Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas.

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.

Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma.

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.

Pathology-based staging for HPV-positive squamous carcinoma of the oropharynx.

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.

Phase III randomized trial of amifostine as a radioprotector in head and neck cancer.

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.

Future directions in toxicity prevention.

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.

Radiotherapy and concurrent chemotherapy for the treatment of locally advanced head and neck squamous cell carcinoma.

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.

Cyclophosphamide, doxorubicin, vincristine, and prednisone for primary central nervous system lymphoma: short-duration response and multifocal intracerebral recurrence preceding radiotherapy.

The activity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the treatment of primary central nervous system lymphoma (PCNSL) prior to radiotherapy was studied in six patients. Primary lesions were reduced by 80% or more on contrast-enhancing cross-sectional area in four patients and to a lesser extent in two others after two cycles of chemotherapy. The primary lesion sites demonstrated no contrast enhancement in the three patients who completed four cycles of therapy. However, concurrent with response at the primary disease sites, multiple lesions occurred at distant, noncontiguous CNS parenchymal sites in five patients after two to four cycles of chemotherapy. Median survival was 8.5 months for the six enrolled patients and 16.5 months for the four patients completing craniospinal radiotherapy. PCNSL is highly responsive to standard systemic non-Hodgkin's lymphoma chemotherapy regimens, but the pattern and rapidity of relapse suggest mechanisms of failure including inherent or rapidly evolving antineoplastic drug resistance and perhaps limited drug delivery to occult sites of disease in the brain.

Failure patterns and survival in pediatric soft tissue sarcoma.

We retrospectively analyzed 44 patients with localized soft tissue sarcomas who were seen and treated at the JCRT, DFCI, and TCH between 1970-1984. Patients with rhabdomyosarcoma were excluded. Primary tumors were located in the following sites: extremities 19 (43%), head and neck 9 (20%), and trunk 16 (37%). Median follow-up for survivors was 7.7 years (range 24 mo-16 years). Surgery was the initial aspect of treatment for all patients. All patients also received post-operative irradiation, 43 at presentation and one at local relapse, and 26 received adjuvant chemotherapy. Radiation was delivered to a dose of 4000 cGy (median) followed by a boost to a median dose of 5760 cGy (range 4500-7000 cGy). Actuarial 5- and 10-year disease-free survivals (DFS) were 70% and 59% while the actuarial 5- and 10-year overall survivals (OS) were both 75%. All parameters were assessed for significance by univariate analysis. OS was significantly affected by presenting stage when analyzed according to both the Intergroup Rhabdomyosarcoma Staging System (IRS) and the American Joint Committee on Cancer system (AJCC). For the IRS, OS at 10 years was 100% for Stage I, 72% for Stage II, and 54% for Stage III (p = 0.04). For the AJCC, OS at 10 years was 100% for Stage I and 65% for Stage II and III (p = 0.05). Primary site, histology, and use of adjuvant chemotherapy did not influence OS or DFS. Fourteen patients failed: 8 local, 1 distant, and 5 combined local and distant. There was no LF among the 9 pts. with primary lesions less than 5 cm compared to 11/29 (39%) whose tumor was greater than 5 cm (p = 0.04). Pts. with gross residual disease had a local DFS of 42%, but those with no residual or microscopic residual had a local DFS of 71% (p = 0.02). In conclusion, childhood STS has an excellent OS (75% at 10 years). Tumor size and residual tumor after surgery strongly predicted for local failure. Of interest, the pattern of failure is predominantly local in our series. This suggests that more aggressive local treatment is indicated in management of children with STS. Higher doses of irradiation as used for adult STS are probably indicated for patients with gross residual disease.

Comparison of two head and neck immobilization systems.

PURPOSE: Accurate and reproducible patient positioning is fundamental to the success of fractionated radiotherapy. Concurrent with the introduction of three-dimensional treatment planning capabilities at our institution, a head and neck immobilization system consisting of a standard foam rubber head support and three casting strips was replaced by a customized mask-based device. This study was performed to analyze the impact of the customized immobilization system on the reproducibility of patient setup during irradiation of head and neck and brain tumors. METHODS AND MATERIALS: Patients treated from 1989-1991 were immobilized with the strip system while those treated from 1991-1995 were immobilized with the mask. All treatment fields were simulated and were treated on a 4 MV (where the strip, but not the mask, system was fixed to the treatment couch) or > or = 6 MV (where both the strip and the mask systems were fixed to the couch) accelerator. Port films were taken on the initial treatment day, routinely during treatment, and following shifts (requested). The number, magnitude, and direction of any isocenter shifts were retrospectively reviewed. A two-tailed chi square test was used to compare the differences in requested shifts in the strip and mask groups. RESULTS: The study population consisted of 69 brain tumor (35 strip, 34 mask) and 71 head and neck (37 strip, 34 mask) patients. A total of 1575 port films representing 1070 isocenter placements were analyzed. No differences between the immobilization systems was seen on the 4-MV accelerator (where the mask system was not fixed to the couch). On the > or = 6-MV units, the frequency of shifts was 16.1% versus 6.2% (p = 0.002) with the strips and mask, respectively. Almost all of the benefit was seen in the routine films, where the corresponding rates were 13.2% and 4.1% (p = 0.007). For the mask system, the rate of requested shifts on routine films was 4.1% (8/197) for the > or = 6-MV units and 14.5% (24/166) for the 4-MV unit (p = 0.001). CONCLUSION: Using the frequency of physician-requested isocenter shifts as an indicator of the accuracy of patient repositioning, the newer mask system appears to be an improvement over the previously used strip system, provided that the immobilization device is secured to the treatment couch. Increased accuracy of daily setup provides an opportunity to improve the therapeutic ratio both by increased likelihood of tumor control and decreased risk of normal tissue complications.

Radiation techniques for the treatment of Hodgkin's disease with combined modality therapy or radiation 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.

A comparison of tumor and normal tissue microvascular hematocrits and red cell fluxes in a rat window chamber model.

This laboratory has previously used a window chamber model to measure red blood cell velocity in mammary tumors and normal granulation tissues of the F-344 rat. Because red cell flux and hematocrit more accurately reflect the oxygen carrying potential of blood, we used this model to measure these parameters. Red blood cells were labelled with fluorescein isothiocyanate, and 0.2 ml. packed cells were injected intravenously into rats bearing an 8 to 10 day old R-3230 mammary carcinoma. beta-phycoerythrin (0.15 mg.) was also injected and served as a plasma dye to outline the blood vessels. A sample of peripheral blood was then taken and analyzed by flow cytometry to determine the labeled fraction of red blood cells. Flowing tumor and normal tissue vessels were recorded onto a VCR, and these video images were used to determine vascular length and diameter, RBC flux and velocity, and hematocrit. Median vessel diameter and loge (red blood cell flux) were significantly greater in tumors than in normal tissues (p = 0.007 and p < 0.025, respectively). After controlling for these variables, the median tumor hematocrit of 19% was not significantly greater than the median normal tissue hematocrit of 15%. This technique provides a nontoxic and reproducible method that is now being used to assist in the in vivo definition of tumor oxygenation.

Patterns and variability of tumor oxygenation in human soft tissue sarcomas, cervical carcinomas, and lymph node metastases.

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.

Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck.

PURPOSE: Tumor hypoxia adversely affects short term clinical radiation response of head and neck cancer lymph node metastases and long term disease-free survival (DFS) in cervix carcinoma. This study was performed to evaluate the relationship between tumor hypoxia and DFS in patients with squamous carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Pretreatment tumor pO2 was assessed polarographically in SCCHN patients. All patients were AJCC Stage IV and had pretreatment oxygen measurements taken from locally advanced primaries (T3 or T4) or neck nodes > or = 1.5 cm diameter. Treatment consisted of once daily (2 Gy/day to 66-70 Gy) or twice daily irradiation (1.25 Gy B.I.D. to 70-75 Gy) +/- planned neck dissection (for > or = N2A disease) according to institutional treatment protocols. RESULTS: Twenty-eight patients underwent tumor pO2 measurement. The average pre-treatment median pO2 was 11.2 mm Hg (range 0.4-60 mm Hg). The DFS at 12 months was 42%. The DFS was 78% for patients with median tumor pO2 > 10 mm Hg but only 22% for median pO2 < 10 mm Hg (p = 0.009). The average tumor median pO2 for relapsing patients was 4.1 mm Hg and 17.1 mm Hg in non-relapsing (NED) patients (p = 0.007). CONCLUSION: Tumor hypoxia adversely affected the prognosis of patients in this study. Understanding of the mechanistic relationship between hypoxia and treatment outcome will allow for the development of new and rational treatment programs in the future.

Pretreatment oxygenation profiles of human soft tissue sarcomas.

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.

Artificial neural network model of survival in patients treated with irradiation with and without concurrent chemotherapy for advanced carcinoma of the head and neck.

PURPOSE: This study was performed to investigate the feasibility of predicting survival in squamous cell carcinoma of the head and neck (SCCHN) with an artificial neural network (ANN), and to compare ANN performance with conventional models. METHODS AND MATERIALS: Data were analyzed from a Phase III trial in which patients with locally advanced SCCHN received hyperfractionated irradiation with or without concurrent cisplatin and 5-fluorouracil. Of the 116 randomized patients, 95 who had 2-year follow-up and all required data were evaluated. ANN and logistic regression (LR) models were constructed to predict 2-year total survival using round-robin cross-validation. A modified staging model was also examined. RESULTS: The best LR model used tumor size, nodal stage, and race to predict survival. The best ANN used nodal stage, tumor size, stage, and resectability, and hemoglobin. Treatment type did not predict 2-year survival and was not included in either model. Using the respective best feature sets, the area under the receiver operating characteristic curve (Az) for the ANN was 0.78 +/- 0.05, showing more accurate overall performance than LR (Az = 0.67 +/- 0.05, p = 0.07). At 70% sensitivity, the ANN was 72% specific, while LR was 54% specific (p = 0.08). At 70% specificity, the ANN was 72% sensitive, while LR was 54% sensitive (p = 0.07). When both models used the five predictive variables best for an ANN, Az for LR decreased [Az = 0.61 +/- 0.06, p < 0.01 (ANN)]. The models performed equivalently when using the three variables best for LR. The best ANN also compared favorably with staging [Az = 0.60 +/- 0.07, p = 0.02 (ANN)]. CONCLUSIONS: An ANN modeled 2-year survival in this data set more accurately than LR or staging models and employed predictive variables that could not be used by LR. Further work is planned to confirm these results on larger patient samples, examining longer follow-up to incorporate treatment type into the model.

Effect of amifostine on patient assessed clinical benefit in irradiated head and neck cancer.

PURPOSE: To determine if head and neck (H/N) cancer patients receiving daily amifostine during radiation therapy (RT) experienced clinical benefit (improvement in their ability to carry out normal functions with reduced discomfort) compared to nonamifostine treated patients. METHODS AND MATERIALS: This was an open-label, multi-institutional randomized trial in 303 H/N cancer patients treated with RT +amifostine. Clinical benefit was measured using an 8-item validated Patient Benefit Questionnaire (PBQ) during and up to 11 months after RT. RESULTS: 301 patients completed one or more PBQ assessments. Amifostine patients had significantly better PBQ scores (p < 0.05) than controls. The improvement in PBQ scores was most significant during chronic xerostomia. CONCLUSIONS: Amifostine use results in improved Patient Benefit Questionnaire (PBQ) scores, which is indicative of improved oral toxicity related outcomes and improved clinical benefit. Less oral toxicity should lead to preservation of late dental and oral health, and improvements in activities such as diet, nutrition, and sleep.

The radiation dose-response relationship in a human glioma xenograft and an evaluation of the influence of glutathione depletion by buthionine sulfoximine.

We have used an extensively characterized human glioma cell line in an athymic mouse model to evaluate new therapeutic approaches for human supratentorial high grade gliomas. The tumor, D-54MG, is a subline of a human anaplastic glioma. Eight days after homozygous nu/nu BALB/c athymic mice received intracranial (IC) injections of a tumor homogenate, the whole brain was irradiated with either single fractions of 4, 8, 9, and 12 Gy or twice daily fractions, separated by least 6 hr, of 2.28 Gy x 2 or 7.53 Gy x 2. To evaluate whether or not glutathione depletion influenced animal survival, animals at each dose level received either intraperitoneal (IP) buthionine sulfoximine (BSO) alone or I.P. BSO plus BSO in the drinking water. There was a stepwise prolongation of animal survival with increasing doses of external beam radiation. Mean survival in 9 of the 10 control groups (8-12 animals per group) ranged from 14.1 to 18.8 days. Mean survival ranged from 15.3 to 22.5 days at 4 Gy, 25 to 30 days at 8 Gy, 22.3 to 29.7 days at 9 Gy, and 32.9 to 33.6 days at 12 Gy single dose irradiation. At 2.28 Gy x 2 split dose irradiation mean survival was 29.3 days, for 7.53 Gy x 2 mean survival was over 47 days. The data for single fraction irradiation fit a linear regression line (r = 0.908) of mean animal survival = (1.22 [dose in Gy] + 16.7) days. Tumor GSH levels were decreased with all BSO dosing regimens tested. The most aggressive regimen (I.P. BSO+oral BSO for 5 days), reduced tumor GSH to 6.2% of control. Increased survival in irradiated glutathione depleted mice versus mice receiving radiation alone was not seen.

Improved survival in advanced Hodgkin's disease with the use of combined modality therapy.

To compare the effectiveness of combined modality therapy and chemotherapy alone for the treatment of advanced Hodgkin's disease (Stages IIB-IV), records of 154 patients who achieved a complete or partial response to induction combination chemotherapy were analyzed. Sixty-seven patients received consolidation radiotherapy and 87 patients received no further treatment. Thirty of 154 patients participated in a prospective randomized trial of the Southeastern Cancer Study Group (SEG). Ten-year actuarial survival (Hodgkin's disease deaths only) was 93% for the combined modality therapy patients compared with 59% for the chemotherapy alone patients (p less than 0.0005). Combined modality therapy patients had an 87% 10-year actuarial freedom from relapse as opposed to 56% for the chemotherapy alone patients (p less than 0.0005). Relapse occurred in 33 of the chemotherapy alone patients, 28 (85%) being in sites involved at initial diagnosis. Seven combined modality therapy patients recurred with only two true in-field failures. Multi-variate analysis demonstrated treatment (combined modality) as the only variable affecting outcome. Patients prospectively treated with combined modality therapy in the Southeastern Cancer Study Group trial also showed a statistically significant improvement in both survival and freedom from relapse compared with patients receiving chemotherapy only. There was no apparent increase in toxicity from using combined modality therapy compared with chemotherapy. Three chemotherapy patients and one combined modality therapy patients developed acute leukemia.

Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer.

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.

Simultaneous administration of glucose and hyperoxic gas achieves greater improvement in tumor oxygenation than hyperoxic gas alone.

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).