Clinical applications of proton therapy. Experiences and ongoing studies.

Proton therapy offers potentially considerable advantages in the management of slow-growing, poorly resectable or non-resectable tumors resistant to x-rays and located close to critical radiosensitive anatomical structures, such as the brain stem of the spinal cord. Among over 13,000 irradiated patients in the USA, Europe, and Japan, two major clinical indications have been documented: 1. The conservative management of choroidal melanomas, in which 98% 5-year local control can be expected at the price of low toxicity and visual preservation in approximately half of them. 2. The curative management of low-grade chondrosarcomas and chordomas of the base of the skull and cervical spine, leading to, in combination with maximal tumor resection, 84%-94% long-term survival. Other ongoing studies concern prostate, head and neck carcinomas as well as various intracranial tumors. Radiosurgical programs are being conducted generally with single fractions and under stereotactic conditions.

Overall treatment time in advanced cervical carcinomas: a critical parameter in treatment outcome.

PURPOSE: To search for possible influence of overall treatment time on the clinical outcome of advanced cervical carcinomas treated with radiation alone. METHODS AND MATERIALS: Three hundred and eighty-six patients with Stage IIB and III cervical carcinomas treated with external radiation and intracavitary curietherapy between 1973 and 1983 were entered in the study. A multivariate analysis was carried out on data concerning these patients to determine whether overall treatment time was a prognostic factor. RESULTS: Overall treatment time and blood transfusions during treatment were the two most highly significant factors in the multivariate analysis. Loss of local control and overall survival, when treatment exceeded 52 days, was approximately 1% per day in both cases. CONCLUSION: These results suggest that overall treatment time might be a highly significant prognostic factor in the treatment outcome of advanced cervical carcinomas. Prospective randomized studies are strongly warranted to confirm this hypothesis.

Combined radiotherapy and surgery: local control and complications in early carcinoma of the uterine cervix--the Villejuif experience, 1975-1984.

From January 1975 to December 1984, 441 patients were treated by combined radiotherapy and surgery at the Institut Gustave Roussy (IGR) for Stage IB (288) and II (proximal) (103) carcinoma of the uterine cervix. Standard treatment consisted of pre-operative utero-vaginal brachytherapy (60 Gy) using a mould technique followed by a colpo-hysterectomy and external iliac lymphadenectomy. Overall 5 year actuarial survival for the whole population was 87% and disease-free survival 85%. Loco-regional relapse occurred in 23 patients (5%). Of these, 12 were central pelvic failures, 8 regional failures and 3 combined central and regional failures. There were 36 systemic relapses (8%) of which 12 relapsed concurrently in the pelvis. Five year actuarial pelvic disease-free, disease-free and overall survival was 87, 85 and 87%, respectively, for the whole population. 340 patients developed one or more complications [Grade 1: 198/441 (44%), Grade 2: 121/441 (27%) and Grade 3 or 4: 21/441 (4.7%)]. Five year actuarial survival for the whole population was poorer for histologically node positive than for node negative (89 vs. 55%, p less than 0.0001). Pre-operative brachytherapy followed by surgery can provide good local control with acceptable morbidity in early cervical cancer.

Combined radio-surgical treatment in early invasive cervix carcinoma according to prognostic factors. Experience of the Gustave-Roussy Institute.

In the Gustave-Roussy Institute the standard protocol of limited stages (IB, proximal II) of cervix carcinoma, combines endocavitary brachytherapy (low dose rate) and surgery (BSOH + lymphadenectomy) are eventually followed by external beam irradiation. According to age of patients and to prognostic factors adaptations of this combined treatment are discussed: young patient (40 years) with small tumor, large volume of primary tumor (4 cm), lymphatic node involvement. Analysis of the results in 2 series of patients entirely treated at the Gustave-Roussy Institute: survival, local control, metastases, complications.

Twenty years experience of interstitial iridium brachytherapy in the management of soft tissue sarcomas.

From February 1968 to February 1988, 50 patients above 10 years of age with a soft tissue sarcoma were treated with interstitial brachytherapy, combined with a wide excision. After pathologic review, 48 were included in the final analysis. A pathological grading was made possible in 41, which showed a majority of high grades (2 + 3 = 86%). Patients presented mainly with small (less than 5 cm: 36) or mid-size lesions (greater than 5 cm: 12). The tumor was located in the limbs (32), trunk (9), and head and neck (7). Four patients had metastases at the time of treatment. Brachytherapy was part of the initial treatment in 22 cases, and of a salvage procedure after previous excision(s) combined or not with another form of treatment in 26. A uniform technique of iridium 192 wires after-loaded in plastic tubing was used. Sixty Gy median doses were delivered with brachytherapy alone (44) or combined with external beam (4). Sixteen patients also received an adjuvant chemotherapy. Follow up ranged from 16 months to 20 years (median 82 months). At the time of analysis, two patients (4%) only had failed in the irradiated volume, but the marginal failures rate (14:31%) was unexpectedly high. Seven of the patients who failed (43%) were salvaged by a second similar procedure. The 5-year survival was 62% in non-previously treated patients and 56.5% in previously treated ones (pNS). By multivariate analysis, only the tumor location appeared predictive of LF (p less than 0.01), which in turn was strongly correlated with the metastatic outcome (p less than 0.01). Necroses were observed in 17 cases (35%) and associated with a benign course in most of them. High dose brachytherapy combined with conservative surgery is highly effective in small and mid-size soft tissue sarcomas located in the extremities and head and neck, whereas in trunk and in recurrent tumors, the adjunction of large fields external radiotherapy and/or possibly polychemotherapy appears necessary.

[Primary lymphoma of the central nervous system. Review of recent literature data]. / Lymphomes primitifs du système nerveux central. Revue des données récentes de la littérature.

Primary CNS lymphoma is a rare entity. In the last few years, increasing numbers of reports have focused on the clinical, radiological and biological aspects of this tumor. The problem of the therapy of this particular localisation of lymphoma remains mostly unsolved. Radiotherapy still remains the standard approach. However, recent trials combining chemo and radiotherapy have shed promising light on a dark prognosis. These aspects are reviewed based on recent reports in the literature.

Glutathione and cysteine levels in human tumour biopsies.

There is evidence that some human tumours could be treated with a combination of buthionine sulfoximine and hypoxic cell sensitizers. However, clinical application of this technique requires a prior knowledge of the level of non-protein bound sulfhydryl (NPSH) compounds in these tumours. The present study provides data on the levels of glutathione (GSH) and cysteine (CYS) in human tumour biopsies from the cervix and from the head and neck. The NPSH compounds were measured by high performance liquid chromatography. The median GSH values were 20.5 nmol/mg protein (cervix) and 23 nmol/mg protein (head and neck) while the median CYS values were 4.4 (cervix) and 4.2 nmol/mg protein (head and neck). The values varied widely from one patient to another.

External irradiation plus curietherapy boost in 108 base of tongue carcinomas.

From 1960 to 1983, 108 patients underwent an association cobaltherapy plus curietherapy boost for a base of tongue carcinoma. This group included 18 T1 tumors, 39 T2, and 51 T3. Cobaltherapy was delivered to a dose of 45 Gy/4.5 weeks to the primary site and the neck. It was completed by an electron boost or a nodal surgery in case of initial nodal disease. Two techniques of Curietherapy were used: plastic tubes and guide-gutters. As most of these implants have been done before 1975, all the doses have been recalculated on the 85% isodose according to the Paris system. They varied from 22 to 88 Gy. The tolerance of the implantation was excellent. Five-year survival of the whole group is 26%. The local control rate is 85% for T1 tumors, 50% for T2, and 69% for T3. Despite the importance of cumulated doses, a few necrosis were observed. Considering the poor outlook of this cancer, its treatment by exclusive radiotherapy requires very high doses which can only be delivered without major sequellae or complication by a combination of cobaltherapy and curietherapy boost.

Conservative treatment for lower gynecological tract malignancies in children and adolescents: the Institut Gustave-Roussy experience.

Between 1972 and 1986, 37 patients with lower genital tract malignancies were treated with intracavitary or interstitial brachytherapy. Thirteen patients presented with clear cell adenocarcinoma, 14 patients with embryonal rhabdomyosarcoma, 6 patients with endodermal sinus tumor, 3 patients with sarcoma, and 1 patient with an undifferentiated tumor. FIGO classification was: Stage I, 16%; Stage II, 47%; and Stage III, 37%. Treatment policy included initial exploratory laparotomy with lymph node biopsy and ovarian transposition, chemotherapy (except in clear cell adenocarcinoma) and/or external radiotherapy prior to interstitial brachytherapy. Chemotherapy consisted of a combination of VAC-Ad (V = vincristine, A = D actinomycin, C = cyclophosphamide, Ad = adriamycin) in rhabdomyosarcoma and sarcomas, and MAC-Ad (M = methotrexate) in endodermal sinus tumor. External radiotherapy was used in seven patients: in one to reduce a bulky clear cell adenocarcinoma (20 Gy) and in six for pelvic nodal involvement (45 Gy). Brachytherapy techniques depended on tumor site and extent, and on the anatomy of the patients. Vulvar tumors were implanted with iridium-192 wires by an afterloading plastic tube technique. Cervical and vaginal tumors were treated with individually tailored moulded vaginal applicators loaded with either cesium-137 or iridium-192, with or without interstitial implants by plastic tube or guide gutter technique. Computerized dosimetry allowed calculation of treatment volumes and doses delivered on the tumor and adjacent critical organs. The prescribed dose (including external radiotherapy) was 60-75 Gy with 1-3 brachytherapy applications of a low dose rate (0.2 Gy/hr). Six patients are dead: one from chemotherapy complication, three of metastases (two sarcomas, one endodermal sinus tumor) and two of pelvic failures and metastases (two clear cell adenocarcinoma). The overall disease free 5-year survival is 72%. Actuarial 5-year local control is 84%, but including salvage is 94%: three (two rhabdomyosarcoma, one clear cell adenocarcinoma) of the five local failures were salvaged by surgery, chemotherapy and/or brachytherapy. Metastases occurred in six patients, one (sarcoma) salvaged by chemotherapy and external radiotherapy. Complications requiring surgery occurred in five patients: two hydronephroses, one urethral stricture, one ileo-cecal obstruction, and one vesicovaginal fistula. Twelve of the 17 patients (71%) over 12 years of age are normally menstruating. Two patients have produced three normal children. This multidisciplinary management of lower gynecological tract tumors including brachytherapy is both conservative and effective.

Second malignant tumors in patients with laryngeal carcinoma: diagnosis, treatment, and prevention.

Although the survival rates reported for patients with larynx carcinoma are quite good, there is a risk of developing second malignant tumors (SMT) in this population. The prognosis for SMT is poor, particularly with tumors of the lung and esophagus. The Rochester series was analyzed for larynx stage and specific SMT sites, possible common etiologic factors, and survival of the population as a whole, as well as for the SMT group. From a total of 235 patients with larynx carcinoma and a median follow-up of 10 years, 50 patients with 61 SMT were identified. The overall incidence of developing a SMT was 21%, with 44% of the SMT in the lung. The median survival from SMT diagnosis was 8.74 months and the 2-year survival was only 26%. More than twice as many SMT were observed than would be expected in the population at risk, with an observed-to-expected ratio (OER) for lung SMT of 5.3, and 8 times as many head and neck SMT occurring in our population. These SMT are not treatment related but are most likely caused by a combination of exposure to a common carcinogen, that is, tobacco smoke and alcohol, and to inherent factors, notably "condemned mucosa syndrome." Follow-up procedures, from the perspective of SMT development in larynx cancer patients, are addressed in an attempt to improve survival. The focus of this study is the high incidence of lung primaries that could be mistaken for metastatic disease, which is relatively uncommon in early larynx cancer patients.

Whole abdominal irradiation following chemotherapy in patients with minimal residual disease after second look surgery in ovarian carcinoma.

From January 1981 through December 1985, 65 patients with epithelial carcinoma of the ovary were treated with the following protocol: surgery, combination chemotherapy, second-look surgery documenting tumor less than or equal to 2 cm, and whole abdominal irradiation. Chemotherapy consisted of a combination of cyclophosphamide, adriamycin, and cisplatinum in 89% of the patients. The median number of cycles was eleven. Second-look surgery documented no residual tumor in 23 patients, microscopic disease in three patients, and macroscopic disease less than or equal to 2 cm in 39 patients. Whole abdominal irradiation was given with an open field technique up to 20 Gy without renal or hepatic shield. A pelvic boost of 15-30 Gy was subsequently added in 17 patients with macroscopic disease in the pelvis at the time of second-look surgery. Fifteen patients received complementary chemotherapy mostly hexamethylmelamine. All but two patients completed whole abdominal irradiation: one refused further radiotherapy after 3 Gy and one developed disease progression with bowel obstruction after 1 Gy. The median follow-up was 69 months. The 3-year and 6-year no evidence of disease survival rates were 60% (95% CI: 48-71) and 33% (95% CI: 21-46), respectively. The 3-year and 6-year recurrence rates were 33% (95% CI: 22-45) and 54% (95% CI: 40-67), respectively. The 3-year and 6-year metastasis rates were 22% (95% CI: 13-34) and 43% (95% CI: 30-58), respectively. A multivariate analysis showed that residual disease after second-look surgery was the only significant prognostic factor with a relative risk of death or local or distant failure of 4.2 (95% CI: 1.9-9.5, p less than 10(-4)). Two patients developed mean-term gastrointestinal complications (small bowel obstructions requiring surgery). Survival remains poor with high level of failure even with aggressive multimodal treatment.

Prognostic value of hemoglobin concentrations and blood transfusions in advanced carcinoma of the cervix treated by radiation therapy: results of a retrospective study of 386 patients.

A retrospective study was carried out on 386 patients with advanced cervical carcinomas treated with radiation therapy between 1973 and 1983. The influence of hemoglobin concentrations and blood transfusions before and/or during treatment on the occurrence of distant and/or local regional failures were examined in a univariate and multivariate analyses. In the multivariate analysis hemoglobin concentrations were prognostic only during treatment and patients with at least one value below the threshold of 10 gm% had a significantly higher risk of local regional failure than the patients with all their values above the threshold. Moreover 70% of these high risk patients had less than half of their values below the threshold. It is possible that blood transfusions might be beneficial when given before treatment. However, although it was not significant, blood transfusions given during treatment tended to be an adverse prognostic factor suggesting that blood transfusions might not have completely offset acute anemia prior to transfusion. Our study suggests that anemia during treatment, even of short duration might be detrimental to patients.

Interstitial and external radiotherapy in carcinoma of the soft palate and uvula.

Forty-three patients, all male, with limited epidermoid carcinoma of the soft palate and uvula were treated by interstitial implant usually associated with external radiotherapy. Most patients received 50 Gy external irradiation to the oropharynx and neck followed by 20-35 Gy by interstitial iridium-192 wires using either guide gutters or a plastic tube technique. Twelve primary tumors and two recurrences after external irradiation alone had implant only for 65-75 Gy. Total actuarial local control is 92% with no local failures in 34 T1 primary tumors. Only one serious complication was seen. Overall actuarial survival was 60% at 3 years and 37% at 5 years but cause-specific survivals were 81% and 64%. The leading cause of death was other aerodigestive cancer, with an actuarial rate of occurrence of 10% per year after treatment of a soft palate cancer. Interstitital brachytherapy alone or combined with external irradiation is safe, effective management for early carcinoma of the soft palate and uvula but second malignancy is a serious problem.

Feasibility study of an alternating schedule of radiotherapy and chemotherapy in advanced uterine cervical carcinoma.

From July 1981 to April 1982, 36 patients with advanced cervical carcinoma stage III (24 patients) and stage IV (12 patients) entered a feasibility study of a radiotherapy and chemotherapy combination. The first three chemotherapy courses consisted of cis-platinum alone (50 mg/m2) and were interdigitated with radiotherapy. Six more courses composed of an association of cis-platinum (50 mg/m2) and cyclophosphamide (400 mg/m2) were given after the completion of radiotherapy. Radiotherapy was delivered in two courses of 25 Gy separated by a gap of 2 weeks. The overall 4-year survival rate was 35% (95% CI: 22%). The 4-year survival rate, cumulative loco-regional failure rate, and cumulative metastasis rate were respectively 44% (95% CI: 20%), 56% (95% CI: 21%), and 30% (95% CI: 21%) in stage III and 28% (95% CI: 27%), 83% (95% CI: 21%) and 74% (95% CI: 30%) in stage IV. The incidence of immediate and late complications was low: no patient had her radiotherapy stopped because of an intolerance and two patients had their chemotherapy stopped because of an haematological intolerance. Only one patient presented a severe late clinical complication (small bowel injury).

Is prophylactic para-aortic irradiation worthwhile in the treatment of advanced cervical carcinoma? Results of a controlled clinical trial of the EORTC radiotherapy group.

From November 1977 to July 1981, 441 patients with cervical carcinoma were randomized between pelvic irradiation and pelvic and para-aortic irradiation. Included were patients with stage I and IIB with proximal vaginal and/or parametrial involvement with positive pelvic lymph nodes either on lymphangiogram or at surgery, and stage IIB with distal vaginal and/or parametrial involvement and III regardless of pelvic node status on lymphangiogram. Patients with clinically or surgically involved para-aortic nodes were not included. The external beam dose to the para-aortic area was fixed at 45 Gy. There was no statistically significant difference between the two treatment arms in terms of local control, overall distant metastases and survival with no evidence of disease (NED), although the incidence of para-aortic metastases and distant metastases without tumor at pelvic sites was significantly higher in patients receiving pelvic irradiation alone (pelvic group). The 4-year NED survival rate was 51%. The incidence of severe digestive complications was significantly higher in patients receiving para-aortic irradiation (para-aortic group). Routine para-aortic irradiation for all high risk patients with cervical carcinoma is of limited value, but patients with a high probability of local control can benefit from extended field irradiation, despite an increase in severe digestive complications.

C-myc proto-oncogene expression and prognosis in early carcinoma of the uterine cervix.

Expression of the c-myc gene was studied by northern blot and slot blot hybridisation in 72 specimens of stage I or II squamous cell carcinoma of the uterine cervix. In 25 of the 72 tumours c-myc proto-oncogene was overexpressed (ie, at levels 4-20 times higher than in normal tissues). Patients whose tumours showed c-myc overexpression had an eight-fold greater incidence of early relapse than the other patients (p = 0.001). The 18-month relapse-free survival rates were, respectively, 49% and 90% for these two groups of patients.

[Computed tomography of uterine and ovarian cancer]. / La tomodensitométrie dans les cancers de l'utérus et de l'ovaire.

The authors try to specify the place of Tomodensitometry in utero-ovarian cancers. The examination technique presents no particularities: at best, the interval and the depth of the cuts must be selected. In cervical cancers, the poor appreciation on TDM of adnexal and vaginal involvement renders this examination unsuitable for staging. On the contrary, it is absolutely necessary in order to make the diagnosis of recurrences. In cancers of the body of the uterus, almost always operated on, TDM presents very little interest for the initial work-up except for patients who are difficult to examine or are going to undergo irradiation. As for ovarian tumors, TDM may be useful to detect intra-hepatic metastases before the first operation, to monitor patients undergoing chemotherapy: peritoneal carcinosis is inconstantly detected and TDM cannot replace a second look.

[Value of x-ray computed tomography in the monitoring of cancer of the ovary. Apropos of 69 cases]. / Intérêt de l'examen tomodensitométrique dans la surveillance des cancers de l'ovaire. A propos de 69 observations.

The authors have studied retrospectively, a group of 69 patients with primitive carcinoma of the ovary who underwent at most one CT examination following the first surgical treatment. In 26 out of these, CT was done within the three months following a second surgical operation. Peritoneal metastases were inconsistently seen (5 true positive, 9 true negative, 0 false positive, 9 false negative). The sensitivity is 36%, the specificity 100% and the accuracy 65%. The score is better in the detection of lymphatic, hepatic and intestinal metastases.

[Advanced cancer of the ovary. Treatment and results]. / Le cancer de l'ovaire étendu. Traitement et résultats.

The management of advanced ovarian carcinoma (stages IIb, III, IV) is presented together with the results of treating a series of 65 patients at Gustave-Roussy Institute. The response rate was 43 p. cent with 16 complete remissions and 12 partial remissions out of 65 patients. Fourth year survival without recurrences was 12/65; 9/16 after complete remission at 2nd look, and 3/12 after partial remission. Treatment was by surgery--chemotherapy--2nd look surgery; radiotherapy and/or chemotherapy are decided on after 2nd look surgery. Each treatment should be agressive, prolonged, and multi-disciplinary.