A comparison of outcomes for patients with oral squamous cell carcinoma at intermediate risk of recurrence treated by surgery alone or with post-operative radiotherapy.

Controversy remains about which patients at intermediate risk of recurrence of oral squamous cell carcinoma would benefit from radiotherapy. A retrospective review of computerised database and medical records for 462 consecutive patients at the Regional Maxillofacial Unit in Liverpool who were treated with primary surgery with or without post-operative radiotherapy was carried out. We classified 29% (134) of patients as being at 'low' risk of disease recurrence (pT1-2, N0 with clear margins), 29% (135) at 'high' risk (involved margins or lymph node extracapsular spread) and the remaining 42% (193) at 'intermediate' risk. Of those at intermediate risk, 41% (80/193) received adjuvant radiotherapy and their 5 year survival (SE) was 54% (6%) compared to 71% (5%) for those with primary surgery alone (P=0.002). A higher proportion of patients having radiotherapy had loco-regional recurrence (19/80 24%) compared to those treated by surgery alone (17/113 15%). The improved salvage rate for recurrent disease in the surgery alone group (8/17 53%), compared to those receiving radiotherapy (2/19 13%, P=0.05), indicates an advantage in withholding radiotherapy for patients at intermediate risk of recurrence. This study indicates a potential disadvantage associated with the use of postoperative radiotherapy for patients at intermediate risk of recurrence. A randomised trial comparing a watch and wait policy to postoperative radiotherapy in patients with an intermediate risk of recurrence is required to confirm the trend indicated in this retrospective data.

Re-irradiation of advanced tumors of the head and neck with fast neutrons.

Twenty-eight patients who had received radical treatment with X rays to tumors of the head and neck presented with advanced recurrent tumors, 23 of them had also undergone surgery and 10 had more than one operation. Seven had also received chemotherapy. They were treated with neutrons to a tumor dose of 1560 cGy in 12 fractions over 26 days using the techniques of the Hammersmith Unit. Twenty-three of the tumors (82%) underwent complete regression that was maintained in 15 for at least 12 months. Despite the damage done by the previous radiation and surgery to the normal tissues, 15 patients had no complications following neutron therapy. In six patients, there was major necrosis, in seven others, this was minor. Eight tumors recurred. Five patients responded with partial regression of their tumors. The median survival was 20 months (range 4-69 months).

The implications of improved treatment of malignant salivary gland tumors by fast neutron radiotherapy.

The conventional treatment for cancer of the salivary glands is surgery, with or without X ray therapy. In advanced tumors (Stage III and IV), local control and 5-year survival rates are less than 35%. Radical surgery severs the facial nerve in the majority of operations on parotid gland tumors. Local control of unresectable salivary gland tumors was achieved, in 74% of cases, by fast neutron therapy. From the MRC cyclotron at Hammersmith Hospital neutrons were given to 65 patients, with locally advanced or recurrent tumors, 89% of which were Stage IV. Local control and 5-year survival rates were 72% and 50%, respectively. The facial nerve was not damaged by neutron therapy. In patients with parotid gland tumors, 77% regained or maintained function. Function was lost in 14% through recurrence and 9% remained paralyzed. The results were achieved using beams from primitive machines with serious disadvantages. The results from neutrons implicate improvements for locally advanced tumors of non-epidermal origin in other sites of the body, especially with the high energy neutrons now available from modern cyclotrons.

A comparison of clinical and laboratory data on neutron therapy for locally advanced tumors.

Experimental results suggest advantages for neutrons where cells are hypoxic, in tumors which are slowly growing and also in a relative sparing of bone damage. The neutrons available at Hammersmith were of 7.5 MeV energy and produced a poorly penetrating beam, unsuitable for treating tumors in the pelvis and abdomen. Patients with locally advanced tumors in superficial sites were therefore selected to assess the effects of neutrons on normal and malignant tissues. One hundred and eight-nine patients had between them 191 locally advanced (T4 N0-3) tumors in the oral cavity, paranasal sinuses, salivary glands, and breast. Neutron therapy resulted in complete regression in 84% of which 13% subsequently recurred. Median survival for the whole group was 32 months. Twenty-eight other patients had advanced tumors of the head and neck which were recurrent after X ray therapy and other treatments; 82% of these completely regressed for more than 1 year. Complications appeared in 27% of patients not previously treated and in 46% who had already undergone X ray therapy. Seventy-four per cent of complications started in the skin. With neutrons of this energy there is minimal sparing of the skin and uneven distribution of dose resulting in "hot" spots. These affected skin, subcutis, and muscle. The high rates of control in these large tumors, the low incidence of bone necrosis, and the repair of some bones eroded by tumor correlate well with the experimental data. There was rapid regression of the tumor and close correlation between early and late effects on skin and subcutis. These two observations may relate to the fractionation, total dose, and overall time of treatment of 1560 cGy neutron dose given in 12 fractions over 28 days.

Fast neutron therapy for soft tissue sarcoma.

Seventy-nine patients with soft tissue sarcoma were treated with fast neutron therapy at the Hammersmith Hospital, MRC Cyclotron Unit. Sixty-six of these, treated between 1971 and 1983 were assessable. The histology was reviewed and graded in 82% of cases and tumors divided into groups according to maximum diameter. In sixteen patients, who were irradiated following complete macroscopic removal of tumor, there was 94% local control and 86% survived 5 years. Of the 50 patients who had gross tumors present 62% were greater than 10 cm in diameter, and 20 were recurrent after previous radiotherapy or surgery or both. Sixty-eight per cent of gross tumors completely regressed and local control was 52%. The main cause of death was metastatic spread, and median survival was 63 months for Grade 1 patients, 9 months for Grade 2, and 7 months for Grade 3. Thus, there was a significant advantage to patients with Grade 1 tumor but little difference between Grades 2 and 3. Twenty-seven patients experienced late complications of treatment, 67% of which involved the skin predominantly and were related to the low energy of neutrons used. Seventeen of the 27 had received previous radiotherapy. Neutron therapy given in this dose and fractionation produced a higher local control rate than photon therapy, but complications were more frequent. Since these mainly involved the skin a lower level of complications may be anticipated using higher energy neutrons which will have a more even distribution of dose and lower skin dosage. Forty-eight per cent of patients developed metastatic disease, indicating the need for effective systemic therapy, especially in Grades 2 and 3 tumors.

Fast-neutron therapy in advanced head and neck cancer: a collaborative international randomized trial.

PURPOSE: To compare the efficacy of fast-neutron radiotherapy with that of conventionally fractionated photon therapy in the management of patients with locally advanced squamous cell carcinoma of the head and neck. METHODS AND MATERIALS: Patients with Stage III or IV disease were randomized to receive either 20.4 Gy/12 fractions/4 weeks of neutrons or 70 Gy/35 fractions/7 weeks of photons (control). Between April 1986 and March 1991, 178 patients were entered, 169 of whom were eligible for analysis. The treatment arms were balanced for age, stage, and performance status, but not for primary site of origin. RESULTS: Complete response occurred in 70 and 52% with neutrons and photons, respectively (p = 0.006). Local regional failure at 3 years for all patients was 63% for neutrons and 68% for photons. Actuarial overall survival curves were virtually identical in both study arms, falling to 27% at 3 years. Acute toxicity was similar in the two arms, but late grade 3-5 toxicity was 40% with neutrons compared to 18% with photons (p = 0.008). CONCLUSION: Although the initial response rate was higher with neutrons, permanent local control and survival were not improved, and the incidence of late normal tissue toxicity was increased. As a result, fast-neutron therapy for advanced squamous cell carcinoma of the head and neck can only be recommended for patients in whom the logistic benefit of treatment in 12 sessions over 4 weeks outweighs the increased risk of late toxicity.

Alternating six-drug combination chemotherapy induction for intermediate and high-grade non-Hodgkin's lymphoma.

31 patients with intermediate and high-grade non-Hodgkin lymphomas were treated by a six-drug alternating regime comprising four cycles of 200 mg/m2 i.v. methotrexate on days 8, 15, 28 and 35, 50 mg/m2 i.v. Adriamycin on day 1, 40 mg/m2 oral prednisolone on days 1-7 and 21-27, 120 mg/m2 i.v. etoposide on days 21-23, 600 mg/m2 i.v. cyclophosphamide on day 21 and 1.4 mg/m2 i.v. vincristine on day 1 (MAPECO). In all, 3 patients had stage I disease, 12 stage II, 6 stage III and 10 stage IV. Of 28 evaluable patients, 19 were complete responders (68%) and 9 were partial responders (32%); at 2 years, the actuarial relapse-free survival of the 19 patients achieving complete remission is 80%, and 5 patients remain in complete remission at 3 years. This is a preliminary report of an effective intensive regime with acceptable toxicity.

Fast neutrons in the treatment of locally advanced breast cancer.

The clinical investigation of fast neutrons at Hammersmith Hospital included 17 patients who between them had 20 T4 breast cancers. The majority of these tumours were ulcerated and all were painful. Ten had recurred after multiple other therapies. Complete local regression was achieved in all but one (95%) and no tumour recurred. Symptoms were relieved in all cases. Median survival was 26 months. Three patients developed small areas of skin necrosis following trauma of previous radiation. All the neutron treated breasts became fibrosed, but this was painless. Neutron treatment needed only 12 attendances over 28 days, in contrast to the best results from photon therapy which required 6-7 weeks followed by implant of radioactive wire and/or surgical excision. One patient who had bilateral tumours received neutrons to the left breast and X-ray therapy (photons) to the right. The photon treated tumour did not completely regress and recurred. The neutron treated one completely regressed and did not recur. Neutrons were also more effective than tamoxifen which causes complete regression in only about 30% of cases. It is suggested that neutron therapy is indicated for locally advanced tumours which do not respond to hormones. Since metastases were a common cause of death, there remains a need for an effective adjuvant treatment, acceptable to elderly patients.

Predictive factors for the development of rubeosis following proton beam radiotherapy for uveal melanoma.

AIMS/BACKGROUND: Proton beam radiotherapy can effectively treat primary uveal melanomas of any size. Some patients, however, develop adverse late effects following treatment and the purpose of this study was to determine which factors give rise to a poor local outcome. METHODS: The hospital records from a first cohort of 127 patients treated by protons from 1989 to 1992 were reviewed retrospectively. The presence of rubeosis was selected as a measure of significant ocular damage. Split file analysis was performed with 73 cases forming a test group with the remaining 54 cases acting as a validation group. RESULTS: Large tumour size and the presence of retinal detachment were significant, independent risk factors for developing rubeosis for both the test and validation groups. These factors also predicted subsequent enucleation for uncontrolled ocular pain. Patients with tumours too large to plaque and with an associated retinal detachment had a 90% chance of developing rubeosis within 4 years of proton beam radiotherapy. CONCLUSIONS: Patients with a uveal melanoma too large for plaque therapy and an associated retinal detachment run a very high risk of developing rubeosis after proton beam radiotherapy and one third of individuals developing rubeosis required enucleation for pain even if local tumour control was satisfactory.

Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection.

The outcome of 200 patients with squamous cell carcinoma of the oral/oropharyngeal mucosa managed by primary radical surgery and simultaneous neck dissection and followed for 2.2-8.5 years is reported and related to the pathological features. Ninety-nine patients (50%) had cervical lymph node metastases including 16 (8%) with bilateral metastases. Actuarial (life tables) survival analysis showed the overall 2-year survival probability was 72%, falling to 64% at 5 years. The 5-year survival probability was 81% for patients without metastasis, 64% for patients with intranodal metastases and 21% for patients with metastases showing extracapsular spread. A total of 60 patients (30%) died of/with their cancer: 36 (18%) of local recurrence; 4 (2%) of a metachronous primary tumour; 14 (7%) of regional disease, and 6 (3%) with systemic metastases. A further 15 patients (8%) had relapsed but were clinically disease-free after additional surgery. In all, 7% of the series developed metachronous primary tumours. In addition to nodal metastasis, survival was related to the site and stage of the primary tumour, the histological grade and pattern of invasion, status of the resection margins and pathological TNM stage. For patients with lymph node metastasis, extracapsular spread was an important indicator of tumour behaviour and we recommend its use as a criterion for pathological N staging.

Sequential combination chemotherapy and radiotherapy in locally advanced non-small cell carcinoma of the bronchus.

The feasibility, effectiveness and toxicity of a new four drug intensive combination chemotherapy regime has been assessed in 36 patients with inoperable non-small cell lung cancer. Three cycles of adriamycin, vindesine, ifosfamide and cisplatin were given to 36 patients followed by sequential radiotherapy to 25 patients. The overall response rate to chemotherapy was 33%, and median progression free interval was 6 months. Median survival was 8.5 months. Grade 4 WHO neutropenia was seen in 12 patients, there were three episodes of neutropenic fever and one death in which toxicity may have been contributory. Radiotherapy was not associated with serious toxicity. This study demonstrates that a significant response rate can be achieved with short intensive chemotherapy in unresectable non-small cell lung cancer and that it is feasible to combine this with radiotherapy.

Accelerated fast neutron therapy: a pilot study.

The clinical role of fast neutron therapy has been limited by excessive late normal tissue damage. A pilot study of accelerated fractionation of fast neutron therapy was performed, based on the rationale that this should result in an increase in the response in acute reacting tissues (normal and malignant), with no change in late damage and a consequent increase in the therapeutic ratio. Further accelerated fractionation should improve the local control of rapidly proliferating tumour, without the potential problem of inadequate reoxygenation inherent in accelerated photon schedules. 6 or 12 fractions of 62 MeV (p-Be) neutrons were given over 12 days to 27 sites in 23 patients with locally advanced tumours. With a dose reduction of 12% (18 Gy), acceptable skin and oral mucosa early reactions were obtained. A larger dose reduction (15%) was required at pelvic sites. The incidence of late EORTC/RTOG grade 4 toxicity was 46%. The overall response rate was 76% with a complete response rate of 16%. For locally advanced breast cancer, the complete response rate was 9%, which compares unfavourably with previous results with conventional neutron fractionation schedules. The combination of a low overall complete response rate and excessive late normal tissue toxicity suggests that accelerated fractionation of fast neutrons does not lead to an improvement in the therapeutic ratio, and that late normal tissue damage will continue to be dose limiting.

Early closure of a randomized trial: surgery and postoperative radiotherapy versus radiotherapy in the management of intra-oral tumours.

Tumours of the oral cavity/oropharynx occur relatively infrequently in the UK. The management of such lesions, especially the squamous cell carcinomas, is still a little controversial. Some centres advocate radiotherapy while others adopt surgery and radiotherapy. In an attempt to resolve the question of which approach gives the better results, a multicentre randomized trial was established to compare surgery plus postoperative radiotherapy with radical radiotherapy alone. It was anticipated that 350 patients would be required to give a statistically significant result, but, after 35 patients had been entered, the trial was closed prematurely with a marked difference in overall survival in favour of the combination arm (P = 0.0006). At this analysis, carried out 23 months after trial closure, the survival difference between the two arms remains statistically significant for all causes of mortality (P = 0.001; relative death rate = 0.24; 95% CI 0.10-0.59).

Advanced carcinoma of the paranasal sinuses treated with 7.5 MeV fast neutrons.

The poor prognosis of paranasal sinus carcinoma relates to its often late and advanced presentation. There are difficulties in achieving local control of the tumour and improving the quality and duration of survival with combinations of surgery and megavoltage radiotherapy. In this series of 43 patients with advanced sinus tumours treated with neutrons, the median survival was 33 months with a 75% local control rate. At 5 years the local control rate was 50% with 30% surviving. The complication rate was 5% at 12 months rising to 30% by 27 months with no further increase after this. The possible benefits of neutron therapy in treating the advanced tumours are discussed. Despite the disadvantages of low energy (7.5 MeV) neutron beams and the poor general condition of many of the patients in this series and the advanced nature of their tumours, a high local tumour control rate was observed and major facial surgery avoided.

High energy neutron treatment for pelvic cancers: study stopped because of increased mortality.

OBJECTIVE: To compare high energy fast neutron treatment with conventional megavoltage x ray treatment in the management of locally advanced pelvic carcinomas (of the cervix, bladder, prostate, and rectum). DESIGN: Randomised study from February 1986; randomisation to neutron treatment or photon treatment was unstratified and in the ratio of 3 to 1 until January 1988, when randomisation was in the ratio 1 to 1 and stratified by site of tumour. SETTING: Mersey regional radiotherapy centre at Clatterbridge Hospital, Wirral. PATIENTS: 151 patients with locally advanced, non-metastatic pelvic cancer (27 cervical, 69 of the bladder, seven prostatic, and 48 of the rectum). INTERVENTION: Randomisation to neutron treatment was stopped in February 1990. MAIN OUTCOME MEASURES: Patient survival and causes of death in relation to the development of metastatic disease and treatment related morbidity. RESULTS: In the first phase of the trial 42 patients were randomised to neutron treatment and 14 to photon treatment, and in the second phase 48 to neutron treatment and 47 to photon treatment. The relative risk of mortality for photons compared with neutrons was 0.66 (95% confidence interval 0.40 to 1.10) after adjustment for site of tumour and other important prognostic factors. Short term and long term complications were similar in both groups. CONCLUSIONS: The trial was stopped because of the increased mortality in patients with cancer of the cervix, bladder, or rectum treated with neutrons.

Proton beam therapy and iris neovascularisation in uveal melanoma.

PURPOSE: Local treatment of uveal melanoma by radiotherapy involves the use of brachytherapy with radioactive plaques attached to the sclera, or proton irradiation. Both treatments induce growth arrest within the tumour and its slow involution over several years. Although ocular retention rates are excellent, regrowth of tumours due to resistance and neovascular glaucoma leads to enucleation of up to 10% of affected eyes. Proton irradiation involves part of the iris in most cases and we noticed that neovascularisation only occurred in the part of the iris that was not irradiated. We therefore conducted this study to determine the relationship between the development of iris neovascularisation and iris irradiation. METHODS: A total of 21 enucleation specimens from patients who had previously had proton irradiation were collected from the files of the Department of Pathology, Moorfields Eye Hospital during the 5-year period from 1994 to 1999. Sections of these eyes were assessed for VEGF-A, bFGF, and von Willebrand Factor (vWF) by immunohistochemistry. Ophthalmic notes and radiotherapy records were reviewed to assess the extent of iris irradiation. RESULTS: In all, 11 cases showed clinical evidence of iris neovascularisation and were selected for further study. Three of these eyes also showed clinical evidence of regrowth of the tumour. Histological evidence of iris neovascularization was noted in all 11 of the eyes examined, and was only present in the nonirradiated side of the iris in 8/11 eyes. NVI was present on both sides of the iris in three cases, but was less severe in the irradiated part. Expression of VEGF-A was at most weak within the tumour, but was present in the detached retina and in the epithelium of both ciliary body and iris. Some bFGF staining was noted around vessels in the iris stroma. CONCLUSIONS: Our results suggest that irradiation leads to iris atrophy, and that atrophic, irradiated iris is resistant to the development of neovascularisation.