Juliana Denekamp

Late effects toxicity scoring: the SOMA scale

The two large organizations that initiate and coordinate multicenter clinical trials in Europe and in North America, the EORTC and the RTOG, have recently formed specific subcommittees or working groups to update their systems for assessing the late injury to normal tissues. This is regarded as necessary in order to standardize and improve the recording so that there can be uniform reporting of toxicity, at agreed and regular intervals in different clinical studies. Many centres have devised their own scales for recording such injury, some of which record all the raw data as it is derived from the patient, while others give a single score on a scale of l-5 to indicate the severity of the overall response. With such a variability in detailed recording of the information on morbidity it is difficult, or even impossible, to compare the outcome of different clinical studies, separated either geographically or chronologically, and indeed there is even a risk of drift within a study in the long period from initiation through to its completion, In the European cooperative studies there is the further need to ensure that the recording of data is uniform against a background of many different languages being used in the consultation between the doctor and the patient By autumn 1993, the EORTC and RTOG working groups had each reached a quite advanced stage in their own organizations towards rationalizing the scoring of late injury. It was then recognized that there would be a great advantage if these two organizations could agree on a common scale, to enable direct comparison of the benefits emerging from the different therapeutic approaches that are being investigated by them.

A review of αβ ratios for experimental tumors: Implications for clinical studies of altered fractionation

Clinical interest in the use of more and smaller dose fractions in radical radiotherapy has been stimulated by recent reviews of experimental results with normal tissues. It has been found that if the dose per fraction is reduced (i.e., in hyperfractionation) there is sparing of late responding normal tissues relative to those which respond early. This phenomenon can be understood in terms of the shapes of the underlying dose effect relationships, which can be described using the linear quadratic equation. The ratio (alpha/beta) of the linear (alpha) and quadratic (beta) terms is a useful measure of the curviness of such dose effect curves. Low alpha/beta values (1.5 to 5 Gy) have been observed for late responding normal tissues and indicate that radiation damage should be greatly spared by the use of dose fractions smaller than the 2 Gy used in conventional radiotherapy. By contrast the high alpha/beta values (6-14 Gy) observed for acutely responding normal tissues indicate that the response is relatively linear over the dose range of clinical interest. Hence less extra sparing effect is to be expected if lower doses per fraction are administered. If tumors respond in the same way as acutely responding normal tissues then hyperfractionation might confer a therapeutic gain relative to late responding normal tissues. We have reviewed published results for experimental tumors irradiated in situ and either assayed in situ or after excision. The alpha/beta ratios were usually at least as high as those for acutely responding normal tissues, and 36/48 tumors gave values greater than 8 Gy. Low values of less than 5 Gy were obtained for only 4/48 tumors. There are considerable technical problems in interpreting these experiments, but the results do suggest that hyperfractionation might confer therapeutic gain relative to late responding normal tissues on the basis of differences in repair capability. In clinical practice more efficient reoxygenation, cell cycle redistribution and decreased overall treatment time might also confer therapeutic gain.

Vascular attack as a therapeutic strategy for cancer

SummaryThe blood supply to all solid tumours consists of parasitized normal vessels and new vessels which have been induced to grow by the presence of the tumour. These vessels are inadequate in many respects, being tortuous, thin-walled, chaotically arranged, lacking innervation and with no predetermined direction of flow. The walls consist of a basement membrane lined with rapidly proliferating immature endothelial cells, and are more permeable than normal vessels. The spacing of the vessels and their average diameters are not optimal for nutrient provision.This paper focuses on the evidence that many existing therapies may already have, as part of their action, a vascular mediated process of killing tumour cells. This may result from local changes within individual vessels or from systemic alterations in blood pressure, viscosity, coagulability etc. The hallmarks of vascular injury are identified and the dangers of discarding useful anticancer agent by failing to understand their mechanism of action are highlighted.

Changes in the rate of repopulation during multifraction irradiation of mouse skin

Abstract The skin reaction on the feet of albino mice has been used to investigate the relative effects of repopulation and repair of sublethal injury at various stages during a course of “daily” 300 rad fractions. Previous two-dose experiments have shown that with increasing time after a priming dose of 1,000 rads, additional dose is needed to produce a given skin reaction. 500 rads were required after the first 24 hours, whereas only 30 rads per day were needed to counteract the subsequent repopulation. In the present series the average dose increment that was required between 4 or 9 daily fractions was almost 200 rads per interval, and was not attributable to repopulation. Between the 9th and 14th fractions this average dose increment increased because of a contribution from an increased rate of repopulation. After 4 fractions there was no measurable repopulation for two weeks. After 9 fractions approximately 50 rads per day were needed to counteract repopulation. After 14 fractions approximately 130 r...

Late effects toxicity scoring: The soma scale

The two large organizations that initiate and coordinate multicenter clinical trials in Europe and in North America, the EORTC and the RTOG, have recently formed specific subcommittees or working groups to update their systems for assessing the late injury to normal tissues. This is regarded as necessary in order to standardize and improve the recording so that there can be uniform reporting of toxicity, at agreed and regular intervals in different clinical studies. Many centres have devised their own scales for recording such injury, some of which record all the raw data as it is derived from the patient, while others give a single score on a scale of l-5 to indicate the severity of the overall response. With such a variability in detailed recording of the information on morbidity it is difficult, or even impossible, to compare the outcome of different clinical studies, separated either geographically or chronologically, and indeed there is even a risk of drift within a study in the long period from initiation through to its completion, In the European cooperative studies there is the further need to ensure that the recording of data is uniform against a background of many different languages being used in the consultation between the doctor and the patient By autumn 1993, the EORTC and RTOG working groups had each reached a quite advanced stage in their own organizations towards rationalizing the scoring of late injury. It was then recognized that there would be a great advantage if these two organizations could agree on a common scale, to enable direct comparison of the benefits emerging from the different therapeutic approaches that are being investigated by them.

Vascular endothelium as the vulnerable element in tumours.

The difference between blood vessels in tumours and normal tissues has been recognised for a long time, but little has been done to exploit this in cancer therapy. An overview is presented of the possible contribution of vascular mediated injury with several existing forms of treatment. Interventive radiology and, to some extent, hyperthermia are most obviously mediated through ischaemic cell death. The successful cure of many tumours with radiation, and the complete regressions seen with systemic chemotherapy may also be partially due to a vascular component of damage. The proliferation characteristics of endothelial cells in normal and tumour blood vessels are summarised. These have been derived from single injections or repeated administration of tritiated thymidine. A very large and consistent difference exists between the turnover times. The tumour endothelium is proliferating 20 to 2 000 times faster than any normal tissue endothelium in the adult. The single exception is the placenta which has even more rapid proliferation than the tumour endothelium. The large difference in proliferation rates, coupled with the poor wall structure, lack of innervation and lack of collateral supply, make the blood vessels an attractive target for tumour therapy. Possible means of utilizing this are outlined.

Cell Kinetics and Radiation Biology

The cell cycle, the growth fraction and cell loss influence the response of cells to radiation in many ways. The variation in radiosensitivity around the cell cycle, and the extent of radiation-induced delay in cell cycle progression have both been clearly demonstrated in vitro. This translates into a variable time of expression of radiation injury in different normal tissues, ranging from a few days in intestine to weeks, months or even years in slowly proliferating tissues like lung, kidney, bladder and spinal cord. The radiosensitivity of tumours, to single doses, is dominated by hypoxic cells which arise from the imbalance between tumour cell production and the proliferation and branching of the blood vessels needed to bring oxygen and other nutrients to each cell. The response to fractionated radiation schedules is also influenced by the cell kinetic parameters of the cells comprising each tissue or tumour. This is described in terms of repair, redistribution, reoxygenation and repopulation. Slowly cycling cells show much more curved underlying cell survival curves, leading to more dramatic changes with fractionation, dose rate or l.e.t. Rapidly cycling cells redistribute around the cell cycle when the cells in sensitive phases have been killed, and experience less mitotic delay than slowly proliferating cells. Reoxygenation seems more effective in tumours with rapidly cycling cells and high natural cell loss rates. Compensatory repopulation within a treatment schedule may spare skin and mucosa but does not spare slowly proliferating tissues. Furthermore, tumour cell proliferation during fractionated radiotherapy may be an important factor limiting the overall success of treatment.

Dose response and latency for radiation-induced fibrosis, edema, and neuropathy in breast cancer patients.

PURPOSE To study the incidence of various forms of late normal tissue injuries to determine the latency and dose-response relationships. METHODS We retrospectively analyzed the clinical records of 150 breast cancer patients treated with radiotherapy after mastectomy in the mid to late 1960s. None of the patients had received chemotherapy as a part of their primary treatment. Radiotherapy was delivered to the parasternal, axillary, and supraclavicular lymph node regions. Almost all the patients continued to be checked at regular 3-month to 1-year intervals at our Oncology Department. Detailed records were available for the entire 34 years of the follow-up period. The patients were divided into 3 groups. The prescribed dose was either 11 x 4 Gy (treated with 60Co photons) or 11 x 4 Gy or 14-15 x 3 Gy (treated with both 60Co photons and electrons). The dose recalculation at the brachial plexus where the axillary and supraclavicular beams overlapped was performed in the early 1970s and expressed in cumulative radiation effect (CRE) units. It varied widely among the individual patients. The received dose has now been converted to biologic effective dose(3) units, and from that into the equivalent dose in 2-Gy fractions to plot the dose-response relationships. RESULTS We present a comparison of the latency and frequency of fibrosis, edema, brachial plexus neuropathy, and paralysis in the three different subgroups and the total group. Dose-response relationships are shown at 5, 10, and 30 years after irradiation. CONCLUSION The use of large daily fractions, combined with hotspots from overlapping fields, was the cause of the complications. Clear dose-response curves were seen for late radiation injuries. The incidence seen at 5 years did not represent the full spectrum of injuries. Doses that seem safe at 5 years can lead to serious complications later.

Timescale of evolution of late radiation injury after postoperative radiotherapy of breast cancer patients

PURPOSE To evaluate the incidence and prevalence of various signs of late morbidity, their time of appearance and pattern of progression during an observation period up to 34 years in breast cancer patients treated with postoperative radiation therapy after radical mastectomy. METHODS AND MATERIALS A group of 71 breast cancer patients received in 1963-1965 aggressive postoperative telecobalt therapy to the parasternal, axillary, and supraclavicular lymph node regions after total mastectomy and axillary clearance. None of the patients received chemotherapy either prior to, or after the irradiation as part of their primary treatment. The prescribed dose to the three lymph node regions was 44 Gy in 11 fractions. Only two of the three fields were treated per day. This total dose was given in 16-17 fractions over 3-4 weeks. Because of the overlap of the supraclavicular and axillary fields, the dose received by the brachial plexus was not the dose that was prescribed. A retrospective dose calculation showed that the total dose to the brachial plexus was 57 Gy, delivered as a complex combination of 1.8 Gy, 3.4 Gy, and 5.2 Gy fractions. This cohort of patients has now been followed to 34 years and the late side effects of the treatment evaluated and scored. RESULTS This series is unique in the literature. There is no comparable report of a detailed long-term follow-up in a homogeneously treated group of patients with such a high survival, especially among the younger women, where it is almost 50% at 30 years. This is the reason that they were able to develop some of the very slowly evolving injuries. There was progression of many of the late effects in the period between 5 and 34 years. The more serious morbidities have increased progressively over the whole 34-year follow-up period. Ninety-two percent of the long-term survivors have paralysis of their arm. Other neurological findings included unilateral vocal cord paralysis among 5% of the patients, who developed the disease after a median time of 19 years. All of them were left-sided, indicating a mediastinal involvement of the recurrent nerve. Local recurrence or the appearance of a new primary tumor infiltrating or causing pressure on the recurrent nerve were vigorously investigated and excluded as possible causes of these symptoms. CONCLUSION The greatest risk for all cancer patients is the inadequate treatment of their disease, because this is inevitably lethal. The aggressiveness of the therapy and the acceptable risk of complications must therefore be balanced against the risk of recurrence. The neuropathy seems to be closely linked to the development of fibrosis around the nerve trunks. The use of large daily fractions, combined with hot spots from overlapping fields contributed to the severity of the complications.

Vinca alkaloids: Anti-vascular effects in a murine tumour

We have investigated the blood flow modifying effects of the vinca alkaloids, vincristine and vinblastine in the murine carcinoma CaNT. Vinblastine at doses of 7.5 or 10 mg/kg induced profound and chronic reductions in tumour blood flow as measured by 86RbCl extraction. Following the maximum tolerated dose of 10 mg/kg, blood flow was reduced to 10% of pretreatment values after 2 h and remained below 20% of pretreatment values 24 h after drug administration. These findings are consistent with the early induction of necrosis by vinblastine and suggest that vascular-mediated cell death may account for a large part of the 11 day growth delay induced by this drug dose. In contrast to the large reductions in tumour blood flow, in skin, kidney, liver and muscle, blood flow reductions did not, at any time examined, exceed 40%. In all the normal tissues studied, blood flow had fully recovered by 6 h after vinblastine administration. Similar results, albeit less pronounced, have been obtained with vincristine at the maximum tolerated dose of 3 mg/kg. The results clearly show that both vinblastine and vincristine can induce, with some selectivity, a dramatic and prolonged reduction in tumour blood flow and that this may contribute to the anti-tumour effects against the CaNT tumour.