Small cell neuroendocrine carcinoma of larynx: case series and literature review.

BACKGROUND: Primary small cell neuroendocrine carcinoma of larynx is a rare, aggressive type of malignancy. As only about 200 cases worldwide have been reported, any larger institutional experience is valuable. This study reports our experience in managing this rare entity. METHODS: Of the nine patients identified, three had metastatic cancer at the time of diagnosis. Four patients underwent radical treatment: one was managed surgically followed by adjuvant chemotherapy and consolidation radiotherapy; the remaining three were treated with neoadjuvant chemotherapy and definitive radiotherapy. RESULTS: Of the 4 patients treated with radical intent, 1 was alive and disease free after 99 months, 2 died of metastatic disease after 22 and 26 months, and 1 was alive after 20 months with a diagnosis of recurrent disease. CONCLUSION: Our relatively small number of patients confirms other centres' experiences. This cancer has a poorer prognosis than most other head and neck cancers. Although the logistics would be challenging, there is a need for international multicentre trials for this disease modelled on those performed for other cancers, as has been done for paediatric malignancies.

Priorities for the head and neck cancer patient, their companion and members of the multidisciplinary team and decision regret.

AIMS: To compare the treatment outcome priorities of patients, their companions and members of the multidisciplinary team (MDT), and also to determine if the former two groups suffered from regret of their decision. MATERIALS AND METHODS: Patients were eligible if attending with a companion at least 6 months after radiotherapy for head and neck cancer given with curative intent. They were interviewed by two clinicians separately with questions from the Chicago Priority Scale and Ottawa Decision Regret Scale. RESULTS: In total, 30 patients, 30 companions and 25 members of the MDT were evaluated. 'Being cured of my cancer', 'living as long as possible', 'having no pain' and 'being able to swallow all foods and drinks' were the top four priorities for all three groups. Patients ranked 'having no pain' lower than either companions (P=0.003) and members of the MDT (P=0.006). Patients ranked 'keeping my appearance unchanged' as less important than members of the MDT (P=0.013) and 'keeping my normal sense of taste and smell' as more important than members of the MDT (P=0.013). The post-treatment regret score was 12.50 for patients and 10.33 for companions out of 100 (P value was not significant). CONCLUSIONS: There was a strong agreement between patients, their companions and members of the MDT with regards to priorities in head and neck cancer outcomes and low post-treatment regret for patients and their companions. These results suggest that the patients' companions and members of the MDT are able to exercise good judgment when it comes to supporting patients in decision making.

Clinical challenges in the implementation of a tomotherapy service for head and neck cancer patients in a regional UK radiotherapy centre.

OBJECTIVE: Intensity-modulated radiotherapy (IMRT) is increasingly being used to treat head and neck cancer cases. METHODS: We discuss the clinical challenges associated with the setting up of an image guided intensity modulated radiotherapy service for a subset of head and neck cancer patients, using a recently commissioned helical tomotherapy (HT) Hi Art (Tomotherapy Inc, WI) machine in this article. We also discuss the clinical aspects of the tomotherapy planning process, treatment and image guidance experiences for the first 10 head and neck cancer cases. The concepts of geographical miss along with tomotherapy-specific effects, including that of field width and megavoltage CT (MVCT) imaging strategy, have been highlighted using the first 10 head and neck cases treated. RESULTS: There is a need for effective streamlining of all aspects of the service to ensure compliance with cancer waiting time targets. We discuss how patient toxicity audits are crucial to guide refinement of the newly set-up planning dose constraints. CONCLUSION: This article highlights the important clinical issues one must consider when setting up a head and neck IMRT, image-guided radiotherapy service. It shares some of the clinical challenges we have faced during the setting up of a tomotherapy service. Implementation of a clinical tomotherapy service requires a multidisciplinary team approach and relies heavily on good team working and effective communication between different staff groups.

Preoperative short-term radiation therapy (25 Gy, 2.5 Gy twice daily) for primary resectable rectal cancer (phase II).

To evaluate the feasibility, effectiveness, and long-term bowel function of preoperative hyperfractionated accelerated radiotherapy in primary resectable rectal cancer. A total of 184 consecutive patients (median age 65 years, male : female=2 : 1) with clinical T3Nx rectal adenocarcinoma received preoperative pelvic radiation therapy with single fractions of 2.5 Gy twice daily (interval 6 h between fractions) to a total dose of 25 Gy within 1 week. Surgery was conducted the following week. Postoperative histology revealed UICC stage I in 33%, stage II in 26%, stage III in 34%, and stage IV in 7% of the patients. Median follow-up was 43 months (53 months for surviving patients). The actuarial 4-year-local-recurrence rate was 2.1%, overall recurrence 23%. Disease-specific and disease-free survivals at 4 years (excluding stage IV) were 82 and 69%, respectively. Overall survival for 4 years was 68%. Postoperative mortality was 0.5% (one patient), early anastomotic leakage occurred in 11.4%, and anastomotic stenosis requiring treatment in 6%, of 132 patients with primary anastomosis. Seven of 184 patients (3.8%) died of abdominal complications, all within the first year. Bowel function was satisfactory after more than 5 years. Local control in primarily resectable rectal cancer after 10 x 2.5 Gy is excellent, warranting further evaluation of this treatment.

Hyperfractionated accelerated radiochemotherapy (HFA-RCT) with mitomycin C for advanced head and neck cancer.

To investigate efficacy and feasibility of hyperfractionated accelerated radiotherapy combined with mitomycin C, patients with locally advanced unresectable squamous cell carcinomas of the head and neck region were administered 64-66 Gy in four weeks and mitomycin C (20 mg/m(2)) on day five. Twenty-one consecutive patients were included between November 1997 and June 1999 (median age: 57 years). All tumours were stage T3-4 and 18/21 were N2-3. Eighteen patients experienced grade 3 and three patients grade 2 mucosal toxicity. With median follow up for surviving patients of 42 months, loco-regional control was 55% at three years, overall survival was 33% at three years. This treatment is at the edge of local tolerability, but there is a good curative chance even for very advanced localised tumours, provided a complete remission is induced at primary treatment.

Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers.

BACKGROUND AND PURPOSE: Radiation therapy is often the primary treatment for advanced cases of head and neck cancers not considered suitable for radical surgery. In these cases locoregional tumour control rates are low and has warranted innovative treatment modifications, such as altered fractionation schedules and combination with chemotherapy. PATIENTS AND METHODS: From October 1990 to December 1997, 239 patients with squamous cell cancers originating in the head and neck region were randomized to one of three treatment options. Standard therapy consisting of conventional fractionation with 70 Gy in 7 weeks in 35 fractions (CF). The second treatment option consisted of a continuous hyperfractionated accelerated radiotherapy delivering a total dose of 55.3 Gy in 33 fractions over 17 consecutive days (V-CHART). The third study arm had identical fractionation and dose as the above accelerated treatment, with the additional administration of 20 mg/m(2) mitomycin C (MMC) on day 5 of treatment (V-CHART+MMC). RESULTS: Main toxicity resulted from accelerated fractionation in confluent mucositis (Grade 3-4 in 95%) requiring nasogastral tube feeding, analgetics and antiphlogistics in the majority of cases. Haematological toxicity Grade 3-4 was seen after MMC administration in 18%. MMC administration did not influence mucosal reaction. Overall duration of mucositis was not different in the three treatment groups. Loco-regional tumour control was 31% after CF, 32% after V-CHART and 48% after V-CHART+MMC, respectively (P<0.05). Overall crude survival was 24% after CF, 31% following V-CHART and 41% after V-CHART+MMC, respectively (P<0.05). Median follow up was 48 months (assessment performed in February 1999). CONCLUSION: Following shortening overall treatment time from 7 weeks to 17 consecutive days and dose of radiotherapy from 70 to 55.3 Gy the results in the radiotherapy only treated patients are identical. A significant improvement regarding local tumour control and survival was seen following administration of MMC to the accelerated fractionated treatment.

Ambulant photodynamic therapy of superficial malignomas with 5-ALA in combination with folic acid and use of noncoherent light.

This study reports our first results of ambulant photodynamic treatment with 5-aminolevulinic acid (5-ALA) in combination with folic acid and subsequent illumination with a noncoherent light source. The compound was topically applied to avoid total body skin sensitivity which occurs in the case of systemic administration. If no therapeutic response could be proved, we added folic acid to 5-ALA for a further treatment attempt. Illumination was performed by broad band red thermic light to also excitate reaction products with absorption bands located near to that of the sensitizer. As a result, we observed a response in all cases, however, in some cases only after the addition of folic acid.

The value of pretreatment cell kinetic parameters as predictors for radiotherapy outcome in head and neck cancer: a multicenter analysis.

PURPOSE: The aim of this study was to assess the potential of pre-treatment cell kinetic parameters to predict outcome in head and neck cancer patients treated by conventional radiotherapy. MATERIALS AND METHODS: Data from 11 different centers were pooled. Inclusion criteria were such that the patients received radiotherapy alone, and that the radiotherapy was given in an overall time of at least 6 weeks with a dose of at least 60 Gy. All patients received a tracer dose of either iododeoxyuridine (IdUrd) or bromodeoxyuridine (BrdUrd) intravenously prior to treatment and a tumor biopsy was taken several hours later. The cell kinetic parameters labeling index (LI), DNA synthesis time (Ts) and potential doubling time (Tpot) were subsequently calculated from flow cytometry data, obtained on the biopsies using antibodies against I/BrdUrd incorporated into DNA. Each center carried out their own flow cytometry analysis. RESULTS: From the 11 centers, a total of 476 patients conforming to the inclusion criteria were analyzed. Median values for overall time and total dose were 49 days and 69 Gy, respectively. Fifty one percent of patients had local recurrences and 53% patients had died, the majority from their disease. Median follow-up was 20 months; being 30 months for surviving patients. Multivariate analysis revealed that T-stage, maximum tumor diameter, differentiation grade, N-stage, tumor localization and overall time correlated with locoregional control, in decreasing order of significance. For the cell kinetic parameters, univariate analysis showed that only LI was significantly associated with local control (P=0.02), with higher values correlating with a worse outcome. Ts showed some evidence that patients with longer values did worse, but this was not significant (P=0.06). Tpot showed no trend (P=0.8). When assessing survival in a univariate analysis, neither LI nor Tpot associated with outcome (P=0.4, 0.4, respectively). Surprisingly, Ts did correlate with survival, with longer values being worse (P=0.02). In the multivariate analysis of local control, LI lost its significance (P=0.16). CONCLUSIONS: The only pretreatment kinetic parameter for which some evidence was found for an association with local control (the best end-point for testing the present hypothesis) was LI, not Tpot, and this evidence disappeared in a multivariate analysis. It therefore appears that pretreatment cell kinetic measurements carried out using flow cytometry, only provide a relatively weak predictor of outcome after radiotherapy in head and neck cancer.

Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancer.

PURPOSE: To evaluate the effect of mitomycin C to an accelerated hyperfractionated radiation therapy. The aim was to test a very short schedule with/without mitomycin C (MMC) with conventional fractionation in histologically verified squamous cell carcinoma of the head and neck region. METHODS AND MATERIALS: From October 1990 to December 1996, 188 patients entered the trial. Tumors originated in the oral cavity in 54, oropharynx in 82, larynx in 20, and hypopharynx in 32 cases, respectively. Patients' stages were predominantly T3 and T4 (158/188, 84%) and most patients had lymph node metastases (144/188, 77%) at diagnosis. Only 22 patients were female, 166 were male, the median age of patients was 57 years (range 34 to 76 years). Patients were randomized to one of the following three treatment options: conventional fractionation (CF) consisting of 70 Gy in 35 fractions over 7 weeks (65 patients) or continuous hyperfractionated accelerated radiation therapy (V-CHART; 62 patients) or continuous hyperfractionated accelerated radiation therapy with 20 mg/sqm MMC on day 5 (V-CHART + MMC; 61 patients). By the accelerated regimens, the total dose of 55.3 Gy was delivered within 17 consecutive days, by 33 fractions. On day 1, a single dose of 2.5 Gy was given, from day 2 to 17 a dose of 1.65 Gy was delivered twice: the interfraction interval was 6 hours or more. RESULTS: Mucositis was very intense after accelerated therapy, most patients experiencing a grade III/IV reaction. The mucosal reaction did not differ whether MMC was administered or not. Patients treated by accelerated fractionation experienced a confluent mucosal reaction 12-14 days following start of therapy and recovered (no reaction) within 6 weeks. The skin reaction was not considered different in the three treatment groups. Those patients treated with additional chemotherapy experienced a grade III/IV hematologic toxicity in 12/61 patients. Initial complete response (CR) was recorded in 43% following CF, 58% after V-CHART, and 67% after V-CHART + MMC, respectively (p < 0.05). Actuarial survival (Kaplan-Meier) was significantly improved in the combined treated patients. Local tumor control was 28%, 32%, and 56% following CF, V-CHART, and V-CHART + MMC, respectively (p < 0.05). CONCLUSION: We conclude that our continuous hyperfractionated accelerated radiation therapy regimen is equal to conventional fractionation, suggesting that by shortening the overall treatment time from 7 weeks to 17 days a reduction in dose from 70 Gy to 55.3 Gy is possible, with maintenance of local tumor control rates. The administration of MMC to the accelerated regimen is tolerable and improves the outcome for patients significantly.

Postoperative irradiation of laryngeal carcinoma--the prognostic value of tumour-free surgical margins.

Between 1972 and 1987, two hundred and five carcinoma patients were treated with surgery and postoperative radiotherapy. The histological confirmation of tumour-free margins was only predictive of significant differences in locoregional control in locally advanced disease. In addition, macroscopically assessed margins in advanced cases were predictive of survival probability. We suggest that the adjuvant radiotherapy was able to reduce the incidence of locoregional recurrence in the early stage microscopic positive group, hence the lack of a significant difference in the control rates. The effect on survival is therefore indirect. The advanced cases showed significantly reduced locoregional control rates and disease-specific survival times after macroscopic assessment of positive margins, possibly a sign of tumour extension beyond the margins of the radiation field. We compare our results with published reports of cases not receiving adjuvant therapy.

Conventional vs accelerated fractionation in head and neck cancer.

From October 1990 to March 1994, 90 patients entered a prospectively randomised trial in head and neck cancer. All patients had verified squamous cell carcinoma and were referred for primary radiation therapy. Tumours originated in the oral cavity in 25, oropharynx in 37, larynx in 15 and hypopharynx in 13 cases. Patients' stages were predominantely T3 and T4 (71/90) and had lymph node metastases (60/90). Seventy-nine male patients and 11 female patients, with a median age of 57 years (range 37-76 years) were treated. Patients were randomised to one of three treatment options: conventional fractionation (CF) consisting of 70 Gy in 35 fractions over 7 weeks or continuous hyperfractionated accelerated radiation therapy (Vienna-CHART) or Vienna-CHART with administration of a single dose of mitomycin C on day 5 of treatment (V-CHART + MMC). By the accelerated regimen a total dose of 55.3 Gy was given in 33 fractions within 17 consecutive days. Acute mucositis was the main toxicity recorded in those patients treated by accelerated fractionation, although the overall duration of mucosal reaction did not differ in the three treatment groups. There was no influence on local toxicity if MMC was added to radiation therapy or not. Those patients treated with additional MMC experienced a grade III/IV haematological toxicity in 4/28 cases. Complete remission (CR) was recorded in 48% following CF, 79% after Vienna-CHART (P < 0.05) and 71% after Vienna-CHART + MMC. The overall local failure rates were 73%, 59% and 42% (P = NS) for patients treated by CF, Vienna-CHART and Vienna-CHART + MMC respectively.

High-dose cyclophosphamide, adriamycin, and vincristine (HD-CAV) in children with recurrent solid tumor.

A dose-intensive regimen of cyclophosphamide (140 mg/kg over 2 days), doxorubicin (Adriamycin, 75 mg/m2 over 3 days), and vincristine (1 mg/m2 on days 1, 2, and 3 and 1.5 mg/m2 on day 9) was tested in 18 children and adolescents with poor-prognosis recurrent or refractory solid tumors. Nine were affected by neuroblastoma, 3 by Ewing's tumors, 2 by rhabdomyosarcoma, 2 by synovial sarcoma, 1 by hepatocellular carcinoma, and 1 by osteogenic sarcoma. All enrolled patients were heavily pretreated, including 2 patients after bone marrow transplantation. Forty courses were applied (median, 2). The overall response rate was 33% (2 complete remissions and 4 partial remissions). Responses were obtained in children with neuroblastoma, Ewing's tumors, and hepatocellular carcinoma. Myelosuppression [World Health Organization (WHO) grade IV after all courses] and cardiac toxicity (3 WHO grade I, 5 WHO grade III, and 3 WHO grade IV) were the main side effects. Nephrotoxicity and hepatoxicity were not observed. With further therapy consisting of surgery, radiotherapy, and high-dose chemotherapy [cisplatin, carboplatin/etoposide (VP16), or ifosfamide/VP16 with or without autologous stem cell reinfusion after conditioning with melphalan/VP16/carboplatin], 3 complete remissions and 5 very good partial remissions were obtained. Ten of 18 patients are alive after a median follow-up of 16 months.

[Atypical fractionation in advanced squamous-cell carcinomas of the head-neck area]. / Atypische Fraktionierung bei fortgeschrittenen Plattenepithelkarzinomen der Kopf-Hals-Region.

From May 1990 to May 1991, 23 patients with advanced, inoperable squamous cell cancers, clinically staged as III or IV, were treated by unconventional fractionation radiotherapy. Treatment consisted of a continuous hyperfractionated accelerated radiotherapy, delivering a total dose of 55.3 Gy within 17 consecutive days. In ten patients radiation therapy was combined with chemotherapy; 20 mg mitomycin C/m2, administered by intravenous bolus injection on day 5 of treatment. Apart from a confluent mucositis, treatment tolerance was good. Haematological toxicity from mitomycin C was minor and did not require any specific therapy. The mucosal reaction lasted six weeks (median duration) and was not thought to be increased by additional chemotherapy. In twelve of 23 patients a complete remission of the primary tumour was seen, in patients with lymph node metastases there was a complete response in 14 out of 20 patients. After a median follow-up of 18 months, ten of 23 patients have survived (8/23 without evidence of disease). Eleven patients have died due to local tumour progression and one patient died with distant metastases, being without evidence of local tumour. The advantage of this unconventional fractionation, which takes the described short potential tumour doubling time for head and neck cancers into account, is discussed.

Mitomycin C, 5-fluorouracil and radiation in advanced, locally recurrent rectal cancer.

15 patients with inoperable presacral recurrent rectal cancer following surgery were treated with combined radiation and chemotherapy. Treatment consisted of split-course radiotherapy with 50 Gy in 25 fractions over 5 weeks and, after 4 weeks, an additional 20 Gy in 10 fractions over 2 weeks. At the start of treatment and following the split course, chemotherapy was administered. Mitomycin C was given on Day 1 (dose: 15 mg/m2 i.v. bolus) and 5-fluorouracil from Day 1 to Day 5 (dose: 750 mg/m2/24 h, continuous i.v. infusion). Owing to considerable, predominantly haematological and gastrointestinal toxicity, only six out of 15 patients received treatment according to the protocol. The symptomatic relief of symptoms was good. Pain was controlled in seven of eight symptomatic patients. Seven of the patients showed response according to computed tomography, but in none of these cases was a complete remission seen. After a follow-up of at least 30 months, only three patients are alive. The 1-, 2- and 3-year survival rates are 9/15, 6/15 and 3/12, respectively. The median survival is 14 months (range 4-60+ months). In comparison with historical data from the same institution, combined radio-chemotherapy did not show any prolongation of survival or increased response rate, but increased toxicity excessively, when compared with radiation alone.

Mode of interaction of 5-fluorouracil, radiation, and mitomycin C: in vitro studies.

An examination of the effects of radiation combined with either 5-fluorouracil, Mitomycin C, or both drugs in vitro has been made using a mouse squamous tumor cell line SCC VIITo and cell viability as an endpoint. Depending on how the survival endpoint was calculated, the interaction of 5-fluorouracil, Mitomycin C, or 5-fluorouracil plus Mitomycin C with radiation was greater than additive (plating efficiency) or only additive (viable cells per flask). These results suggest that the cytostatic effect of these drugs may be an important aspect of their action clinically.

Combined radiation therapy, mitomycin C, and 5-fluorouracil for locally recurrent rectal carcinoma: results of a pilot study.

Twenty-two patients underwent combined radiation therapy (XRT), mitomycin C (MMC), and 5-fluorouracil (5FU) for rectal carcinoma, locally recurrent following either abdominoperineal or anterior resections. All patients presented with symptomatic unresectable pelvic cancer. The protocol XRT doses were 45-50 Gy/20/4-6 weeks. Chemotherapy consisted of MMC 10 mg/m2 on day 1, and 5FU 15 mg/kg/day on days 1, 2, and 3 of XRT, both given by intravenous bolus injection. Only 2 of 22 patients remained NED at 5 years following treatment. All but four patients eventually experienced progression of pelvic disease. Ten of 22 patients were unable to complete the treatment protocol because of excessive acute hematological and gastrointestinal toxicity. Five patients developed neutropenic sepsis, one of whom died. Combined XRT, MMC, and 5FU as used in this study had no apparent advantage over XRT alone in terms of pelvic disease or survival, and produced significant toxicity.

[Incidence of osteoradionecrosis after combined radiotherapy-chemotherapy of head and neck tumors]. / Inzidenz der Osteoradionekrose nach kombinierter Radio-Chemotherapie von Kopf- und Halstumoren.

Combined modality therapy, consisting of radiation, chemotherapy and surgery are used to treat primary tumours aiming to preserve function and increase tumour control. In the present prospective trial 112 patients underwent combined preoperative radio-chemotherapy, 35 patients were treated with combined radio-chemotherapy as only treatment. At a median follow-up of 26 months eight patients (2.8%) have developed an osteo-radionecrosis, which is comparable with data from the literature. When known risk factors are avoided the incidence of osteo-radionecrosis is not increased following combined therapy. The most important factors for development of osteo-radionecrosis following radio-chemotherapy are large tumours and tumour infiltration in the mandible.

Combined modality treatment of advanced cancers of the oral cavity and oropharynx.

From May 1985 to June 1988, 70 evaluable patients with advanced squamous cell cancers of the oral cavity and the oropharynx were treated with preoperative combined radio-chemotherapy. Treatment consisted of 50 Gy/25 fractions/5 weeks, combined with concomitant administration of mitomycin C on day 1 (15 mg/m2, i.v. bolus) and 5-fluorouracil during the first 5 days of irradiation (750 mg/m2/24 hours, continuous infusion). Surgery was performed 3 to 5 weeks following irradiation. Treatment tolerance was good and local mucosal reaction was increased, but no major systemic side effects were recorded. At surgery, 3-5 weeks following irradiation, 48.6% of the operation specimens did not contain any histologically detectable residual tumor. Overall survival is 61%, being 69% in T2 and T3, while none of the patients with bone invasion has survived. Median survival is 28, 26, and 9 months in T2, T3 and T4 stages, respectively. Loco-regional relapses have been recorded in 33% of the patients, occurring in 27% of T2, 25% of T3, and 88% of T4 stages. Patients have been spared mutilating radical neck dissection because of combined presurgical treatment without impaired survival or loco-regional relapse rate.