Karen K. Fu

Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.

PURPOSE The Southwest Oncology Group (SWOG) coordinated an Intergroup study with the participation of Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.

A radiation therapy oncology group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003

Abstract Purpose: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation. Methods and Materials: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1.2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. Results: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control ( p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival ( p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. Conclusions: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.

Intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: an update of the UCSF experience

PURPOSE To update our experience with intensity-modulated radiotherapy (IMRT) in the treatment of nasopharyngeal carcinoma (NPC). METHODS AND MATERIALS Between April 1995 and October 2000, 67 patients underwent IMRT for NPC at the University of California-San Francisco (UCSF). There were 20 females and 47 males, with a mean age of 49 (range 17-82). The disease was Stage I in 8 (12%), Stage II in 12 (18%), Stage III in 22 (33%), and Stage IV in 25 (37%). IMRT was delivered using three different techniques: 1) manually cut partial transmission blocks, 2) computer-controlled auto-sequencing segmental multileaf collimator (SMLC), and 3) sequential tomotherapy using a dynamic multivane intensity modulating collimator (MIMiC). Fifty patients received concomitant cisplatinum and adjuvant cisplatinum and 5-FU chemotherapy according to the Intergroup 0099 trial. Twenty-six patients had fractionated high-dose-rate intracavitary brachytherapy boost and 1 patient had gamma knife radiosurgery boost after external beam radiotherapy. The prescribed dose was 65-70 Gy to the gross tumor volume (GTV) and positive neck nodes, 60 Gy to the clinical target volume (CTV), 50-60 Gy to the clinically negative neck, and 5-7 Gy in 2 fractions for the intracavitary brachytherapy boost. Acute and late normal tissue effects were graded according to the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. The local progression-free, local-regional progression-free, distant metastasis-free rates, and the overall survival were calculated using the Kaplan-Meier method. RESULTS With a median follow-up of 31 months (range 7 to 72 months), there has been one local recurrence at the primary site. One patient failed in the neck. Seventeen patients developed distant metastases; 5 of these patients have died. The 4-year estimates of local progression-free, local-regional progression-free, and distant metastases-free rates were 97%, 98%, and 66% respectively. The 4-year estimate of overall survival was 88%. The worst acute toxicity documented was as follows: Grade 1 or 2 in 51 patients, Grade 3 in 15 patients, and Grade 4 in 1 patient. The worst late toxicity was Grade 1 in 20 patients, Grade 2 in 15 patients, Grade 3 in 7 patients, and Grade 4 in 1 patient. At 3 months after IMRT, 64% of the patients had Grade 2, 28% had Grade 1, and 8% had Grade 0 xerostomia. Xerostomia decreased with time. At 24 months, only one of the 41 evaluable patients had Grade 2, 32% had Grade 1, and 66% had Grade 0 or no xerostomia. Analysis of the dose-volume histograms (DVHs) showed that the average maximum, mean, and minimum dose delivered were 79.3 Gy, 74.5 Gy, and 49.4 Gy to the GTV, and 78.9 Gy, 68.7 Gy, and 36.8 Gy to the CTV. An average of only 3% of the GTV and 3% of the CTV received less than 95% of the prescribed dose. CONCLUSION Excellent local-regional control for NPC was achieved with IMRT. IMRT provided excellent tumor target coverage and allowed the delivery of a high dose to the target with significant sparing of the salivary glands and other nearby critical normal tissues.

Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis

BACKGROUND Several trials have studied the role of unconventional fractionated radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this meta-analysis was to assess whether this type of radiotherapy could improve survival. METHODS Randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic HNSCC were identified and updated individual patient data were obtained. Overall survival was the main endpoint. Trials were grouped in three pre-specified categories: hyperfractionated, accelerated, and accelerated with total dose reduction. FINDINGS 15 trials with 6515 patients were included. The median follow-up was 6 years. Tumours sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (International Union Against Cancer, 1987). There was a significant survival benefit with altered fractionated radiotherapy, corresponding to an absolute benefit of 3.4% at 5 years (hazard ratio 0.92, 95% CI 0.86-0.97; p=0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at 5 years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at 5 years, p=0.02). There was a benefit on locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at 5 years; p<0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (hazard ratio 0.78 [0.65-0.94] for under 50 year olds, 0.95 [0.83-1.09] for 51-60 year olds, 0.92 [0.81-1.06] for 61-70 year olds, and 1.08 [0.89-1.30] for over 70 year olds; test for trends p=0.007). INTERPRETATION Altered fractionated radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation has the greatest benefit.

Comparison of treatment plans involving intensity-modulated radiotherapy for nasopharyngeal carcinoma

PURPOSE To compare intensity-modulated radiotherapy (IMRT) treatment plans with conventional treatment plans for a case of locally advanced nasopharyngeal carcinoma. METHODS AND MATERIALS The study case was planned using two types of IMRT techniques, as well as a three-dimensional conformal radiotherapy technique (3D-CRT), and a traditional treatment method using bilateral opposing fields. These four plans were compared with respect to dose conformality, dose-volume histogram (DVH), dose to the sensitive normal tissue structures, and ease of treatment delivery. RESULTS The planned dose distributions were more conformal to the tumor target volume in the IMRT plans than those in the conventional plans. With similar dose coverage of the clinical target volume (CTV), defined as delivery of minimum of 60 Gy to >/= 95% of CTV, the IMRT plans achieved better sensitive normal tissue structure sparing, while concomitantly delivering a minimum dose of 68 Gy to >/= 95% of the gross tumor volume (GTV) at a higher dose per fraction. CONCLUSIONS Compared to conventional techniques, IMRT techniques provide improved tumor target coverage with significantly better sparing of sensitive normal tissue structures in the treatment of locally advanced nasopharyngeal carcinoma. With improvement of the delivery efficiency, IMRT should provide the optimal treatment for all nasopharyngeal carcinoma. Further studies are needed to establish the true clinical advantage of this new modality.

Three-dimensional intensity-modulated radiotherapy in the treatment of nasopharyngeal carcinoma: the University of California–San Francisco experience

PURPOSE To review our experience with three-dimensional intensity-modulated radiotherapy (IMRT) in the treatment of nasopharyngeal carcinoma. METHODS AND MATERIALS We reviewed the records of 35 patients who underwent 3D IMRT for nasopharyngeal carcinoma at the University of California-San Francisco between April 1995 and March 1998. According to the 1997 American Joint Committee on Cancer staging classification, 4 (12%) patients had Stage I disease, 6 (17%) had Stage II, 11 (32%) had Stage III, and 14 (40%) had Stage IV disease. IMRT of the primary tumor was delivered using one of the following three techniques: (1) manually cut partial transmission blocks, (2) computer-controlled autosequencing static multileaf collimator (MLC), and (3) Peacock system using a dynamic multivane intensity-modulating collimator (MIMiC). A forward 3D treatment-planning system was used for the first two methods, and an inverse treatment planning system was used for the third method. The neck was irradiated with a conventional technique using lateral opposed fields to the upper neck and an anterior field to the lower neck and supraclavicular fossae. The prescribed dose was 65-70 Gy to the gross tumor volume (GTV) and positive neck nodes, 60 Gy to the clinical target volume (CTV), and 50-60 Gy to the clinically negative neck. Eleven (32%) patients had fractionated high-dose-rate intracavitary brachytherapy boost to the primary tumor 1-2 weeks following external beam radiotherapy. Thirty-two (91%) patients also received cisplatin during, and cisplatin and 5-fluorouracil after, radiotherapy. Acute and late normal tissue effects were graded according to the Radiation Therapy Oncology Group (RTOG) radiation morbidity scoring criteria. Local-regional progression-free, distant metastasis-free survival and overall survival were estimated using the Kaplan-Meier method. RESULTS With a median follow-up of 21.8 months (range, 5-49 months), the local-regional progression-free rate was 100%. The 4-year overall survival was 94%, and the distant metastasis-free rate was 57%. The worst acute toxicity was Grade 2 in 16 (46%) patients, Grade 3 in 18 (51%) patients and Grade 4 in 1 (3%) patient. The worst late toxicity was Grade 1 in 15 (43%), Grade 2 in 13 (37%), and Grade 3 in 5 (14%) patients. Only 1 patient had a transient Grade 4 soft-tissue necrosis. At 24 months after treatment, 50% of the evaluated patients had Grade 0, 50% had Grade 1, and none had Grade 2 xerostomia. Analysis of the dose-volume histograms (DVHs) showed that the average maximum, mean, and minimum dose delivered were 79.5 Gy, 75.8 Gy, and 56.5 Gy to the GTV, and 78.9 Gy, 71.2 Gy, and 45.4 Gy to the CTV, respectively. An average of only 3% of the GTV and 2% of the CTV received less than 95% of the prescribed dose. The average dose to 5% of the brain stem, optic chiasm, and right and left optic nerves was 48.3 Gy, 23.9 Gy, 15.0 Gy, and 14.9 Gy, respectively. The average dose to 1 cc of the cervical spinal cord was 41.7 Gy. The doses delivered were within the tolerance of these critical normal structures. The average dose to 50% of the right and left parotids, pituitary, right and left T-M joints, and ears was 43. 2 Gy, 41.0 Gy, 46.3 Gy, 60.5 Gy, 58.3 Gy, 52.0 Gy, and 52.2 Gy, respectively. CONCLUSION 3D intensity-modulated radiotherapy provided improved target volume coverage and increased dose to the gross tumor with significant sparing of the salivary glands and other critical normal structures. Local-regional control rate with combined IMRT and chemotherapy was excellent, although distant metastasis remained unabated.

Quantification of combined radiation therapy and chemotherapy effects on critical normal tissues

In order to determine the modification of radiation effect on critical normal tissues which occurs with combinations of radiation and cancer chemotherapy, a review of laboratory and clinical data has been carried out. Information on 10 different normal tissues is available. It is clear that the antibiotic cancer chemotherapeutic agents are the most likely to enhance radiation injury, with increased levels reported in all tissues except the central nervous system. The second most common type of injury with combination therapy appears to occur with drugs causing injury to the normal tissue on their own, such as adriamycin in the heart and methotrexate in the central nervous system. Quantification of the dose‐effect factor is only available on a limited number of tissues and, primarily, in experimental animals. From these limited data, it is clear that dose‐effect factors between 1.1 and 1.8 are seen, indicating that radiation doses must be reduced by 10–80% for the same level of injury when combined with chemotherapy. The augmentation of radiation damage by cancer chemotherapeutic agents is a serious problem in a wide range of tissues, but a problem which can be dealt with by accurate knowledge as to the dose‐effect factor and appropriate modification of the radiation treatment.

Osteonecrosis in patients irradiated for head and neck carcinoma.

One hundred patients irradiated for cancers of the oral cavity, oropharynx, and nasopharynx were evaluated for the occurrence of osteonecrosis and associated predisposing factors. Selection was based on availability of complete dental records, a minimum of six months follow‐up, and treatment fields, which included maxilla and/or mandible. Bone doses were calculated by using radiotherapy treatment records, port films, and isodose distributions. Osteonecrosis developed in 19 of 78 dentulous patients and in 3 of 22 edentulous patients. The time of development of osteonecrosis varied; in 15 cases osteonecrosis occurred more than one year after treatment. The most important risk factor for the development of osteonecrosis was the radiation dose to bone, particularly in the less vascular mandible. Osteonecrosis developed in 85% of the dentulous patients and in 50% of the edentulous patients who received more than 7500 rads to the bone. None of the patients who received less than 6500 rads developed osteonecrosis. The risk was significantly greater when teeth were removed after therapy compared with those individuals with extractions before radiation or no extractions at all.

Carcinoma of the major and minor salivary glands. Analysis of treatment results and sites and causes of failures

Treatment results of 100 cases of previously untreated malignant epithelial tumors of the major and minor salivary glands were analyzed with respect to stage, treatment modality and histology. For carcinoma of the parotid gland, the 5‐ and 10‐year determinate survivals decreased from 88% and 83% for Stage I disease to 76% and 76% for Stage II, to 49% and 32% for Stage III and 0% for Stage IV disease. The 5‐ and 10‐year determinate survivals were 96% and 96% for mucoepidermoid carcinoma, 80% and 80% for acinic cell carcinoma, 72% and 62% for adenocarcinoma, 57% and 57% for squamous cell carcinoma, 65% and 29% for adenoid cystic carcinoma and 44% and 22% for undifferentiated carcinoma. Postoperative radiotherapy improved the local control rates of adenoid cystic carcinoma and advanced local disease, its effectiveness related directly to the extent of tumor present. Radiotherapy was highly effective for microscopic disease and the incidence of local recurrence was 14% for patients who received postoperative radiotherapy and 54% for those who did not when there was known microscopic disease at or close to surgical margin. No significant difference in response to radiotherapy was seen between the different histological types. Most failures occurred at the primary tumor site or at the site of distant metastasis, whereas failure in regional lymph nodes was uncommon. When the cause of failure could be determined, it most often appeared to have been tumor remaining at the surgical margin with no postoperative radiotherapy given. Cancer 40:2882‐2890, 1977.

Combined radiotherapy and chemotherapy with bleomycin and methotrexate for advanced inoperable head and neck cancer: update of a Northern California Oncology Group randomized trial.

Between 1978 and 1984, the Northern California Oncology Group (NCOG) conducted a randomized trial to study the efficacy of combined radiotherapy (RT) and chemotherapy (CT) for stage III or IV inoperable head and neck cancer. One hundred four patients were randomized to receive: (1) RT alone, or (2) RT plus CT. RT consisted of 7,000 cGy to the involved areas and 5,000 cGy to uninvolved neck at 180 cGy/fraction, five fractions/wk. CT consisted of bleomycin, 5 U intravenously (IV), twice weekly during RT, followed by bleomycin, 15 U IV, and methotrexate, 25 mg/m2 IV weekly for 16 weeks after completion of RT. Fifty-one patients in the RT alone group and 45 in the combined treatment group were evaluable. The local-regional complete response (CR) rate was 45% v 67% (P = .056); the 2-year local-regional control rate, including salvage surgery, was 26% v 64% (P = .001); and the incidence of distant metastasis was 24% v 38% (P greater than .25), for the RT alone and RT plus CT groups, respectively. The relapse-free survival curves were significantly different (P = .041), favoring the combined treatment. However, the survival curves were not significantly different (P = .16). Patient compliance to maintenance CT was poor. Bleomycin significantly increased the acute radiation mucositis, although the difference in late normal tissue toxicity was not statistically significant. Thus, bleomycin and concurrent RT produced a more favorable CR rate, local-regional control rate, and relapse-free survival, but the difference in survival was not statistically significant.