The optimal combination of hyperthermia and carbogen breathing to increase tumor oxygenation and radiation response

Purpose: To determine the most effective combination of carbogen breathing with mild temperature hyperthermia (MTH) to increase the oxygenation and radiation response in murine tumors.Methods and Materials: MTH at 41.5°C for 60 min was applied by immersion of the tumor in a precisely controlled water bath. The tumor pO₂ was measured with a polarographic microelectrode. The radiation response of the tumor was determined using the in vivo/in vitro assay for surviving tumor cells.Results: In the FSaII fibrosarcoma the median pO₂increased from a control value of 6.5 ± 0.5 mm Hg to 16.6 ± 1.1 mm Hg immediately after MTH and was 10.9 ± 1.3 mm Hg 24 h later. Carbogen breathing for 5 min increased the FSaII pO₂ to 19.9 ± 2.1 mm Hg. Carbogen breathing for 5 min beginning immediately after MTH increased the median pO₂ more than 5 times to 35.4 ± 3.8 mm Hg. This combined treatment also substantially increased the response of the tumors to a radiation exposure of 20 Gy. In another tumor model, the SCK mammary carcinoma, MTH treatment increased the median pO₂ from the control level of 4.4 ± 0.2 mm Hg to 12.6 ± 1.2 mm Hg, and it returned to 4.3 ± 0.3 mm Hg 24 h later. Carbogen breathing for 5 min increased the SCK tumor pO₂ to 17.1 ± 1.4 mm Hg. The median SCK pO₂ was increased about 7 times to 31.2 ± 4.2 mm Hg when MTH was followed immediately with carbogen breathing for 5 min. The radiation response was also markedly increased by this combination. When the animals breathed carbogen for 15 or 30 min, the pO₂ and radiosensitivity in both tumor types either remained the same or was lower than that after 5 min of breathing. In addition, both FSaII and SCK tumors were radiosensitized 24 h after MTH treatment alone or with 5 min of carbogen breathing.Conclusions: A shorter carbogen breathing time immediately after MTH causes the most tumor radiosensitization. The results of this study also demonstrate that MTH increases radiosensitivity with and without carbogen breathing up to 24 h after the mild hyperthermia treatment.     

Oxygenation of cervical cancers during radiotherapy and radiotherapy + cis-retinoic acid/interferon

PURPOSE: We have evaluated the tumor tissue pO2 in cervical cancers during radiotherapy with special emphasis on the course of the pO2 in primarily hypoxic tumors and in patients treated with radiotherapy plus 13-cis-retinoic acid/interferon-alpha-2a. METHODS AND MATERIALS: From June 1995 through April 1997, 49 patients with squamous cell carcinoma FIGO IIB-IVA of the cervix who were treated with definitive radiotherapy with curative intent underwent polarographic measurement of tumor tissue pO2 with an Eppendorf pO2-histograph prior to and during radiation treatment. Radiotherapy consisted of external irradiation with 50.4 Gy in 28 fractions of 1.8 Gy plus high dose rate (HDR) brachytherapy. Twenty-two patients had additional treatment with 13-cis-retinoic acid (cRA, isotretinoin) and interferon-alpha-2a (IFN-alpha-2a). Therapy with cRA/IFN in these patients started 2 weeks before radiotherapy; during this induction period, cRA was administered in a dosage of 1 mg per kilogram body weight orally daily and IFN-alpha-2a in a dosage of 6x10(6) I.U. subcutaneously daily. After start of external radiotherapy (XRT), cRA/IFN was continued concomitantly with radiotherapy in reduced doses (0.5 mg cRA per kg body weight orally daily plus 3x10(6) I.U. IFN-alpha-2a subcutaneously three times weekly until the end of the radiation treatment). PO2 measurements were performed prior to radiotherapy, at 20 Gy, and at the end of radiotherapy. RESULTS: A poor oxygenation defined as a median pO2 of 10 mm Hg or less was present in 15/38 tumors (39%) in which measurements prior to any treatment were done. Low pO2 readings below 5 mm Hg were present in 70% of all tumors prior to treatment. In 13 of 15 hypoxic tumors, pO2 measurements at 19.8 Gy were performed. In these tumors, a significant increase of the median pO2 from 6.0+/-3.1 mm Hg to 20.7+/-21.2 mm Hg was found, p<0.01. The increase in the median pO2 was more pronounced in patients with radiotherapy plus additional cRA/IFN treatment as compared to patients treated with irradiation alone (median pO2 raised from 7.0+/-3.5 mm Hg to 40.9+/-21.3 mm Hg versus 5.7+/-3.1 mm Hg to 14.7+/-17.9 mm Hg). In a multivariate analysis, both the effect of radiation dose (pretreatment versus 19.8 Gy) and the type of treatment (XRT alone versus XRT plus cRA/IFN) had significant impact on the pO2 (P = 0.003 and p = 0.04). In patients with well-oxygenated tumors (pretreatment median pO2>10 mm Hg), 20/23 (87%) achieved a clinically complete response. In patients with primarily hypoxic tumors, 6/6 patients whose primarily hypoxic tumors showed an increase of the median pO2 above 10 mm Hg at 19.8 Gy achieved a complete remission (CR). In contrast, only 4/7 patients with a low pretreatment and persisting low median pO2 achieved a CR. CONCLUSIONS: There are evident changes in the oxygenation of cervical cancers during a course of fractionated radiotherapy. In primarily hypoxic tumors, a significant increase of the median pO2 was found. An additional treatment with cis-retinoic acid/interferon further improved the oxygenation. An impact of the different patterns of oxygenation on local control is to be evaluated.     

Tumour oxygenation is increased by hyperthermia at mild temperatures

The effects of hyperthermia on the oxygenation status in R3230 AC tumours of Fischer rats were measured using a polarographic oxygen electrode system. The median pO₂ in about 10 mm diameter tumours grown s.c. in the leg of rats was 3.7 ± 0.3 mm Hg and it significantly increased upon heating at modest temperatures. For example, the tumour pO₂ measured within 10–15 min after heating for 30 min at 42.5°C was about three-fold greater than that in the control tumours. About 62% of pO₂ values measured in control tumours were <5 mm Hg. After heating at 42.5°C for 30 min, 37% of pO₂ values were <5 mm Hg. Such an increase in tumour oxygenation or reoxygenation of hypoxic cells appeared to result from an increase in tumour blood flow caused by the mild temperature hyperthermia. The presence of hypoxic cells in tumours is believed to be a major factor in limiting the effectiveness of radiotherapy, certain chemotherapy drugs and phototherapy. Hyperthermia at mild temperatures easily achievable with the use of presently available clinical hyperthermia devices may be an effective means to overcome the hypoxic protection in the treatment of human tumours.     

Tumour oxygenation is increased by hyperthermia at mild temperatures

The effects of hyperthermia on the oxygenation status in R3230 AC tumours of Fischer rats were measured using a polarographic oxygen electrode system. The median pO₂ in about 10mm diameter tumours grown s.c. in the leg of rats was 3·7 ± 0·3 mm Hg and it significantly increased upon heating at modest temperatures. For example, the tumour pO₂ measured within 10–15 min after heating for 30 min at 42·5°C was about three-fold greater than that in the control tumours. About 62% of pO₂ values measured in control tumours were < 5 mm Hg. After heating at 42·5°C for 30min, 37% of pO₂ values were < 5 mm Hg. Such an increase in tumour oxygenation or reoxygenation of hypoxic cells appeared to result from an increase in tumour blood flow caused by the mild temperature hyperthermia. The presence of hypoxic cells in tumours is believed to be a major factor in limiting the effectiveness of radiotherapy, certain chemotherapy drugs and phototherapy. Hyperthermia at mild temperatures easily achievable with the use of presently available clinical hyperthermia devices may be an effective means to overcome the hypoxic protection in the treatment of human tumours.     

Anemia in cervical cancers: impact on survival,patterns of relapse,and association with hypoxia and angiogenesis

PURPOSE: The prognostic impact of anemia in cervical cancers is well established. We have investigated the impact of anemia on prognosis and patterns of relapse in cervical cancers. Furthermore, we analyzed the relationship between anemia, tumor hypoxia, and angiogenesis. METHODS AND MATERIALS: Eighty-seven patients (mean age 58 years) with squamous cell cancer of the cervix (Stage IIB: n = 19; Stage IIIB: n = 59; Stage IVA: n = 9) were prospectively enrolled in the study from 1995 through 1999. Patients underwent definitive radiotherapy with a combination of external beam radiotherapy (45-50.4 Gy) and high-dose-rate brachytherapy (5 x 7 Gy). Tumor oxygenation was measured with the Eppendorf pO(2)-histograph before radiotherapy and after 19.8 Gy. Angiogenesis was determined by measuring the microvessel density in pretreatment biopsies in 46 patients. The impact of tumor oxygenation (at 0 Gy and 19.8 Gy), hemoglobin (hb) level (at 0 Gy and 19.8 Gy), angiogenesis and clinical parameters on survival and relapse was investigated. RESULTS: The 3-year overall survival rate (after a median follow-up of 42 months) was 57% for the whole group of patients, 72% for Stage IIB, 60% for Stage IIIB, and 22% for Stage IVA. The presence of pretreatment anemia had a significant impact on the relapse rate. However, the midtherapy hb level (at 19.8 Gy) had the strongest impact on local failure rate and survival: 3-year local failure rate was 6% in 20 patients with a hb > 13 g/dL at 19.8 Gy, 15% in 47 patients with an hb between 11 and 13 g/dL, and 67% in 20 patients with an hb < 11 g/dL, p = 0.0001. This was associated with a significant impact on the 3-year overall survival, 79% vs. 64% vs. 32%. Twenty-three tumors were poorly oxygenated at both measurements (oxygen pressure [median pO(2)] < 15 mm Hg before therapy and at 19.8 Gy). This group had a significantly lower 3-year overall survival as compared with patients with high pO(2) before and/or at 19.8 Gy (38% vs. 68%, p = 0.02), and these poorly oxygenated tumors had also a significantly increased microvessel density. In a multivariate model, the midtherapy hb level maintained an overwhelming impact on local failure rate and survival. CONCLUSION: Hemoglobin level during radiotherapy was the strongest prognostic factor for local control and survival. We could further identify a poor prognostic subgroup with persisting hypoxia during radiotherapy, low hb levels, and increased angiogenesis. According to these findings, an association between anemia, poor tumor oxygenation, and angiogenesis is likely.     

Oxygenation of squamous cell carcinoma of the head and neck: comparison of primary tumors,neck node metastases,and normal tissue

Background: Most previous oxygenation measurements of head and neck tumors have mainly been performed in neck nodes. We investigated, therefore, the relationship between the pO₂ status of primary tumors, cervical neck node metastases and normal tissues.Patients and Methods: 30 patients with histologically proven advanced stage III–IV squamous cell carcinoma of head and neck underwent pretreatment polarographic pO₂ measurements with a pO₂ histograph (Eppendorf, Hamburg, Germany). We obtained data on oxygenation of 23 primary tumors, of 22 neck node metastases, and of 30 contralateral sternocleidomastoid muscles. In 15 cases, we were able to perform measurements in all three regions in the same individual.Results: A highly significant correlation existed between the median pO₂ of primary tumors and their neck node metastases (p = 0.0001), as well as between the proportion of pO₂ values ≤2.5 mmHg and ≤5.0 mmHg (p = 0.0001, p = 0.001) in both anatomic sites. The average pretreatment median pO₂ was 14.7 mmHg (range 0.2–58.5 mmHg) in primary tumors, 13.7 mmHg (range 1.9–50.3 mmHg) in neck node metastases, and 43.8 mmHg (range 20.8–67.7 mmHg) in sternocleidomastoid muscles. In all cases, the oxygenation of malignant tissue was below that of the corresponding muscle. There was also a weak, but significant, correlation between hemoglobin level and the median pO₂ of the primary tumors, as well as between hemoglobin concentration and the proportion of values below 5 mmHg at the primary site (p = 0.017, p = 0.003).Conclusions: Primary tumors and their regional lymph node metastases in advanced squamous cell carcinoma of the head and neck show comparable patterns of oxygenation in terms of the median pO₂ and the proportion of hypoxic measurements. This report suggests that, in patients with such carcinomas, the oxygenation data obtained at one site are related to tumor oxygenation at other sites, so that measurements in any anatomic site would be sufficient to estimate a tumor’s oxygenation status. The weak correlation between pO₂ and hemoglobin level requires further investigation.     

Variability in blood flow and pO2 in tumors in response to carbogen breathing

Purpose: There is speculation that the CO₂ in carbogen (95% O₂, 5% CO₂) can block the vasoconstrictive effects of oxygen. However, it has recently been shown that blood flow in human tumors is variable while patients breathe carbogen. Furthermore, we have shown a consistent decrease in tumor blood flow (TBF) with carbogen breathing in the rat window chamber model. Also, we have previously shown that there is no significant difference in tumor growth time after radiation with air vs. carbogen breathing. This study was designed to investigate the effects of carbogen breathing on blood flow and oxygen levels in a solid tumor.Methods: Measurements were made in Fischer-344 rats with 8–10 mm diameter R3230Ac tumors transplanted either within the quadriceps muscle (n = 16) or subcutis (n = 14). Nontumor-bearing quadriceps muscle was studied in six other rats. After a 20-minute air-breathing baseline, rats breathed carbogen for an additional 40 minutes. Partial pressure of oxygen (pO₂) was continuously monitored at one position for 60 minutes using 9–12 μm diameter oxygen microelectrodes. Blood flow was simultaneously monitored in all animals using laser Doppler flowmetry (1–2 probes/tumor).Results: Blood flow changes during carbogen breathing were variable in all tissues and intratumoral heterogeneity was observed. Despite variability in blood flow, pO₂ consistently increased in normal muscle but varied in both tumor sites. During carbogen breathing, the percent pO₂ measurements greater than the baseline average were 99.5% ± 0.4% (mean ± SEM), 42.7% ± 13.8%, and 79.8% ± 11.0% in normal muscle, subcutaneous tumor, and muscle tumor, respectively. To show the magnitude of change, average pO₂ values during air and carbogen breathing were calculated for each site. Normal muscle increased from 14.9 ± 2.3 to 39.0 ± 6.4 mm Hg (paired t-test; p = 0.009). Muscle tumors showed a rise from 14.6 ± 3.2 to 34.5 ± 8.2 mm Hg (p = 0.019). However, pO₂ in subcutaneous tumors remained unchanged, with a pO₂ of 7.3 ± 2.0 mm Hg on air and 7.3 ± 4.1 mm Hg (p = 0.995) during carbogen breathing.Conclusions: Carbogen had no consistent effect on blood flow and was ineffective at increasing tumor pO₂. These results may partially explain why carbogen breathing failed to improve the efficacy of radiation in this tumor model when transplanted subcutaneously.     

Radiation dose response in patients with favorable localized prostate cancer (Stage T1-T2, biopsy Gleason < or = 6, and pretreatment prostate-specific antigen < or = 10)

PURPOSE: To study the radiation dose response as determined by biochemical relapse-free survival in patients with favorable localized prostate cancers, i.e., Stage T1-T2, biopsy Gleason score (bGS) < or = 6, and pretreatment prostate-specific antigen (iPSA) < or = 10 ng/mL. METHODS AND MATERIALS: A total of 292 patients with favorable localized prostate cancer were treated with radiotherapy alone between 1986 and 1999. The median age was 69 years. Sixteen percent of cases (n = 46) were African-American. The distribution by clinical T stage was as follows: T1/T2A, 243 (83%); and T2B/T2C, 49 (17%). The distribution by iPSA was as follows: < or = 4 ng/mL, 49 (17%); and > 4 ng/mL, 243 (83%). The mean iPSA level was 6.2 (median, 6.4). The distribution by bGS was as follows: or = 5 in 89 cases (30%) and 6 in 203 cases (70%). The median radiation dose was 70.0 Gy (range, 63.0-78.0 Gy). Doses of < or = 70.0 Gy were delivered in 175 cases, 70.2-72.0 Gy in 24 cases, 74 Gy in 30 cases, and 78 Gy in 63 cases. For patients receiving < 72 Gy, the median dose was 68 Gy, vs. 78 Gy for patients receiving > or = 72 Gy. A conformal technique was used in 129 (44%) of cases. The median follow-up was 43 months (range, 3-153). RESULTS: For the entire cohort, the projected 5- and 8-year biochemical relapse-free survival (bRFS) rates were both 81%. For patients receiving > or = 72 Gy, the 5- and 8-year bRFS rates were both 95% vs. only 77% for patients receiving < 72 Gy, p = 0.010. For patients receiving 74 Gy, the 4-year bRFS rate was 94% vs. 96% for patients receiving 78 Gy, p = 0.90. A multivariate analysis for factors affecting bRFS rates using Cox proportional hazards was performed for all cases using the following variables: age (continuous variable), race (black vs. white), iPSA (continuous variable), bGS (< or = 5 vs. 6), Stage (T1-2A vs. T2B-C), radiation dose (continuous variable), and radiation technique (conformal vs. standard). From the multivariate analysis, only iPSA (p = 0.017, chi(2) = 5.7), and radiation dose (p = 0.021, chi(2) = 5.3) were independent predictors of outcome. Age (p = 0.94), race (p = 0.89), stage (p = 0.45), biopsy GS (p = 0.40), and radiation technique (p = 0.45) were not. CONCLUSION: There is a clear radiation dose response in patients with favorable localized prostate cancers (i.e., Stage T1-T2, biopsy Gleason score < or = 6, and iPSA < or = 10 ng/mL). At least 74 Gy should be delivered to the prostate and periprostatic tissues. With our cohort of patients, longer follow-up will be needed to assess the importance of doses exceeding 74 Gy.     

The effect of smoking on tumour oxygenation and treatment outcome in cervical cancer

Aim: Tumour hypoxia is associated with an increased risk of cervical tumour recurrence and death. Because smoking is a modifiable behaviour, it is important to establish the importance of smoking as a prognostic factor. We hypothesized that there is an association between smoking and tumour hypoxia, and that smoking adversely affects radiation response and survival. Methods: A smoking history was obtained from 100 of 115 patients with cervical cancer entered into a prospective study of tumour oxygenation. Eighty-seven of these had clinically evident disease and radiation therapy alone was the planned treatment. Patients who smoked within 2 weeks of commencing radiation therapy were considered smokers, and the amount that they smoked was recorded in packs per day. Patients who had never smoked or quit at least 2 weeks prior to radiation therapy were considered non-smokers. Tumour oxygenation was determined using the Eppendorf polarographic oxygen electrode and tumour oxygenation is represented by the hypoxic proportion HP₅ (% of pO₂ measurements <5 mmHg). Results: There was no significant association between smoking and tumour hypoxia (P=0.3), haemoglobin (P=0.6) nor tumour size (P=0.1). Progression-free survival at 3 years was 56% for non-smokers and 44% for smokers (P=0.23). In both univariate and multivariate analysis, neither smoking status nor amount smoked were significant predictors of progression-free survival or local control. Conclusions: There was no significant association between smoking and tumour hypoxia, treatment response or survival in this study of patients with cervix cancer.Copyright 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.     

Mature results of a pilot study of pelvic radiotherapy with concurrent continuous infusion intra-arterial 5-FU for stage IIIB-IVA squamous cell carcinoma of the cervix.

PURPOSE: To evaluate the long-term results of continuous infusion intra-arterial 5-fluorouracil (CI IA 5-FU) given with concurrent pelvic radiotherapy (RT) for FIGO stage IIIB-IVA carcinoma of the cervix. METHODS AND MATERIALS: Between 1965 and 1974, 27 patients with extensive FIGO Stage IIIB (22 patients) or Stage IVA (5 patients) squamous cell carcinoma of the cervix were treated with CI IA 5-FU and RT. Twenty-one patients (78%) had bilateral pelvic wall involvement, 25 (93%) had massive tumors (> or =8 cm in diameter), 7 (27%) had involvement of the lower one-third of the vagina, and 15 (56%) presented with hydronephrosis. All patients underwent routine clinical staging, transperitoneal para-aortic lymph node dissection, and bilateral hypogastric artery catheter placement. 5-FU was continuously infused at a dose rate of 10 mg/kg/day on Days 1-15 of RT. The median dose of 5-FU was 376 mg/m2/day (range 270-692). All patients received concurrent pelvic RT to a median dose of 50 Gy at 2.0 Gy per fraction. Only 4 patients received intracavitary RT. The median follow-up of surviving patients was 190 months. RESULTS: The overall 5-year survival rate was 37%. For the 22 patients with FIGO Stage IIIB disease, the 5-year survival rate was 41%. The survival rate for 18 patients treated with only external beam radiation and chemotherapy for Stage IIIB disease was 33%. Four of 10 patients treated with only 50 Gy of external beam radiation and CI IA 5-FU were long-term survivors. Acute complications, including hematologic toxicity and skin reactions, were severe, with 1 death from neutropenic sepsis. Severe late complications were only observed in patients treated with > or =60 Gy of external beam radiation. CONCLUSIONS: While this series is small, the fact that 4 patients with massive Stage IIIB tumors survived after a total radiation dose of only 50 Gy suggests that RT with CI IA 5-FU deserves further study. Modifications in dose, technique, and route of administration should reduce toxicity, and the addition of intracavitary RT should improve the local effectiveness of combined treatment.     

Long-term performance of interstial fluid pressure and hypoxia as prognostic factors in cervix cancer.

OBJECTIVES: Hypoxia and high interstitial fluid pressure (IFP) have been shown to independently predict for nodal and distant metastases, as well as survival, in patients with cervix cancer. Using data from our prospective trial, we updated a cohort of patients treated with definitive radiation alone without chemotherapy, to assess the long-term prognostic impact of these microenvironmental features. METHODS: Between April 1994 and January 1999, 107 eligible patients with cervix cancer were entered into a prospective study of tumor oxygenation and IFP prior to primary radiation therapy. Oxygenation data are presented as the hypoxic proportion, defined as the percentage of pO(2) readings <5 mm Hg (abbreviated as HP(5)). Patients with HP(5) values >50% were considered to have hypoxic tumors. IFP is presented in mmHg, divided into high and low IFP groups by the median value. Patients ranged in age from 23 to 78 years with a mean of 53 years. The maximum tumor size ranged from 2 to 10 cm, with a median diameter of 5 cm. FIGO stage was IB in 28 patients, IIA in 4, IIB in 42 and IIIB in 33 patients. Twenty-two patients (21%) had evidence of pelvic lymph node involvement on staging CT abdomen/pelvis or MR pelvis. HP(5) ranged from 0% to 99% with a median of 48%. IFP ranged from -3 to 48 mm Hg (median 19 mm Hg). Median follow-up was 6.7 years (range 0.9-10.6). RESULTS: Disease-free survival (DFS) at 5 years was 50%. Five year DFS was 42% for patients with hypoxic tumors (HP(5)>50%), and 58% in patients with oxygenated tumors (HR 1.01 per %, p=0.05). DFS at 5 years was 42% for patients with interstitial hypertension (IFP >19 mm Hg), and 63% in patients with IFP 相似文献   

Pretreatment prognostic factors in patients with early-stage (I/II) non-small-cell lung cancer treated with hyperfractionated radiation therapy alone

PURPOSE: To investigate influence of various pretreatment prognostic factors in patients with early stage (I/II) non-small-cell lung cancer (NSCLC) treated with hyperfractionated radiation therapy alone. PATIENTS AND METHODS: One hundred and sixteen patients were treated with tumor doses of 69.6 Gy, 1.2-Gy, twice-daily fractionation. There were 49 patients with Stage I and 67 patients with Stage II. Eighty patients had Karnofsky performance status (KPS) 90-100 and 95 patients had <5% weight loss. Peripheral tumors were observed in 57 patients. Squamous histology was observed in 70 patients and the majority of patients had concomitant disease (n=72). RESULTS: The median survival time for all patients was 29 months; 5-year survival was 29%. The median time to local progression and the distant metastasis were not achieved, whereas 5-year local progression-free and distant metastasis-free survivals were 50% and 72%, respectively. Multivariate analysis identified KPS, weight loss, location, histology, and the reason for not undergoing surgery as prognostic factors for survival. KPS, location, and histology influenced local progression-free survival, whereas only KPS and weight loss influenced distant metastasis-free survival. CONCLUSIONS: This retrospective analysis identified KPS and weight loss as the most important prognostic factors of outcome in patients with early-stage NSCLC treated with hyperfractionation radiation therapy.     

Preliminary results of quadrantectomy and radiation therapy for breast cancer

Between November 1987 and December 1992, a total of 200 breast carcinomas in 199 patients were treated by definitive radiation therapy following quadrantectomy and level III axillary dissection. One patient with simultaneous bilateral breast cancers was excluded and 198 patients with breast cancer were enrolled in this study. There were 9 Stage 0, 117 Stage I and 72 Stage II tumors by the UICC tumor classification system (1987). Histological examination revealed that 9 tumors were non-invasive carcinomas and 189 were invasive carcinomas. For radiation therapy, a total of 50 Gy was delivered to the ipsilateral breast using⁶⁰Co γ rays. In three cases with level III lymph node involvement, the ipsilateral supraclavicular and parasternal regions were also irradiated. Boost irradiation was given to 8 of 12 margin-positive patients, and 2 of 24 patients in whom tumor cells were present within 5 mm from the margin. We used a CT simulator for the treatment planning of radiation therapy in 196 tumors. During follow-up for 16-77 months (median: 35 months), 2 patients died of unrelated causes and 6 developed distant metastasis (4 to bone and 2 to lung). Local recurrence was noted in 1 patient. Acute reactions to radiation therapy included moist desquamation involving the tip of the breast and the axilla in 14 and 5 patients, respectively, as well as bright erythema in 7 patients. Late reactions included arm edema in 12 patients, patchy depigmentation at the tip of the breast in 5 patients, moderate telangiectasia in 1 patient, and symptomatic radiation pneumonitis in 1 patient. The actuarial overall survival, cause-specific survival, disease-free survival, and relapse-free survival rates at 5 years were97.2%, 100%, 93.5%, and 93.0%, respectively. This excellent locoregional control, together with a highly acceptable toxicity strongly suggests the usefulness of quadrantectomy and radiation therapy for Japanese women with breast cancer. The possible indications include clinical Stage 0 and, I breast cancer, and clinical Stage II cancer in patients with relatively large breasts and with the primary tumor not located close to the nipple.     

Tumor hypoxia in pelvic recurrences of cervical cancer

We have previously demonstrated in primary cancer of the uterine cervix that tumor hypoxia, as determined polarographically, is strongly associated with clinical malignant progression of the disease. Having applied a similar methodological approach to investigate loco-regional relapses, we found a pronounced shift to more hypoxic oxygenation profiles in the recurrent tumors than in the primary tumors. Median pO₂ values in 53 pelvic recurrences were significantly lower than the median pO₂ values of 117 primary tumors of comparable sizes (7.1 ± 1.1 mmHg vs. 12.1 ± 1.0 mmHg, p = 0.0013). The differences in tumor oxygenation between primary and recurrent tumors mirrored the differences in the patients' 5-year survival probabilities. In the cohort of patients with pelvic relapses, median tumor pO₂ < 4 mmHg indicated a significantly shorter median survival time as compared to median tumor pO₂ ≥ 4 mmHg. Our results further support our thesis that in cervical cancer, tumor hypoxia and clinical aggressiveness in terms of resistance to therapy and tumor dissemination, are interrelated. Int. J. Cancer (Pred. Oncol.) 79:365–369, 1998. © 1998 Wiley-Liss, Inc.     

Conventional external-beam radiation therapy alone or with androgen ablation for clinical stage III (T3, NX/N0, M0) adenocarcinoma of the prostate.

PURPOSE: To evaluate the outcome of clinical Stage III (T3, N0/NX, M0) prostate cancer treated by conventional radiation alone or with adjuvant androgen ablation. METHODS AND MATERIALS: Three hundred forty-four men with T3, N0/NX, M0 adenocarcinoma of the prostate who received conventional radiation alone (260) or with androgen ablation (84) were analyzed for relapse or rising prostate-specific antigen (PSA), using univariate and multivariate techniques. RESULTS: With a median follow-up of 68 months, the 260 men treated with radiation alone had a 10-year actuarial rate of relapse or rising PSA of 76%. Pretreatment PSA level (< or = 10 ng/ml vs. > 10 < or = 20 ng/ml vs. > 20 ng/ml) and radiation dose (< 68 Gy vs. > or = 68 Gy) were the only independently significant determinants of biochemical failure; Gleason score (2-7 vs. 8-10) was an additional determinant of metastatic relapse. Patients treated to doses < 68 Gy experienced 6-year failure rates exceeding 50% regardless of PSA level. Patients with PSA < or = 10 ng/ml and receiving 68-70 Gy had a 6-year failure of 24%, but those with PSA > 10 ng/ml had relapse rates exceeding 50% even at doses of 70 Gy. At a median follow-up of 44 months, the 84 patients treated with radiation and androgen ablation had a 6-year biochemical failure rate of 22%. The only significant determinant of outcome in this group was pretreatment PSA; patients with PSA < or = 80 ng/ml had a 6-year failure rate of only 12% compared to a failure rate of 53% for those with PSA > 80 ng/ml. The outcome for those treated with combined modalities was significantly better than for those treated with radiation alone in all PSA strata. CONCLUSION: Conventional radiation alone has little curative potential for Stage III disease. Doses < 68 Gy are particularly ineffective. Patients with PSA < or = 10 ng/ml may be candidates for conventional radiation to a dose of 70 Gy. Other patients are probably best served by combined radiation-androgen ablation or high-dose conformal radiation.     

Stereotactic radiosurgical boost following radiotherapy in primary nasopharyngeal carcinoma: impact on local control

PURPOSE: Treatment of patients with nasopharyngeal carcinoma using external beam radiation therapy (EBRT) alone results in significant local recurrence. Although intracavitary brachytherapy can be used as a component of management, it may be inadequate if there is extension of disease to the skull base. To improve local control, stereotactic radiosurgery was used to boost the primary tumor site following fractionated radiotherapy in patients with nasopharyngeal carcinoma. METHODS AND MATERIALS: Twenty-three consecutive patients were treated with radiosurgery following radiotherapy for nasopharyngeal carcinoma from 10/92 to 5/98. All patients had biopsy confirmation of disease prior to radiation therapy; Stage III disease (1 patient), Stage IV disease (22 patients). Fifteen patients received cisplatinum-based chemotherapy in addition to radiotherapy. Radiosurgery was delivered using a frame-based LINAC as a boost (range 7 to 15 Gy, median 12 Gy) following fractionated radiation therapy (range 64.8 to 70 Gy, median 66 Gy). RESULTS: All 23 patients (100%) receiving radiosurgery as a boost following fractionated radiation therapy are locally controlled at a mean follow-up of 21 months (range 2 to 64 months). There have been no complications of treatment caused by radiosurgery. However, eight patients (35%) have subsequently developed regional or distant metastases. CONCLUSIONS: Stereotactic radiosurgical boost following fractionated EBRT provides excellent local control in advanced stage nasopharynx cancer and should be considered for all patients with this disease. The treatment is safe and effective and may be combined with cisplatinum-based chemotherapy.     

Disease control of uterine cervical cancer: relationships to tumor oxygen tension, vascular density, cell density, and frequency of mitosis and apoptosis measured before treatment and during radiotherapy.

Identification of biological parameters of major importance for the control of malignant diseases can be useful for the design of optimal treatment regimes for individual patients. Tumor oxygen tension (pO2), vascular density, cell density, and frequency of mitosis and apoptosis were measured before treatment (40 patients) and after 2 weeks of radiotherapy (22 patients) in patients with uterine cervical cancer. The aim was to investigate whether one of the parameters was more important for disease control than the others. Three sets of data were considered; the pretreatment parameters, the parameters measured after 2 weeks of radiation, and the changes in the parameters during this time. The pO2 was measured polarographically; the other parameters were determined by histological analyses of tumor biopsies. Hypoxic subvolume (HSV5), ie., the fraction of pO2 readings <5 mm Hg multiplied with tumor volume, showed the strongest correlation to control. Patients with a small HSVs before treatment had a higher control probability after a median follow-up time of 50 months than patients with a large HSV5 (P < 0.001). All other parameters or changes in parameters showed impaired correlation to control compared with pretreatment HSV5. The present results suggest that pretreatment oxygenation is more important for disease control of cervical cancer than the oxygenation after 2 weeks of radiotherapy or the changes in oxygenation during this time. Moreover, vascular density, cell density, and frequency of mitosis and apoptosis before treatment or after 2 weeks of therapy are probably not as important as pretreatment oxygenation as well. Although significant correlations between disease control and some of the parameters other than pretreatment oxygenation can occur in studies based on a large number of patients, the specificity of these parameters in the prediction of control is probably not as high as for oxygenation.     

Planned preoperative radiation therapy for advanced laryngeal carcinoma

One hundred ten patients with predominantly advanced laryngeal carcinoma were treated in the period 1969–1978 with planned preoperative radiation therapy followed by surgery. Site distribution was: 63 supraglottic, 26 glottic, 15 transglottic and 6 subglottic. There were 4 Stage II patients, 66 Stage III and 40 Stage IV. Preoperative radiation therapy consisted of Telecobalt irradiation to a total dose of 25 Gy given to a target volume encompassing the larynx and regional neck nodes, given in 5 equal daily fractions of 5 Gy in 5 consecutive days. Surgery was performed 2 days later. Total laryngectomy was performed on 48 patients, total laryngectomy with neck dissection on 55 patients, supraglottic laryngectomy on 5 and supraglottic laryngectomy with neck dissection on 2 patients. Crude actuarial 5 and 10 year survival probability for the whole group is 71 and 61%, respectively. The corrected 5 and 10 year survival is 75%. For patients with T₃T₄N₀ tumors 5 and 10 year survival probability is: crude 65 and 58%, and corrected 70% respectively. For T₃T₄N , crude: 75 and 60% and corrected: 78%.Of 110 patients, one died postoperative, three died of intercurrent disease, five died as a result of second malignancy, and 23 died of their larynx carcinoma: $\text{12}\text{23}$ because of locoregional failure, and $\text{11}\text{23}$ because of distant metastasis. We concluded that short intensive preoperative radiation therapy and surgery offer a high cure rate in the treatment of advanced resectable laryngeal carcinoma. The merits of this technique are outlined in the text.     

Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome.

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.     

Rotational 3D-conformal radiation therapy (conformation therapy) combined with hormone therapy for the treatment of stage B2/C prostate cancer in Japanese men

BACKGROUND AND PURPOSE: In our institution, rotational 3D-conformal radiation therapy (also called conformation therapy) has been applied since the late 1970s to conform the target volume of high-dose radiation to the cancerous tissue while minimizing radiation to the surrounding normal tissues. This technique has been used most commonly to treat prostate cancers in combination with hormonal therapy. The results of Stage B2/C prostate cancer treated with this method were analyzed. PATIENTS AND METHODS: Between 1987 and 1997, 33 cases of prostate cancer were definitively treated with this method: 9 Stage B2 tumors and 24 Stage C tumors. Of these 33 tumors, 3 were well differentiated, 18 were moderately differentiated, and 12 were poorly differentiated. The average patient age was 75.6 years. The median pretreatment PSA value was 23.8 ng/ml. The total radiation dose ranged from 60 Gy to 70 Gy (average: 63.5 Gy) with conventional fractionation. Hormone therapy was administered permanently; the primary hormonal agent was diethylstilbestrol phosphate. RESULTS: The overall survival rate after 5 years was 58.2% and that after 10 years was 29.6%. The biochemical relapse-free rate after 5 years was 87.0% and that after 10 years was still 87.0%. There were 4 cases of biochemical failure, but no cases of death from prostate cancer. Stage, differentiation, and pretreatment PSA value were not prognostic factors. One of the 2 cases with delayed complications was a case of RTOG Grade 3 gastrointestinal complication. CONCLUSIONS: Rotational 3D-conformal radiation therapy combined with hormone therapy might be promising for the treatment of prostate cancer.