Search

We prospectively evaluated whether delivering a thermal dose of ≥10 cumulative equivalent minutes at 43°C to >90% of the tumour sites monitored (CEM43° T[sub 90]) would produce a pathologic complete response (pCR) in ≥ 75% of high-grade soft tissue sarcomas treated pre-operatively with thermoradiotherapy. The impact of thermal dose on local failure (LF), distant metastasis (DM), and toxicity was also assessed. Thirty-five patients ≥ 18 years old with grade 2 or 3 soft tissue sarcomas accessible for invasive thermometry were enrolled on the protocol. All patients received megavoltage external beam radiotherapy (RT) in daily fractions of 1.8-2.0Gy, five times a week, to a median total dose of 50Gy and an initial hyperthermia treatment (HT) of 1h duration utilizing the BSD 2000 with Sigma 60 or MAPA applicators at frequencies of 60-140MHz. Further HT was given for patients with CEM43° T[sub 90] > 0.5 after initial HT ('heatable' patients), twice a week to a maximum of 10 HT or CEM43° T[sub 90] > 100. Of the 35 patients entered, 30 had heatable tumours, one of which was inevaluable for pCR or LF as the patient died of DM prior to surgery, leaving 29 evaluable patients. Of these 29 patients, 15 (52%) had a pCR (95% CI: 37-73%), significantly less than the projected rate of ≥75% (p = 0.02). Of the 25 heatable tumours that achieved CEM43° T[sub 90] ≥10, 14 (56% ) had a pCR (95% CI: 39-78%) significantly less than the projected rate (p = 0.06). Three of the 29 patients (10% ) with heatable tumours had a LF, versus 1/5 unheatable tumours (p = 0.48). Fourteen of the 30 patients (47%) with heatable tumours developed DM, versus 2/5 unheatable tumours (p = 1.00). Ten of the 30 patients (33%) with heatable tumours developed treatment-induced toxicity. Thus, no correlation of thermal dose with histologic response was observed. Prospective control of CEM43° T[sub 90] failed to achieve the projected pCR rate following pre-operative thermoradiotherapy for high-grade soft tissue sarcomas, despite excellent local control. Possible explanations for this outcome are discussed. [ABSTRACT FROM AUTHOR]

Discusses a study on the contribution of thermochemoradiotherapy to the improvement of oxygenation in locally advanced breast cancer. Evaluation of the toxicity and efficacy of the treatment that consisted of concurrent taxane, radiotherapy and hyperthermia; Impact of the therapy on tumor hypoxia; Criticisms of the benefits of the actual treatment regimen.

Objective: The rapid worldwide rise in incidence of human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) has generated studies confirming this disease as an entity distinct from traditional OPSCC. Based on pathology, surgical studies have revealed prognosticators specific to HPV-positive OPSCC. The current AJCC/UICC staging and pathologic nodal (pN)-classification do not differentiate for survival, demonstrating the need for new, HPV-specific OPSCC staging. The objective of this study was to define a pathologic staging system specific to HPV-positive OPSCC., Methods: Data were assembled from a surgically-managed, p16-positive OPSCC cohort (any T, any N, M0) of 704 patients from five cancer centers. Analysis was performed for (a) the AJCC/UICC pathologic staging, (b) newly published clinical staging for non-surgically managed HPV-positive OPSCC, and (c) a novel, pathology-based, "HPVpath" staging system that combines features of the primary tumor and nodal metastases., Results: A combination of AJCC/UICC pT-classification and pathology-confirmed metastatic node count (⩽4 versus ⩾5) yielded three groups: stages I (pT1-T2, ⩽4 nodes), II (pT1-T2, ⩾5 nodes; pT3-T4, ⩽4 nodes), and III (pT3-T4, ⩾5 nodes), with incrementally worse prognosis (Kaplan-Meier overall survival of 90%, 84% and 48% respectively). Existing AJCC/UICC pathologic staging lacked prognostic definition. Newly published HPV-specific clinical stagings from non-surgically managed patients, although prognostic, showed lower precision for this surgically managed cohort., Conclusions: Three loco-regional "HPVpath" stages are identifiable for HPV-positive OPSCC, based on a combination of AJCC/UICC primary tumor pT-classification and metastatic node count. A workable, pathologic staging system is feasible to establish prognosis and guide adjuvant therapy decisions in surgically-managed HPV-positive OPSCC., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background and Purpose: Quantification of both baseline variability and intratreatment change is necessary to optimally incorporate functional imaging into adaptive therapy strategies for HNSCC. Our aim was to define the baseline variability of SUV on FDG-PET scans in patients with head and neck squamous cell carcinoma and to compare it with early treatment-induced SUV change., Materials and Methods: Patients with American Joint Committee on Cancer stages III-IV HNSCC were imaged with 2 baseline PET/CT scans and a third scan after 1-2 weeks of curative-intent chemoradiation. SUVmax and SUVmean were measured in the primary tumor and most metabolically active nodal metastasis. Repeatability was assessed with Bland-Altman plots. Mean percentage differences (%ΔSUV) in baseline SUVs were compared with intratreatment %ΔSUV. The repeatability coefficient for baseline %ΔSUV was compared with intratreatment %ΔSUV., Results: Seventeen patients had double-baseline imaging, and 15 of these patients also had intratreatment scans. Bland-Altman plots showed excellent baseline agreement for nodal metastases SUVmax and SUVmean, but not primary tumor SUVs. The mean baseline %ΔSUV was lowest for SUVmax in nodes (7.6% ± 5.2%) and highest for SUVmax in primary tumor (12.6% ± 9.2%). Corresponding mean intratreatment %ΔSUVmax was 14.5% ± 21.6% for nodes and 15.2% ± 22.4% for primary tumor. The calculated RC for baseline nodal SUVmax and SUVmean were 10% and 16%, respectively. The only patient with intratreatment %ΔSUV above these RCs was 1 of 2 patients with residual disease after CRT., Conclusions: Baseline SUV variability for HNSCC is less than intratreatment change for SUV in nodal disease. Evaluation of early treatment response should be measured quantitatively in nodal disease rather than the primary tumor, and assessment of response should consider intrinsic baseline variability.

Purpose: Hypoxia shifts the balance of cellular energy production toward glycolysis with lactate generation as a by-product. Quantitative bioluminescence imaging allows for the quantitation of lactate concentrations in individual tumors. We assessed the relationship between pretreatment tumor lactate concentrations and subsequent development of metastatic disease in patients with newly diagnosed head-and-neck cancer., Methods and Materials: At the time of biopsy of the primary site, a separate specimen was taken and flash-frozen for subsequent quantitation of lactate concentration using a luciferase bioluminescence technique. The two-dimensional spatial distribution of the bioluminescence intensity within the tissue section was registered directly using a microscope and an imaging photon counting system. Photon intensity was converted to distributions of volume-related tissue concentrations (micromol per gram wet weight). Treatment consisted of either surgery and postoperative radiotherapy or primary radiotherapy, based on presenting disease stage and institutional treatment policies. The subsequent development of metastatic disease constituted the primary clinical endpoint., Results: Biopsies obtained from 40 patients were evaluable in 34. The larynx was the most frequent primary site (n = 25). Other sites included oropharynx (n = 5), hypopharynx (n = 3), and oral cavity (n = 1). Most patients (74%) presented with an advanced stage T3 or T4 primary tumor. Nodal involvement was present in 19 (54%) patients. The median tumor lactate concentration was 7.1 micromol/g. Tumors were classified as having either low or high lactate concentrations according to whether these values were below or above the median. The median follow-up time for surviving patients is 27 months. Two-year actuarial survival was 90% for patients with low-lactate-concentration tumor vs. 35% for patients with high-lactate-concentration primaries (<0.0001). Two-year metastasis-free survival was adversely influenced by high tumor lactate concentrations (90% vs. 25%, p < 0.0001). The median lactate concentration for tumors that subsequently metastasized was 12.9 micromol/g vs. 4.8 micromol/g for patients who remained continuously free of disease (p < 0.005). Lactate concentration was not correlated with presenting T stage or N stage., Discussion: Elevated tumor lactate concentrations are associated with the subsequent development of nodal or distant metastases in head-and-neck cancer patients. This more aggressive malignant phenotype is probably associated with hypoxia-mediated radioresistance and the upregulation of metastasis-associated genes.

Purpose: To test the feasibility of hyperglycemic reduction of oxygen consumption combined with oxygen breathing (O(2)), to improve tumor oxygenation., Methods and Materials: Fischer-344 rats bearing 1 cm R3230Ac flank tumors were anesthetized with Nembutal. Mean arterial pressure, heart rate, tumor blood flow ([TBF], laser Doppler flowmetry), pH, and pO(2) were measured before, during, and after glucose (1 or 4 g/kg) and/or O(2)., Results: Mean arterial pressure and heart rate were unaffected by treatment. Glucose at 1 g/kg yielded maximum blood glucose of 400 mg/dL, no change in TBF, reduced tumor pH (0.17 unit), and 3 mm Hg pO(2) rise. Glucose at 4 g/kg yielded maximum blood glucose of 900 mg/dL, pH drop of 0.6 unit, no pO(2) change, and reduced TBF (31%). Oxygen tension increased by 5 mm Hg with O(2). Glucose (1 g/Kg) + O(2) yielded the largest change in pO(2) (27 mm Hg); this is highly significant relative to baseline or either treatment alone. The effect was positively correlated with baseline pO(2), but 6 of 7 experiments with baseline pO(2) < 10 mm Hg rose above 10 mm Hg after combined treatment., Conclusion: We demonstrated the feasibility of combining hyperglycemia with O(2) to improve tumor oxygenation. However, some cell lines are not susceptible to the Crabtree effect, and the magnitude is dependent on baseline pO(2). Additional or alternative manipulations may be necessary to achieve more uniform improvement in pO(2).

Effective radiotherapy for patients with cancer should include maximal tumor cell killing with minimal injury to normal tissue. Radiation doses that can be delivered, without causing severe damage to surrounding normal tissues, can be insufficient to eradicate a tumor. Agents have been developed to protect normal tissue from the toxicities of radiation. The aminothiol amifostine (Ethyol) is the subject of extensive research as a protector. Several studies have demonstrated that amifostine protects normal tissues from both acute and late radiation damage without protecting the tumor. This article reviews the physicochemical basis of radiation therapy on biologic tissues and the mechanisms responsible for the protective effects of amifostine. The increasing body of biochemical, preclinical, and clinical data can justify the use of protectors such as amifostine with radiotherapy to provide improved therapeutic efficacy and quality of life for the patient. This article will review the current understanding of the nature of toxicity resulting from radiation therapy and the benefits that can be derived from using protection to increase the tolerance of normal tissue to radiation damage.

The existence of hypoxic regions in tumors has long been recognized as a key factor leading to radiation resistance. More recently, it has been found that low oxygen levels also affect drug resistance, angiogenesis, cytokine production, cell cycle control, apoptosis, and metastatic propensity of tumors. Until now, most approaches to eliminating hypoxia have been empirical. However, improved understanding of the underlying mechanisms may permit the development of more soundly based, effective approaches. As discussed in this review, critical evaluation of the factors governing oxygen transport in tumors requires a thorough understanding of the methods used to study this process. Many experimental methodologies can be used to address these issues. In this review, the emphasis is placed on techniques that measure parameters on the scale of the diffusion distance of oxygen. Studies at the microregional level provide the most detailed physiological information on such processes. Over the past few years, significant progress in technology has allowed us to measure tumor oxygenation, yet spatial and temporal heterogeneities continue to provide significant challenges to obtaining clear knowledge of oxygen transport.

Purpose: Radiotherapy for head and neck cancer causes acute and chronic xerostomia and acute mucositis. Amifositine and its active metabolite, WR-1065, accumulate with high concentrations in the salivary glands. This randomized trial evaluated whether amifostine could ameliorate these side effects without compromising the effectiveness of radiotherapy in these patients., Patients and Methods: Patients with previously untreated head and neck squamous cell carcinoma were eligible. Primary end points included the incidence of grade > or =2 acute xerostomia, grade > or =3 acute mucositis, and grade > or =2 late xerostomia and were based on the worst toxicity reported. Amifostine was administered (200 mg/m(2) intravenous) daily 15 to 30 minutes before irradiation. Radiotherapy was given once daily (1.8 to 2.0 Gy) to doses of 50 to 70 Gy. Whole saliva production was quantitated preradiotherapy and regularly during follow-up. Patients evaluated their symptoms through a questionnaire during and after treatment. Local-regional control was the primary antitumor efficacy end point., Results: Nausea, vomiting, hypotension, and allergic reactions were the most common side effects. Fifty-three percent of the patients receiving amifostine had at least one episode of nausea and/or vomiting, but it only occurred with 233 (5%) of 4,314 doses. Amifostine reduced grade > or =2 acute xerostomia from 78% to 51% (P<.0001) and chronic xerostomia grade > or = 2 from 57% to 34% (P=.002). Median saliva production was greater with amifostine (0.26 g v 0.10 g, P=.04). Amifostine did not reduce mucositis. With and without amifostine, 2-year local-regional control, disease-free survival, and overall survival were 58% versus 63%, 53% versus 57%, and 71% versus 66%, respectively., Conclusion: Amifostine reduced acute and chronic xerostomia. Antitumor treatment efficacy was preserved.

Purpose: The objectives of this study were to evaluate effects of hyperthermia on tumor oxygenation, extracellular pH (pHe), and blood flow in 13 dogs with spontaneous soft tissue sarcomas prior to and after local hyperthermia., Methods and Materials: Tumor pO2 was measured using an Eppendorf polarographic device, pHe using interstitial electrodes, and blood flow using contrast-enhanced magnetic resonance imaging (MRI)., Results: There was an overall improvement in tumor oxygenation observed as an increase in median pO2 and decrease in hypoxic fraction (% of pO2 measurements <5 mm Hg) at 24-h post hyperthermia. These changes were most pronounced when the median temperature (T50) during hyperthermia treatment was less than 44 degrees C. Tumors with T50 > 44 degrees C were characterized by a decrease in median PO2 and an increase in hypoxic fraction. Similar thermal dose-related changes were observed in tumor perfusion. Perfusion was significantly higher after hyperthermia. Increases in perfusion were most evident in tumors with T50 < 44 degrees C. With T50 > 44 degrees C, there was no change in perfusion after hyperthermia. On average, pHe values declined in all animals after hyperthermia, with the greatest reduction seen for larger T50 values., Conclusion: This study suggests that hyperthermia has biphasic effects on tumor physiologic parameters. Lower temperatures tend to favor improved perfusion and oxygenation, whereas higher temperatures are more likely to cause vascular damage, thus leading to greater hypoxia. While it has long been recognized that such effects occur in rodent tumors, this is the first report to tie such changes to temperatures achieved during hyperthermia in the clinical setting. Furthermore, it suggests that the thermal threshold for vascular damage is higher in spontaneous tumors than in more rapidly growing rodent tumors.

Background: This study sought to determine whether sucralfate prophylaxis during a course of high dose radiation therapy (RT) for head and neck cancer decreases acute side effects., Methods: Patients receiving curative intent RT for advanced head and neck cancers participated in a single institution double-blind randomized trial comparing sucralfate to placebo. Patients were stratified according to fractionation, use of concurrent chemotherapy, Karnofsky performance status (KPS), age, and pretreatment presence of a feeding gastrostomy. Patients were prospectively evaluated during weekly treatment checks, and analyzed with regard to time (measured in terms of dose) until development of the following: weight loss, mucositis, pain, nutritional intake, and need for a treatment break. After completion of RT, time until healing was similarly compared., Results: Fifty-two patients received sucralfate and 50 received placebo. The mean (+/-SD) prescribed dose was 69 +/- 7 Gy. Sixty-nine patients received BID fractionation and 27 received concurrent chemotherapy. No difference was detected in any outcome measure in the direct comparison between the two groups. On multivariate analysis, weight loss >5% or >10% occurred more frequently in patients receiving chemotherapy (p < 0.01 and p = 0.05, respectively). Grade 3 mucositis was more common in patients receiving chemotherapy (p = 0.05) or BID fractionation (p = 0.04) or having a poor KPS (p = 0.02). Interval to healing was not associated with any of the pretreatment- or treatment-related factors. Sucralfate did not result in any additional toxicity., Conclusions: Prophylactic treatment with sucralfate during high-dose head and neck RT did not decrease acute treatment side effects. Other modalities should be investigated., (Copyright 1999 John Wiley & Sons, Inc. Head Neck 21: 760-766, 1999.)

Purpose: To explore the use of a novel program of preoperative radiation and hyperthermia in the management of high-grade soft tissue sarcomas (STS)., Methods and Materials: Eligible patients were adults over 18 with Grade 2 or 3 STS, surgically resectable without a local excision prior to referral to Duke University Medical Center and without distant metastases. Patients were staged generally with CT and/or MR imaging. The diagnosis was established with fine needle aspiration or incisional biopsy. Patients were then treated with 5000 to 5040 cGy, 180-200 cGy per fraction. Chemotherapy was usually not employed. Generally two hyperthermia treatments per week were given with a planned thermal dose of 10-100 CEM 43 degrees T90. Invasive thermometry and thermal mapping were done in all patients. Surgical resection was planned 4-6 weeks after the completion of radiation and hyperthermia., Results: Ninety-seven patients were treated on study between 1984 and 1996. Follow-up ranged from 12 to 155 months (median 32). All tumors were high-grade in nature, 44 greater than 10 cm in size (maximum tumor diameter), 43 5-10 cm in size, 10 less than 5 cm. Seventy-eight of the 97 tumors were located in an extremity. Of the 97 patients, 48 remain alive and continually free of disease following initial therapy. Of the remaining 49 patients, 44 have relapsed (34 dead, 10 living with disease), 3 have died secondary to complications of therapy, and 2 have died of unrelated causes. Ten-year actuarial overall survival, cause-specific survival, and relapse-free survival are 50, 47, and 47% respectively. The predominant pattern of failure has been distant metastases with only 2 patients developing local failure alone. Ten-year actuarial local control for extremity tumors is 94%, 63% for the 19 patients with tumors at sites other than the extremity. Of the 78 patients with extremity lesions, 63 have had limb preservation and remain locally controlled. Overall 38 patients experienced 57 major complications. There were 3 deaths, one due to adriamycin cardiomyopathy and two secondary to wound infections. Four patients required amputation secondary to postoperative wound healing problems. Complications directly attributable to hyperthermia occurred in 15 patients with 11 instances of second- or third-degree burns and two instances of subcutaneous fat necrosis. The hyperthermia complications were generally not severe and either healed readily or were excised at the time of surgical resection of the primary tumor., Conclusions: For these aggressive high-grade soft tissue sarcomas, this treatment program of preoperative thermoradiotherapy provided excellent local regional control for extremity lesions (95%) and satisfactory local regional control (63%) of nonextremity sarcomas, but did not appear to influence the rate of distant metastases or survival. Complications were frequent but apart from the direct thermal burns, not too different from those reported for preoperative radiotherapy alone. More effective adjuvant systemic therapy is necessary to impact favorably on survival.

Background and Purpose: To evaluate the long term clinical significance of tumor oxygenation in a population of head and neck cancer patients receiving radiotherapy and to assess changes in tumor oxygenation during the course of treatment., Methods and Materials: Patients with head and neck cancer receiving primary RT underwent pretreatment polarographic tumor oxygen measurement of the primary site or a metastatic neck lymph node. Treatment consisted of once daily (2 Gy/fraction to a total dose of 66-70 Gy) or twice daily irradiation (1.25 Gy/fraction to 70-75 Gy) to the primary site. Twenty-seven patients underwent a second series of measurements early in the course of irradiation., Results: Sixty-three patients underwent pretreatment tumor oxygen assessment (primary site, n = 24; nodes, n = 39). The median pO2 for primary lesions was 4.8 mmHg, and it was 4.3 mmHg for cervical nodes. There was a weak association between anemia and more poorly oxygened tumors, but many non-anemic patients still had poorly oxygenated tumors. Repeat assessments of tumor oxygenation after 10-15 Gy were unchanged compared to pretreatment baselines. Poorly oxygenated nodes pretreatment were more likely to contain viable residual disease at post-radiation neck dissection. Median follow-up time for surviving patients was 20 months (range 3-50 months). Hypoxia (tumor median pO2 <10 mmHg) adversely affected 2 year local-regional control (30 vs. 73%, P = 0.01), disease-free survival (26 vs. 73%, P = 0.005), and survival (35 vs. 83%, P = 0.02)., Conclusion: Tumor oxygenation affects the prognosis of head and neck cancer independently of other known prognostic variables. This parameter may be a useful tool for the selection of patients for investigational treatment strategies.

Purpose: Compare dose distributions of traditional versus conformal beam orientations in paranasal sinus malignancies., Materials and Methods: Maximum normal tissue doses, dose volume histograms (DVH), normal tissue complication probabilities (NTCP), and the percentage of each normal tissue receiving >80% of the average target dose (V80) were calculated., Results/conclusions: Conformal planning reduced the V80 to the optic nerves and chiasm as well as the normal tissue maximum doses to the ipsilateral and contralateral optic nerves and chiasm, and mean NTCPs.

The modern practice of radiation therapy has developed over several decades, taking into consideration the anatomic location of the tumor, technical aspects of radiation delivery, combined treatment modalities, and patient comorbidity. Improved understanding of tumor biology and kinetics has resulted in a more intensive application of multimodality therapy for many forms of cancer in the endeavor to increase treatment efficacy. However, increased treatment intensity carries a risk of increased toxicity. Conversely, reduction of toxicity by lessening treatment intensity incurs the risk of reduced efficacy. Preventing or minimizing toxicity while maintaining or increasing efficacy is necessary for overall improvement in the therapeutic ratio. New methods for reducing toxicity are currently being explored and include identification of risk factors associated with increased toxicity, the development of radioprotectants, and the use of growth factors to accelerate the replacement of damaged cells.

Cure of locally advanced squamous cell carcinoma of the head and neck (SCCHN) is uncommon with radiotherapy alone. The desire for organ preservation in advanced resectable SCCHN and the need for better local therapy for unresectable disease have led to the development of treatment using radiotherapy and concurrent chemotherapy (RT/CCT). RT/CCT is an attractive strategy because the appropriate drug(s) may enhance radiation effects and independently contribute to local cytotoxicity. Concurrent treatment may combat tumor repopulation and provide the earliest possible treatment of distant micrometastases. RT/CCT may be integrated in synchronous or alternating schemes. Most randomized trials of RT/CCT versus radiation alone show superior local control, disease-free survival, and survival with combined modality treatment. Improved efficacy with RT/CCT is accompanied by increased acute toxicity, which necessitates compromises in the treatment design of most programs. Consequently the most effective RT/CCT regimen has not been defined. Chemical modifiers of toxicity are now under investigation in clinical trials and may allow for improved integration of RT/CCT.

Background: Radiotherapy is often the primary treatment for advanced head and neck cancer, but the rates of locoregional recurrence are high and survival is poor. We investigated whether hyperfractionated irradiation plus concurrent chemotherapy (combined treatment) is superior to hyperfractionated irradiation alone., Methods: Patients with advanced head and neck cancer who were treated only with hyperfractionated irradiation received 125 cGy twice daily, for a total of 7500 cGy. Patients in the combined-treatment group received 125 cGy twice daily, for a total of 7000 cGy, and five days of treatment with 12 mg of cisplatin per square meter of body-surface area per day and 600 mg of fluorouracil per square meter per day during weeks 1 and 6 of irradiation. Two cycles of cisplatin and fluorouracil were given to most patients after the completion of radiotherapy., Results: Of 122 patients who underwent randomization, 116 were included in the analysis. Most patients in both treatment groups had unresectable disease. The median follow-up was 41 months (range, 19 to 86). At three years the rate of overall survival was 55 percent in the combined-therapy group and 34 percent in the hyperfractionation group (P=0.07). The relapse-free survival rate was higher in the combined-treatment group (61 percent vs. 41 percent, P=0.08). The rate of locoregional control of disease at three years was 70 percent in the combined-treatment group and 44 percent in the hyperfractionation group (P=0.01). Confluent mucositis developed in 77 percent and 75 percent of the two groups, respectively. Severe complications occurred in three patients in the hyperfractionation group and five patients in the combined-treatment group., Conclusions: Combined treatment for advanced head and neck cancer is more efficacious and not more toxic than hyperfractionated irradiation alone.

This article reviews radiation techniques including field arrangements, anatomic borders, and doses for the treatment of Hodgkin's disease when radiotherapy is being used as the sole treatment and when it is part of a planned combined modality program with chemotherapy. We describe the techniques currently in use at Duke University Medical Center. Particular emphasis is placed on the evidence regarding the appropriate extent of the treatment field and the doses of radiation necessary to achieve local control. These issues assume increasing importance as we attempt to maintain high cure rates for Hodgkin's disease but lower the frequency of serious long-term complications.

Background and Objectives: The median of pO2 values in tumor measured by Eppendorf "Histograph" with a needle-type electrode has been used as a prognostic indicator in cancer patients. However, it is not established that a pretreatment measured pO2 value can be used as a universal predictor of local control probability, because the variation in pO2 values, especially in hypoxic tissue, among institutes may not allow comparison of measured "absolute pO2 values." The purpose of this study was to examine the variation in oxygen tension measurement by Eppendorf "Histograph" among six laboratories using a single batch of mice and tumors and the same detailed protocol. These results were also compared to the immunohistochemical staining of 2-nitromidazole adducts., Methods: C3H mice bearing FSaII murine fibrosarcoma subcutaneously were shipped to all laboratories, and the oxygen status in tumors and in normal subcutis was examined using Eppendorf "Histograph" and immunohistochemical hypoxic marker., Results: All laboratories showed that the FSaII tumor was hypoxic with at least 77% of measured points under 10 mmHg in pO2 and with a median pO2 value less than that of normal subcutis. These results were further confirmed immunohistochemically. These findings are interpreted as evidence that the pO2 values measured by Eppendorf "Histograph" can be useful. However, the median values of tumor pO2 varied from 1.5 mmHg to 5.6 mmHg among the laboratories, and pO2 of normal subcutis also varied from 28 mmHg to 38 mmHg. There were also significant differences in hypoxic fraction, defined as the fraction under a given oxygen partial pressure (i.e., under 2.5, 5, or 10 mmHg), among institutes., Conclusions: Caution needs to be exercised in using the absolute, median, or distribution of pO2 values measured by the Eppendorf "Histograph" to compare the data between laboratories or to predict the radiation response in an individual subject.

This laboratory previously demonstrated that hyperbaric oxygen and hyperbaric carbogen improved oxygenation in the R3230Ac tumor, but normobaric 100% O2 and carbogen did not. The current study assessed tumor growth after exposure to radiation plus either hyperbaric oxygen, carbogen or carbogen/nicotinamide and the relationship between pretreatment tumor oxygenation and growth time. R3230Ac carcinomas were grown in the flanks of F344 rats. Animals were randomized to one of seven radiation treatment groups: sham irradiation or irradiation plus room air, hyperbaric oxygen (100% O2/3 atmospheres), nicotinamide (0.3 mg/g intraperitoneally 20 min before irradiation), carbogen, carbogen/nicotinamide or hyperbaric oxygen/nicotinamide. Tumors received 20 Gy in a single dose. Median growth times were 6, 18, 18, 20, 22, 28 and 27 days for controls and irradiation plus room air, carbogen, nicotinamide, carbogen/nicotinamide, hyperbaric oxygen and hyperbaric oxygen/nicotinamide, respectively. Irradiation with hyperbaric oxygen, hyperbaric oxygen/ nicotinamide and carbogen/nicotinamide increased growth time (P < 0.001, P < 0.001 and P = 0.003, respectively) relative to room air. Hyperbaric oxygen was significantly more effective than carbogen/nicotinamide (P = 0.001). Growth times for all tumors exposed to hyperbaric oxygen were longer than those of the most fully oxygenated tumors (no baseline pO2 values < 10 mm Hg) not exposed to hyperbaric oxygen (P < 0.001). These results suggest that hyperbaric oxygen may improve radiation response by additional mechanisms separate from overcoming the oxygen effect.

The adverse prognostic impact of tumor hypoxia has been demonstrated in human malignancy. We report the effects of radiotherapy and hyperthermia (HT) on soft tissue sarcoma oxygenation and the relationship between treatment-induced changes in oxygenation and clinical treatment outcome. Patients receiving preoperative radiotherapy and HT underwent tumor oxygenation measurement pretreatment after the start of radiation/pre-HT and one day after the first HT treatment. The magnitude of improvement in tumor oxygenation after the first HT fraction relative to pretreatment baseline was positively correlated with the amount of necrosis seen in the resection specimen. Patients with <90% resection specimen necrosis experienced longer disease-free survival than those with > or = 90% necrosis. Increasing levels of tumor hypoxia were also correlated with diminished metabolic status as measured by P-31 magnetic resonance spectroscopy.

Carbogen is thought to be more effective than normobaric oxygen in reducing tumour hypoxia because it may reduce hyperoxic vasoconstriction. In this study, tumour and normal arteriolar diameters were measured simultaneously with perivascular pO2 during air breathing followed by either carbogen or 100% oxygen to determine whether the action of carbogen is the result of alterations in feeding vessel diameter. Fischer-344 rats bearing dorsal flap window chambers, with or without implanted R3230AC tumours, were the experimental subjects. Arteriolar diameters were measured using optical techniques and perivascular pO2 was measured using recessed-tip electrodes (3-6 microns tip diameter). Baseline arteriolar pO2 averaged 30-50% of blood gas pO2 (mean = 97 mmHg). Both hyperoxic gases increased blood gas pO2 by 4-to 5-fold, but relative improvements in arteriolar pO2 were < or = 2.5 for all arterioles studied. This means that these normobaric high O2 gases are not very efficient in increasing O2 delivery to tumours. In addition, improvements in tumour arteriolar pO2 were transient for both hyperoxic gases. Oxygen and carbogen caused no change and mild vasodilatory responses in tumour arterioles, respectively. Normal arterioles on the other hand, tended toward vasoconstriction by carbogen breathing. Peri-arteriolar pO2 in tumours increased within the first 5 min of breathing either hyperoxic gas, followed by a decline back toward values seen with air-breathing. These results suggest that temporal changes in tumour oxygenation after exposure to carbogen or O2 may not be due to changes in perfusion. Other factors, such as changes in O2 consumption rate may be involved.

This study was performed to explore the relationship between tumor oxygenation and treatment outcome in human soft tissue sarcoma. Twenty-two patients with nonmestastatic, high-grade, soft tissue sarcomas underwent preoperative irradiation and hyperthermia and pretreatment measurement of tumor oxygenation. The 18-month actuarial disease-free survival was 70% for patients with tumor median oxygen pressure (pO2) values of >10 mm Hg but only 35% for those with median pO2 values of <10 mm Hg (P=0.01). There were eight treatment failures; the first site of recurrence was lung in all patients. Median pO2 was 7.5 mm Hg for metastasizing tumors versus 20 mm Hg for nonmetastasizing tumors (P=0.03). Potential mechanisms and implications for clinical trial design are discussed.

Purpose: The validity of tumor pO2 measurement as a predictive outcome assay depends upon demonstrating that intrapatient pO2 variation is less than interpatient variation. No consensus exists regarding the appropriate distance between individual measurements. This distance could affect the calculation of the hypoxic fraction (% pO2s < 5 mm Hg) and the assessment of intra/interpatient heterogeneity. This study was performed to evaluate tumor oxygenation and to assess the effects of two different measurement intervals on pO2 heterogeneity in three different sets of patients., Materials and Methods: Fifteen patients with soft tissue sarcoma, nine patients with cervical carcinoma, and eight patients with squamous carcinoma metastatic to lymph nodes underwent pretreatment polarographic pO2 measurements. Two grossly distinct sites were studied in each tumor, and 2-3 linear tracks were measured at each site. Track lengths varied from 20-36 mm. Distance between measured points was either 0.7-0.8 mm or 0.4 mm. Mean pO2, median pO2, and hypoxic fraction were calculated for each track. Data for each patient were also averaged across all tracks obtained for that patient. Track-specific data were used to evaluate intrapatient variation. The range of average values for each patient was used to assess interpatient heterogeneity. The ratio of these measures provided an assessment of within- vs. between-patient heterogeneity., Results: The median number of pO2 measurements/patient was 200 (range: 88-356). The average length of hypoxic regions varied from 4.5-5.6 mm. Median tumor pO2s for the cervix, lymph node, and sarcoma patients were 4.5 mm Hg, 12.6 mm Hg, and 18.0 mm Hg, respectively (p = 0.07). Median hypoxic fractions were 0.61, 0.36, and 0.31, respectively (p = 0.07). Intrapatient heterogeneity was less than interpatient heterogeneity for all parameters in all patients, except for mean pO2 for the cervix patients measured at 0.7-mm increments (1.51). Assessment of oxygenation was not affected by the distance between samples., Conclusions: Heterogeneity of tumor oxygenation within tumors is less than that between tumors. Both 0.4 mm and 0.7-0.8 mm sampling increments provide similar data. Longer term follow-up of large numbers of uniformly treated patients is required to define the value of tumor oxygen measurement as a predictor of treatment outcome.

Purpose: Tumor oxygenation is thought to influence the radiocurability of many malignancies. Advances in polarographic electrode technology have facilitated the in situ measurement of human tumor pO2. The optimal method of defining a "hypoxic" tumor is not known. Characterization of intra-tumor and intertumor pO2 heterogeneity could help with this process. This study was performed to evaluate pretreatment tumor oxygenation status and pO2 heterogeneity in patients with soft tissue sarcoma., Methods and Materials: Nine patients with soft tissue sarcomas underwent pretreatment pO2 measurements with the Eppendorf pO2 histograph. Two grossly distinct anatomic sites within each tumor were measured in all but one patient; these were localized under computerized tomography guidance to ensure that all measurements were obtained from tumor tissue. Multiple probe tracks were studied at each site. Measurements were performed in resting, awake patients., Results: A total of 1588 pO2 readings was obtained (mean = 176/patient). Measurement path lengths ranged from 22-36 mm. The average hypoxic fraction (pO2 < 5 mm Hg) was 29% (range 0-76%). Arterial pO2 was positively correlated with mean and median tumor pO2. Tumor hypoxic fraction increased with increasing tumor volume. Linear pO2 profiles and frequency histograms provided similar estimates of the extent of hypoxia in individual tumors. Marked variation in oxygenation existed both within and between individual tumors. The intertumor variation was greater than the intratumor variation., Conclusion: Radiobiologic hypoxia exists in human soft tissue sarcomas. The pO2 variation within individual tumors is less than the variation between tumors. Further study is necessary to identify the best parameter for defining tumor hypoxia and to discern the relationship between tumor pO2 and treatment outcome.

Background: Positron emission tomography (PET) provides a noninvasive modality for evaluating the biochemical processes of normal and pathologic tissue. Preliminary reports of F-18 fluorodeoxyglucose (FDG) PET indicate its potential usefulness in evaluating head and neck tumors. The current study was performed to explore the relationship between changes in tumor FDG metabolism and local control in patients receiving hyperfractionated radiotherapy and concurrent chemotherapy., Methods: The study group consisted of six patients with locally advanced, nonmetastatic squamous cell carcinoma of the head and neck. FDG studies were performed prior to, during, and 24 months post-therapy. Ratios of tumor to nontumor FDG uptake in regions of interest (ROI) were compared., Results: All pretherapy studies demonstrated a focal hypermetabolic abnormality corresponding to the known tumor. The pretherapy tumor to nontumor FDG ratios declined significantly during therapy (p < 0.05) with a similar continued trend post-therapy (p < 0.07)., Conclusion: The treatment-induced decrease in tumor hypermetabolism as seen on serial FDG PET parallels the clinical response in squamous carcinoma of the head and neck. Two-year follow-up scans also suggest that continued low tumor to nontumor ratios reflect eradication of local disease. Because of its high cost, a study of larger numbers of patients is necessary to better define the role of PET in the management of head and neck cancer.

Purpose: This study was designed to test the toxicity and efficacy of a regimen of twice daily irradiation and concurrent multiagent chemotherapy for patients with locally advanced squamous cell carcinoma of the head and neck., Methods and Materials: This was a prospective Phase I/II trial. Patients received 125 cGy b.i.d. to 7000 cGy with a 6 hr interfraction interval. Chemotherapy was given during weeks 1 and 6 of irradiation and consisted of a 5 day infusion of 5-fluorouracil at 600 mg/M2/day and 5 daily injections of cisplatin at 12 mg/M2/day. Two additional cycles of chemotherapy were given after the completion of radiotherapy., Results: Forty-six patients were evaluable: 28 had technically unresectable disease and 18 had resectable tumors. All had Stage III or IV disease: 84% had T3 or T4 primaries while 53% had > or = N2 neck disease. The primary acute toxicity, confluent mucositis, was seen in 74% of patients. Late side effects occurred in four patients. Median follow-up is 36 months (range 25-44 months). Kaplan-Meier estimates of 2-year disease-free survival and overall survival are 65% and 73%, respectively, while 2-year local regional control and distant disease-free survival are 72% and 88%, respectively. Multivariate analysis revealed that resectability and receiving > 2 cycles of chemotherapy significantly influenced local regional control while age < 60 significantly influenced disease-free survival., Conclusion: This form of treatment can be delivered safely. The encouraging results have led to the initiation of a Phase III trial comparing this regimen with b.i.d. radiation alone.