Showing papers in "International Journal of Radiation Oncology Biology Physics in 1986"

SR-4233: a new bioreductive agent with high selective toxicity for hypoxic mammalian cells.

Abstract: We have examined the effects of the benzotriazine di-N-oxide SR-4233 (3-amino-1,2,4-benzotriazine-1,4 (dioxide) on a variety of aerobic and hypoxic cells in culture, and on tumors in mice. The cell lines used were Chinese hamster ovary (HA-1), mouse 10T1/2, RIF-1, and SCC VII cells, and the human cell lines HCI'-8, AG1522, and A549. The effect of SR 4233 in combination with irradiation was also examined in the SCC VII tumor growing in the flank of C3H mice using clonogenic assay (tumors excised 24 hr after irradiation). We found SR-4233 to be a potent and selective killer of hypoxic cells. Cell killing as a function of time for the various cell lines was exponential, with no shoulder. Drug concentrations producing equivalent levels of cell killing were 75–200 fold lower in hypoxic than in aerobic cells for the mouse and hamster lines, and 15–50 fold lower for the human cells. In vivo experiments showed that the non-toxic dose of 0.3 mmole/kg of SR-4233 enhanced radiation-induced tumor cell kill when the drug was given between 1 hr before and 2 hr after the radiation dose. We have also shown that the drug metabolizes more rapidly under hypoxic than aerobic conditions, both in vitro and in vivo. The toxic product(s) is unknown, but could be the I -electron reduction product, the radical anion, because the mono N-oxide (the 2-electron reduction product) did not display cytotoxicity or selective killing under hypoxic conditions. This compound could therefore be a useful tool in tumor biology, as well as being a new lead in the development of bioreductive cytotoxic agents for cancer therapy.

Edema of the arm as a function of the extent of axillary surgery in patients with stage I-II carcinoma of the breast treated with primary radiotherapy.

Abstract: Edema of the arm can be a significant complication following treatment of breast cancer. To determine the risk of arm edema and factors associated with this risk in patients treated with primary radiotherapy, we reviewed the records of 475 women with early breast cancer treated between 1968 and 1980. During this period, the use of axillary surgery prior to radiation gradually increased, and all patients received full axillary irradiation until late in the series. Based on the surgeon's report, the extent of axillary surgery was classified as either a sampling, a lower dissection, or a full dissection. Edema of the arm was scored on clinical grounds and ranged from mild hand swelling to an increased arm circumference of 8 cm. At 6 years, the actuarial risk of developing arm edema was 8% for the entire study population. This risk was 13% for 240 patients who had axillary surgery and 4% for 235 patients not undergoing axillary surgery (p = 0.006). For patients undergoing axillary surgery, the risk of arm edema was 37% with full dissection compared to 5% with sampling (p = 0.0003), and 8% with lower dissection (p = 0.03). The risk of arm edema at 6 years was 28% if more than ten nodes were removed, and 9% if one to ten nodes were removed (p = 0.03). However, the extent of axillary dissection was stronger predictor of subsequent edema than was the number of nodes obtained. The role of axillary irradiation could not be evaluated since 91% of patients received axillary irradiation. The use of chemotherapy, the site or size of the primary tumor, clinical nodal status, patient age and weight, type of suture, the use of a drain, and subsequent local or distant failure did not appear to be significant risk factors. We conclude that the combination of full dissection and full axillary irradiation results in an unacceptably high risk of arm edema.

Postoperative radiotherapy in breast cancer--long-term results from the Oslo study.

Abstract: The long-term results of a randomized clinical trial evaluating the effect of postoperative radiotherapy as an adjuvant to radical mastectomy are presented. There were 1115 patients including 27 protocol deviants. The follow-up time is 11–20 years. In the first part a conventional roentgen unit was used, and in the second part a 60 Co unit, with considerably increased dosage and altered treatment plan. Both types of radiation techniques lowered the incidence of loco-regional recurrences significantly, but had no significant influence on the overall survival. The relapse-free survival was significantly improved by 69 Co radiation in Stage II patients, but was unaffected by radiation in the other subgroups. Regarding survival, Stage II patients with medially located tumors seemed to benefit more from 60 Co radiation than those with lateral tumors. A significant increase in the number of deaths caused by myocardial infarction was observed in Stage I patients having 60 Co radiation, indicating that the radiation dose to the heart is of significance.

Impact of tumor control on survival in carcinoma of the lung treated with irradiation

Abstract: The long-term results in tumor response, intrathoracic tumor control and survival are reported in patients with medically inoperable or unresectable non-oat cell and small cell carcinoma of the lung. In 376 patients with stages T1-3, NO-2 carcinoma of the lung tumors, accessioned to a Radiation Therapy Oncology Group (RTOG) randomized study to evaluate different doses of irradiation, a higher complete response rate (24%), intrathoracic tumor control (67%) and three year survival (15%) was observed with 6000 cGy, compared with lower doses of irradiation (4000 or 5000 cGy). Increased survival was noted in patients with complete tumor response. Three year survival in complete responders was 23%, in partial responders, 10%, and in patients with stable disease, 5%. Patients treated with 6000 cGy had an overall intrathoracic failure rate of 33% at 3 years, compared with 42% for those treated with 5000 cGy, 44% for patients receiving 4000 cGy with split course, and 52% for those treated with 4000 cGy continuous course (p = 0.02). Patients surviving 6 or 12 months exhibited a statistically significant increased survival when the intrathoracic tumor was controlled. Patients treated with 5000-6000 cGy, showing tumor control, had a three year survival of 22%, versus 10%, if they had intrathoracic failure (p = 0.05). In patients treated with 4000 cGy (split or continuous), the respective survival was 20% and 10%, if the intrathoracic tumor was controlled (p = 0.001). In patients surviving 12 months after treatment with 5000-6000 cGy, on whom the intrathoracic tumor was controlled, the median survival was 29 months, in contrast to 18 months, if they developed intrathoracic failure (p = 0.05). In patients treated with 4000 cGy, the median survival was 23 months with control and 18 months without control of the intrathoracic tumor [corrected] (p = 0.008). In another RTOG study for patients with more advanced tumors (T4 or N3), those with local tumor control at 12 months had a three year survival rate of 25%, compared with 5% for those with thoracic failures. These differences are statistically significant (p = 0.006). Higher doses of irradiation yield a greater proportion of complete response, higher intrathoracic tumor control and better survival in non-oat cell medically inoperable or unresectable carcinoma of the lung.(ABSTRACT TRUNCATED AT 400 WORDS)

A prospective study of treatment techniques to minimize the volume of pelvic small bowel with reduction of acute and late effects associated with pelvic irradiation

Abstract: The volume, distribution, and mobility of opacified pelvic small bowel (PSB) were determined by fluoroscopy and orthogonal radiographs in 150 consecutive patients undergoing pelvic irradiation. Various techniques including uteropexy, omental transposition, bladder distention, inclining the patient, and anterior abdominal wall compression in the supine and prone treatment position were studied for their effect on the volume and location of small bowel within the pelvis. Abdominal wall compression in the prone position combined with bladder distention was selected for further investigation because of its simplicity, reproducibility, patient comfort, and ability to displace the small bowel. Factors correlating with the volume of pelvic small bowel (PSB) included prior pelvic surgery, pelvic irradiation (XRT), and body mass index. After pelvic surgery, especially following abdominoperineal resection (APR), there was a greater volume of PSB which was also less mobile. The severity of acute gastrointestinal effects positively correlated with the volume of irradiated small bowel. Overall, 67% of patients experienced little or no diarrhea, 30% developed mild diarrhea, and no patient required treatment interruption. Late gastrointestinal effects correlated with the prior pelvic surgery and with the volume of small bowel receiving greater than 45 Gy. Small bowel obstruction was not observed in 75 patients who had no previous pelvic surgery. However, following pelvic surgery excluding APR, 2/50 patients and following APR, 3/25 patients developed small bowel obstruction.

Acute hypoxia in tumors: Implications for modifiers of radiation effects

Abstract: Radioresistant hypoxic cells have been shown to occur in nearly all the animal tumors studied to date. Furthermore, there is a large amount of evidence, albeit indirect, that hypoxic cells exist and impair the effectiveness of radiation therapy in some human cancers. Surprisingly little is known, however, about the natural history of such hypoxic e cells. Recently in our laboratories, we have developed methods which enable us to select and analyse cells from tumor as a function of their distance from the tumor blood supply. Utilizing this technique, we have been able to demonstrate using SCCVII tumors ⩾500 mg that even cells close to the blood supply may become hypoxic at any s particular time. This information provides direct evidence that, at least for that tumor, hypoxia can result from transient fluctuations in blood perfusion. The existence of acutely, as well as, chronically hypoxic cells within tumors has several implications for treatment strategies. Treatments designed to increase oxygen content in the blood may not be particularly effective in sensitizing acutely hypoxic cells. However small, freely diffusable radiosensitizers would distribute throughout the tumor, and should be equally effective in sensitizing both acutely and chronically hypoxic cells to radiation. Acute hypoxia may thus be the best possible indicator for the use of chemical radiosensitizers in radiation therapy.

Primary radiotherapy of larynx and pharynx carcinoma--an analysis of some factors influencing local control and survival.

Abstract: An analysis of 950 patients with carcinoma of the larynx and pharynx was performed to identify factors of importance for local control and survival other than the TNM-classification. All patients were treated with primary radiotherapy, with doses ranging between 60–68 Gy in 6–7 weeks. The achievement of local-regional control by primary radiotherapy was highly correlated with disease-free survival (98% actuarial 5 year probability), which was significantly better than in patients who failed in the primary treatment but were salvaged by radical surgery. Furthermore, occurrence of distant metastases were almost all associated with failure to control the primary tumor. Sex was found to be a dominant prognostic factor, and in all sites and stages, women had a significantly better prognosis both with regard to local control and survival. The degree of histopathological differentiation was not significantly correlated with local control but with the incidence of distant metastases, which was significantly higher in patients with poorly differentiated tumors. In both males and females the pre-treatment hemoglobin concentration was correlated with the probability of primary tumor control and survival but only in patients with pharyngeal and to a lesser degree supraglottic tumors. In these groups, patients with hemoglobin levels above 13 g% (females) and 14.5 g% (males) had a significantly better prognosis than comparable patients with lower hemoglobin values. Such correlation could not be detected in patients with glottic tumors. The influence of tumor size was analyzed in a larger group of 1,060 patients with laryngeal carcinoma. In this group a notable correlation between tumor size and prognosis was observed within the various T-categories, indicating the tumor size as a significantly important parameter related to both probability of local control and survival. The study reveals that head and neck cancer is a heterogeneous disease and it is demonstrated that attention should be given to the various prognostic parameters since important therapeutic achievement is otherwise lost.

The significance of anemia in clinical radiation therapy

Abstract: The time is appropriate for the publication of the excellent review by David G. Hirst of the experimental and clinical evidence for an association between anemia and an increased local relapse rate following radiation therapy.6 The subject needs to be discussed because there is a continuing uncertainty amongst physicians as to whether RBC transfusions, to correct a chronic anemia, indeed decrease the risk of local relapse following a radical course of radiation therapy. Although acute blood loss can be demonstrated experimentally to be detrimental to the oxygenation of tumors, this is not so for chronic anemia. Thus, as Hirst points out, we do not know the mechanism which underlies the clinical association of a chronically low Hb level with an increased risk of relapse after an established protocol for radiation therapy. The systems used in experimental animals do not provide an adequate explanatory model for the complexity of the clinical situation. Hi&s review provides references to the clinical reports which document the prognostic significance of Hb level for the control of malignancies in patients undergoing radiation therapy. The patient groups in these reports are restricted to those with cancer of the cervix or of the head and neck. Note, criteria for defining a low Hb varies with the report. Some Hb levels at which an increased rate of local relapse has been noted lie in what otherwise might have been classed as the normal range. Nevertheless, there is a heavy weight of clinical evidence, particularly for those patients with cancer of the cervix, which indicates that, given a patient population with a range of Hb levels during treatment, the largest proportion of patients with local relapses will be in those with a Hb level in the low end of that range. 1 will illustrate the point with data from the Princess Margaret Hospital (PMH). Together with my associates at the PMH I have previously reported that for patients with locally advanced cancer of the cervix the average Hb level during radiation therapy is a significant prognostic factor.2*3 How powerful a prognostic factor is that Hb level? To show the relative power I have ranked the Hb level using a Cox regression analysis.4 Used in the analysis are all those patients with Stage IIB or III cancer of the cervix seen and treated with radiation therapy between the years 1965 and 1975 at the PMH. Patients who did not receive both intracavitary 13’Cs and external radiation therapy have been excluded. By keeping the analysis to the years 19651975 all patients will have been followed 10 years or longer. Also, the treatment protocols varied little over that period. The prognostic factors ranked in the Cox regression analysis were Stage (IIB v. III), age (~50 v. r50), central dose (~7000 v. 27000 mixed rads), lateral pelvic dose (~4500 v. 24500 mixed rads), and average Hb level during treatment (~10 v. 10-l 1.9 v. 12-13.9 v. rl4gm%). For both local relapse and overall relapse, stage is ranked first and Hb level second with both having a p value of less than 0.000 1. Age was just significant at a p value of 0.046. With the exclusion of patients with incomplete treatment as noted above, central and peripheral doses were not significant in this particular analysis. Clearly, then, the Hb level is a significant and independent prognostic factor for patients with cancer of the cervix, Stages IIB and III. The question to be answered is whether a low Hb level is just a marker of disease which has an inherently poor prognosis or whether it predicts a poor prognosis because of the relative inefficacy of radiation therapy when a low Hb is present during treatment. To provide information which might help to answer the question just posed, I carried out a log-rank analysis of the same patient data described above, adjusting for stage, central dose, side wall dose and age, and determined the relative control rates at different Hb levels.* Shown in Table 1 are the relative rates for local relapse (LRR), distant relapse (DRR), and total relapse (RR). As can be seen for these patients with Stage IIB and III cancer of the cervix, the major influence of the Hb level during treatment is on the LRR and RR and not the DRR. The LRR decreases from a high of 46% for Hb levels less than lOgm% to 20% for those with a Hb level greater than 12gm%. Note that the effect of bulk of disease as defined

A system for stereotactic radiosurgery with a linear accelerator and its performance evaluation

Abstract: A small field irradiation technique to deliver high doses of single fraction photon radiation to small, precisely located volumes (0.5 to 8 cm3) within the brain has been developed. Our method uses a modified Brown-Roberts-Wells (BRS), CT-guided, stereotactic system and a 6 MV linear accelerator equipped with a special collimator (diameters of 12.5 mm to 30.0 mm projected to isocenter) located 23 cm from isocenter. Target localization via planar angiography has been added. Treatment consists of a series of arcing beams using both gantry and couch rotations. During treatment, the patient's head is immobilized independently of the radiotherapy couch and is precisely positioned without reference to room lasers or light field. A precise verification of alignment precedes each treatment. Extensive performance tests have shown that a target, localized by CT, can be irradiated with a positional accuracy of 2.4 mm in any direction with 95% confidence. If angiography is used for localization, the results are better. The dose 1.0 cm outside the target volume is less than 20% of the prescribed dose for a medium sized collimator.

Distribution of radiation sensitivities for human tumor cells of specific histological types: Comparison of in vitro to in vivo data

Abstract: The radiosensitivities of human tumor cell lines, grouped into 6 histological categories, have been studied using data from the published literature. The parameters alpha, beta, n, D0, D, and the surviving fraction to 2 Gy (S2) and 8 Gy (S8) were calculated. Only the two parameters mainly derived from the initial part of the survival curve, alpha and D, together with S2, provided data which were correlated with the clinical radioresponsiveness of each histological group. Thus, there are intracellular factors which influence clinical radioresponsiveness whose relative importance varies from one histological cell type to another. The value of D gave the most precise characterization of the average group radiosensitivity. It was possible to compare the in vivo radiosensitivities of non-severely hypoxic cells with those of tumor cells irradiated in vitro for 7 tumor lines grown as xenografts in mice. The average radiosensitivity was 1.9 times less in vivo than in vitro. This difference indicates that, in addition to the intrinsic factors of radioresistance demonstrated in vitro, and independently of severe hypoxia, there are other factors which specifically reduce radiosensitivity in vivo.

Squamous cell carcinoma of the head and neck treated with radiation therapy: the role of neck dissection for clinically positive neck nodes.

Abstract: This is an analysis of 161 patients with squamous cell carcinoma of the head and neck treated with irradiation to the primary site and neck followed by a neck dissection(s) for clinically positive neck nodes. Patients were treated between October 1964 and December 1982; there was a minimum 2-year follow-up. Fifty-two patients were deleted from analysis of neck disease control because they died of intercurrent disease or cancer less than 2 years from treatment with the neck continuously disease-free. All patients are included in the analysis of complications. Neck disease control rate was the same for radiation plus neck dissection or radiation therapy alone for solitary nodes less than 3 cm. As the size and number of nodes increased, there was a higher rate of neck disease control for combined treatment as compared with irradiation alone. The neck disease control rate, size for size, was lower for patients with fixed nodes and for those with residual tumor in the pathologic specimen. There was no difference in neck disease control as a function of the interval between irradiation and neck dissection. For nodes ≤6 cm, a minimum node dose of 5000 rad appeared to be sufficient for control, whereas for nodes > 6 cm, at least 6000 rad appeared to be required for optimal control. Fixed nodes required a higher dose compared to mobile masses. The incidence of postoperative complications was increased with maximum subcutaneous doses of ≥6000 rad. There was also an increased incidence of postoperative complications for patients undergoing simultaneous, as compared with staged, bilateral neck dissection.

Local control and survival of breast cancer treated by limited surgery followed by irradiation.

Abstract: Between 1960 and 1978, 324 patients with early breast cancer were treated by lumpectomy with or without axillary dissection followed by radiation therapy. All were followed for a minimum of 5 years. All patients were, retrospectively, classified T1, T2, N0, N1a, in the TNM (U.I.C.C.) Classification. The retrospective analysis of the local-regional patterns of failure revealed that young age (less than or equal to 32 years) and premenopausal status were associated with an increased rate of local failure, whereas tumor size and location showed no influence. No pathological features were associated with an increased risk of local recurrence, whether pathological subtypes, Scarff Bloom and Richardson grading, intraductal associated component, or vascular involvement. The absolute 5 year disease-free survival rate was 87% in patients who recurred and 93% in those who did not. The absolute 10 year disease-free survival rates were 75 and 82%, respectively. Therefore, these results confirm that loco-regional failure does not significantly influence the disease-free survival.

Potential for increasing the differential response between tumors and normal tissues: Can proliferation rate be used?☆

Abstract: Rapid proliferation of malignant cells has not previously been emphasized as a major source of failure to control tumors. Evidence is presented that the effective doubling times of clonogenic cells in human tumors during multifraction radiotherapy are in the range of a few days, that is, similar to the pre-treatment Potential Doubling Times and much shorter than Volume Doubling Times. Evidence from animal tumor studies leads to the same conclusion. Accelerated fractionation should be considered for individual human tumors whose LI is measured (e.g., by flow cytometry and the BUR antibody) and found to be high.

Arm lymphedema in patients treated conservatively for breast cancer: relationship to patient age and axillary node dissection technique

Abstract: Arm lymphedema (ALE) was evaluated in 74 patients treated conservatively for breast cancer. ALE was defined based upon measurements performed upon 35 volunteer subjects who did not have and were never treated for breast cancer. Multiple variable statistical analysis of 74 breast cancer patients revealed that age at diagnosis was the most important factor related to the subsequent development of ALE. ALE appeared in 7 of 28 patients (25%) 60 years of age or older but in only 3 of 46 (7%) younger patients (p less than 0.02). Axillary node dissection (AND) was the only other statistically significant factor. For the younger patients, obesity and post-operative wound complications appeared to be contributing factors. For the older patients, AND technique was the only significant factor. ALE developed in only 1 of 10 (10%) of the older patients who underwent AND without splitting the pectoralis minor muscle (PMM), but in 6 of 11 (55%) who underwent AND with PMM split (p less than 0.03). Splitting the PMM during AND did not yield more lymph nodes for pathological analysis nor did it yield a higher incidence of patients with nodal metastases. Neither the use of lymph node radiation therapy fields, radiation to the full axilla, nor systemic chemotherapy was associated with ALE. We conclude that older patients are at higher risk of ALE and that this complication can possibly be reduced by not splitting the PMM during axillary node dissection.

Binding of 3H-misonidazole to solid human tumors as a measure of tumor hypoxia

Abstract: Treatment-resistant, chronically hypoxic tumor cells have been assumed to exist in some solid human tumors, limiting their curability. To date, six patients with different types of tumors have been studied using radioactive labelled electron affinic compounds that bind to hypoxic cells. Although the gross clinical appearance of the tumors in all six patients was of a large and fixed mass which might on clinical grounds be expected to contain hypoxic cells, we have observed drug binding to hypoxic regions in only two, a rapidly growing small cell lung cance (SCLC) and a malignant melanoma. The hypoxic fraction of the malignant melanoma was found to be 6% and the SCLC tumor approximately 10%. We have observed that areas of maximum adduct formation can be found in tumor cells immediately adjacent to blood vessels, suggesting that blood flow over the labelling interval was restricted. These preliminary studies suggest that sensitizer adduct formation in human tumor tissue may be a useful measure of tissue pO 2 at the cellular level and that tumor hypoxia might be more related to the rate of tumor growth and histological grading than to tumor size.

The role of radiotherapy in recurrent and metastatic malignant melanoma: a clinical radiobiological study

Abstract: A review of the literature and our data has been completed to analyze the clinical radiobiology of malignant melanoma. Six hundred eighteen radiotherapy-treated malignant melanoma lesions were analyzed with regard to radiobiological parameters such as total dose, dose per fraction, treatment time, tumor volume, and various fractionation models. Forty-eight per cent of the treated tumors achieved complete response, which was persistent in 87% after 5 years. Neither total dose, treatment time, nor various modifications of the NSD concept showed any well-defined correlation with response. There was, however, a significant relationship between dose per fraction and response, and a high dose per fraction yielded a significantly better response (59% CR for doses greater than 4 Gy versus 33% CR for doses per fraction less than or equal to 4 Gy). The lack of treatment time influence allowed analysis of the data according to the linear-quadratic model, resulting in an alpha/beta ratio of 2.5 Gy. Using this ratio, an iso-effect for different fractionation schedules could be estimated by the extrapolated total-dose (ETD). The ratio was further improved when corrected for the tumor volume. Thus, an iso-effect formula for malignant melanoma could be calculated as: ETDvol (Gy) = D X [d + 2.5)/2.5) X M-.33, where D and d are total dose and dose per fraction in Gy, respectively, and M is the mean tumor diameter in cm. Based on a logit analysis, a complete response level of 50% appeared at an ETDvol value of 83 Gy. The formula is currently the best way to determine an optimal radiation schedule for an effective radiation treatment of malignant melanoma. The tumor response was further improved in 134 additional cases receiving adjuvant hyperthermia. Here, a thermal enhancement ratio (TER) of 2.0 was observed. In a group of 131 patients with only local or regional disease, a 5 year survival rate of 49% was observed in 77 patients with persistent local tumor control, but only 3% survived among the 54 patients in whom local therapy failed. It is therefore, highly important to the probability of survival in recurrent melanoma that proper local treatment be performed.

Impact of improved local control on survival.

Abstract: Estimates of the gain in survival, if all local failures were eliminated, indicate that many more patients could be cured provided the efficacy of treatment of the primary and regional disease were substantially improved. The expected gain in survival is assumed to be the gain in local control, less the loss due to distant metastases and intercurrent disease among the new local control subjects. The observed incidence of DM among local failure patients may be higher than among local control patients; this excess in incidence of DM is assumed to result from metastases established secondary to the persistent or recurring tumor. A powerful argument that higher local control rates would result in more cured patients is the high incidence of long-term survivors after salvage surgery for local failures. Examples of higher survival associated with more effective local therapy are presented from the literature for medulloblastoma, ependymoma, carcinoma of the oral cavity-oropharynx, carcinoma of the urinary bladder, carcinoma of the prostate and carcinoma of the rectum. For Stage I-II cancer of the breast, the reduction of an already low local failure rate by combining surgery and radiation has a very small impact. For tumors, such as, early stage breast cancer, where the possible decrease in local failure is small and the loss due to DM is high, a demonstrable gain in survival is not likely. The potential increase in number of survivors among the U.S. cancer population, if the primary-regional disease were regularly treated successfully, indicates large gains for patients with cancer of the uterine cervix, oral cavity-oropharynx, ovary, colo-rectum, non-oat cell cancer of lung, prostate cancer, and bladder cancer. These provide powerful bases for aggressive investigation of new approaches to improvement of local-regional therapies.

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

Abstract: 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.

Malignant salivary gland tumors

Abstract: A retrospective review of 403 patients with salivary gland tumors seen between 1958 and 1980 and a mean follow-up of 10 years is reported The median age was 58 (7–94) years and the male to female ratio 13:1 There were 293 (72%) parotid, 83 (21%) submaxillary and 27 (7%) tumors developed at other sites Among these were 84 (22%) mucoepidermoid (all degrees of differentiation), 87 (22%) adenocystic carcinomas, 70 (17%) adenocarcinomas, 25 (6%) acinic, 26 (6%) squamous cell, 44 (11%) undifferentiated, 52 (13%) mixed and 12 (3%) nonspecified carcinomas A painless lump was the first symptom in 338 (84%) patients The first planned treatment was surgery in 110 (27%), radiotherapy in 50 (12%), and surgery and radiotherapy combined in 239 (59%) patients Following the first treatment, the primary parotid tumor was controlled by surgery in 1770 (24%), by irradiation in 639 (15%) and surgery and radiation combined in 134182 (74%) patients Altogether, regional metastases developed in 36 (12%) and distant metastases in 36 (12%) of 293 patients with parotid tumors For the submandibular tumors the primary tumor was controlled by surgery in 931 (29%), 04 (0%) by irradiation, and in 3246 (70%) by surgery and irradiation Here, regional and distant metastases developed in 1684 (19%) and 1984 (23%) patients Among the other sites the primary tumor was controlled by surgery in 49 (44%), 07 (0%) by irradiation, and in 811 (73%) by surgery and radiotherapy combined In this group 427 (15%) and 527 (18%) patients developed regional and distant metastases The 5- and 10-year cause specific survival rates were 65 and 59% for the parotid tumors, 61 and 48% for the submaxillary tumors and 62 and 52% for the other sites These results clearly demonstrate the advantages of combining surgery and radiotherapy as the first planned treatment for most tumors

Local control and survival in early breast cancer: the Milan trial.

Abstract: From 1973 to 1980, 701 patients with breast cancer measuring less than 2 cm in pathological diameter and with no palpable axillary lymph nodes were randomized to Halsted mastectomy (349) or to "quadrantectomy" with axillary dissection and radiotherapy to the ipsilateral breast tissue (QUART) (352). The two groups were comparable in age distribution, size and site of primary tumor; menopausal status; and frequency of axillary metastases. At 8 years, the disease-free survival was 77% for the Halsted patients and 80% for the "quadrantectomy" patients, while overall survival was 83% and 85%, respectively. Disease-free and overall survival curves show no difference between the two groups. Breast cancer of small size (less than 2 cm) may be safely treated with conservative treatment. Mutilating operations are not justified.

90Yttrium antiferritin--a new therapeutic radiolabeled antibody.

Abstract: A new radiolabel 90 Yttrium has been chelated to antiferritin antibodies for the treatment of hepatocellular cancer. The isotope 90 Yttrium has the advantage of no significant external radiation to other individuals, that is, outpatient therapy and potentially more therapeutic power with an increase from 0.3 Mev 131 I beta radiation to 0.9 Mev 90 Yttrium pure beta radiation. Six patients treated in the Phase 1 study have had modest hematologic toxicity and two have had partial remissions of their primary tumors. One of these patients has had complete remission of a pulmonary metastasis. The use of external radiation (900 rad) to the primary tumor in advance of radiolabeled antibody administration has increased antibody uptake and increased tumor dose rate and total dose. An extensive study of 90 Yttrium antiferritin is planned.

Induction characteristics of oxygen regulated proteins.

Abstract: Extreme hypoxia induces many changes in the biology of cells, including the enhanced synthesis of oxygen regulated proteins (ORPs). We investigated the conditions required for the induction of ORPs and by modifying culture conditions, eliminated variables other than oxygen concentration. Several exponentially growing rodent and human cell lines were examined before, during, and after various periods of extreme hypoxia. The following responses were analyzed: cell growth, clonogenic survival, glucose consumption, lactate production, media pH, total protein synthesis, and specific protein synthesis. EMT6/Ro cells did not increase in cell number or progress through the cell cycle after initiation of extreme hypoxia. Cell morphology and cell survival were nearly normal for up to 12 hr of hypoxia. During this period, media pH remained constant, with the concentrations of glucose and lactate being virtually indistinguishable from aerobic cultures or initial values. Associated with these conditions, a marked inhibition of total protein synthesis was observed for EMT6/Ro cells, such that the hypoxic protein synthesis rate was about 60% of the aerobic rate. However, enhanced synthesis of a set of proteins, designated as ORPs, was preferentially induced in less than 6 hr. The molecular weights of the five major ORPs are 260, 150, 100, 80 and 33 kD. Under these conditions, the primary inducing agent was a low concentration of oxygen. This set of ORPs was distinctly different from the set of heat induced (heat-shock) proteins, but included the major 100 kD and 80 kD glucose regulated proteins. Although the functions of ORPs are unknown, their induction under conditions that are known to modify the sensitivity of cancer cells to therapeutic agents suggests that the presence of ORPs should be further investigated to determine their possible value in diagnosis and predicting treatment response.

Dose volume histogram analysis of liver radiation tolerance.

Abstract: Eleven patients with carcinoma of the pancreas or biliary system received heavy charged particle radiation treatments and whole liver heavy charged particle radiation at Lawrence Berkeley Laboratory. Doses to the whole liver ranged from 10 to 24 Gray-equivalent (the biological equivalent of 10 to 24 Gray of low-LET photon radiation), whereas the dose to the primary lesion ranged from 53.5 to 70 Gray-equivalent (GyE). The fraction size was 2 to 3 GyE. The liver received partial as well as whole organ irradiation. Integral dose volume histograms for the liver were obtained in all 11 patients. An integral dose volume histogram displays on the ordinate the percentage of liver that was irradiated in excess of the dose specified on the abcissa. In this study, the clinical liver radiation tolerance of these patients is correlated with the information contained in an integral dose volume histogram. One patient developed radiation hepatitis. The integral dose volume histogram of this patient differed from the dose volume histograms of the other 10 patients. This difference was greatest in the range of doses between 30 and 40 GyE. Our results suggest that liver doses in excess of 30 to 35 GyE should be limited to 30% of the liver or less when 18 GyE of whole liver radiation is delivered at 2 GyE per fraction in addition to primary radiation of the pancreas or biliary system.

Correlation of radiotherapeutic parameters and treatment related morbidity--analysis of RTOG Study 77-06

Abstract: The current report is an updated and detailed analysis of treatment related morbidity in RTOG 77-06, a Phase III randomized study comparing prostatic irradiation versus pelvic irradiation followed by a prostatic boost, in patients with Stage A2 and B carcinoma of the prostate without evidence of nodal involvement. A total of 453 analyzable cases were accrued from 1978 to 1983, when the study was closed. All cases of treatment related morbidity were classified as to severity (using a clinical severity grading system). The data were then correlated with a number of radiotherapeutic parameters including treatment volumes (fields), doses, and techniques. Overall, pelvic irradiation, compared to prostate irradiation only, was not associated with a significantly increased incidence of treatment related morbidity. Within the range of pelvic doses used in this study a significant dose effect could not be detected. Total doses to the prostate of more than 7000 cGy were associated with an increased risk of rectal bleeding. Certain treatment techniques, (AP/PA irradiation of the pelvic lymphatics) were associated with an increased incidence of bowel complications.

Observations on the use of adjuvant radiation therapy in patients with stage I and II uterine sarcoma

Abstract: From November 1973 through July 1982, 225 women with Stage I or II uterine srcoma were entered on a protocol which evaluated the use of doxorubicin in the adjuvant setting. Of these, 157 patients had a minimum follow-up of 2 years. Following complete surgical removal of all known clinical disease, consenting patients were randomized to reciece either 30 mg/m 2 of doxorubicin every 3 weeks for eight courses or no further theraphy. The use of radiation therapy in this protocol was optional, and a review of protocol cases was undertaken to determine progression-free interval, survival rates, and site of first recurrence in the radiation therapy and no radiation therapy groups. In patients with Stage I or II leiomypsarcoma of the uterus, there was no difference in the progression-free interval, absolute two-year survival rate, or site of first recurrence in the two groups. There was no difference in the progression-free interval groups. However, those who received radiation therapy to the pelvis experienced a statistically significant reduction of recurrence within the radiation treatment field.

Tumor control in definitive irradiation of localized carcinoma of the prostate

Abstract: At the Mallinckrodt Institute of Radiology, Washington University, 343 patients with carcinoma of the prostate were treated with definitive radiotherapy. All patients are available for minimal 3 year follow-up; the median period of observation is 5.2 years. The incidence of pelvic recurrence with or without distant metastases was 0% in 10 patients with Stage A2, 11% in 113 patients with Stage B, 34% in 204 patients with Stage C, and 40% in 16 patients with Stage D1. There was no significant difference in pelvic tumor control when correlated with the degree of differentiation of the tumors in each stage. In Stage B, patients who exhibited complete regression 3 months after completion of therapy had a pelvic failure rate of 5%, those with 50-75% regression-8% and less than 50% regression-18%. In Stage C, patients with more than 50% tumor regression had a pelvic failure rate of 25%, in contrast to 37% when less than 50% regression was noted at 3 months after completion of irradiation. However, there was no correlation between tumor regression and NED survival. In patients with Stage B, there was no significant correlation between doses of irradiation ranging from 6000 to 7000 cGy and pelvic tumor control. In Stage C, patients receiving doses higher than 6500 cGy had a probability of failure rate in the pelvis of 25% (40/173), in comparison with 44% with doses between 6000-6500 cGy (15/32). The 10 year NED survival for Stage A2 was 100%, Stage B-70%, and Stage C-40%. In Stage B, there was no correlation between local tumor control and 5 year overall survival. However, at 10 years 88 patients without evidence of local failure or distant metastases had a survival rate of 70% in contrast to only 25% if they recurred. In Stage C, 110 patients without local recurrence or distant metastases had a 40% 10 year survival in contrast to 20% in 55 patients who had pelvic recurrence (with or without distant metastases) and 39 patients with distant metastases only. In 105 patients with Stage B tumor controlled in the pelvis, the incidence of distant metastases was 16%, in contrast to 50% in eight patients with pelvic failure. In Stage C, only 26% of 149 patients with pelvic tumor controlled developed distant disease, versus 60% in 55 patients failing in the pelvis. Ninety-five percent of the pelvic failures and 80% of the distant metastases appeared within 5 years after therapy. The administration of hormones did not significantly influence either the probability of pelvic tumor control or the appearance of distant metastases.

Neurotoxicity in long-term survivors of small cell lung cancer

Abstract: Chronic central nervous system neurotoxicity was studied in 38 long-term survivors (greater than or equal to 3 years) of small cell lung cancer who were treated at the University of Texas M. D. Anderson Hospital and Tumor Institute at Houston between 1971 and 1980. All but one patient received combination chemotherapy with or without chest irradiation. Twenty-four patients received whole brain irradiation (Group I), 22 for "elective" and two for therapeutic purposes, while 14 did not (Group II). Abnormalities in computed tomographic (CT) scans of the brain were more frequently observed in Group I than in Group II (70% vs. 0%, p less than 0.01). Clinical central nervous system neurotoxicity developed in three patients in Group I, while none developed in patients in Group II (p less than 0.05). Patients who received methotrexate and procarbazine after whole brain irradiation were at a higher risk for clinical central nervous system neurotoxicity (p less than 0.05), and for development of periventricular white matter changes in CT brain scans (p less than 0.05) than were patients in Group II. Impaired methylation of the myelin sheath is proposed as a possible underlying pathogenic mechanism.

Late results of a trial of hyperbaric oxygen and radiotherapy in head and neck cancer: a rationale for hypoxic cell sensitizers?

Abstract: 104 patients with head and neck cancer were entered into a prospective controlled trial of radiotherapy in hyperbaric oxygen (HBO). The trial compared 10 fractions of radiotherapy in HBO with 30 fractions of radiotherapy in air. Survival and local control rates were significantly higher in the HBO group. No difference in normal tissue effects were detected. The greatest advantage of HBO was seen in the less advanced tumors.

Radiation therapy in operable breast cancer: Results from the Stockholm trial on adjuvant radiotherapy

Abstract: In a randomized trial, 960 women with Stage 1–3 operable breast cancer were treated by a modified radical mastectomy alone, or by the same procedure, preceded or followed by radiotherapy (4500 rad to the breast/chest wall, and internal mammary, axillary and supraclavicular lymph nodes). Up to ten years after treatment, there is an increasing gap between the recurrence-free survival of the irradiated patients and the surgical controls. Between the two types of radiotherapy, there was no difference. There were significantly fewer distant metastases and a tendency for improved survival in node positive patients treated with postoperative radiotherapy, compared to the surgical controls, this difference was, however, statistically not significant.