Fractionated high-dose-rate brachytherapy in primary carcinoma of the nasopharynx.

PURPOSE: A growing body of data suggests that local control in nasopharyngeal cancer (NPC) is related to the radiation dose administered. We conducted a single-institution study of high-dose radiotherapy (RT), which incorporated high-dose-rate (HDR) brachytherapy (BT). These results were analyzed together with data obtained from controls who did not receive BT. PATIENTS AND METHODS: The BT group comprised 42 consecutive patients of whom 29 patients were staged according to the tumor, node, metastasis system as T1 through 3, 13 patients were T4, and 34 patients were N+ disease. BT was administered on an outpatient basis by means of a specially designed flexible nasopharyngeal applicator, and the dose distributions were optimized. Treatment for T1 through 3 tumors comprised 60 Gy of external-beam radiotherapy (ERT) followed by six fractions of 3 Gy BT (two fractions per day). Patients with parapharyngeal tumor extension and/or T4 tumors received 70 Gy ERT and four fractions of 3 Gy BT. The no-BT group consisted of all patients treated from 1965 to 1991 (n = 109), of whom 82 patients had stages T1 through 3, 27 patients had T4, and 80 patients had N+ disease. Multivariate Cox proportional hazards analyses were performed by using the end points time to local failure (TTLF), time to distant failure (TTDF), disease-free survival (DFS), cause-specific survival (CSS), and the prognostic factors age, tumor stage, node stage, and grade. Because the overall treatment time varied substantially in the no-BT group, the dependence of local failure (LF) on the physical dose as well as the biologic effective dose (BED) corrected for the overall treatment time (OTT) (BEDcor10) was studied. RESULTS: The BT group had a superior 3-year local relapse-free rate (86% v 60%; univariate analysis, P = .004). Multivariate analysis showed hazards ratios for BT versus no-BT of 0.24 for TTLF (P = .003), 0.35 for TTDF (P = .038), 0.31 for DFS (P < .001), and 0.44 for CSS (P = .01). The best prognostic group consisted of patients with T1 through 3, N0 through 2b tumors treated with BT who attained a 5-year TTLF of 94% and CSS of 91%. In contrast, the worst prognostic group, i.e., 5-year TTLF of 47% and CSS of 24%, was composed of patients with T4 and/or N2c through 3 tumors who did not receive BT. CONCLUSION: High doses of radiation (73 to 95 Gy) can be administered to patients with NPC with minimal morbidity by means of optimized HDR-BT. The use of a BT boost proved to be of significant benefit, particularly in patients with T1 through 3, N0 through 2b disease. The steep dose-effect relationship seen for the physical dose and the BEDcor10 indicates that the results are dose related. The analysis has identified a poor prognostic group in whom treatment intensification with chemotherapy (CHT) is indicated.

Muscle invasive bladder cancer treated by transurethral resection, followed by external beam radiation and interstitial iridium-192.

PURPOSE: To evaluate the results of transurethral resection (TUR), external beam radiotherapy (EBRT), and interstitial radiation (IRT) with iridium-192, using the afterloading technique in patients with muscle invasive bladder cancer. METHODS AND MATERIALS: From May 1989 until September 1995, 66 patients with primary, solitary muscle invasive bladder cancer were treated with TUR, EBRT, and IRT, aiming at bladder preservation. According to the protocol, in three patients low-dose EBRT was applied, whereas 63 patients received high-dose EBRT. Immediately prior to IRT, 42 patients underwent a lymphnode dissection, and in 16 cases a partial cystectomy was performed. For IRT, two to five catheters were used and IRT was started within 24 h after surgery. The majority of patients received 30 Gy of IRT, with a mean dose rate of .58 Gy/h. In three patients, additional EBRT was applied following IRT. Follow-up consisted of regular cystoscopies, mostly done during joint clinics of urologist and radiation oncologist, with urine cytology routinely performed. The median follow-up period was 26 months. The Kaplan-Meier method was used for the determination of survival rates. RESULTS: In seven patients, a bladder relapse developed. The probability of remaining bladder relapse free at 5 years was 88%. The bladder was preserved in 98% of the surviving patients. Metastases developed in 16 patients, and the probability of remaining metastasis free at 5 years was 66%. The cumulative 5-year overall and bladder and distant relapse free survival were 48% and 69%, respectively. Acute toxicity was not serious in the majority of cases; surgical correction of a persisting vesicocutaneous fistula was necessary in two patients, whereas a wound toilet had to be performed in another patient. Serious late toxicity (bladder, RTOG Grade 3) was experienced by only one patient. CONCLUSIONS: Interstitial radiation preceded by TUR and EBRT, in a selected group of patients with muscle invasive bladder cancer, yields an excellent bladder tumor control rate with a high probability of bladder preservation. Survival was mainly dependent on the development of distant metastases. Serious acute and late toxicity was rare.

Fractionated high-dose-rate and pulsed-dose-rate brachytherapy: first clinical experience in squamous cell carcinoma of the tonsillar fossa and soft palate.

PURPOSE: Fractionated high-dose-rate (fr.HDR) and pulsed-dose-rate (PDR) brachytherapy (BT) regimens, which simulate classical continuous low-dose-rate (LDR) interstitial radiation therapy (IRT) schedules, have been developed for clinical use. This article reports the initial results using these novel schedules in squamous cell carcinoma (SCC) of the tonsillar fossa (TF) and/or soft palate (SP). METHODS AND MATERIALS: Between 1990 and 1994, 38 patients with TF and SP tumors (5 T1, 22 T2, 10 T3, and 1 T4) were treated by fr.HDR or PDR brachytherapy, either alone or in combination with external irradiation (ERT). Half of the patients were treated with fr.HDR, which entailed twice-daily fractions of > or = 3 Gy. The other 19 patients were administered PDR, which consisted of pulses of < or = 2 Gy delivered 4-8 times/day. The median cumulative dose of IRT +/- ERT series was 66 Gy (range 55-73). The results in these patients treated by brachytherapy were compared to 72 patients with similar tumors treated in our institute with curative intent, using ERT alone. The median cumulative dose of ERT-only series was 70 Gy (range 40-77). RESULTS: Excellent locoregional control was achieved with the use of IRT +/- ERT, with only 13% (5 of 38) developing local failure, and salvage surgery being possible in three of the latter (60%). Neither BT scheme (fr.HDR vs. PDR) nor tumor site (TF vs. SP) significantly influenced local control rates. The type and severity of the side effects observed are comparable to those reported in the literature for LDR-IRT. These results contrast sharply with our ERT-only series, in which 39% of patients (28 of 72) developed local failure, with surgical salvage being possible only in three patients (11%). Taking the data set of 110 patients, in a univariate analysis IRT, T stage, N stage, overall treatment time (OTT), and BEDcor10 (biological effective dose with a correction for the OTT) were significant prognostic factors for local relapse-free survival (LRFS) and overall survival (OS) at 3 years. Using Cox proportional hazard analysis, only T stage and BEDcor10 remained significant for LRFS (p < 0.001 and 0.008, respectively), as well as for OS (p < 0.001 and 0.003, respectively). With regard to the current (IRT) and historical (ERT) series, for the LRFS at 3 years, dose-response relationships were established, significant, however, only for the BEDcor10 (p = 0.03). CONCLUSION: The 3-year LRFS of approximately 90% for TF and SP tumors reported here is comparable with the best results in the literature, particularly given the fact that 30% of the patients (11 of 38) presented with T3/4 tumors. When compared with our historical (ERT-only) controls, the patients treated with IRT had superior local control. A dose-response relationship was established for the BEDcor10.

Acute morbidity reduction using 3DCRT for prostate carcinoma: a randomized study.

PURPOSE: To study the effects on gastrointestinal and urological acute morbidity, a randomized toxicity study, comparing conventional and three-dimensional conformal radiotherapy (3DCRT) for prostate carcinoma was performed. To reveal possible volume effects, related to the observed toxicity, dose-volume histograms (DVHs) were used. METHODS AND MATERIALS: From June 1994 to March 1996, 266 patients with prostate carcinoma, stage T1-4N0M0 were enrolled in the study. All patients were treated to a dose of 66 Gy (ICRU), using the same planning procedure, treatment technique, linear accelerator, and portal imaging procedure. However, patients in the conventional treatment arm were treated with rectangular, open fields, whereas conformal radiotherapy was performed with conformally shaped fields using a multileaf collimator. All treatment plans were made with a 3D planning system. The planning target volume (PTV) was defined to be the gross target volume (GTV) + 15 mm. Acute toxicity was evaluated using the EORTC/RTOG morbidity scoring system. RESULTS: Patient and tumor characteristics were equally distributed between both study groups. The maximum toxicity was 57% grade 1 and 26% grade 2 gastrointestinal toxicity; 47% grade 1, 17% grade 2, and 2% grade > 2 urological toxicity. Comparing both study arms, a reduction in gastrointestinal toxicity was observed (32% and 19% grade 2 toxicity for conformal and conventional radiotherapy, respectively; p = 0.02). Further analysis revealed a marked reduction in medication for anal symptoms: this accounts for a large part of the statistical difference in gastrointestinal toxicity (18% vs. 14% [p = ns] grade 2 rectum/sigmoid toxicity and 16% vs. 8% [p < 0.0001] grade 2 anal toxicity for conventional and conformal radiotherapy, respectively). A strong correlation between exposure of the anus and anal toxicity was found, which explained the difference in anal toxicity between both study arms. No difference in urological toxicity between both treatment arms was found, despite a relatively large difference in bladder DVHs. CONCLUSIONS: The reduction in gastrointestinal morbidity was mainly accounted for by reduced toxicity for anal symptoms using 3DCRT. The study did not show a statistically significant reduction in acute rectum/sigmoid and bladder toxicity.

Local tumor control in radiation therapy of cancers in the head and neck.

BACKGROUND: A retrospective study of 1,493 head and neck cancer patients was designed to test current radiobiological thinking, postulating the detrimental effect of protracted overall treatment times (OTT) and/or split course (SC) regimes in radiation therapy on local tumor control. METHODS: Primary squamous cell carcinomas of the oral cavity (OC), oropharynx (OP), hypopharynx (HP), nasopharynx (NP), and larynx radiated with a dose of at least 50 Gy were analyzed. Those patients treated by brachytherapy and/or primary surgery were excluded. A detailed analysis of the 997 cancers of the larynx was recently published. This paper focuses on the relationship between local tumor control and treatment characteristics for the 496 tumors originating from the OC, OP, HP, and NP. Total doses of radiation ranged from 50 to 79 Gy, with a mean of 64 Gy. RESULTS: A local failure (LF) was observed for 278 patients. Using Cox regression analysis, T stage and site were strongly related to LF. Corrected for T stage and with reference to OP, tumors in the NP, HP, and OC had a relative LF rate of 0.5, 1.6, and 1.8, respectively. Patients treated with continuous course (CC) and higher doses of radiation therapy fared best. No association was found with OTT and the use of chemotherapy. CONCLUSIONS: The results observed for the OC, OP, HP, and NP are in line with the findings for the larynx. Analyzing all 1,493 patients, for SC regimes lower local control rates were observed as opposed to the CC treatment series. Moreover, for the normalized total doses, a dose-effect relationship could be established. This study corroborates that disruption of the treatment per se and/or the use of suboptimal total doses of RT are detrimental; it is argued that these observations could be of relevance when designing combined modality protocols.

Radiation therapy for cancer of the piriform sinus. A failure analysis.

This paper analyzes the results of 109 piriform sinus (PS) cancers treated between 1973 and 1984 by surgery and/or external beam radiation therapy (EBRT) in a large comprehensive cancer center, and in particular tries to redefine the role of EBRT in the management of these tumors. At the time the policy was to start with EBRT to a dose of 40 Gy. A good response to a first series was to be continued by EBRT (RT-1); in case of poor responding tumors, the primary and neck were to be operated upon (RT-S). Poor responders unfit for S or those refusing S were also carried to a full course of EBRT (RT-2). The RT-S, RT-1, and RT-2 actuarial 5-year locoregional relapse-free survival (LR-RFS) and overall survival (OS) were 60%, 40%, and 20% and 40%, 30%, and 20%, respectively. In a multivariate Cox regression analysis the most important prognostic factor appeared to be N-stage, with hazard ratios of 1.16 (N1), 2.2 (N2), and 3.3 (N3). The RT-S treatment group fared best (hazard ratio 0.5). The risk of relapse for T3,4 was 1.3 times as high as opposed to T1,2. For stage I/II (19/21 treated by EBRT only), a LR-RFS and OS at 5 years of 60% and 40%, respectively, was observed. This analysis supports data for stage III/IV PS cancers to be treated by surgery combined with EBRT; in stage I/II there might be a role for EBRT alone. It is speculated that with further sophistication in RT-techniques, the locoregional control rates by EBRT alone could improve.

In vivo experiments with powder charcoal haemoperfusion (filmadsorber) in a pig model of hepatic failure.

The filmadsorber, an experimental haemoperfusion column containing activated powder charcoal embedded in a colloidal film, has been tested in pigs with ischaemicnecrosis of the liver. Haemoperfusion with a flow of 200 ml/min was performed for a duration of 4 to 6 hours. Bile acid clearances varied between +/- 52 ml/min (1st hour) and +/- 23 ml/min (6th hour). Clearances for aromatic amino acids were initially even higher (phenylalanine 115, tyrosine 112 and methionine 46 ml/min). No ammonia was removed. Side-effects were minimal, although platelets fell 24 +/- 15%. We conclude that haemoperfusion with the filmadsorber is well tolerated and associated with high clearances for bile acids and some amino acids, particularly in the first hours of treatment.

[Visit to the emergency department: primary or secondary character?]. / EHBO-bezoek: eerste- of tweedelijnskarakter?

In a prospective study, 961 patients who came to the Emergency Department were registered and their cases were analysed on the basis of criteria drawn up in consultation with a group of general practitioners. Of this number 74% had presented themselves on their own initiative; 40% had been suffering from the complaint for some time. 66% of the patients who had not been referred and 60% of the total number could have been treated by their GP, at less expense for the National Health Service. It is worth considering for GPs on duty to make use of the facilities provided by the Emergency Departments of hospitals. This would increase patients' understanding of the function and the accessibility of Emergency Departments, enable GPs to work more efficiently and be cost effective.

[Multidisciplinary treatment of superior sulcus (Pancoast) tumors]. / De multidisciplinaire behandeling van sulcus-superior (Pancoast)-tumoren.

Ten patients with a Pancoast tumour, seven with pulmonary carcinoma, three with a soft tissue tumour, were treated surgically with or without preoperative chemotherapy or external radiotherapy, and with postoperative external radiotherapy mostly in combination with brachytherapy using a flexible intraoperative template. The results were highly variable, e.g. one patient died after three months, another was still alive without tumour after 36 months. Optimal treatment requires cooperation of experienced surgeons, radiotherapists and medical oncologists.

The clinical feasibility of deep hyperthermia treatment in the head and neck: new challenges for positioning and temperature measurement.

To apply high-quality hyperthermia treatment to tumours at deep locations in the head and neck (H&N), we have designed and built a site-specific phased-array applicator. Earlier, we demonstrated its features in parameter studies, validated those by phantom measurements and clinically introduced the system. In this paper we will critically review our first clinical experiences and demonstrate the pivotal role of hyperthermia treatment planning (HTP). Three representative patient cases (thyroid, oropharynx and nasal cavity) are selected and discussed. Treatment planning, the treatment, interstitially measured temperatures and their interrelation are analysed from a physics point of view. Treatments lasting 1 h were feasible and well tolerated and no acute treatment-related toxicity has been observed. Maximum temperatures measured are in the range of those obtained during deep hyperthermia treatments in the pelvic region but mean temperatures are still to be improved. Further, we found that simulated power absorption correlated well with measured temperatures illustrating the validity of our treatment approach of using energy profile optimizations to arrive at higher temperatures. This is the first data proving that focussed heating of tumours in the H&N is feasible. Further, HTP proved a valuable tool in treatment optimization. Items to improve are (1) the transfer of HTP settings into the clinic and (2) the registration of the thermal dose, i.e. dosimetry.

Winner of the "New Investigator Award" at the European Society of Hyperthermia Oncology Meeting 2007. The HYPERcollar: a novel applicator for hyperthermia in the head and neck.

The purpose of this work was to define all features, and show the potential, of the novel HYPERcollar applicator system for hyperthermia treatments in the head and neck region. The HYPERcollar applicator consists of (1) an antenna ring, (2) a waterbolus system and (3) a positioning system. The specific absorption rate (SAR) profile of this applicator was investigated by performing infra-red measurements in a cylindrical phantom. Mandatory patient-specific treatment planning was performed as an object lesson to a patient with a laryngeal tumour and an artificial lymph node metastasis. Comfort tests with healthy volunteers have revealed that the applicator provides sufficient comfort to maintain in treatment position for an hour: the standard hyperthermia treatment duration in our centre. By phantom measurements, we established that a central focus in the neck can be obtained, with 50% iso-SAR lengths of 3.5 cm in transversal directions (x/y) and 9-11 cm in the axial direction (z). Using treatment planning by detailed electromagnetic simulations, we showed that the SAR pattern can be optimised to enable simultaneous encompassing of a primary laryngeal tumour and a lymph node metastasis at the 25% iso-SAR level. This study shows that the applicator enables a good control, and sufficient possibilities for optimisation, of the SAR pattern. In an ongoing clinical feasibility study, we will investigate the possibilities of heating various target regions in the neck with this apparatus.