Study Protocol: Prospective Study of Concurrent Chemoradiotherapy with S-1 and Hypofractionated Radiotherapy for Outpatients with Early Glottic Squamous Cell Carcinomas

Background: The recommended treatment strategies for early glottic carcinoma with intent of larynx preservation areprimarily radiotherapy. However, the outcomes of radiotherapy for bulky T1 or T2 glottic carcinoma are unsatisfactory.We designed a protocol consisting of concurrent chemoradiotherapy using S-1 as the radiosensitizer. We have performedthis protocol in patients with favorable T2 lesions and demonstrated its efficacy and safety. In contrast, we havetreated non-bulky T1 glottic carcinomas with 2.25 Gy per fraction, for a total of 25-28 fractions, starting in 2011 toimprove efficacy and shorten the treatment period. Since this treatment strategy was implemented for T1 disease, nolocal failure has occurred to date, and it appears to be almost as safe as radiotherapy using 2.0 Gy per fraction. Withthe aim of improving the local control rate and shortening the treatment period primarily for favorable T2 disease, wechanged the dose of radiation in our protocol from 2.0 Gy to 2.25 Gy per fraction, for a total of 25 fractions (from 30fractions). The present study aims to evaluate the efficacy and safety of this new protocol. Methods: This study willbe conducted as a clinical, prospective, single-armed, non-randomized trial. Patients are to receive S-1 (55.3 mg /m2/day, once daily) and radiotherapy (2.25 Gy per fraction, for a total of 25 fractions). S-1 and radiotherapy are startedon the same day that radiotherapy is performed, 3-6 hours after oral administration of S-1. The primary study aim isthe 3-year local control rate. The secondary study aims are overall survival, voice-preservation survival, disease-freesurvival, complete response rate, completion rate, and toxicity. Result and conclusion: This is the first single-center,non-randomized, prospective study of concurrent chemoradiotherapy with S-1 and hypofractionated radiotherapy tobe conducted. The trial will evaluate the efficacy and safety of our protocol.     

Early glottic cancer: The influence of primary treatment on voice preservation

Retrospective analysis was performed to assess the influence fo primary surgical or irradiation treatment on local control, survival, and final preservation of larynx in comparable groups of patients with T1N0 and T2N0 glottic cancer.

Two hundred sixty-three previously untreated patients with invasive squamous cell carcinoma of the glottis (187T1 and 76T2) were treated with primary radiotherapy (159T1 and 60T2) or primary surgery (28T1 and 16T2) between January 1976 and December 1990, at the University of Ljubljana, Slovenia. Conventional one daily fraction of 2 Gy to doses of 60–74 Gy (median: 65 Gy) were used in 98% of primarily irradiated patients through out the observed period. To enable better comparison between the two treatment groups, primarily irradiated patients were retrospectively stratified by the criteria of suitability for primary voice-sparing operation. Several host, tumor, and treatment parameters were analyzed.

Only the stage of the disease significantly influenced both 10-year recurrence-free and disease-specific survival regardless primary treatment modality (p = 0.0002). In all primary irradiated patients local control was significantly better for those with overall treatment time of less than 48 days (p = 0.007). In patients suitable for voice-sparing operation, local control of primarily operated patients was similar to that of patients primarily irradiated with shorter overall treatment time, which was 93 and 88% for T1 and 67 and 64% for T2 tumors, respectively. Ultimate local control in primary surgery and radiotherapy group was 96 and 96% for T1 and 89 and 88% for T2 tumors, respectively. Equal larynx preservation of 100% in T1 and 90% in T2 patients was achieved in finally cured primarily operated patients and those patients primarily irradiated with a shorter overall treatment time. If treatment time was longer than 48 days, significantly worse final larynx preservation of 84% in T1 and 75% in T2 patients was observed (p = 0.003). In patients unsuitable for voice sparing operation, 87% of T1 and 50% of T2 patients in primary radiotherapy group finally had their larynx preserved.

Stratification based on criteria of possibility for initial voice-sparing operation is important when comparing primary surgery with primary radiotherapy treatment in ealry glottic cancer. The detrimental effect of prolonged treatment time of irradiation resulted not only in inferior local control rate but also in worse final larynx preservation.     

Radiation therapy in early carcinoma of the glottic larynx T1NOMO

: The Purpose of this report is to present the local control rate and survival of patients treated by radiation therapy for T1N0M0 squamous cell carcinoma of the glottic larynx.

: A total of 41 patients squamous cell carcinoma of the glottis were treated at the Veterans Administration Medical Center Minneapolis, MN, between 1976 and 1990. Of the 41 patients, 40 are available for retrospective analysis with a minimum of a 2-year follow-up and a median follow-up of 5.8 years. Treatment was given to all the patients by a 4 MeV linear accelerator. The vast majority of the patients were treated with bilateral laryngeal opposed wedged 6 × 6 cm fields with a dose of 1.75 Gy per fraction to a total of 70 Gy in 40 fractions over 56 elapsed treatment days.

: The data indicated local control and survival of 92.3% at 2 years and 91.8% at 3 years, post irradiation, with ultimate disease-free survival after surgical salvage of 97.4% and 97.2% at 2 years and 3 years, respectively. These local control and survival rates are comparable to those published in the literature when a higher fractional dose was given. No patients developed notable complications with out technique.

: A dose of 1.75 Gy to 1.8 Gy per fraction to a total of 70 Gy in 56 elapsed treatment days is well tolerated and yields ultimate disease free-survival of 97.2% at 3 years. This time-dose fractionation could be used safely for treating patients who demonstrate low tolerance to irradiation with a risk of laryngitis, laryngeal edema, or difficulty of swallowing, with a higher fractional dose.     

Is elective neck treatment indicated for T2N0 squamous cell carcinoma of the glottic larynx?

This is an analysis of 98 patients with T2N0 squamous cell carcinoma of the glottic larynx treated with radiation therapy. Patients received irradiation to the primary lesion alone; the neck was not treated electively. All patients had at least 2 years of follow-up; patients who died within 2 years from treatment with the neck continuously disease-free were excluded from the analysis. The rate of control of neck disease following irradiation was as follows: primary site continuously disease-free, 73/75 (97%); primary tumor recurrence, 18/23 (78%). Salvage treatment was successful in 4 of 7 patients who developed recurrent disease in the neck. We conclude that elective treatment to the clinically negative neck is not indicated for patients with T2N0 squamous cell carcinoma of the glottic larynx. However, patients who develop a local recurrence following irradiation have a substantial risk of harboring disease in the neck and should undergo a neck dissection in conjunction with the surgical procedure selected to resect the recurrent disease at the primary site.     

Glottic laryngeal carcinoma with fixed vocal cord treated with full-dose radiation, total laryngectomy or combined treatment

The results of the therapy of 46 patients with glottic squamous cell cancer with a fixed vocal cord and without regional lymph nodes (glottic T3N0) are reported. Primary surgery (total laryngectomy) in combination with preoperative irradiation gave significantly higher loco-regional control rate and survival rate than surgery alone. Primary radiotherapy with doses of 70 Gy or more and adequate follow-up was found to be an alternative to preoperative radiation and laryngectomy. The result of different treatment modalities speaks in favour of primary irradiation allowing preservation of the larynx and a good voice function. In case of recurrence salvage surgery with total laryngectomy is preferred.     

Treatment results and prognostic factors for advanced squamous cell carcinoma of the larynx treated with concurrent chemoradiotherapy

Objective

To review our experience with concurrent chemoradiotherapy (CCRT) for patients with advanced resectable squamous cell carcinoma (SCC) of the larynx and to evaluate the factors affecting survival and larynx preservation.

Study design

Retrospective study.

Subjects and methods

The records of 102 patients with stage III or IV resectable SCC of the larynx treated with CCRT between February 1994 and March 2009 were reviewed. Of 102 patients, 59 were treated with high-dose regimens, including cisplatin, 5-fluorouracil (5-FU), methotrexate, and leucovorin or docetaxel, cisplatin, and 5-FU, and 43 were treated with low-dose regimens, including carboplatin and uracil-tegafur or S-1. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8–2.0 Gray (Gy), to a total dose of 66.0–70.2 Gy. Overall survival (OS), disease-specific survival (DSS), and DSS with larynx preservation were estimated using Kaplan–Meier methods. The log-rank test and Cox proportional hazards regression were used to identify significant prognostic factors for DSS and DSS with larynx preservation.

Results

The 5-year OS and DSS for all patients treated with CCRT were 63.9 and 70.7 %, respectively. The 5-year DSS with larynx preservation was 54.1 %. On multivariate analysis, N stage, synchronous multiple primary cancers, and the contents of chemotherapy were significant predictors of OS for patients undergoing CCRT; T stage, N stage, and the contents of chemotherapy were significant prognostic factors for larynx preservation.

Conclusion

The treatment method including the indication for CCRT may be determined by the contents of the chemotherapy and the T and N stages of laryngeal SCC. It is important to diagnose multiple synchronous primary cancers before CCRT.     

Two cases of giant metastatic cervical lymphnode from oral cancer responding to concurrent chemoradiotherapy with S-1

We report two cases of giant metastatic cervical lymphnode from oral squamous cell carcinoma, successfully treated with concurrent chemoradiotherapy with S-1. Case 1 was a 80-year-old male who had an ipsilateral occult neck metastasis(52x46 mm mass)at level IV after surgery of the left tongue carcinoma(T2N0M0). Radiotherapy(2.0 Gy/day; 5 days/week)was given at a total dose of 66 Gy. Two courses of oral administration of S-1(61 mg/m2/day)for 2 weeks followed by 1-week rest period as one course was repeated with the concurrent radiotherapy. After the radiotherapy, the oral administration of S-1 alone was continued for 1 year under the same regimen. Case 2 was a 51-year-old male who had left tongue carcinoma(T4bN2cM0)with ipsilateral cervical lymphnode metastasis(88x44 mm mass). The same chemoradiotherapy(1.8 Gy/day; 5 days/week; a total dose of 63 Gy; S-1 53 mg/m2/day)was carried out as in case 1. These giant metastatic lymphnodes of case 1 and 2 disappeared by 3 and 6 months after radiotherapy, respectively, and achieved a complete response. This therapy may be effective not only for primary lesion of oral cancer, but also metastatic regional lymphnodes in some cases.     

Feasibility study on the MammoSite in early‐stage breast cancer: Initial experience

The aims of this study were to evaluate the feasibility, practicality, efficacy and safety of the delivery of accelerated partial breast irradiation using the MammoSite for the boost phase. Six patients aged 53–69 years with stage T1N0, T2N0, Grade I–II invasive ductal carcinoma received 9–10 Gy prescribed at 1 cm from the MammoSite balloon surface in two fractions of 4.5–5 Gy 6 h apart. The MammoSite was inserted 20–37 days postoperatively. External beam radiation therapy to the whole breast commenced 1–5 days after accelerated partial breast irradiation. The maximum skin dose ranged from 3 to 9 Gy. The skin‐cavity distance ranged from 7 to 19 mm. Local discomfort resolved as the scar healed spontaneously within 3–5 days. No Grade III or higher acute toxicity or local infection was recorded. The ease of insertion and accuracy of dosimetry makes the MammoSite suitable for use in properly selected women with early‐stage breast cancer in a trial setting.     

Clinical phase I trial of concurrent chemo-radiotherapy with S-1 for T2NO glottic carcinoma

We conducted a phase I study to determine a recommended dose (RD) of S-1 for chemo-radiotherapy consisting of S-1+ radiotherapy for T 2 N 0 larynx cancer. The method of administration used to assess the RD was irradiation with 2 Gy/day for 5 days a week until a total dose of 60 Gy, and concomitant administration of S-1 once a day for 2 weeks beginning on the day therapy was started followed by 2 weeks off the drug and 2 weeks on the drug with the dose escalating from S-1 60 mg/body/day (level 1) to 80 mg/body/day (level 2), and then to 100 mg/body/day (level 3). 18 patients were enrolled. 4 patients developed an adverse event of grade 3 radiation dermatitis which became a dose-limiting toxicity (DLT) at level 3. We then concluded that 100 mg/body/day was the maximum tolerated dose (MTD) of S-1 and decided that the RD of S-1 was 80 mg/body/day.     

Gimeracil, a component of S-1, may enhance the antitumor activity of X-ray irradiation in human cancer xenograft models in vivo

Chemoradiotherapy is a useful treatment strategy in patients with locally advanced cancers. In particular, combination of 5-fluorouracil (5-FU) with X-ray irradiation is effective for the treatment of some types of gastrointestinal cancers. We investigated the antitumor effects of combination treatment with X-ray and S-1, a unique formulation of 5-FU, on human cancer xenografts in nude mice and compared the efficacy of this treatment to that of radiotherapy combined with cisplatin, UFT, another oral 5-FU prodrug, and intravenous 5-FU. Tumors implanted into the left hind legs of mice were treated with a dose of 2 or 5 Gy X-ray irradiation on days 1 and 8, and S-1, UFT and 5-FU were administered for 14 days. The efficacy of combined treatment with 8.3 mg/kg S-1 and 2 Gy X-ray irradiation in treating non-small cell lung cancer xenografts (Lu-99 and LC-11) was significantly higher than that of treatment with S-1 alone or 2 Gy X-ray irradiation alone, and the antitumor activity of combined treatment was similar to that of 5 Gy X-ray irradiation alone. Although 8.3 mg/kg S-1 and 17.5 mg/kg UFT had equivalent antitumor activity; the antitumor efficacy of combination treatment with S-1 and 2 Gy X-ray irradiation on LC-11 tumors was significantly higher than that of combination treatment with UFT and 2 Gy X-ray irradiation. Combination treatment with S-1 and X-ray irradiation was also more effective against pancreatic tumors than combination treatment with intravenous 5-FU and X-ray irradiation. To elucidate the reason for the increased antitumor efficacy of combination treatment with S-1 and X-ray irradiation, the antitumor effect of gimeracil, one of the components of S-1, was tested in combination with 2 Gy X-ray irradiation. These experiments demonstrated that gimeracil enhanced the efficacy of X-ray irradiation against lung as well as head and neck cancer xenografts in a dose-dependent manner. Furthermore, we observed decreased expression of γ-H2AX protein, a marker of DNA repair, in LC-11 tumors treated with X-ray irradiation and gimeracil compared to that observed in tumors treated with X-ray irradiation alone, suggesting that gimeracil may inhibit rapid repair of X-ray-induced DNA damage in tumors. The present study suggests that chemoradiotherapy using S-1 acts through a novel mechanism and may prove useful in treating patients with locally advanced cancers whose disease progression is difficult to control using chemotherapy alone.     

Phase I/II study of hypofractioned radiation with three-dimensional conformal radiotherapy for clinical T3-4N0-1M0 stage esophageal carcinoma

Compared to conventional fractionated-dose radiotherapy, high hypofractionated-dose radiotherapy could yield tumoricidal effects. However, few clinical trials of hypofractionated radiotherapy in loco-regionally advanced incurable esophageal cancer at present have yet been performed. The purpose of the current study was to evaluate the efficacy and toxicity of hypofractioned radiation with three-dimensional conformal radiotherapy for clinical T3-4N0-1M0 stage esophageal carcinoma. From September 2003 to December 2005, 45 patients with locally advanced esophageal carcinoma were grouped and received three-dimensional conformal hypofractioned radiotherapy (3D-CRT) whose fractionated dose was gradually increase per group. Radiotherapy was administered to a total dose of from 50 to 54 Gy (fractionated dose of from 3.0 to 6.0 Gy, 3 times weekly), over a 3-4 week period. And patients received 4 cycles chemotherapy. The median follow-up period for survivors was 38 months. Treatment tolerance rate was 78.8% with daily dose of from 3 to 5 Gy. There are 21.2% patients occurring Grade ≥ 3 acute toxicities. But patients couldn't tolerate daily dose of 6 Gy (55.6%). The 1-year, 2-year and 3-year local control rates were 62%, 49% and 39% respectively. And the 1-year, 2-year and 3-year overall survival rates were 34%, 21% and 9% respectively. The median overall survival time was 17 months. At the time of following up, 13 patients (31.0%) had occurred esophageal late complications, with mainly esophageal perforation, hemorrhage or stenosis, including initial stenosis aggravation. Therefore hypofractionated irradiation was thought to be feasible for clinical T3-4N0-1M0 stage esophageal carcinoma. And daily dose of ≤5 Gy was comparatively suitable in hypofractionated irradiation for esophageal carcinoma, and the patients tolerated well. But further research was in need also.     

Anal margin carcinoma: 21 cases treated at the Institut Curie by exclusive conservative radiotherapy

Between 1962 and 1980, 21 patients with anal margin carcinoma were treated with exclusive radiotherapy. They were divided into 4 T1, 7 T2, 8 T3 and 2 T4 cases; only 3 cases presented with an N1 lymph node involvement (1 T2 and 2 T3). The tumor dose was 65 Gy in 22 fractions and 55 days; the inguinal dose was 50 Gy in 15 sessions and 50 days for prophylactic irradiation performed in 9/18 N0 patients, and 65 Gy with a limited 15 Gy boost for the 3 N1 cases. The results are: for T1, 4 patients alive and well out of 4; for T2, 3 out of 7; for T3, 2 out of 8; for T4, 2 out of 2. The overall survival was 11 out of 21 after 5 years. Severe complications occurred in 2 patients out of 21. Sphincter preservation was obtained in 9 patients out of 10 cured cases.     

ARCON: experience in 215 patients with advanced head-and-neck cancer

PURPOSE: "ARCON" combines accelerated radiotherapy to counteract tumor repopulation with carbogen breathing and nicotinamide to reduce chronic and acute hypoxia. The aim of this Phase II study was to assess the feasibility, toxicity, and potential effectiveness of ARCON for advanced head-and-neck cancer. METHODS AND MATERIALS: The study included 215 patients with head-and-neck carcinoma distributed as follows: larynx, n = 100; hypopharynx, n = 50; oropharynx, n = 52; oral cavity, n = 13; Stage II, n = 8, Stage III, n = 71, and Stage IV, n = 136. Accelerated radiotherapy was given to a total dose of 64-68 Gy in 2-Gy fractions within 36-38 days. This was combined with carbogen breathing during irradiation and administration of nicotinamide (60-80 mg/kg) 1-1.5 h before irradiation. RESULTS: There was full compliance with carbogen breathing in 88% of the patients. A nicotinamide dose of 80 mg/kg produced severe nausea and vomiting, necessitating discontinuation of the drug, in 31% of the patients. Adjustment of the dose to 60 mg/kg and antiemesis prophylaxis reduced the discontinuation rate to 10%. Confluent mucositis was observed in 91% of the patients with a median duration of 6 weeks. Grade 4 late complications occurred in 5% of the patients. The actuarial 3-year local control rates were 80% for larynx, 69% for hypopharynx, 88% for oropharynx, and 37% for oral cavity tumors. For T3-4 tumors, the local control rates were 80% for larynx, 60% for hypopharynx, 87% for oropharynx, and 29% for oral cavity. Regional control rates were 100% for N0, 93% for N1, and 74% for N2 disease. CONCLUSION: ARCON yields high local and regional control rates in advanced head-and-neck carcinomas, and compliance is satisfactory and morbidity acceptable. The local control rate of 80% for T3 and T4 larynx carcinomas offers excellent possibilities for organ preservation.     

Radiation therapy for T1,2 glottic carcinoma: impact of overall treatment time on local control

Purpose: Local control probabilities of T1,2 glottic laryngeal cancer were evaluated in relation to dose and fractionation of radiation therapy (RT). Materials and methods: Between 1975 and 1993, 96 T1N0M0 glottic cancers and 32 T2N0M0 glottic cancers were treated with definitive RT. Total RT dose was 60–66 Gy/2 Gy for most of the T1 and T2 tumors, although 10 T2 tumors were treated with hyperfractionation (72–74.4 Gy/1.2 Gy bid). Of the 128 patients, 90 T1 glottic tumors and 30 T2 glottic tumors were followed for >2 years after treatment. Multivariate analyses using the Cox proportional hazards model and a logistic regression analysis were performed to evaluate the significance of prognostic variables on local control. Results: The 5-year local control probability for T1 tumors was 85%, whereas that for T2 tumors was 71%. Multivariate analyses demonstrated that only overall treatment time (OTT) was a significant variable for local control. Total RT dose, normalized total doses at a fraction size of 2 Gy, and fraction size were not significant. Local control probability of T1 tumors with an OTT of 42–49 days was significantly higher than that of tumors with an OTT of >49 days (P < 0.02). Only a 1-week interruption of RT, due to holidays, significantly reduced the 5-year local control probability of T1 glottic tumors from 89 to 74% (P < 0.05). Conclusions: These results indicate that OTT is a significant prognostic factor for local control of T1 glottic tumors.     

Overexpression of p53 Protein Does Not Predict Local-Regional Control or Survival in Patients With Early-Stage Squamous Cell Carcinoma of the Glottic Larynx Treated With Radiotherapy

Purpose: Nonfunctional or mutated p53 protein (m-p53) is found in a myriad of solid tumors in humans. m-p53 is believed to confer radioresistance through inhibition of radiation-induced apoptosis. This study was carried out to determine if the overexpression of p53 in squamous cell carcinomas (SCC) of the glottic larynx treated with radiation therapy alone carried a poorer prognosis than normal wild-type p53 (w-p53) and could, therefore, be used as a marker of radioresistance in glottic SCC.Methods & Materials: Eighty-six patients with early-stage glottic SCC (64 T1N0, 25 T2N0 by TMN stage) treated with contemporary radiotherapy techniques to doses of 50–70 Gy were analyzed. Aberrant p53 protein was detected by immunohistochemical (IHC) staining on archival tissue samples containing original tumor specimens. Analysis of prognostic factors and treatment outcome to expression of p53 was performed. All patients were carefully selected to have comparable sites of disease, histology, early-stage disease, and treatment delivered, thus increasing the power of this study by controlling for other independent factors affecting outcome.Results: Sixty percent of patients demonstrated overexpression of p53 in tissue samples. Accumulation of p53 was not predictive of tumor grade, stage, or smoking status prior to diagnosis. p53 status was not predictive of treatment outcome parameters including local-regional failure rate and disease-free survival rate. Factors significantly affecting treatment outcome were stage and dose of radiotherapy in T2 patients (50 Gy vs. > 62 Gy).Conclusion: m-p53 protein detected by IHC staining was not predictive as a prognostic factor for clinical outcome following radiation therapy for early-stage glottic SCC. This is in general agreement with other recently published studies of laryngeal carcinoma patients treated with radiation or surgery. At the present time, p53 status should not be used as a marker for prognosis and clinical outcome in laryngeal SCC.     

A phase I-II study of bi-weekly docetaxel combined with radiation therapy for patients with cancer of the larynx/hypopharynx

BACKGROUND: We performed a phase I/II study of bi-weekly docetaxel in combination with concurrent radiotherapy to enhance the cytotoxic effect and radiosensitization and improve the rate of laryngeal preservation. METHODS: Patients with T2N0-1M0, T3N0M0 hypopharyngeal cancer or T2N0-1M0, T3N0-1M0 larynx cancer were enrolled. Docetaxel was administered bi-weekly (days 1, 15, 29) from the first day of radiotherapy, while 2 Gy/day of radiation was given on 5 days weekly from day 1, reaching a total of 60 Gy in 30 fractions. RESULTS: 12 patients took part in the phase I study. The maximum tolerated dose (MTD) was 40 mg/m2 and the recommended dose (RD) was determined as 35 mg/m2. The phase II study was conducted with docetaxel at 35 mg/m2 for 25 patients. Treatment was completed without interruption in 24 patients, with a protocol implementation rate of 96%. The complete response rate was 100% in laryngeal cancer, and 80% in hypopharyngeal cancer, and total (including partial response) overall response rate was 100%. The laryngeal preservation rate was 96%, and the overall local control rate was 92%. All patients have been alive for at least 3 years without any recurrence. CONCLUSIONS: The chemoradiation therapy using bi-weekly docetaxel is an extremely effective treatment for cancer of the larynx/hypopharynx, provided that it is used for the specified stage of cancer.     

Dosimetric predictors of laryngeal edema

PURPOSE: To investigate dosimetric predictors of laryngeal edema after radiotherapy (RT). METHODS AND MATERIALS: A total of 66 patients were selected who had squamous cell carcinoma of the head and neck with grossly uninvolved larynx at the time of RT, no prior major surgical operation except for neck dissection and tonsillectomy, treatment planning data available for analysis, and at least one fiberoptic examination of the larynx within 2 years from RT performed by a single observer. Both the biologically equivalent mean dose at 2 Gy per fraction and the cumulative biologic dose-volume histogram of the larynx were extracted for each patient. Laryngeal edema was prospectively scored after treatment. Time to endpoint, moderate or worse laryngeal edema (Radiation Therapy Oncology Group Grade 2+), was calculated with log rank test from the date of treatment end. RESULTS: At a median follow-up of 17.1 months (range, 0.4- 50.0 months), the risk of Grade 2+ edema was 58.9% +/- 7%. Mean dose to the larynx, V30, V40, V50, V60, and V70 were significantly correlated with Grade 2+ edema at univariate analysis. At multivariate analysis, mean laryngeal dose (continuum, hazard ratio, 1.11; 95% confidence interval, 1.06-1.15; p < 0.001), and positive neck stage at RT (N0-x vs. N +, hazard ratio, 3.66; 95% confidence interval, 1.40-9.58; p = 0.008) were the only independent predictors. Further stratification showed that, to minimize the risk of Grade 2+ edema, the mean dose to the larynx has to be kept < or =43.5 Gy at 2 Gy per fraction. CONCLUSION: Laryngeal edema is strictly correlated with various dosimetric parameters; mean dose to the larynx should be kept < or =43.5 Gy.     

Comparing treatment outcomes of radiotherapy and surgery in locally advanced carcinoma of the larynx: a comparison limited to patients eligible for surgery

PURPOSE: The use of radical radiotherapy and surgery for salvage (RRSS) in locally advanced squamous cell carcinoma (SCC) of the larynx is controversial. In the absence of randomized studies, it is unclear if RRSS can match the rates of locoregional control and survival reported for primary surgery in this setting. The aim of this study was to compare treatment outcomes of radiotherapy and surgery in comparable patients with CS III-IV SCC of the larynx. METHODS AND MATERIALS: Eighty-two patients with untreated T2N+M0 or T3T4NM0 SCC of the larynx were treated with a policy RRSS at the Toronto-Sunnybrook Regional Cancer Centre between June 1980 and December 1990. The medical records at presentation were reviewed independently by a panel of three surgical oncologists blinded as to treatment outcome to determine patient suitability for laryngectomy and neck dissection using eligibility criteria adopted by recent clinical trials. Treatment outcomes for surgery-eligible patients were compared to results of comparably staged patients in the surgical literature since 1980. RESULTS: Sixty-three patients (77%) were eligible for study. With a median follow-up of 3 years, radiotherapy controlled the primary in 8/20 evaluable glottic primaries and 21/41 evaluable supraglottic primaries. Forty-five percent of patients surviving 5 years retained a functional larynx. Sixteen of 29 relapsing patients were salvaged with surgery. Disease above the clavicles was controlled in 65% of T3T4N0N+ glottic primaries (compared to a published range of 53% to 79%) and 82% of T3N0 glottic primaries (compared to a published range of 69% to 84%). The 5-year overall survival of patients with T3T4 glottic cancer was 54% compared to a published range of 50% to 63%. The cause-specific survival (CSS) of patients with T3N0 glottic primaries (86% at 1 year and 73% at 2 years) was identical to the only published report of CSS in the surgical literature. CONCLUSION: A policy of RRSS offers a good chance of laryngeal conservation without compromising ultimate locoregional control or survival when compared to primary laryngectomy and neck dissection in patients with locally advanced carcinoma of the larynx meeting the surgical eligibility of clinical trials.     

Treatment results and prognostic factors for advanced squamous cell carcinoma of the hypopharynx treated with concurrent chemoradiotherapy

Purpose

The purpose of the study is to review our experience with concurrent chemoradiotherapy (CCRT) for patients with advanced resectable squamous cell carcinoma (SCC) of the hypopharynx and to evaluate the factors affecting survival and larynx preservation.

Study design

Retrospective study.

Methods and materials

The records of 102 patients with Stage III or IV resectable SCC of the hypopharynx treated with CCRT between January 1998 and August 2010 were reviewed. Of the 102 patients, 62 were treated with high-dose regimens including cisplatin, 5-fluorouracil, methotrexate, leucovorin or docetaxel, cisplatin, and 5-fluorouracil. The remaining 40 were treated with low-dose regimens including carboplatin and uracil-tegafur, weekly docetaxel, or S-1. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8–2.0 Gray (Gy), to a total dose of 64.8–70.2 Gy. Overall survival (OS), disease-specific survival (DSS), and DSS with larynx preservation were estimated using Kaplan–Meier methods. The log-rank test and Cox proportional hazards regression were used to identify significant prognostic factors for OS, DSS, and DSS with larynx preservation.

Results

The 5-year OS and DSS for all patients treated with CCRT were 51.3 and 64.3 %, respectively. The 5-year DSS with larynx preservation was 55.5 %. On multivariate analysis, the content of chemotherapy was a significant predictor of OS and DSS for patients undergoing CCRT; N stage was a significant prognostic factor for DSS and larynx preservation.

Conclusion

The treatment method including the indication for CCRT may be determined by the contents of the chemotherapy and the N stages of SCC of the hypopharynx.     

Radiation therapy for early glottic cancer (T1N0M0): I. Results of conventional open field technique

From November 1977 through April 1982, a total of 91 patients with glottic cancer (T1N0M0) were treated with the open field technique of 4 MV X ray using bilateral parallel-opposed fields. Total radiation dose administered was 60 Gy in 30 fractions over a 6-week period. Actuarial 5-year disease-free survival rate was 89%. Significant prognostic factors of local control were tumor length (p = 0.021), tumor width (p = 0.001), tumor type (p = 0.004), tumor response to irradiation at 40 Gy (p = 0.000) and 60 Gy (p = 0.000) by chi-square test. Ultimate local control rate by radiation therapy and salvage surgery was 97% and voice preservation rate was 91%.