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.

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 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.

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.

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.

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.

Electron beam therapy in treatment of parotid neoplasm.

In a retrospective analysis, 42 patients with malignant primary tumor of the parotid gland were evaluated considering survival, local recurrence and tolerance of treatment. All patients referred to radiotherapy were treated by electron beam (10-15 MeV) and followed for more than 5 years. Postoperative radiotherapy after radical operation, with no macroscopic disease, was performed in 18 patients, 7 of whom were treated by radical re-operation and radiation of a recurrent parotid neoplasm. In these groups, the local recurrence rate was 4/18 (22%) and 2/7 (29%), the 5-year survival rate was 9/18 (50%) and 5/7 (71%). In 17 patients, radiotherapy started with gross tumor left behind. This group showed a local recurrence rate of 10/17 (59%) and a 5-year survival of 7/17 (41%). Treatment was well tolerated with no major sequelae. Local tumor control and its impact on survival is discussed.

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.

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.

Treatment of choroid metastases.

Sixteen patients with choroid secondary tumours were treated with irradiation consisting of 40-50 Gy in 3-5 weeks. There were 14 female patients with breast cancer, one male patient with prostatic cancer and one male patient with cancer of unknown origin. In four cases bilateral ocular metastases were seen. Ten out of 20 treated eyes showed complete response to treatment, seven out of 20 showed partial response and three out of 20 were not influenced by irradiation. Survival of patients, all having widespread metastatic disease, was 3-48 months (median 20 months). All patients responding to treatment showed increased quality of life.

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.

Radiotherapy of epidermoid anal canal cancer.

Forty-eight patients with anal canal cancers were treated with surgery and irradiation or irradiation alone during the period 1970-1982. All cases were treated by external megavoltage equipment. The overall 5-year survival was 50%, and the local recurrence rate 33%. According to the therapy, four major groups were analysed: radical surgery followed by post-operative irradiation (5-year survival 43%, local recurrence rate 38%), incomplete major surgery and post-operative irradiation with very inferior prognosis (none of the patients surviving beyond 52 months). Two groups of patients had sphincter-saving procedures: local surgery followed by irradiation (5-year survival 78%, local recurrence rate 22%) and primary irradiation (5-year survival 57%, local recurrence rate 14%). Lymph node positive patients showed a median survival of 24.5 months against 52 months in N0 cases (5-year survival 21% against 50%). Side-effects of radiotherapy were transient and mild, and no late severe sequelae were seen. The data indicate that post-operative external radiotherapy seems insufficient and unable to decrease the local recurrence rate, especially when surgery is incomplete. Both spincter-saving surgery and radiotherapy, as well as primary irradiation, are effective treatment modalities. These data are analysed and future aspects considering combined radiochemotherapy are discussed.

Histological grading of therapy induced regression in squamous cell carcinomas of the oral cavity. A morphological and immunohistochemical study.

Squamous cell carcinomas in the oral cavity and the oropharynx were diagnosed in 84 patients. After verification by biopsy, 79 of these patients were treated preoperatively with mitomycin C and 5-fluro-uracil, radiated and operated 3-5 weeks later. The effectiveness of adjuvant preoperative radio-chemotherapy was evaluated histologically. Serial sections of the entire tumor specimen were investigated and the percentage of vital cancerous tissue in the total tumor area was assessed. Regression was classified into four grades. Grades I and II were regarded as good response to adjuvant preoperative radio-chemotherapy, while grades III and IV stood for bad or no response. Morphologically questionable residual tumor infiltrates could be clarified by immunohistochemical methods with antibodies against vimentin, desmin and Lu-5. The histological assessment of the regression grade of operated tumor specimens allows a clinically relevant, morphologically exact and reproducible evaluation of the effect of preoperative radiochemotherapy.

Interstitial radiotherapy with Ir-192 as a palliative treatment modality in head and neck cancer.

In selected patients with advanced head and neck cancer interstitial radiotherapy with Ir-192 can be used as a palliative treatment. Using two cases as examples, we report on our experiences with 19 patients.

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.

[Combined radio- and chemotherapy of anal cancer]. / Kombinierte Radio-Chemo-Therapie des Analkarzinoms.

The treatment regime in anal carcinoma is changing from being a mainly surgical problem. Combined radio-chemotherapy is of increasing interest as treatment of choice. The new treatment modality, including chemotherapy with Mitomycin C and 5-fluorouracil combined with percutaneous and interstitial radiotherapy is presented. The treatment regimes performed at the University Department for Radiotherapy and Radiobiology Vienna is discussed with regard to tolerance, side effects and local control.

[Cloning of solid tumors in double agar (human tumor stem cell assay]. / Cloning von soliden Tumoren im Doppelagar (human tumour stem cell assay).

62 specimens from 37 patients with solid malignant tumours were cloned by the human tumour stem cell assay (HTSCA). The growth rate, the use of two different disaggregation methods and their influence on vitality and plating efficiency were analyzed as well as the cloning rate from different tumour regions and metastases. The growth rate was 68%, and there was a significant difference in the vitality, depending on which mode of disaggregation was used. Enzymatic disaggregation showed a higher vitality than the mechanical method, although there was no difference in plating efficiency (PE). There was a marked heterogeneity in the PE of specimens from different sites of the same tumour and lymph node metastases (variation coefficient 0.507 and 2.093 respectively). The possibilities and limitations of the HTSCA are discussed with respect to our own results and those in the literature.

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.

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.