.0005) and overall survival (p<0.0001). There was no association with pN, pM, R-status or blood vessel invasion. In multivariate analysis, the prognostic effect of tumour budding was independent of lymph node metastasis, lymphatic invasion and R-status (p<0.0001; HR (95% CI): 3.65 (2.1-6.4)). CONCLUSIONS: Our results show that high-grade tumour budding occurs frequently in PDAC and is a strong, independent and reproducible, highly unfavourable prognostic factor that could be used to guide future individualised therapeutic approaches.

Super-selective hepatic arterial infusions as established technique ('ARETAIEION' Protocol) of [177Lu]DOTA-TATE in inoperable neuroendocrine liver metastases of gastro-entero-pancreatic (GEP) tumors.

AIM: Aim of this study was to evaluate the effectiveness of non-carrier added (n. c. a.) [177Lu]DOTA-TATE in inoperable liver metastases, positive for sst2 receptor overexpression (verified by Octreoscan and confirmed by biopsy) due to neuroendocrine gastroenteropancreatic (GEP) tumors. [177Lu]DOTA-TATE has been infused after selective catheterization of the hepatic artery, minimising in parallel the toxicity of non-target tissues. METHODS: The dose per session administered to each patient (12 cases in total) was 7400 MBq (200 mCi). Repetitions did not exceed 6-fold with treatment intervals of 5-8 weeks. Response assessment was classified according to the therapeutic benefit. Absorbed doses delivered to metastases, kidneys and red marrow were calculated according to OLINDA 1.1 program and the derived values were correlated to the Response Evaluating Criteria in Solid Tumors (RECIST). CT/MRI scans were performed as baseline before, during and after the end of treatment and monthly ultrasound images for follow-up estimation and measurements. Toxicity (World Health Organization criteria) was measured using blood and urine tests of renal, hepatic and bone marrow function. RESULTS: None of the patients resulted complete response (0.0%); partial response was assessed in 8 (66.7%), disease stabilization in 3 (25%) and progressive disease in 1(8.3%). A 14-month median survival time was estimated for all patients, so far. Eight of 12 (66.7%) showed a mean target diameter shrinkage ranging from 33% to 45%. The organ average radiation dose estimation was found as follows: a) liver tumor 20.8 mGy/MBq; b) liver 0.14 mGy/MBq; c) kidneys 0.41 mGy/MBq; d) spleen 1.4 mGy/MBq; and f) bone marrow 0.022 mGy/MBq. The average absorbed dose per session to a tumor for a spherical mass of 20 g was estimated to be 20.8 mGy/MBq, depending on the histotype of the tumor. WHO toxicity grade 2 to 3 erythro-, leuko- and thrombo-cytopenia occurred in 9 (75%) cases observed about after the third session. CONCLUSION: In unresectable metastatic liver lesions positive for somatostatin receptors repeated, trans-hepatic high doses of [177Lu]DOTA-TATE resulted in a more than promising therapeutic outcome with a partial response in 75% of the treated patients. Given the loco-regional modality character of the administration technique, no nephro-toxicity has been so far observed whereas a remarkable myelotoxicity was noticed.

Effect of collagen powder on lymphorrhea after modified radical mastectomy. A randomized controlled trial.

AIM: Postoperative lymphorrhea is a major complication of axillary lymphadenectomy. The aim of our study was to evaluate the impact of type I collagen in postoperative lymphorrhea in mastectomy patients. METHODS: Eighty patients that underwent modified radical mastectomy for breast cancer were randomized in two groups. In group A (collagen group, n = 42) collagen type I (Cellerate RX powder) was applied in the axillary cavity after lymphadenectomy while in group B (control group, n = 38) lymphadenectomy was performed in the standard fashion without the use of a sealant. Suction drains remained in place until the daily amount of lymphatic drainage fell under 30 ml. The total amount and the duration of drainage, as well as the morbidity and severity of arm pain were compared in the two groups. RESULTS: There was a non significant trend towards lower overall drainage in the collagen group. The duration of drainage and postoperative pain were similar in the two groups, as was morbidity. Subgroup analysis of patients according to the number of lymph nodes excised, revealed significantly less lymphorrhea in terms of volume and duration in patients who had more than ten lymph nodes excised. CONCLUSION: Collagen type I (Cellerate RX powder) appears to attenuate postoperative lymphorrhea in patients undergoing axillary lymphadenectomy especially when > 10 lymph nodes are removed.

Biological markers in breast cancer prognosis and treatment.

In this review we will provide a synopsis of the biological markers used in the care of breast cancer patients with emphasis on clinical application. The advent of molecular technology has incorporated new biomarkers along with the older immunohistochemical and serum ones. Serum tumor markers are proteins shed from breast cancer cells. Their levels have long been used as a measure of tumor burden and disease progression or recurrence. However, limitations exist that should be known to those involved in breast cancer management. Historically, immunohistochemical markers have been used to guide treatment decisions. These markers reveal characteristics of the cancer cells and have been used both as prognostic and predictive factors. Molecular markers give information on the expression of certain genes in tumor tissues related to proliferation, invasion, and metastasis and researchers try to correlate them with the use of mathematical modeling with clinical outcomes, hence those markers exhibit prognostic and predictive significance. All these tools can guide personalized treatment by estimating patient prognosis and risk of relapse and tailor accordingly therapeutic approaches.

Carcinosarcomas of the uterus and ovary: a clinicopathologic and immunohistochemical study of 11 cases.

PURPOSE: To further study the clinicopathologic features of carcinosarcomas of the uterus and ovary. METHODS: We retrospectively studied all cases of uterine and ovarian carcinosarcomas diagnosed in our laboratory over the last 5-year period. The pathologic and immunohistochemical findings were correlated with the clinical records of the patients. RESULTS: Eleven cases were retrieved . The commonest presenting symptom was vaginal bleeding (9 cases, 81.8%). Most patients (8 cases, 72.7%) were submitted to total abdominal hysterectomy with bilateral salpingo-oophorectomy and adjuvant chemotherapy was administered to all of them. In the majority of cases the tumor was located in the uterine corpus (7 cases, 63.6%), followed by the ovary (4 cases, 36.4%). The tumor was homologous in ten cases (90.9%) and heterologous in one case (9.1%). Most of our patients (6 cases, 54.6%) were diagnosed at an advanced stage (FIGO Stage III or IV). The sarcomatous element was strongly positive for vimentin in all cases and focally positive for cytokeratin 7 in four cases, while the epithelial component showed a strong positivity for cytokeratin 7 and focal staining for vimentin, cytokeratin 20, CA-125 and CEA. CONCLUSION: Carcinosarcomas of the uterus and ovary are highly aggressive biphasic neoplasms with a prominent epithelial component. Their most common location is the uterine corpus. Although distant metastases are rarely found at the time of diagnosis, the prognosis of these tumors is unfavorable. The optimal chemotherapy remains to be determined.

CEA and CA-19.9 serum tumor markers as prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis.

Most pancreatic adenocarcinoma patients present with locally advanced or metastatic disease at diagnosis. in this retrospective study the authors evaluated the prognostic significance of the CEA and CA-19.9 serum tumor markers in advanced (unresectable) pancreatic cancer in correlation to other prognostic factors (demographic data, clinical parameters, treatment modality) and survival time using univariate and multivariate methods, in 215 patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma. median survival was 29.0 weeks, with 21.9% of patients surviving 36 weeks. Among 24 potential prognostic variables, 19 were associated with shorter survival. Multivariate analysis indicated that ten factors had a significant independent effect on survival: chemotherapy, surgery, tumor localization, elevated C-reactive protein, elevated CeA, CA 19-9 (>30 x nl), jaundice at diagnosis, weight loss >10%, distant metastases, and Karnofsky performance status. Patients who had only palliative therapy had a hazard ratio of 8.94 versus those who underwent palliative surgery and chemotherapy. Although certain clinical, biochemical and biological factors remain important predictors of survival in patients with advanced pancreatic cancer, CA-19.9 serum tumor marker levels retain independent prognostic value for poor survival.

Neoadjuvant chemotherapy followed by radiotherapy versus concurrent chemoradiotherapy for larynx preservation in patients with advanced laryngeal cancer.

PURPOSE: The efficacy and toxicity of neoadjuvant chemotherapy followed by radiotherapy and concurrent chemoradiotherapy and their impact on larynx preservation have been studied in patients with advanced (stage III, IVa, and IVb) squamous cell cancer of the larynx. PATIENTS AND METHODS: Fifty patients were treated with either 2-4 cycles of induction chemotherapy with cisplatin 100 mg/m(2), day 1 and infusional 5-fluorouracil (5-FU 1000 mg/m(2), days 1-5), followed by radiotherapy 70 Gy, 1.8-2 Gy per fraction, or concurrent chemoradiotherapy (the above-mentioned radiotherapy concurrently with carboplatin 300 mg/m(2) every 21 days or weekly paclitaxel 80 mg/m(2)). Patients were allocated in the 2 arms by 1:1 selection. At the end of both protocols, patients without complete response (CR) underwent laryngectomy and/or neck lymph node dissection. Assessed were response and toxicity rates, overall survival (OS) and disease-free survival (DFS). RESULTS: A total of 31 (62%) patients achieved larynx preservation with acceptable organ function. No statistically significant difference in response rate and OS was found between the two treatment arms. Patients submitted to concurrent chemoradiotherapy showed significantly longer DFS (14 vs. 10 months, p= 0.0397) and higher rates of larynx preservation (p <0.05). All grade IV side effects occurred in the concurrent chemoradiotherapy group. CONCLUSION: Concurrent compared to alternating chemoradiotherapy was more toxic, but achieved significantly longer DFS and higher rate of larynx preservation.

Leucovorin and fluorouracil vs levamisole and fluorouracil as adjuvant chemotherapy in rectal cancer.

The aim of this study was to evaluate the effectiveness of 6-month therapy with leucovorin (LV) + 5-fluorouracil (5-FU) vs 12 months of therapy with levamisole (LVZ) + 5-FU, as adjuvant chemotherapy in patients with completely resected Dukes' stage B2 or C rectal cancer. One hundred and fifty patients with surgically resected rectal carcinoma, were enrolled in the present study; Dukes' stage B2 (n=70) or C (n=80), were randomly assigned to chemotherapy with 5-FU + LV x 6 months or 5-FU + LVZ x 12 months. Patient characteristics were equally balanced between the examined groups. Adjuvant CT consisted of LV 20 mg/m(2) intravenously (i.v.) plus 5-FU 450 mg/m(2) i.v., on days 1-5 every 4 weeks for 6 cycles or 5-FU 450 mg/m(2) i.v. every week plus LVZ 50 mg t.i.d x 3 days for 1 year. All patients received radiotherapy with a three-field technique to a total dose of 45 Gy, over 5 weeks. After a median follow-up of 7.4 years there were no significant differences between the two treatment groups with respect to the recurrence rates (P=0.821). Moreover, there was no difference in disease-free survival for patients stage Dukes' B2 (log-rank p=0.73); median for LV group 90 (8-131) months, and for LVZ group 86.5 (3-129) months. No difference was noted in disease-free survival for patients stage Dukes' C (log-rank p=0.73); median for LV group 60 (17-128) months, and for LVZ group 64 (2-123) months. There was no difference in overall survival for patients stage Dukes' B2 (log-rank p=0.75); median for LV group 90 (22-131) months, and for LVZ group 86 (10-129) months. For stage Dukes' C (log-rank p=0.73); median for LV group 67 (17-128) months, and for LVZ group 64 (5-123) months. Toxicities were as follows in the 5-FU + LVZ vs 5-FU + LV group; myelosuppression (leucopenia grade 3, 12% vs 4%, p<0.04), diarrhea (grade 0, 60% vs 76%, p<0.02), and liver toxicity (increase of transaminases >3-fold, 12 patients vs 2, p<0.03), were more frequent in LVZ group. None of the patients stopped chemotherapy because of the toxicity, and there were no toxicity-related deaths. In conclusion, adjuvant chemotherapy in RC with LV + 5-FU for 6 months is equally effective and less toxic than LVZ + 5-FU for 12 months.

Prognostic significance of the immunohistochemical localization and serological detection of CA19-9 tumor antigen in colon carcinoma.

PURPOSE: This study was carried out in order to evaluate the expression of CA19-9 antigen in serum and tissue samples of colon cancer patients in relation with other pathological prognostic factors. MATERIALS AND METHODS: 99 patients diagnosed with colon cancer entered the study. The CA19-9 antigen was measured in the serum by ELISA (cut-off value 37 IU/L) and in malignant tissue samples by immunohistochemistry using Mab 192. Seventy-five tissue samples of normal colon served as controls. RESULTS: In cancer cells the CA19-9 antigen was expressed on the cell membrane, in the lumen and in the cytoplasm. The expression of the antigen in the cytoplasm and also the high serum values of the tumor marker correlated well with more differentiated tumors (grade I and II) and with positive lymph nodes cases. There was also a positive correlation between cytoplasmic localization of CA19-9 and high levels in the serum. CONCLUSION: The presence of CA19-9 in the cytoplasm reflects the malignant potential of the colon cancer cell. In less differentiated tumors (grade III) loss of antigenicity is observed. The two methodologies correlate well with each other and their simultaneous application confers to the better use and understanding of this tumor-associated antigen.

Etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) in 5-FU+LV pre-treated patients with advanced colorectal cancer.

In the present study, we evaluated the efficacy and safety of the weekly combination of etoposide, leucovorin (LV) and 5-fluorouracil (5-FU) when administered as second-line chemotherapy in patients with relapsed/refractory advanced colorectal cancer (ACC), previously treated with weekly LV+5-FU. Etoposide was administered at 3 different dose levels (DLs), in 3 groups of 20 patients each (total: 60); DL-I: etoposide 80 mg/m2, DL-II: etoposide 120 mg/m2, and DL-III: etoposide 180 mg/m2, in 45 min i.v. infusion, and followed in all levels by LV 100 mg/m2 i.v. over 1 hour and 5-FU 500 mg/m2 i.v. bolus. Treatment was administered weekly until disease progression or unacceptable toxicity. No patients at DL-I responded, while 2 patients at DL-II and 3 at DL-III had a partial response (PR). Stable disease (SD) rates were as follows; at DL-I: 2, DL-II: 8 and DL-III: 9. More patients in DL-I progressed (n = 19) compared to DL-II (n=10) and DL-II (n = 8) (p < 0.0007). Time to progression was for DL-I, -II, -III: 17, 15, and 14 weeks, respectively. Median survival was DL-I, -II, -III: 30, 30, and 32.5 weeks, respectively. Toxicity consisted mainly of neutropenia, diarrhea and mucositis at all DLs, and was significantly more severe in DL-III. No difference was noted in responses between DL-II and DL-III. The authors conclude that the combination of etoposide with LV+5-FU has limited activity when administered after failure of weekly LV+5-FU in patients with ACC and should not be recommended for further evaluation.

Irinotecan (CPT-11) in patients with advanced colon carcinoma relapsing after 5-fluorouracil-leucovorin combination.

The purpose of the present study was to investigate the association between performance status (PS) and mean dose of irinotecan (CPT-11) in patients with recurrent advanced colorectal cancer relapsing after 5-fluorouracil and leucovorin chemotherapy. Patients who had completed their last chemotherapy course with 5-fluorouracil and leucovorin for at least 6 weeks and progressed were included. Based on PS, we administered a starting dose of 250 mg/m(2) in patients with a PS 70-80 (group A), and 350 mg/m(2) for those with a PS > 80 (group B). Of a total of 90 treated patients, all were evaluable, 18 had a partial response (PR) (20%), 39 stable disease (43%), and 15 progressed (37%). No significant difference was noticed between patients with PS > or = 90 or < or = 80 (p = 0.925), or between those who received a mean dose of CPT-11 > or = 300 or < or = 300 (p = 0.602), for response, survival and time to progression. Toxicity was increased in group B as expected, with significant differences for acute cholinergic syndrome (p = 0.02), diarrhea after the first 24 h (p = 0.03) and severe diarrhea (p = 0.03). According to these results, we conclude that response to CPT-11 is independent of its dose, and that a dose of 250 mg/m(2) every 3 weeks might be a cost-effective and less toxic alternative in this setting. However, further adequately powered phase II or III randomized studies might be required in order to confirm this observation.

Receptor scintigraphy of non-neuroendocrine cancers with In-111 pentetreotide.

Somatostatin receptors (SR) are surface markers characterizing not only APUDomas associated with neuroendocrine identities but also malignancies without neuroendocrine expression. Recently, the somatostatin analog pentetreotide was labeled with In-111 (OctreoScan 111, Mallinckrodt Medical BV, Petten, Holland) and introduced for the in vivo visualization in man of SR-positive tissues. In the present report, SR-specific scintigraphy is evaluated as a clinical tool for tissue characterization in correlation with histological and radiological examinations. Scintigraphy was focused and performed in cancer types without neuroendocrine tissue expression such as brain (n = 6) and breast tumors (n = 9) and lymphomas (n = 5). Scintigraphy was performed for comparison at 6 and 22 h after i.v. application of 111 MBq (3 mCi) of In-111-Pentetreotide. In the breast cancer group, the primary tumor was visualized in all 9 women as well as in all 4 cases with palpable axillary lymph nodes. Three women with a negative axillary node scan and impalpable nodes had positive biopsy. In two cases, mediastinal lymph node involvement was observed. So far the role of SR-positive breast cancer (BC) scans remains unknown. It is tempting to speculate that in resected women who are histologically and scintigraphically SR positive, it might be of value in the early detection of symptom-free recurrences. High densities of SR were present within both meningiomas, the high-grade astrocytoma and the craniopharyngioma. Differentiation of low- and high-grade astrocytomas could not be successfully achieved because both grades showed intense radioactivity uptake, even though high-grade tumors lack SR. The latter might be due to the damaged blood-brain barrier and the poor radioactivity washout observed in high-grade astrocytomas. All five lymphomas could be detected due to the presence of activated lymphocytes and macrophages that express SR at a sufficient density. In conclusion, SR scintigraphy in non-neuroendocrine malignancies does not seem to be reliable for an initial tumor staging but rather more suitable for a tissue characterization and extremely useful for monitoring changes of SR expression after treatment.

Carboplatin alone compared with its combination with epirubicin and cyclophosphamide in untreated advanced epithelial ovarian cancer: a Hellenic co-operative oncology group study.

We compared, in a multicentric randomised prospective study, the efficacy and toxicity of carboplatin 400 mg/m2 as a single agent (CB) to a combination of carboplatin 300 mg/m2, epirubicin 50 mg/m2 and cyclophosphamide 500 mg/m2 (CB-EC) in advanced ovarian cancer patients. The treatment was scheduled to be administered every 3 weeks for six courses. Following initial laparotomy and cytoreductive surgery, 130 previously untreated patients entered the study. 73 patients were treated with carboplatin alone while 57 received the combination chemotherapy. In the majority of the patients, the regimens had to be given every 4 weeks due to myelosuppression. Nausea, vomiting and alopecia were more severe in the CB-EC arm. Overall, clinical complete response was observed in 73 (56%) and partial response in 20 (15%) patients. The median time to progression was 16.89 months and median survival was 29.54 months. No significant differences in response rate, time to progression, disease-free survival and overall survival were observed between the two treatment arms. The prognostic role of residual disease after initial surgery, complete remission at second-look laparotomy, tumour stage and performance status was confirmed.

Cyclophosphamide, mitoxantrone, fluorouracil versus conventional CMF as adjuvant treatment in node-positive breast cancer patients. A Hellenic Cooperative Oncology Group Study.

362 evaluable node-positive patients with stage II breast cancer were randomized, receiving either 6 cycles of conventional CMF or 6 cycles of the combination of cyclophosphamide (500 mg/m2), mitoxantrone (Novantrone 10 mg/m2), and fluorouracil (500 mg/m2; CNF). After a median follow-up of 51 months, 64 (36%) patients relapsed in the CMF group and 60 (33%) in the CNF group (p=0.8276). By Cox multivariate analysis, tumor size, menopausal status and number of involved nodes were retained as independently significant variables. Toxicities were remarkably similar in both groups. It appears that after a median follow-up of 51 months there is no significant difference in relapse-free survival between node-positive patients with breast cancer who received either 6 cycles of the conventional CMF or the CNF combination as adjuvant treatment.

Computed tomography of ovarian carcinoma.

Forty-seven patients with ovarian carcinoma were examined with computed tomography (CT). Fourteen were evaluated before laparotomy (group I), 25 following surgical treatment (group II), and 8 were followed by CT in the course, or following chemotherapy with or without radiation therapy (group III). CT provided accurate estimates of the size, shape and structure of the ovarian tumor in 8 patients in group I and contributed to diagnosis in 3 others. Primary ovarian tumors were incorrectly diagnosed in 3 cases. CT examination was valuable for detection of metastases in the mesenterium, omentum, peritoneum, abdominal organs and lymph nodes. The detection of small (1 cm diameter) metastatic implants on the peritoneal surface, omentum and liver capsule was facilitated by the presence of ascites. CT proved useful for patient follow-up, either after surgical treatment or when chemotherapy with or without radiation therapy was used.