Biomedical subjects
Publications and source records attributed to K K Fu.
This article presents a brief review of the mechanisms by which chemotherapy can be combined with radiotherapy to improve the therapeutic ratio, the possible mechanisms of interaction between chemotherapy and radiotherapy, the various factors that may influence their combined effects, and future perspectives in this area of clinical and laboratory research.
A prospective, randomized Phase Ilate/II trial of hyperfractionated radiation therapy was conducted: 1.2 Gy minimum tumor dose was administered twice daily with a minimum interval of 4 hr, 5 days per week. Patients with Stage III and IV carcinomas of the oral cavity, oropharynx, nasopharynx, hypopharynx, and supraglottic larynx were stratified by site, presence or absence of nodal metastases, and performance status. They were assigned to four total doses between 67.2 Gy and 81.6 Gy to all known tumors. The highest dose arm was opened after preliminary assessment indicated acceptable late morbidity rates with the three lower doses. Of 479 patients entered, 260 patients were randomized to the three lower total doses and 237 were analyzed for this preliminary report: 63 were assigned to receive 67.2 Gy, 58 to 72.0 Gy, and 116 to 76.8 Gy. Estimates of grade 4 necrosis at 2 years were 10.0%, 5.1%, and 13.9%, respectively, for patients who received total doses of 67.2 Gy, 72.0 Gy, and 76.8 Gy. There was a suggestion of a trend toward increased local control at 24 months (Kaplan-Meier estimates of 25% for 67.2 Gy, 37% for 72.0 Gy, and 42% for 76.8 Gy) (p = .08). No difference was observed in survival. Assessment of the results using Cox regression models to correct for slight inequalities of pretreatment prognostic variables supported a total dose-tumor control relationship (p = .054). Results for the lowest dose arm were comparable to previous RTOG studies of common fractionation with similar total doses. The higher local control rates with 72.0 and 76.8 Gy using hyperfractionated radiation therapy suggest an improvement in outcome with radiation therapy for advanced carcinomas of the upper aerodigestive tracts. These preliminary findings have led to a Phase III comparison of hyperfractionated radiation therapy with 1.2 Gy b.i.d. with standard fractionation.
Phosphorus metabolite levels were measured non-invasively using 31P magnetic resonance spectroscopy (MRS) in SCCVII/SF tumors, subcutaneously transplanted into the legs of unanesthetized C3Hf/Sed mice. Shortly after MRS measurements, tumors were irradiated with a single dose of 20 Gy, and cell survival and radiobiologic hypoxic fraction were determined with an in vitro cloning assay. Significant correlations were found between tumor size and surviving fraction, hypoxic fraction, pH, and phosphorus metabolite ratios. With increase of tumor size, surviving fraction and hypoxic fraction both increased, the ratios of inorganic phosphate and phosphomonoesters to nucleoside triphosphates (Pi/NTP and PME/NTP, respectively) and inorganic phosphate to phosphocreatine (Pi/PCr) increased and pH decreased. However, considerable heterogeneity of MRS spectral parameters, even in tumors of similar size, precluded accurate prediction of hypoxic fraction and cell survival after radiotherapy.
High-dose-rate (HDR) remote afterloading intracavitary brachytherapy has been widely used in the treatment of carcinoma of the cervix in Europe and Asia since the 1960's. Recently, there has been an increase of interest in the use of this technique in North America. Most of the non-randomized studies suggest similar survival, local control, and complication rates using fractionated high-dose-rate remote afterloading intracavitary brachytherapy combined with external beam irradiation compared to historical or concurrent low-dose-rate (LDR) controls. However, the techniques as well as the dose fractionation schedules used in different institutions are variable. The optimal technique and dose fractionation scheme has yet to be established through systematic clinical trials.
Twelve consecutive patients with advanced stage mycosis fungoides (MF) were treated with combined total body X ray irradiation (TBI) and total skin electron beam radiotherapy (EBRT). Six had generalized plaque disease and dermatopathic nodes, three had tumor stage disease and node biopsy positive for mycosis fungoides, and three had erythroderma/Sezary syndrome. The treatment regimen consisted of split course total body X ray irradiation, given in twice weekly 15 cGy fractions to 75 cGy, then total skin electron beam radiation therapy given in once weekly 400 cGy fractions to a total dose of 2400 cGy. Underdosed areas and areas of greatest initial involvement were boosted 400 cGy twice weekly for an additional 1200 cGy. This was followed by a second course of total body X ray irradiation, to a total dose of 150 cGy. The total skin electron beam radiotherapy technique is a modification of an established six position EBRT technique for mycosis fungoides. Measurements to characterize the beam with and without a lexan scattering plate, demonstrated that the combination of no-plate beams produced better dose uniformity with a much higher dose rate. This improved technique is particularly advantageous for elderly and/or frail patients. Nine (75%) of the 12 patients achieved complete response (CR). The other three had significant improvement with greater than 80% clearing of their disease and resolution of symptoms. All six patients with generalized plaque disease achieved complete response and remained free of disease from 2 to 16 months. Two of three node positive patients also achieved complete response; one, with massive biopsy-documented mycosis fungoides nodal disease and deep open tumors, remained relapse-free over 2 years. Only one of the three patients with erythroderma/Sezary syndrome achieved a complete response, which was short lived. Therapy was well tolerated. No significant hematological toxicity occurred. Although total body X ray irradiation and total skin electron beam radiotherapy produced excellent palliation of patients with advanced stage mycosis fungoides, new strategies to provide more effective systemic treatment are needed.
I-125 sources are being used in temporary interstitial implants of various sites. Radiation safety considerations favor its use over other available radioisotopes. Cost containment is achieved by using the same sources for a number of patients. Loading I-125 seeds into implant catheters at our institutions permit customized source arrangement to optimize the implant dose patterns. Clinical examples are given for which the dose distributions achieved with customized source loading are superior to those achievable with standard Ir-192 ribbons.
Our purpose of this study was to determine whether whole-body, continuous low-dose-rate irradiation (CLDRI) alters the plasma and/or tumor platinum pharmacokinetics after ip bolus injection or ip infusion as a possible mechanism of interaction between CLDRI and cisplatin. The C3Hf/Sed mice bearing SCCVII/SF tumors were given 6 mg cisplatin/kg ip by bolus injection or an ip infusion of 0.25 mg cisplatin.kg-1.hour-1 for 48 hours with and without CLDRI at 0.56 Gy/hr for 24 or 48 hours. Plasma and tumor platinum concentrations were determined with an atomic absorption spectrophotometer at appropriate intervals during infusion and up to 48 hours after drug administration. Both total and ultrafilterable plasma platinum followed a biphasic elimination after ip bolus injection, whereas only a prolonged single-phase elimination was seen after ip infusion. Tumor uptake of platinum appeared to follow a passive diffusion pattern with a prolonged cellular retention of platinum. Whole-body CLDRI had no apparent effect on the pharmacokinetics of plasma and tumor platinum administered by ip bolus injection or prolonged continuous infusion.
Seventeen patients with advanced or recurrent salivary gland cancer were treated with cisplatin, doxorubicin, and 5-fluorouracil combination chemotherapy (PAF). Two patients achieved a complete response and four patients achieved a partial response, for an overall response rate of 35%. Six of the nine patients who received PAF in the neoadjuvant setting did not respond and proceeded to surgery and/or radiation therapy. No difference in response rate was found between those patients treated for recurrent disease v those treated with neoadjuvant chemotherapy. All three patients with adenocarcinoma responded. The response duration in patients with metastatic or recurrent disease ranged from 6 to 15 months. The PAF regimen was delivered primarily in the outpatient setting and was associated with acceptable toxicity. PAF demonstrates activity in salivary gland malignancies, and further evaluation of this combination seems warranted.
Between 1978 and 1984, the Northern California Oncology Group (NCOG) conducted a randomized trial to study the efficacy of combined radiotherapy (RT) and chemotherapy (CT) for stage III or IV inoperable head and neck cancer. One hundred four patients were randomized to receive: (1) RT alone, or (2) RT plus CT. RT consisted of 7,000 cGy to the involved areas and 5,000 cGy to uninvolved neck at 180 cGy/fraction, five fractions/wk. CT consisted of bleomycin, 5 U intravenously (IV), twice weekly during RT, followed by bleomycin, 15 U IV, and methotrexate, 25 mg/m2 IV weekly for 16 weeks after completion of RT. Fifty-one patients in the RT alone group and 45 in the combined treatment group were evaluable. The local-regional complete response (CR) rate was 45% v 67% (P = .056); the 2-year local-regional control rate, including salvage surgery, was 26% v 64% (P = .001); and the incidence of distant metastasis was 24% v 38% (P greater than .25), for the RT alone and RT plus CT groups, respectively. The relapse-free survival curves were significantly different (P = .041), favoring the combined treatment. However, the survival curves were not significantly different (P = .16). Patient compliance to maintenance CT was poor. Bleomycin significantly increased the acute radiation mucositis, although the difference in late normal tissue toxicity was not statistically significant. Thus, bleomycin and concurrent RT produced a more favorable CR rate, local-regional control rate, and relapse-free survival, but the difference in survival was not statistically significant.
Explore the source record for details and available documents.
A retrospective analysis of 171 patients with carcinoma of the tonsillar region is presented. The majority of patients (79%) presented with stage III and IV disease. Three year determinate survival was 81% - T1, 74% - T2, 59% - T3, and 20% - T4. The presence of nodal disease decreased survival by one half. Radiotherapy alone was highly successful in controlling early T1 and T2 lesions of the tonsillar fossa. Surgery alone or combined radiotherapy and surgery was more successful than radiotherapy in controlling early T1 and T2 lesions of the tonsillar pillar. More advanced T3 and T4 lesions also did poorly with radiotherapy alone. An analysis of these results and a review of the literature is presented.
The ultimate goal of combining chemotherapy and radiotherapy is to improve the therapeutic ratio. When chemotherapy is combined with radiotherapy, improved therapeutic effects may occur as a result of the following: (1) spatial cooperation; (2) enhancement of tumor response with less or no enhancement of normal tissue injury, and (3) diminution of normal tissue injury with less or no diminution of tumor response. Possible mechanisms of interaction between chemotherapeutic agents and radiation that result in an enhanced effect include (1) changes in the slope of the dose response curve, (2) decreased accumulation or inhibition of repair of sublethal damage, (3) decreased recovery from potentially lethal damage, (4) perturbation in cell kinetics with an increase of proportion of cells in the sensitive cell cycle phase and proliferative state, (5) decreased tumor bulk and improved blood supply leading to reoxygenation and recruitment and increased radiosensitivity and chemosensitivity, and (6) increased drug delivery and uptake. The combined effects may be influenced by (1) tumor and normal tissue type, (2) drug type, (3) drug dose and schedule, (4) time sequence between drug and radiation administration, (5) radiation dose and fractionation schedule, and (6) radiation dose rate. Most experimental and clinical data suggest that enhanced tumor effects most often result from simple additivity and therefore do not require direct interaction between drug and radiation, whereas enhanced normal tissue effects are observed most often when drugs are administered in close temporal proximity to radiation. Thus, for the optimal therapeutic effect, it would seem more advantageous to administer chemotherapeutic drugs and radiation in a sequential or alternating manner rather than simultaneously.
The influence of time sequence of cis-dichlorodiammine platinum (cisplatin) administration and continuous low dose rate irradiation (CLDRI) on their combined effects was studied in the SCC VII/SF tumor, a murine squamous cell carcinoma. Concurrent cisplatin i.p. infusion at 0.22 mg/kg/hr and CLDRI at 0.6 Gy/hr had a supraadditive effect on the survival of the SCC VII/SF tumor cells. Cisplatin by itself was more effective against the SCC VII/SF tumor when given by bolus injection than by continuous infusion i.p. However, when cisplatin at a dose of 6 mg/kg was given by bolus i.p. injection either immediately before or after CLDRI, the combined effects on the SCC VII/SF tumor cell survival were no more than additive. Exposure to CLDRI at 0.6 Gy/hr for 24 hours did not sensitize the SCC VII/SF tumor to subsequent treatment with cisplatin. These results suggest that when cisplatin is combined with CLDRI, for the optimal anti-tumor effect, it is best to infuse the cisplatin continuously during the course of CLDRI.
The combined effects of continuous low dose rate irradiation (CLDRI) and concurrent infusion of bleomycin, cyclophosphamide, cis-platinum, 5-fluorouracil, actinomycin D, and mitomycin C were studied in the SCC VII/SF tumor, a squamous cell carcinoma and the jejunal crypt cells in the mouse. For the SCC VII/SF tumor, enhanced cell killing was seen with each of the six drugs when infused concurrently with CLDRI; the greatest enhancement was seen with mitomycin C and cis-platinum. For the jejunal crypt cells, enhanced cell killing was seen primarily with bleomycin. At a dose of 20 Gy, the dose effect factor (DEF) ranged from 1.13-1.64 for the SCC VII/SF tumor and 0.92-1.19 for the jejunal crypt cells. Our results suggest a therapeutic gain with concurrent CLDRI and chemotherapy infusion for five of the six chemotherapeutic drugs studied with the exception of bleomycin.
Addition of solid doxorubicin or solutions to pre-formed liposomes proved to be the optimal method for incorporating the drug into liposomes whilst maintaining their size distribution and hence ability to accumulate in the lung. Liposomes prepared in this way lost doxorubicin only slowly on dialysis but dilution with an equal volume of saline at 37 degrees C resulted in the loss of 80% of the incorporated doxorubicin within 30 min. These liposomes were thus ineffective in altering doxorubicin disposition in vivo and produced no enhanced activity compared with free drug and a non-lung-accumulating carrier liposome in the EMT6 cell-Balb/c mouse model lung tumour.
Laryngeal edema persisting for more than three months following radiotherapy developed in 38 of 247 (15.4%) patients irradiated for carcinoma of the vocal cord. In 17 (44.7%) of these patients, the laryngeal edema was associated with persistent or recurrent disease, although only 25.4% of the patients with uncontrolled disease had laryngeal edema. The incidence of laryngeal edema was 13.1% for T1 disease, 23.8% for T2, and 21.4% for T3 and T4 disease. It increased significantly with increase of minimum tumor dose greater than or equal to 7000 rads or with NSD greater than 1900 ret, being 46.2% with minimum tumor dose greater than or equal to 7000 rad and 13.7% with minimum tumor dose less than 7000 rad and 43% with NSD greater than 1900 ret and 17% with NSD less than or equal to 1900 ret. It also increased with increase of field size, being 13.4% with field sizes less than 6.0 x 6.0 cm2, and 24.4% with field sizes greater than or equal to 6.0 x 6.0 cm2. When laryngeal edema is progressive and unresponsive to conservative measures, multiple biopsies should be performed to establish the presence of persistent or recurrent disease before salvage surgery is attempted. However, if it is mild, stable, no visible recurrence develops, and especially if it is limited to the arytenoids, no biopsy should be attempted because of the risk of inducing laryngeal necrosis.
One hundred patients irradiated for cancers of the oral cavity, oropharynx, and nasopharynx were evaluated for the occurrence of osteonecrosis and associated predisposing factors. Selection was based on availability of complete dental records, a minimum of six months follow-up, and treatment fields, which included maxilla and/or mandible. Bone doses were calculated by using radiotherapy treatment records, port films, and isodose distributions. Osteonecrosis developed in 19 of 78 dentulous patients and in 3 of 22 edentulous patients. The time of development of osteonecrosis varied; in 15 cases osteonecrosis occurred more than one year after treatment. The most important risk factor for the development of osteonecrosis was the radiation dose to bone, particularly in the less vascular mandible. Osteonecrosis 7500 rads to the bone. None of the patients who received less than 6500 rads developed osteonecrosis. The risk was significantly greater when teeth were removed after therapy compared with those individuals with extractions before radiation or no extractions at all.