Accelerated hyperfractionation (AHF) compared to conventional fractionation (CF) in the postoperative radiotherapy of locally advanced head and neck cancer: influence of proliferation.

Based on the assumption that an accelerated proliferation process prevails in tumour cell residues after surgery, the possibility that treatment acceleration would offer a therapeutic advantage in postoperative radiotherapy of locally advanced head and neck cancer was investigated. The value of T(pot) in predicting the treatment outcome and in selecting patients for accelerated fractionation was tested. Seventy patients with (T2/N1-N2) or (T3-4/any N) squamous cell carcinoma of the oral cavity, larynx and hypopharynx who underwent radical surgery, were randomized to either (a) accelerated hyperfractionation: 46.2 Gy per 12 days, 1.4 Gy per fraction, three fractions per day with 6 h interfraction interval, treating 6 days per week or (b) Conventional fractionation: 60 Gy per 6 weeks, 2 Gy per fraction, treating 5 days per week. The 3-year locoregional control rate was significantly better in the accelerated hyperfractionation (88 +/- 4%) than in the CF (57+/- 9%) group, P=0.01 (and this was confirmed by multivariate analysis), but the difference in survival (60 +/- 10% vs 46 +/- 9%) was not significant (P=0.29). The favourable influence of a short treatment time was further substantiated by demonstrating the importance of the gap between surgery and radiotherapy and the overall treatment time between surgery and end of radiotherapy. Early mucositis progressed more rapidly and was more severe in the accelerated hyperfractionation group; reflecting a faster rate of dose accumulation. Xerostomia was experienced by all patients with a tendency to be more severe after accelerated hyperfractionation. Fibrosis and oedema also tended to be more frequent after accelerated hyperfractionation and probably represent consequential reactions. T(pot) showed a correlation with disease-free survival in a univariate analysis but did not prove to be an independent factor. Moreover, the use of the minimum and corrected P-values did not identify a significant cut-off. Compared to conventional fractionation, accelerated hyperfractionation did not seem to offer a survival advantage in fast tumours though a better local control rate was noted. This limits the use of T(pot) as a guide for selecting patients for accelerated hyperfractionation. For slowly growing tumours, tumour control and survival probabilities were not significantly different in the conventional fractionation and accelerated hyperfractionation groups. A rapid tumour growth was associated with a higher risk of distant metastases (P=0.01). In conclusion, tumour cell repopulation seems to be an important determinant of postoperative radiotherapy of locally advanced head and neck cancer despite lack of a definite association between T(pot) and treatment outcome. In fast growing tumours accelerated hyperfractionation provided an improved local control but without a survival advantage. To gain a full benefit from treatment acceleration, the surgery-radiotherapy gap and the overall treatment time should not exceed 6 and 10 weeks respectively.

Aberrant expression of cyclin A in head and neck cancer.

Cyclin A expression was studied in a series of 65 squamous cell carcinomas of the head and neck (HNSCC) and compared with known markers of proliferation, iododeoxyuridine (IdUrd) and Ki-67, to assess whether aberrant expression was prevalent. Patients had previously been administered IdUrd to study cell kinetics in relation to outcome of radiotherapy. The data showed that all three parameters were highly correlated although the absolute values were different. The median labelling indices (LI) for IdUrd, cyclin A and Ki-67 were 10.7, 17.1 and 30.8% respectively, reflecting the known pattern of differential cell cycle expression. However, there were a significant number of cases in which an unexpected relationship between cyclin A and either IdUrd or Ki-67 was present. Some of these were attributable to overexpression but others indicated underexpression. Although the greater variability and range of cyclin A expression, coupled with its more closely associated role in cell cycle regulation, might suggest that it may be a more informative marker for cell proliferation than Ki-67, the aberrant expression seen in over one third of cases would indicate that caution should be exercised in interpreting cyclin A as a surrogate marker of proliferation in HNSCC.

Accelerated versus conventional fractionation in the postoperative irradiation of locally advanced head and neck cancer: influence of tumour proliferation.

Fifty-six patients with locally advanced head and neck squamous cell carcinoma were subjected to adjuvant radiotherapy after radical surgery with randomisation to either conventional fractionation (CF), comprising 50 Gy/25 F/5 weeks, or to accelerated hyperfractionation (AHF) to a dose of 42 Gy/30 F/11 days (3 F/day), a dose/F of 1.4 Gy and an interfraction interval of 4 h. The in vitro [3H]thymidine labelling index (TLI) was determined as an indicator of tumour proliferation. Early mucosal reactions were somewhat more severe after AHF than after CF and the peak was attained earlier. The actuarial 3-year complication rate was significantly lower in the AHF (64%) than in the CF group (87%). This is probably related to a smaller fraction size and a lower total dose. The overall 3-year disease-free survival amounted to 46 +/- 7%. Sex, the anatomical site, the nodal status, the performance status and TLI have been shown to be significant prognostic factors, but only the latter two proved to be independent covariates. Overall, the type of fractionation did not seem to influence survival. However, AHF seemed to offer higher survival probabilities in fast growing tumours and this attained a significant level for tumours with TLI > 10.4% (Tpot < 4.5 days). However, CF and AHF were associated with similar survival rates in slowly growing tumours. The relative effectiveness of the CF and AHF schedules is predictable on the basis of the linear-quadratic system. In the case of tumour response, a time factor has to be included assuming that accelerated repopulation of microscopic residues occurs from the outset.(ABSTRACT TRUNCATED AT 250 WORDS)

Postoperative radiotherapy of carcinoma in bilharzial bladder: improved disease free survival through improving local control.

Two hundred thirty-six patients with T3 bladder cancer who survived radical surgery and proved to have P3a, P3b, or P4a tumors were randomized in two phases into three groups: (a) no further treatment (83 patients); (b) postoperative radiotherapy multiple daily fractionation (MDF), using 3 daily fractions of 1.25 Gy each, with 3 hr between fractions, up to a total dose of 37.5 Gy in 12 days (75 patients); and (c) postoperative radiotherapy conventional fractionation (CF), for a total dose of 50 Gy/5 weeks (78 patients). The tolerance of the patients to postoperative radiotherapy was quite acceptable, with equal acute reactions in MDF and CF groups. The 5-year disease-free survival (DFS) rates amounted to 49 and 44% in MDF and CF postoperative radiotherapy groups, respectively, compared to 25% in the cystectomy-alone group. The 5-year local control rates were 87% and 93% for those treated with multiple daily fractionation and conventional fractionation while it was 50% in the surgery-alone group. The therapeutic benefit of postoperative irradiation was consistent for all tumor types, histological grades, and pathological stages for both the disease-free survival and local control. Patients with nodal metastases demonstrated lower recurrence rates in the postoperative radiotherapy groups, but this was not associated with improved disease-free survival. Multivariate analysis using the Cox Model confirmed these results. The independent prognostic factors affecting both disease-free survival and local control were the addition of postoperative radiotherapy, the nodal status, the pathological stage, and the tumor grade. Late complications of radiotherapy in the skin, small intestine, rectum, and the anastomotic site of the urinary division were lower with MDF than with conventional fractionation.

Late tissue reactions after single-fraction sequential half-body irradiation (HBI) in patients with non-Hodgkin's lymphomas.

Lung and hepatic toxicities constituted the main radiation-related damage after half-body irradiation (HBI) used as the treatment for patients with non-Hodgkin's lymphomas (NHL). Liver damage was mostly transient after a single dose of 8 Gy and could be well monitored by serum enzyme levels. A dose-response relationship could be shown for lung damage in the single dose range of 6.25-9.25 Gy, but the relationship did not reach statistical significance. A significant dose-rate effect could be shown. Mediastinal involvement by lymphoma seemed to increase the risk of pneumonitis. In a radical setting half-body irradiation is recommended to be used at a low dose-rate or as a multifraction irradiation in order to reduce the risk of liver and lung toxicities.

Pharmacokinetics of etanidazole (SR-2508) in bladder and cervical cancer: evidence of diffusion from urine.

Following an IV infusion of 2.0 g/m2 of Etanidazole, the mean tumor concentration 40 min after injection was 126 micrograms/g in bladder cancer and 65 micrograms/g in cervical cancer. The tumor/plasma concentration ratio was 1.88 in bladder and 0.85 in cervical cancer. This high tumor concentration in bladder cancer could be accounted for by diffusion from a highly concentrated urine. This renders bladder cancer a suitable clinical model for testing this sensitizer.

Discrepancies in dose and dose specification in interstitial implants.

The first step in the execution of an interstitial implant is the decision on size and location of the target volume. Several implant systems, e.g. the Paterson-Parker system and the Paris system, give instructions for the optimal arrangement of sources to assure that the planned target volume is adequately covered. They also give guidelines to calculate the reference dose rate encompassing the planned target volume. These systems provide different solutions for the source arrangement for the same planned target volume, and vice versa, resulting in different reference dose rates. The problem of dose specification is discussed. For a number of theoretical implants predicted reference dose rates for the planned target volume were compared with the computer calculated dose rates for that volume. Discrepancies increase when moderate digressions from the adopted implant system rules are allowed, such as could commonly occur clinically. For a number of examples the degree of change in dose rate, if over 10%, and the position where this deviation is likely to occur are described. For optimal results the clinician should be well aware of these variations.

Postoperative radiotherapy of carcinoma in bilharzial bladder using a three-fractions per day regimen.

Patients with T3 bladder cancer who survived surgery and proved to have P3a, P3b or P4a tumors were randomized to either no further treatment (61 patients) or postoperative total pelvic irradiation (55 patients). A three-fraction per day regime was adopted with a dose per fraction of 125 cGy and an interval of 3 h between fractions. The total dose amounted to 3750 cGy divided into 30 fractions over 12 days. Patients of the postoperative radiotherapy group were re-randomized to radiotherapy alone or radiotherapy plus misonidazole (MISO) in a daily dose of 1 g/m2 given orally 2 h before the first daily fraction. The 2-year disease-free survival rate in the cystectomy alone group was 33 +/- 6% compared to 65 +/- 6% in the postoperative radiotherapy group. The therapeutic benefit applied to the two cell types, all histological grades and stages and to patients with or without nodal metastases. The benefit of postoperative irradiation was also verified by the Cox's multivariant analysis which adjusts for the relative representation of the important prognostic factors particularly pathological stage and nodal involvement. MISO did not seem to add to the therapeutic gain. No late complications were encountered in the wall of the rectum, small bowel or uretero-intestinal anastomotic sites. This is suggested to be due to the small dose per fraction used. However, early small bowel reactions were dose-limiting.

Intercapillary distance measurement as an indicator of hypoxia in carcinoma of the cervix uteri.

The mean tumor intercapillary distance (ICD) was measured in 44 patients in Stages IIB and III carcinoma of the cervix uteri using a histo-chemical procedure for staining capillary endothelial cells. A mean ICD of 304 +/- 30 microns was obtained, which was independent of the clinical stage and histological grade of differentiation. For each tumor, the proportion of ICD's greater than an arbitrarily chosen value of 300 microns (approximately twice the maximum oxygen diffusion range) was calculated using the normal frequency distribution statistics. The mean ICD and this proportion decreased progressively during the course of external beam pelvic irradiation up to a dose of 4000 cGy. The mean ICD was greater in patients who suffered local recurrence within two years than in patients whose tumors remained controlled. This applied to pre-treatment values and measurements performed after the delivery of 2000 and 4000 cGy. The proportion of ICD's greater than 300 microns showed a similar trend. No significant correlation was found between the hemoglobin concentration at time of presentation and either the mean ICD, or the probability of local control. It is proposed that ICD measurement may be a useful tool to identify subgroups of tumors where hypoxia can interfere with the effectiveness of radiotherapy.

Relation between local cure and dose-time-volume factors in interstitial implants.

The dose and volume data of 119 patients treated with radium or iridium-192 implants for cancer of the tongue, bladder or perineum are presented. The computer dosimetry system used in the Antoni van Leeuwenhoek Hospital permitted analysis of data regarding treated volume, dose variation inside the treated volume, patterns of geographical defects and their impact on the result of treatment. Dose was expressed in a number of ways, including prescribed (reference) and average dose and the CRE (Cumulative Radiation Effect) level attained. The CRE value included a time correction and a volume correction. The average dose proved to be the best predictor of local result in case of tongue and perineal implants. Great care is needed in case of tongue carcinoma to avoid a geographical miss by an inadequate treatment volume or geometric defects. The hypothesis that a dose reduction factor is necessary, in case of a high dose rate, could not be validated.

Experience in the radical radiotherapy of cancer in the bilharzial bladder: the use of misonidazole.

The results of application of a protracted split-course radiotherapy regimen in T3 carcinoma in the bilharzial bladder are presented. A total dose of 70 Gy spread over 61 days was divided into four courses separated by gaps of 1, 2 and 1 week, respectively. Each of the first three sessions comprised eight fractions, 2.5 Gy each, while four such fractions were given during the fourth course. Patients were randomized between radiotherapy alone (32 patients) and radiotherapy plus misonidazole (MIS) (30 patients). The drug was given in a daily oral dose of 0.5 g/m2, 3.5 h prior to each radiation treatment. The treatment was well tolerated and MIS did not augment the radiation reaction. Mild or moderate peripheral neuropathy was experienced by 63% of patients of the group. Age and degree of upper obstructive uropathy were the most important determinants of the risk of neuropathy. The 2-year disease-free actuarial survival rates amounted to 58% and 44% in the MIS and radiotherapy alone groups respectively; the difference is not significant. The results were significantly better in case of transitional cell (67%) than squamous cell cancer (29%) but were independent of the histological grade. A strong correlation was found between the magnitude of tumour volume reduction after 40 Gy and the long-term end results.

The use of misonidazole in association with a three-fractions per day regimen in advanced head and neck epidermoid cancer. A pilot study.

Twenty-one patients with Stage III or IV head and neck epidermoid cancer were treated by a three-fractions per day radiotherapy regime plus misonidazole (MIS). An initial course of 45 Gy was used, spread over 12 days and divided into 30 fractions 1.5 Gy each with a 3-hour interval between fractions. A daily MIS dose of 1 g/m2 was given 2 hours prior to the first fraction. A boost dose of 22.5 Gy/5 days was given to 10 patients, 4 weeks after the initial course, using the same fractionation scheme. The local acute and chronic reactions were acceptable. Eight patients suffered mild reversible peripheral neuropathy. The mean MIS blood level corresponded to an enhancement ratio of about 1.45. The 1-year disease-free survival rate was 9/21 and was significantly greater in patients receiving the boost irradiation. The control rate of nodal disease was encouraging. Based on this pilot study, a prospective trial is proposed aiming at testing the usefulness of MIS in MDF regimens in advanced head and neck cancer, either as the sole method of treatment or as a preoperative measure.

The topical use of misonidazole in bladder cancer.

Penetration studies of MIS after intravesical administration showed adequate concentrations with a gradient across the tumor. After instillation of 2.5 g in 50 ml water the concentration in the deep parts of the tumor amounted to about 100 microgram per ml. This corresponds to a SER for hypoxic cell of the order of 1.7. A more uniform tissue distribution of the drug was noted 3.5 hours after an oral dose of 3 g/meter square. The concentration in the deep parts of the tumor and perivesical tissue was of the order of 100 micrograms/g. The concentration in these regions are relevant to preoperative irradiation which aims at sterilizing the deep infiltrating margins. The intravesical use with or without oral augmentation is suitable for use in association with concentrated preoperative radiotherapy regimens. The topical use of MIS in such regimens markedly reduces the risk of neurotoxicity. The tissue concentration resulting from the two routes proved to be additive. The higher concentration in lymph nodes after the oral route the greater concentration and prolonged contact after combined administration may have therapeutic merits.

Misonidazole in the preoperative and radical radiotherapy of bladder cancer.

Measurement of intercapillary distances suggests the presence of significant cell hypoxia in Bilharzial bladder cancer. This tumor seems to be capable of reoxygenation in view of the existence of a correlation between prognosis and immediate tumor shrinkage after irradiation. Two programs are presented: 1) Use of misonidazole with concentrated preoperative irradiation where the reoxygenation properties are not used fully. A prospective randomized study is presented whereby cystectomy alone is compared with cystectomy plus preoperative irradiation (6.5 Gy X 2F/1 week) with or without misonidazole. the drug is given either orally (in two doses 3 g/m2 each given 3.5 hours prior to each fraction; blood levels: 90-110 micrograms/ml) or intravesically. The intravesical administration is designed in the light of penetration studies and seems to have the advantage of the complete lack of systemic drug toxicity. Twenty-eight patients were included in this study and no drug toxicity was recorded. A second preoperative irradiation study is presented whereby cystectomy alone is compared with cystectomy plus preoperative irradiation (4.0 Gy X 5F) with or without misonidazole in individual doses of 2 g/m2. 2) Two radical radiotherapy regimes are presented. One protocol involves a split course (SC) protracted regime making full use of spontaneous reoxygenation. The drug is given in 0.5 g/m2 daily doses (total dose 14 g/m2 spread over 61 days, blood level: 15-20 micrograms/ml). A second protocol involves hyperfractionation stimulating continuous low-dose-rate irradiation. Higher blood levels are attained (60-80 micrograms/ml) after daily doses of 2 g/m2 (total dose: 14 g/m2 spread over 35 days). In a phase II study using SC technic, reversible grade 1 peripheral neuropathy was encountered in 5 of 22 patients. Complete tumor regression 3 months after irradiation was achieved in 18 of 22 patients with 3T tumors. No neuropathy was encountered in four patients subjected to the HF regimen who also showed complete tumor regression.

Cell proliferation of carcinoma in Bilharzial bladder: an autoradiographic study.

The rate of cell production in thirty-five cases of carcinoma in Bilharzial bladder was evaluated from the labelling index after in vitro incubation with [3H]TdR. Squamous cell carcinoma was the most frequent histological type in this series and had a median LI of 8.0% which corresponds to a potential doubling time of 5.9 days. In squamous cell tumours the LI increased with the histological grade. Transitional cell tumours had a somewhat greater LI. In all histological types the LI was significantly greater in the deep infiltrating parts of the tumour than in the superficial parts. The discrepancy between the estimated potential doubling time and the growth rate normally attributed to such tumours suggests the existence of an extensive cell loss factor. Areas of focal or diffuse mucosal hyperplasia were associated with increased LI.

The dose-time relationship in the radiotherapy of carcinoma of the cervix uteri: an application of the CRE formalism.

A correlation could be obtained between the likelihood of control of central and nodal disease and the corresponding local CRE levels attained in a group of 79 cases of carcinoma of the cervix uteri treated according to a multistage protocol involving a combination of external telecobalt irradiation and intracavitary radium application. A nodal CRE level of 1700 reu and a central CRE value of 2900 reu seemed to be optimal for control of modal metastases and central disease respectively. These CRE levels seemed to be well tolerated even if salvage surgery had to be performed.

Penetration of misonidazole after intravesical administration in cases of carcinoma of the bilharzial bladder.

The penetration of misonidazole was studied by a semiquantitative T.L.C. method after intravesical administration 2 h before total cystectomy in cases of carcinoma of the Bilharzial bladder. In 5 out of 7 cases misonidazole was found at a concentration of the order of 0.4 mg/g in the superficial and deep parts of the tumour, but not in normal bladder tissues.

Studies in dose-time-volume relationships in bladder and tongue radium implants.

The clinical results of 26 tongue and 31 bladder radium implants were analysed in terms of proposed dose specification parameters that describe the dose-time-volume relationships of the implant. Tongue cases that recurred within two years were mostly those with a relatively short treatment time and in which a relatively large dose reduction factor had to be applied. The dose-time factor did not differ significantly in the groups of bladder implants having different clinical results. A higher incidence of necrosis was noted in bladder cases. This was associated with a significantly higher mean dose and a somewhat greater degree of dose inhomogeneity. Recurrences were generally linked with greater mean dose, target volume and dose inhomogeneity. These unfavourable dose-volume relationships were frequently associated with poor distribution of needles. The reported experimental and clinical findings pertinent to the differential sparing of normal tissues associated with protraction of continuous irradiation are outlined. In the light of these, it is felt that the results of tongue implants could have been improved by omission of the dose-time adjustment factor for treatment time of 3-10 days without undue risk of necrosis. However, bladder results could have been improved by attainment of a better implantation technique while keeping the treatment time within 6-8 days in view of the lower tolerance.