Impact of adjuvant radiotherapy on biological and clinical parameters in right-sided breast cancer.

PURPOSE: In patients with right-sided breast cancer (BC) the liver might be partially irradiated during adjuvant radiotherapy (RT). Thus, we performed a prospective observational study to evaluate the dose delivered to the liver, and its potential biological impact. PATIENTS AND METHODS: We enrolled 34 patients with right-sided BC treated with adjuvant RT. The RT schedules were either the Canadian (42.5Gy in 16 fx) or standard fractionated (50Gy in 25 fx) regimen respectively with 9 (26.5%) and 25 (73.5%) patients each, ± a boost of 10-16Gy. Each patient had a complete blood count and liver enzymes analysis, before starting and during the last week of treatment. RESULTS: A significant decrease in white blood cells and thrombocytes counts was observed during RT. We observed a significant correlation between certain hepatic parameters and the volume of the irradiated liver and/or the mean liver dose. A significant correlation between the volume of the right lung and the liver mean dose was found (P=0.008). In the bivariate analysis, a significant correlation between fatigue and the white blood cell count's evolution was observed (P<0.025). CONCLUSION: With the standard RT technique, incidental irradiation of the liver was documented in a large number of patients, and some significant hepatic parameters alterations were observed, without an apparent clinical impact, but this study cannot exclude them. The liver mean dose was correlated with the right lung volume suggesting that deep inspiration breath hold (DIBH) techniques may represent a way to decrease the liver dose. These findings need to be evaluated in further larger studies.

An efficient procedure for tomotherapy treatment plan verification using the on-board detector.

In this work, a fast and simple procedure for tomotherapy treatment plan verification using the on-board detector (OBD) has been developed. This procedure allows verification of plans with static and dynamic jaws (TomoEDGE). A convolution-based calculation model has been derived in order to link the leaf control sinogram from the treatment planning system to the data acquired by the OBD during a static couch procedure. The convolution kernel has been optimized using simple plans calculated in the Tomotherapy Cheese phantom. The optimal kernel has been found to be a lorentzian function, whose parameter Γ is 0.186 for the 1 cm jaw opening, 0.232 for the 2.5 cm jaw opening and 0.373 for the 5 cm jaw opening. The evaluation has been performed with a γ-index analysis. The dose criterion was 3% of the 95th percentile of the dose distribution and the distance-to-agreement criterion is 2 mm. In order to validate the procedure, it has been applied to around 50 clinical treatment plans, which had already been validated by the Delta4 phantom (Scandidos, Sweden). 96% of the tested plans have passed the criteria. Concerning the other 4%, significant discrepancies between the leaf pattern in the leaf control sinogram and the OBD data have been shown, which might be due to differences in the leaf open time. This corresponds also to a higher sensitivity of this method over the Delta4, adding the possibility of better monitoring the treatment delivery.

Guillain-Barré syndrome as an atypical manifestation of an esophageal carcinoma.

Guillain-Barré syndrome (GBS) is an acute demyelinating polyradiculoneuropathy normally associated with a preceding infection, but sometimes it can be linked to a subjacent malignancy. We report an unusual case of GBS occurring as the first clinical manifestation of an esophageal adenocarcinoma in a 65-year-old patient. A GBS neuropathy of undetermined origin may be associated with an underlying tumor and esophageal cancer has to be considered in the differential diagnosis.

[Pretherapeutic and posttherapeutic laryngeal imaging]. / Prä- und posttherapeutische Larynxbildgebung.

Cross-sectional imaging with CT, MRI and more recently PET CT plays an indispensable complementary role to endoscopy in the pretherapeutic diagnostic and staging of laryngeal neoplasms and in the evaluation of the operated or irradiated larynx. Adequate interpretation of the CT, PET CT and MR images requires a thorough knowledge of the patterns of submucosal spread and familiarity with the diagnostic signs of neoplastic invasion as seen with each modality. In addition, one should be aware of the implications of imaging for staging and treatment. Both CT and MR imaging are highly sensitive for the detection of neoplastic invasion of the preepiglottic and paraglottic spaces, subglottic region and cartilage. The high negative predictive value of both CT and MRI allows a relatively reliable exclusion of neoplasm cartilage invasion. The specificity of both CT and MRI is, however, moderately high and both methods may, therefore, overestimate the extent of tumor spread. However, recent investigations have shown that the specificity of MRI may be significantly improved by using new diagnostic criteria which allow differentiation of tumor from peritumoral inflammation in many instances. Both cross-sectional imaging methods also significantly improve the pretherapeutic staging accuracy of laryngeal tumors if used in addition to clinical examination and endoscopic biopsy. In the presence of a submucosal mass, CT and MRI play a key role for the diagnosis, as they may characterize the lesion, reliably depict its submucosal extent and guide the endoscopist to perform deep biopsies which allow the definitive histological diagnosis. Cross-sectional imaging also plays a key role in the evaluation of laryngoceles, recurrent laryngeal nerve paralysis and fractures.

Treatment strategies for the management of advanced colorectal liver metastases detected synchronously with the primary tumour.

The review summarises the contributions of chemotherapy, interventional radiology and surgery to the improved survival observed in patients with colorectal liver metastases. The rationale in favour of modern neoadjuvant chemotherapy regimens, of pro-generative manoeuvres to increase the volume of the future remnant liver, and of resection techniques that preserve its function is discussed. For advanced synchronous colorectal metastases, the arguments in favour of a reversed approach with systemic chemotherapy, liver surgery and colon surgery in that order, as opposed to the traditional approach of colon surgery first, or to a simultaneous liver and large bowel resection, are presented.

Complete closure of cancer-related anovaginal and anoperineal fistulas in locally advanced anal canal carcinomas by upfront intra-arterial chemotherapy followed by combined radiochemotherapy: report of two cases.

PURPOSE: Cancer-related fistulas are a major problem in locally advanced anal canal carcinoma, because conservative radiochemotherapy may not be recommended in this setting. Therefore, it is usually recommended to proceed to an abdominoperineal resection with definitive colostomy in the presence of such lesions. METHODS: Because chemotherapy can lead to closure of cancer-related fistulas and local intra-arterial chemotherapy is effective in locally advanced anal canal cancer, we treated two anal canal carcinoma patients presenting with cancer-related fistulas with upfront intra-arterial chemotherapy followed by radiochemotherapy, leading to complete closure of fistulas. RESULTS: Both patients are free of colostomy and in complete remission after more than four years of follow-up. CONCLUSIONS: This conservative approach combining local intra-arterial chemotherapy and standard radiochemotherapy is feasible and should be considered in the management of such locally advanced anal canal carcinoma.

Carbogen breathing combined with radical radiotherapy in advanced head and neck cancer patients with severe co-morbidities.

AIMS: To assess the feasibility of carbogen breathing combined with radical radiotherapy in patients with advanced head and neck cancer who are unfit to receive concomitant chemotherapy. MATERIALS AND METHODS: Twenty patients (median age 66 years) with advanced squamous cell carcinoma of the head and neck were treated with either concomitant boost radiotherapy (75%) or mono-fractionated radiotherapy (25%) combined with carbogen breathing. The median tumour dose was 69.5 Gy. The main sites of disease were the oropharynx in 50%, the oral cavity in 15% and the hypopharynx in 30%. All but one patient had stage III (25%) or IV (70%) disease. The median follow-up for the surviving patients was 26 months (range 6-50 months). RESULTS: Carbogen breathing was well tolerated, permitting its delivery throughout the radiotherapy course. Three patients had treatment interruption because of acute toxicities (median 15 days; range 3-30 days). Grade 3 Radiation Therapy Oncology Group acute toxicity was observed in 80% of the patients (mainly mucositis), and nutritional support was required in eight patients (40%). Grade 2 late toxicity occurred in 30%; one patient presented with grade 4 late toxicity (bone necrosis). The 2-year actuarial locoregional control for all patients and for those treated with accelerated radiotherapy was 56% and 67%, respectively. The corresponding rates for disease-free survival were 45% and 53%. CONCLUSIONS: Considering the poor results of radiotherapy alone in advanced head and neck cancer, these results suggest that carbogen breathing may be a valid alternative for patients with severe co-morbidities who are unfit to receive concomitant chemotherapy.

Cyclin D1, cyclin E, and p21 have no apparent prognostic value in anal carcinomas treated by radiotherapy with or without chemotherapy.

The purpose of this study was to assess the potential prognostic and/or predictive value of the expression of cyclin D1, cyclin E, and p21 protein in a series of 98 anal carcinomas (T1-4, N0-3) treated by radiotherapy with (51) or without (47) chemotherapy in one institution. Correlation with Mib1 index and p53 expression was also investigated. Median follow-up for surviving patients was 124 months (range: 30-266). Immunohistochemical staining was performed on pretreatment biopsies, applying a standard ABC technique for cyclin D1 (clone DSC6, DAKO, 1 : 300), cyclin E (clone 13A3, Novocastra, 1 : 100), p21(WAF/CIP1) (clone SX118, DAKO, 1 : 50), p53 (clone DO7, DAKO, 1 : 200), and Mib1 (Ki-67, Dianova, 1 : 20). Tumours were classified into low- or high-expression groups according to the expression level of the protein considered. High expression was found in 51% of tumours for cyclin E, in 33.7% for cyclin D1, and in 65% for p21. None of those factors were significantly associated with clinical variables such as advanced T or N categories. In a monovariate analysis, advanced T and N categories and longer overall treatment time were the only variables that correlated significantly with low rate of local control (LC) and disease-free survival. However, in a subgroup analysis, high p21 expression correlated with a trend for significantly higher 5-year LC (87 vs 68%, P=0.07) in the N0 patients. The results of this study suggest that the cell-cycle proteins investigated are unlikely to be clinically useful in predicting treatment response or prognosis in patients with anal carcinomas.

Motility-related protein-1 (MRP-1/CD9) expression can predict disease-free survival in patients with squamous cell carcinoma of the head and neck.

CD9 is a transmembrane protein that has been implicated in cell adhesion, motility and proliferation, and numerous studies have demonstrated the prognostic value of its expression in different solid tumours. The purpose of this study is to determine the predictive value of CD9 in squamous cell carcinoma (SCC) of the head and neck. A total of 153 cases were examined for CD9 expression using immunohistochemistry applied on formalin-fixed, paraffin-embedded tissue. Cases were stratified in two categories depending on CD9 expression, as positive (>/=50% positive cells) or reduced (<50%). In all, 108 cases were positive for CD9 (85 cases with membranous, and 23 with both membranous and cytoplasmic staining) and 45 reduced expression. Reduced CD9 expression was significantly associated with high grade (P=0.0007) and lower disease-free survival (DFS) (P=0.017). The latter retained its significance in the multivariate analysis. When the 23 cases with both membranous and cytoplasmic patterns were studied as a separate subgroup, there were significant associations between CD9 expression and tumour grade (P=0.025) (95% CI 11-68), tumour stage (P=0.08) (95% CI 3.5-86) and the occurrence of any failure (P=0.083) (95% CI -1.7-57). Immunohistochemical CD9 expression proved to be an independent prognostic factor in SCC of the head and neck, and it may detect patients at a high risk of recurrence. In addition, the cytoplasmic pattern seems to have an even more significant value. However, this finding is limited to the small number of cases with this pattern.

Neoadjuvant radiochemotherapy for locally advanced gastric cancer: a phase I-II study.

BACKGROUND: To study in a phase I-II trial the maximum tolerated dose, the toxicity, and the tolerance of adding radiotherapy to systemic chemotherapy administered preoperatively in patients with locoregionally advanced gastric adenocarcinoma. PATIENTS AND METHODS: Patients with adenocarcinoma of the stomach (T(3)(-)(4)N(any) or T(any)N+), performance status

Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review.

BACKGROUND: The authors reviewed treatment results in patients with nasal and paranasal sinus carcinoma from a large retrospective cohort and conducted a systematic literature review. METHODS: Two hundred twenty patients who were treated between 1975 and 1994 with a minimum follow-up of 4 years were reviewed retrospectively. A systematic review of published articles on patients with malignancies of the nasal and paranasal sinuses during the preceding 40 years was performed. RESULTS: The 5-year survival rate was 40%, and the local control rate was 59%. The 5-year actuarial survival rate was 63%, and the local control rate was 57%. Factors that were associated statistically with a worse prognosis, with results expressed as 5-year actuarial specific survival rates, included the following: 1) histology, with rates of 79% for patients with glandular carcinoma, 78% for patients with adenocarcinoma, 60% for patients with squamous cell carcinoma, and 40% for patients with undifferentiated carcinoma; 2) T classification, with rates of 91%, 64%, 72%, and 49% for patients with T1, T2, T3, and T4 tumors, respectively; 3) localization, with rates of 77% for patients with tumors of the nasal cavity, 62% for patients with tumors of the maxillary sinus, and 48% for patients with tumors of the ethmoid sinus; 4) treatment, with rates of 79% for patients who underwent surgery alone, 66% for patients who were treated with a combination of surgery and radiation, and 57% for patients who were treated exclusively with radiotherapy. Local extension factors that were associated with a worse prognosis included extension to the pterygomaxillary fossa, extension to the frontal and sphenoid sinuses, the erosion of the cribriform plate, and invasion of the dura. In the presence of an intraorbital invasion, enucleation was associated with better survival. In multivariate analysis, tumor histology, extension to the pterygomaxillary fossa, and invasion of the dura remained significant. Systematic review data demonstrated a progressive improvement of results for patients with squamous cell and glandular carcinoma, maxillary and ethmoid sinus primary tumors, and most treatment modalities. CONCLUSIONS: Progress in outcome for patients with nasal and paranasal carcinoma has been made during the last 40 years. These data may be used to make baseline comparisons for evaluating newer treatment strategies.

The impact of gap duration on local control in anal canal carcinoma treated by split-course radiotherapy and concomitant chemotherapy.

PURPOSE: To investigate the potential benefit of reducing the intersequence gap in patients with anal cancer treated with split-course chemoradiotherapy. METHODS: The study group consisted of 90 patients with anal squamous carcinoma treated between 1981 and 1998, using concomitant chemotherapy (CT) and radiation (RT). Median age was 65 years (range 41-87). RT was delivered in a split course, with a median gap of 37.5 days (range 4-97) between sequences. First (pelvic) sequence delivered a median dose of 40 Gy (range 36-50.4), using AP/PA megavoltage photon beams. Boost treatment (median dose 20 Gy, range 13-26) consisted of either Iridium-192 implantation (49 patients) or external beam RT (41 patients). CT consisted of 1-2 cycles of a 5-day continuous infusion of 5-fluorouracil and bolus mitomycin C, usually administered during the first week of each RT course. Median follow-up was 76.2 months. Univariate and multivariate analyses were performed to determine the factors associated with locoregional control (LRC). RESULTS: Five-year actuarial LRC was 72.5%. Factors associated with poorer LRC (univariate) were: age < or = 65, male gender, and gap > 37.5 days. Number of CT cycles (1 vs. 2 or more), boost technique (brachytherapy vs. external), and T-stage were not significantly associated with LRC. In multivariate analysis, only age (p = 0.01), and gap (p = 0.02) retained their significance. In patients older than 65 years, LRC was 92.3% and 75% for shorter and longer gaps, respectively. In younger patients, the corresponding values for LRC were 73.7% and 50%. CONCLUSION: In anal cancers, split-course RT with > 50 Gy dose delivery is difficult to avoid because of acute toxicity. The present analysis suggests that shortening the gap contributes to optimizing LRC. Gaps longer than 5 weeks correlated with poorer LRC, with especially unsatisfactory results observed in younger patients.

Sphincter-conserving treatment of carcinomas of the anal margin.

Between April 1982 and December 1997 24 patients with carcinoma of the anal margin were treated with radiation therapy (RT) (10 patients) or RT-chemotherapy (CT) (14 patients). External beam RT (EBRT) was delivered in 18 patients, combined with brachytherapy in 5 patients, while one patient was treated with brachytherapy alone. Inguinal nodes were irradiated in 17 patients. Chemotherapy was based on 5-fluorouracil and mitomycin-C. At 5 years, the overall survival rate was 56% and the locoregional rate was 69.5%. Anal sphincter was preserved in 16/24 treated patients. Grade 4 late complications were observed in 3 patients. This study reinforces the notion that radical RT +/- CT provides a high probability of cure and sphincter preservation in patients presenting with this rare condition. Major late toxicity is uncommon; a better adaptation of treatment technique to the individual clinical situation may prevent some of the more severe complications in the future.

Assessment of target dose delivery in anal cancer using in vivo thermoluminescent dosimetry.

PURPOSE: To measure anal dose during external beam radiotherapy (EBRT) using in vivo dosimetry, to study the difference of measured from prescribed dose values, and to evaluate possible associations of such differences with acute and late skin/mucosal toxicity and anorectal function. MATERIALS: Thirty-one patients with localized anal carcinoma underwent in vivo measurements during the first EBRT session. Themoluminescent dosimeters (TLD) were placed at the center of the anal verge according to a localization protocol. No bolus was used. Patients received a median dose of 39.6 Gy (range: 36-45 Gy) by anteroposterior opposed AP/PA pelvic fields with 6 or 18 MV photons, followed by a median boost dose of 20 Gy (range: 13-24 Gy). Concomitant chemotherapy (CCT), consisting of 1-2 cycles of continuous infusion 5-fluorouracil (5-FU) and bolus mitomycin-C (MMC), was usually administered during the first weeks of the pelvic and boost EBRT courses. Acute and late skin/mucosal reactions were recorded according to the Radiation Therapy Oncology Group (RTOG) toxicity scale. Anal sphincter function was assessed using the Memorial Sloan Kettering Cancer Center (MSKCC) scale. RESULTS: TLD anal doses differed by a mean of 5.8% (SD: 5.8) in comparison to the central axis prescribed dose. Differences of at least 10% and at least 15% were observed in eight (26%) and three (9.7%) patients, respectively. TLD doses did not significantly correlate with acute or late grade 2-3 skin or mucosal toxicity. However, patients having good-fair MSKCC anal function had a significantly greater mean difference in anal TLD dose (10.5%, SD: 5.9) than patients having excellent function (3.8%, SD: 4.6) (P = 0.004). Prescribed dose values, length of follow-up, and age at diagnosis did not correlate with late sphincter function. CONCLUSIONS: These data show that AP/PA fields using megavoltage photons deliver adequate dose to the anal verge. However, in about one quarter of patients treated with this technique the anal dose varied from the prescribed dose by at least 10%. The observed correlation of TLD values and late sphincter function suggests that direct measurement of the dose delivered to the anal verge might be clinically relevant.

Esthesioneuroblastoma: a meta-analysis and review.

Our objective was to review recent developments in diagnosis, staging, and treatment of esthesioneuroblastoma (ENB). A meta-analysis of publications between 1990 and 2000 was carried out, and studies were classified according to their main subject: origin/aetiology of ENB, histopathological diagnosis, and treatment. Data so far point to the basal progenitor cells of the olfactory epithelium as the origin of ENB. Histopathological diagnosis remains difficult and is based on results of antigen expression detected through a panel of antibodies by immunohistochemistry. RT-PCR of HASH expression could be a specific marker of ENB. Overall and disease-free survival at 5 years averaged 45% (SD 22) and 41% (SD 21) in the studies included in the meta-analysis. Survival in Hyams' grades I-II was 56% (SD 20) compared with 25% (SD 20) in grades III-IV (odds ratio 6.2). In patients with metastases in cervical lymph nodes (on average 5% of the total) survival was 29%, compared with 64% for patients with N0 disease (odds ratio 5.1). Survival according to treatment modalities was 65% for surgery plus radiotherapy, 51% for radiotherapy and chemotherapy, 48% for surgery, 47% for surgery plus radiotherapy and chemotherapy, and 37% for radiotherapy alone. The histopathological grading according to Hyams and the presence of cervical lymph-node metastases emerged as prognostic factors. A combination of surgery and radiotherapy seems to be the optimum approach to treatment. The exact role of chemotherapy in treatment protocols is still unclear. The role of elective neck dissection is unclear.

Endoscopic neck dissection in human cadavers.

OBJECTIVE: To evaluate the feasibility and efficacy of endoscopic neck dissection (END) in human cadavers. STUDY DESIGN: Experimental self-controlled study. METHODS: END on five human cadavers through three openings: one for the camera, one for the dissecting instrument, and one for a grasping one. The tissue specimens removed were divided into traditional neck groups (I to V). After the completion of END, open neck dissection was performed using standard surgical techniques and the remaining tissue within each neck group was retrieved. The important neck structures (carotid artery, internal jugular vein, cranial nerves X, XI, and XII, phrenic nerve) were evaluated for lesions. A pathologist evaluated each specimen, without knowing its exact origin in terms of neck group or side, and type of surgical technique used. For each specimen, the number of retrieved lymph nodes and their anatomic integrity was analyzed. RESULTS: Ten neck dissections were performed on 5 cadavers, without any major difficulty. An injury of the internal jugular vein occurred twice and once the phrenic nerve was cut. Little tissue was usually left for open surgical dissection. The average number of retrieved lymph nodes by endoscopy was 4.9 +/- 2.7 (mean +/- standard deviation). Completion open neck dissection retrieved an additional 0.5 +/- 0.5 lymph nodes. Efficacy of END was 92 +/- 10%. The majority of retrieved lymph nodes were intact but exhibited important postmortem autolysis artifacts. CONCLUSIONS: Endoscopic neck dissection is possible in human cadavers and is free of lesions to major structures. The majority of neck lymph nodes can be removed endoscopically.

Intra-arterial chemotherapy in locally advanced or recurrent carcinomas of the penis and anal canal: an active treatment modality with curative potential.

The prognosis of locally advanced or recurrent carcinomas of the penis (PE) and of the anal canal (AC) after conventional treatment is dismal. We report 16 patients (eight with AC carcinomas and eight with PE cancers) treated by intra-arterial (IA) chemotherapy. Fifteen of them were treated for locally advanced or recurrent disease and one in an adjuvant setting. The chemotherapy was administered via a femoral IA catheter with its tip located above the aortic bifurcation, under the inferior mesenteric artery. It consisted of eight push injections, given over a 48-h period, of the following drug combination: cisplatin 8.5 mg m(-2), 5-FU 275 mg m(-2), methotrexate 27.5 mg m(-2), mitomycin C 1.2 mg m(-2), and bleomycin 4 mg m(-2). Leucovorin was given po, 4 x 15 mg day(-1), during the chemotherapy and for 3 days thereafter. A total of 52 cycles of treatment were administered. Of the 15 patients evaluable for response, six obtained a CR (three PE, three AC) and eight a PR. Among the complete responders, four are alive and disease-free 2-15 years after treatment. The other patients enjoyed an objective response lasting 3-25 months (median 7 months). Four patients developed grade III/IV haematological toxicity with three episodes of febrile neutropenia, one of them with a fatal outcome due to patient's failure to obtain medical attention at the onset of his fever, one a grade III mucositis of the glans, and four a grade III/IV cutaneous toxicity, the latter caused by the IA administration of bleomycin. In conclusion, IA chemotherapy is effective and potentially curative in locoregionally advanced or recurrent carcinomas of the penis and of the anus. Its contribution in the primary management of advanced penile or anal carcinoma should be prospectively investigated.

Combined radioimmunotherapy and radiotherapy of liver metastases from colorectal cancer: a feasibility study.

BACKGROUND: A combination of radioimmunotherapy (RIT) and radiotherapy (RT) should allow one to increase the dose of radiation targeting a particular tumour without the concomitant increase of toxic side effects. This might be obtained if the dose limiting side effect of each individual radiation therapy concerned different organs. METHODS: Six patients with limited liver metastatic disease from colorectal cancer were treated with 6.9 GBq (range 4.7 to 8.4 GBq) 131I-labelled anti-CEA MAb F(ab')2 fragments combined with 20 Gy RT to the liver. Both treatments were given in close association, according to timing schedules evaluated in animals that gave the best results. RESULTS: Reversible bone marrow and liver toxicity was observed in 6 and 5 patients, respectively. Three patients who first received 20 Gy RT to the liver, showed a significant platelet drop upon completion of RT. Repeat computerized tomography (CT) after 2 months showed a minor response in 1 patient and stable disease in 3 patients. CONCLUSION: The study shows potential ways of combining RIT and RT, suggesting that this combination is feasible for the treatment of liver metastases.