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J F Fowler

Publications and source records attributed to J F Fowler.

At least 73 records · Page 4Linked to original sources
PubMed1996

A modelled comparison of the effects of using different ways to compensate for missed treatment days in radiotherapy.

There is much evidence for the detrimental effect on tumour control of missed treatment days during radiotherapy, amounting for example to approximately a 1.6% absolute decrease in local control probability per day of treatment prolongation in the case of head and neck squamous cell cancer. Various methods to compensate for missed treatment days are compared quantitatively in this article, using the linear-quadratic formalism. The overall time and fraction size can be maintained by either treating on weekend days (the preferred way (Method 1a), although with unsocial hours and at extra cost) or using two fractions per day to "catch up' (Method 1b). The latter might incur a small loss of tolerance regarding late reactions, when intervals of 6-8 h are used rather than 24 h, and there may be logistical/scheduling difficulties with larger numbers of patients in some centres when using this method. A second type of strategy retains overall treatment time, and also one fraction per day, but the size of the dose per fraction is increased. For example, this may be done for the same number of "post-gap' days as gap days (Method 2). However, with this method, calculated isoeffect doses regarding late reactions indicate a probable decrease in tumour control rate (Method 2a). Otherwise, isoeffective doses regarding tumour control result in an increase in late reactions (Method 2b). In addition, this method is unsuitable for short regimens already using high doses per fraction. To reduce this problem, overall treatment time can also be retained by using fewer fractions, all of greater size in the case of planned gaps (statutory holidays), or larger remaining fractions after unplanned gaps (Method 2c). The problem also with this method is that equivalence for tumour control gives an increase in late reactions. The least satisfactory strategy (Method 3) is to accept the protraction caused by the missed treatment days, and give either the same prescribed number of (slightly larger) fractions or the planned treatment followed by one (or more) extra fraction to compensate for the gap. This would retain the expected local control rate, but there would be an increase in late reactions. An example of this, using average parameter values, is that a 3-day gap (necessitating four extra days to complete treatment with one fraction of 2.4 Gy) might maintain a 70% local control rate for glottic carcinoma, but severe reactions might rise from 1% to 4% and minor/moderate reactions from 37% to 50%. In this example, the inclusion of an extra weekend would increase the required extra dose and hence may further increase the morbidity rates. A final point is that the effect of treatment interruptions for an individual patient is expected to be greater than that for a group of patients because of interpatient heterogeneity tending to flatten dose-response curves. Calculations show that the above value of 1.6% loss of local control per day for a group of patients may reflect values for individual patients that range around a median value of as much as 5% per day, so stressing further the importance of gaps in treatment. It is concluded that, wherever possible, treatment days should not be missed. If they are missed, it is important to compensate for them, preferably by one of the first of the above methods (1a or 1b), in order to keep as close as possible to the original/standard prescription in terms of total dose, dose per fraction and overall time.

Brachytherapy↗
PubMed1996

A retrospective evaluation of patch testing in patients diagnosed with allergic contact dermatitis.

One reason given by clinicians for not using patch testing in patients with dermatitis is that it may not improve the treatment outcome. The main objectives of this retrospective study were to determine the frequency of use of patch testing as an aid to the diagnosis of allergic contact dermatitis (ACD), to determine the ACD-related costs before and after diagnosis of the disease, and to determine the benefit of the diagnosis of ACD, with or without patch testing, to the patient's treatment outcome. This study will also provide definite direction for a prospective outcome study. Medical records of 270 patients with ACD were utilized retrospectively to study the benefit of patch testing. Patch testing was performed on 56 percent of these patients. Patch testing was found to bring about a larger decrease in the disease severity index and percentage disease activity from prediagnosis to postdiagnosis than diagnosis without patch testing. In the group of patients with a prediagnosis disease duration of two months to one year, the postdiagnosis duration was considerably less for those patch tested and treated than those that were treated without patch testing. Patch testing was found to be the most cost-effective in patients with a disease duration of two months to one year.

Adult↗
PubMed1996

The limiting radiosensitisation of tumours by S-phase sensitisers.

The aim of this study was to improve local control and survival of patients with radioresistant tumours by sensitising proliferating cells using halogenated analogues of thymidine, with emphasis on increasing the proportion of tumour cells that incorporate the sensitiser. It has been found clinically that 2 weeks of continuous infusion of IUdR at 1000 mg m-2 per day can be tolerated, followed after a gap by a third week of the same. The sensitising compound is taken up only into those cells which are in S-phase at the time of administration. It is assumed that if the same total dose of 3 g m-2 were administered spread evenly over a longer period, it would be tolerated at least as well, and a higher proportion of tumour cells would become sensitised (labelled with IUdR). The question then arises: is the reduced concentration of IUdR enough to cause significant radiosensitisation? This question was investigated in two contrasting lines of human colon cancer in vitro. It is essential that at least 90% of all clonogenic tumour cells should be labelled with the IUdR (that is 1 log), or else the sensitiser enhancement ratio (SER) cannot be expected to exceed 1.1. Similarly, to reach an SER of 1.2, we should label 99% of cells (2 logs labelled). To achieve such proportions labelled, infusions would have to be 5 or 10 times longer than the population doubling time of clonogenic cells Tpot that is of several weeks duration. The infusion should be either continuous or perhaps better-by repeated small boluses at intervals of less than T (duration of DNA synthesis), so that no proliferating cells escape being exposed to the IUdR. It is shown that LIs (labelling indices) of 94% can be obtained with SERs ranging from 1.5 to 3.0 and 99% with SERs from 1.2 to 2.4, in the two most contrasting human colon cancer cell lines for which data are available. Longer, lower dose infusions than previously used should be considered so as to emphasise the importance of not allowing any potentially clonogenic tumour cells to pass through S-phase without labelling.

Cell Survival↗
PubMed1995

Further analysis of radiobiological parameters from the First and Second British Institute of Radiology randomized studies of larynx/pharynx radiotherapy.

PURPOSE: This retrospective analysis of 1345 patients treated for cancer of the larynx or pharynx by randomization into two groups in each center in two separate trials of fractionated radiotherapy was carried out in an attempt to extract the radiobiological parameters alpha (dose), beta (fraction size), and gamma (overall time) from the data. METHODS AND MATERIALS: Details of the trials have been published previously. In the first, 734 patients were randomized to either five or three fractions per week, in centers each using their own overall time, which varied from 3 to 7 weeks in different centers. In the second trial, 611 patients were randomized to "short" (< or = 4 weeks) or "long" (4-7 weeks) overall time. We combine the data from both studies and use the linear-quadratic formula with logistic regression and maximum-likelihood methods to obtain the radiobiological factors, taking into account other variables such as stage or age, when significant. RESULTS: The parameters calculated for local tumor control showed significant estimates of alpha, very small estimates of beta, and significant values of gamma. The derived estimates of alpha/beta were large, but very variable. The time-dose tradeoff--gamma/alpha was 0.76 Gy/day for larynx and 0.3 Gy/day for pharynx tumors (not significantly different from each other). Late complications gave indeterminate alpha/beta ratios and a time-dose factor not significantly different from zero. Acute normal-tissue effects gave alpha/beta estimates of 8-9 Gy and time factors of 0.8-0.9 Gy/day. CONCLUSIONS: The results are consistent with other published values with the exception that significant time factors for late complications could not be excluded.

Age Factors↗
PubMed1995

The adverse effect of treatment prolongation in cervical carcinoma.

PURPOSE: Proliferation of surviving tumor clonogens during a course of protracted radiation therapy may be a cause of local failure in cervical carcinoma. The effect of total treatment time was analyzed retrospectively in relation to pelvic control and overall survival for squamous cell carcinomas of the uterine cervix. METHODS AND MATERIALS: Two hundred and nine patients (Stage IB-IIIB) treated with a combination of external beam and low dose rate intracavitary irradiation were evaluable for study. Multivariate analysis and Kaplan-Meier statistical methods were used to determine the effect of treatment time on pelvic control and survival at 5 years. RESULTS: The median treatment duration was 55 days. For all stages combined, the 5-year survival and pelvic control rates were significantly different with treatment times < 55 days vs. > or = 55 days: 65 and 54% (p = 0.03), 87 and 72% (p = 0.006), respectively. By stage, a shorter treatment duration (i.e., < 55 days vs. > or = 55 days) was significant for 5-year overall survival and pelvic control for Stages IB/IIA and III, but not for Stage IIB: Stage IB/IIA (81 and 67%, 96 and 84%), Stage III disease (52 and 42%, 76 and 55%) and Stage IIB (43 and 50%, 74 and 80%, respectively). Survival decreased 0.6%/day and pelvic control decreased 0.7%/day for each additional day of treatment beyond 55 days for all stages of disease. Additionally, significant late complications were not influenced by treatment time. CONCLUSION: These results suggest that prolongation of treatment time is associated with decreased local control and survival in patients with cervical carcinoma. This is consistent with emerging data from other institutions. Therapeutic implications include avoidance of unnecessary treatment breaks, the design of fractionation schemes that decrease treatment duration, and possibly the use of tumor cytostatic drugs during conventional radiation.

Brachytherapy↗
PubMed1995

Postoperative vaginal cuff irradiation using high dose rate remote afterloading: a phase II clinical protocol.

PURPOSE: In September 1989, a postoperative Phase II high dose rate (HDR) brachytherapy protocol was started for International Federation of Gynecology and Obstetrics (FIGO) Stage I endometrial adenocarcinoma. This review reports the overall survival, local control, and complication rates for the initial 63 patients treated in this Phase II study. METHODS AND MATERIALS: High dose rate brachytherapy was delivered using an Iridium-192 HDR remote afterloader. Sixty-three patients were entered into the Phase II protocol, each receiving two vaginal cuff treatments 1 week apart (range 4-12 days) with vaginal ovoids (diameter 2.0-3.0 cm). No patient received adjuvant external beam radiation. A dose of 32.4 Gy in two fractions was prescribed to the ovoid surface in 63 patients. The first three patients treated at our institution received 15, 16.2, and 29 Gy, respectively, to determine acute effects. RESULTS: At a median follow-up of 1.6 years (range 0.75-4.3 years) no patient has developed a vaginal cuff recurrence. One regional recurrence (1.6%) occurred at 1.2 years at the pelvic side wall. This patient is alive and without evidence of disease 7 months after completion of salvage irradiation, which resulted in the only vaginal stenosis (1.6%). Fourteen patients (22%) experienced vaginal apex fibrosis by physical exam, which was clinically symptomatic in four patients. Two patients reported stress incontinence; however, these symptoms were noted prior to their HDR therapy. One patient died 2.4 years after HDR therapy due to cardiovascular disease without evidence of cancer at autopsy. CONCLUSION: Preliminary results of our phase II HDR vaginal cuff protocol for postoperative FIGO Stage IA, Grade 3 or Stage IB, Grade 1-2 patients demonstrate that 32.4 Gy in two fractions is well tolerated by the vaginal cuff mucosa. Local control appears comparable to our prior experience and others with low dose rate (LDR) brachytherapy. Additional patient accrual and further follow-up will better determine the late morbidity, local control, and overall survival of these patients.

Adult↗
PubMed1995

A rationale for fractionation for slowly proliferating tumors such as prostatic adenocarcinoma.

PURPOSE: The incidence of carcinoma of the prostate has recently begun to exceed that of carcinoma of the lung in males in the United States. Although survival and local tumor control after treatment are good for early stages, improvements are being sought for more locally advanced stages. Dose escalation might be of benefit and might be accomplished using "three-dimensional" conformal radiotherapy or hyperfractionation. Because carcinoma of the prostate is known to be a generally slowly growing tumor, there may be more scope for extreme hyperfractionation, even with prolongation to allow for the extra number of very small fractions. This article explores only the hyperfractionation approach, and only theoretically, to investigate when treatments might become too hyperfractionated. METHODS AND MATERIALS: The major problem was what to assume for proliferation rates in human adenocarcinomas. A literature search yielded labeling indices (S-phase proportions) often averaging about 1%, but spreading up to 6% or more in individual cases. These data are reviewed, and three bands of rate of loss of local control were chosen for the subsequent calculations: 0.5%, 1%, and 2% loss of local control per week of prolongation. Calculations were done using the linear-quadratic model for a series of doses per fraction of 1.2, 1.0, 0.8, and 0.6 Gy, given twice a day (b.i.d.) in 7, 9, 12, and 17 weeks, respectively. They were compared with a "standard" 36 fractions of 2 Gy = 72 Gy in 7 weeks. Total doses for equal late effects were calculated assuming a late alpha/beta of 3 Gy; the tumor Biologically Effective Doses were calculated assuming tumor alpha/beta values of 30, 10, and 5 Gy. The possible increases of local tumor control were estimated assuming a gamma-37 slope of 2% (per percent increase in total tumor dose). RESULTS: Graphs are presented of the estimated local control as a function of dose per fraction (and overall time), for advanced tumors (starting at 30% LC) and for less advanced tumors (starting at 70%). The largest increase is always for the change from 2 Gy once a day (q.d.) to 1.2 Gy b.i.d. Further changes of local control with hyperfractionation depend upon tumor proliferation rate and on the shape of the tumor cell survival curve. The largest gains are for the more advanced tumors. CONCLUSIONS: There is no great encouragement to proceed to more hyperfractionated and prolonged schedules than 1.2-1.0 Gy b.i.d. in 7-9 weeks. We await developments that might more reliably enable potential doubling time and cell survival curve shapes to be routinely determined for individual tumors, before further hyperfractionation might be considered. In the absence of tumor kinetic measurements, we might consider low grade tumors to be the ones to select for prolonged fractionation, whereas high grade tumors would be more suitable for 1.2 Gy b.i.d. with no prolongation, or for dose escalation using conventional fraction sizes and conformal radiotherapy.

Adenocarcinoma↗
PubMed1995

The decreased influence of overall treatment time on the response of human breast tumor xenografts following prolongation of the potential doubling time (Tpot).

PURPOSE: Repopulation during fractionated radiotherapy has been postulated to result in a significant loss in local control in rapidly proliferating tumors. Clinical data suggest that accelerated fractionation schedules can overcome the influence of repopulation by limiting the overall treatment time. Unfortunately, accelerated therapy frequently leads to increased acute reactions, which may become dose limiting. An alternative to accelerated fractionation would be to decrease the rate of repopulation during therapy. To test the potential efficacy of this alternative, we examined the effect of reducing tumor proliferation rate on the response of MCF-7 human breast carcinoma xenografts treated with a short vs. a long course of fractionated therapy. To reduce the proliferation rate, we deprived nude mice transplanted with MCF-7 xenografts of the growth-stimulating hormone estradiol (E2). We have previously reported that E2 deprivation increases the potential doubling time (Tpot) for MCF-7 xenografts from a mean of 2.6 days to 5.3 days (p < 0.001). METHODS AND MATERIALS: E2-stimulated and E2-deprived MCF-7 breast carcinoma xenografts were clamped hypoxically and irradiated with four fractions of 5 Gy each, using either a short (3-day) or long (9-day) treatment course. E2 stimulation was restored in all animals at the completion of irradiation. Radiation response was determined by regrowth time and regrowth delay of the irradiated tumors as compared to unirradiated controls. RESULTS: Prolongation of therapy in rapidly proliferating, E2-stimulated tumors (Tpot approximately 2.6 days) resulted in a significant decrease in regrowth time in two identical experiments. With results pooled for analysis, the regrowth times for the short and long treatments were 62 and 32 days, respectively (combined p < 0.001). The shorter regrowth times suggest that there was less overall tumor damage with the longer fractionated radiotherapy course. No significant difference in regrowth time was observed in the more slowly proliferating, E2-deprived tumors (Tpot approximately 5.3 days) treated with either the short or long regimen. Median regrowth times were 48 and 54.5 days for the short and long treatments, respectively (combined p = 0.14). Similar changes were observed in regrowth delay. CONCLUSIONS: Reduction in the rate of cell proliferation, induced by E2 deprivation in MCF-7 human breast xenografts during fractionated radiotherapy, resulted in a significantly decreased dependence on overall treatment time in comparison to the more rapidly proliferating E2-stimulated tumors. This model suggests that pharmacologically induced reduction in the rate of tumor cell proliferation during a course of fractionated radiotherapy may be a viable alternative to accelerated fractionation for the treatment of rapidly proliferating tumors.

Animals↗
PubMed1995

Impact of "optimized" treatment planning for tandem and ring, and tandem and ovoids, using high dose rate brachytherapy for cervical cancer.

PURPOSE: Different treatment techniques are used in high dose rate (HDR) remote afterloading intracavitary brachytherapy for uterine cervical cancer. We have investigated the differences between "optimized" and "nonoptimized" therapy using both a tandem and ring (T/R) applicator, and a tandem and ovoids (T/O), applicator. METHODS AND MATERIALS: HDR afterloading brachytherapy using the Madison System for Stage IB cervical cancer was simulated for 10 different patients using both a T/R applicator and a T/O applicator. A treatment course consists of external beam irradiation and five insertions of HDR afterloading brachytherapy. Full dosimetry calculations were performed at the initial insertion for both applicators and used as a reference for the following four insertions of the appropriate applicator. Forty dosimetry calculations were performed to determine the dose delivered to Point M (similar to Point A), Point E (obturator lymph nodes), vaginal surface, bladder, and rectum. "Optimized" doses were specified to Point M and to the vaginal surface. "Nonoptimized" doses were specified to Point M only. Using the linear-quadratic equation, calculations have been performed to convert the delivered dose using HDR to the biologically equivalent doses at the conventional low dose rate (LDR) at 0.60 Gy/h. RESULTS: Major differences between "optimized" and "nonoptimized" LDR equivalent doses were found at the vaginal surface, bladder, and rectum. Overdoses at the vaginal surface, bladder, and rectum were calculated to be 208%, nil, and 42%, respectively, for the T/R applicator with "nonoptimization." However, for the T/O applicator, the overdoses were smaller, being nil, 32%, and 27%, respectively, with "nonoptimization." CONCLUSION: Doses given in high dose rate intracavitary brachytherapy border on tissue tolerance. "Optimization" of either applicator decreases the risk of a dose that may have potential for complications. Optimization of a tandem and ovoids best ensures that the doses are not diminished at the treatment sites, and that the potential for overdose is reduced.

Brachytherapy↗
PubMed1995

Effect of time, dose and fractionation on local control of nasopharyngeal carcinoma.

To study the effect of radiation factors on local control of nasopharyngeal carcinoma, 1008 patients with similarly staged T1N03M0 disease (Ho's classification) were retrospectively analyzed. All patients were treated by megavoltage irradiation alone using the same technique. Four different fractionation schedules had been used sequentially during 1976-1985: with total dose ranging from 45.6 to 60 Gy and fractional dose from 2.5 to 4.2 Gy. The median overall time was 39 days (range = 38-75 days). Both for the whole series and 763 patients with nodal control, total dose was the most important radiation factor. The hazard of local failure decreased by 9% per additional Gy (p < 0.01). Biological equivalents expressed in terms of Biologically Effective Dose or Nominal Standard Dose also showed strong correlation. Fractional dose had no significant impact. The effect of overall treatment time was insignificant for the whole series, but almost reached statistical significance for those with nodal control (p = 0.06). Further study is required for elucidation, as 85% of patients completed treatment within a very narrow range (38-42 days), and the possible hazard is clinically too significant to be ignored.

Actuarial Analysis↗
PubMed1995

Prevention of poison ivy and poison oak allergic contact dermatitis by quaternium-18 bentonite.

BACKGROUND: Poison ivy and poison oak are the most common causes of allergic contact dermatitis in North America. OBJECTIVE: We investigated whether a new topical lotion containing 5% quaternium-18 bentonite prevents experimentally induced poison ivy and poison oak allergic contact dermatitis. METHODS: A single-blind, paired comparison, randomized, multicenter investigation was used to evaluate the effectiveness and safety of quaternium-18 bentonite lotion in preventing experimentally induced poison ivy and poison oak allergic contact dermatitis in susceptible volunteers. One hour before both forearms were patch tested with urushiol, the allergenic resin from poison ivy and poison oak, 5% quaternium-18 bentonite lotion was applied on one forearm. The test patches were removed after 4 hours and the sites interpreted for reaction 2, 5, and 8 days later. The difference in reactions between treated and untreated patch test sites was statistically analyzed. RESULTS: Two hundred eleven subjects with a history of allergic contact dermatitis to poison ivy and poison oak were studied. One hundred forty-four subjects had positive reactions to urushiol. The test sites pretreated with quaternium-18 bentonite lotion had absent or significantly reduced reactions to the urushiol compared with untreated control sites (p < 0.0001) on all test days. When it occurred, the reaction consistently appeared later on treated than on control sites (p < 0.0001). One occurrence of mild, transient erythema at the application site was the only side effect from the quaternium-18 bentonite lotion. CONCLUSION: Quaternium-18 bentonite lotion was effective in preventing or diminishing experimentally produced poison ivy and poison oak allergic contact dermatitis.

Administration, Cutaneous↗
PubMed1994

T1 nasopharyngeal carcinoma: the effect of waiting time on tumor control.

PURPOSE: To study the effect of unperturbed tumor growth on the control of nasopharyngeal carcinoma. METHODS AND MATERIALS: This is a retrospective analysis of 290 patients with T1N0-3M0 disease (Ho's classification) treated by the same technique and dose schedule to the nasopharyngeal region. The median interval from diagnosis to commencement of irradiation was 26 days (range: 8-68 days). Cox proportional hazards analyses were performed to study the independent effect of waiting time on the probability of failure at various sites. Actuarial failure-free survival of patients with delay < 22 days, 22-28 days and > 28 days were also compared to illustrate the clinical observation. RESULTS: Both tests showed that waiting time had no significant impact on local failure: The N-stage stratified hazard ratio was 0.985 per day, and the 10-year local failure-free survival for the three groups was 76%, 80%, and 82%, respectively. A similar result was obtained for nodal control in patients with our scheduled neck irradiation. Although the p value of all tests failed to reach statistical significance, the N-stage stratified hazard ratio for distant failure was 1.020 per day, and the corresponding metastasis-free survival in patients with N2-3 disease was 70%, 65%, and 52%, respectively. For node-negative patients without elective neck irradiation, the hazard ratio was 1.019 per day, with the corresponding regional failure-free rates at 57%, 62%, and 33%, respectively. CONCLUSION: Delay in initiation of treatment to the primary target (within the range observed) did not affect the control rate at irradiated sites, but there was a trend (though statistically insignificant) towards increase in failures at untreated sites that were clinically too serious to be ignored.

Adult↗
PubMed1994

A comparison of the efficacy and complication rates of low dose-rate versus high dose-rate brachytherapy in the treatment of uterine cervical carcinoma.

PURPOSE: To compare the outcome and complication rates for treatment of uterine cervical carcinoma with low dose-rate (LDR) vs. high dose-rate (HDR) brachytherapy at the University of Wisconsin Comprehensive Cancer Center (UWCCC). METHODS AND MATERIALS: One-hundred ninety-eight evaluable patients with cervical carcinoma, Stages IB to IIIB, treated with curative intent with a combination of megavoltage teletherapy and LDR brachytherapy from 1977 to 1988 were the subject of an initial review. In 1989, a HDR treatment program was initiated where all patients with cervical carcinoma were subsequently treated with a combination of HDR brachytherapy and teletherapy. Using the linear-quadratic model (LQ), the dose and schedule of HDR brachytherapy and teletherapy were designed to give similar tumor control and late effects as LDR therapy. Technically, the HDR schedule required meticulous attention to treatment geometry to limit severe late effects. Forty patients treated with the HDR program with 2-4 year follow-up were reviewed and compared to the previous LDR patient group. The LDR and HDR treatment groups were comparable with regards to age, weight, stage distribution, bulk of disease, and histology. RESULTS: No significant difference in survival was found between the LDR and HDR groups with 3-year actuarial overall survival being 66% and 77%, respectively. Three-year actuarial pelvic control rates were similar at 80% and 77% for the LDR and HDR groups, respectively. No significant difference in late treatment complications requiring hospitalization or surgery was found between the two treatment groups with a complication rate of 10% (20/198) for the LDR patients and 2.5% (1/40) for the HDR patients. CONCLUSION: As predicted by our LQ calculations, treatment results for LDR and HDR brachytherapy were similar with respect to survival, pelvic control and late complications in the treatment of cervical carcinoma. The HDR brachytherapy program at the UWCCC appears to be a safe and effective alternative to LDR therapy in the treatment of cervical carcinoma.

Adolescent↗
PubMed1994

Tumor cell kinetics using two labels and flow cytometry.

A flow cytometry based, single sampling method employing sequential bromodeoxyuridine (BrdUrd) and iododeoxyuridine (IdUrd) labeling with an intervening interval is examined. BrdUrd-specific and nonspecific monoclonal antibodies and flow cytometry are used to estimate the duration of DNA synthesis and the potential doubling time in tumor cell populations using a single sampling or biopsy. A correction for labeled, divided cells allows postlabel incubation intervals to exceed the length of the G2/M phase of the cell cycle. The method yields reliable results when tested in experimental tumor systems in vitro and in situ, as well as in nine human tumors labeled in situ. It uses a somewhat simpler analysis than the alternative relative movement method, requiring only labeling indices, rather than both a labeling index and relative movement, but doses require the administration of two, rather than one, label. It provides an independent verification of and a useful single sampling alternative to the relative movement method for the estimation of the length of S phase and, from this, the potential doubling time in experimental or clinical human tumors.

Animals↗
PubMed1994

Kinetics of cell labeling and thymidine replacement after continuous infusion of halogenated pyrimidines in vivo.

PURPOSE: Iododeoxyuridine (IdUrd) is a halogenated pyrimidine which has been recognized as a clinical radiosensitizer. It is generally agreed that the extent of radiosensitization correlates with the degree of thymidine substitution in DNA. Controversy exists regarding the optimal administration schedule to achieve maximum radiosensitization. To obtain more information relating to this problem, we present experiments on an in vivo human tumor xenograft continuously exposed to a fixed serum concentration of halogenated pyrimidines so as to study the kinetics of cell labeling and thymidine replacement. METHODS AND MATERIALS: Human colon tumor (HCT-116) cells were injected subcutaneously into nude mice. After 10 days, most animals (> 90%) developed measurable tumor nodules with a volume doubling time of 5 +/- 1 days. Once the tumors reached a cross-sectional area of 0.25-0.30 cm2, miniosmotic pumps were implanted to deliver a dose of 100 mg/kg/day of IdUrd by continuous infusion. After an IdUrd exposure time of 1-7 days, blood and tumor tissue were collected. RESULTS: The steady state serum IdUrd concentration was 0.95 +/- 0.1 microM, which is a clinically relevant concentration for a prolonged continuous intravenous infusion. The tumor cell potential doubling time (Tpot) was 25 +/- 2 h. The percent IdUrd thymidine replacement and the fraction of cells labeled, followed exponential saturation kinetics with a halflife of 33 +/- 9 and 27 +/- 2 h, respectively. After 5 days of exposure (congruent to 5 x Tpot), the thymidine replacement in tumor cells was 2.0 +/- 0.2% and the fraction of tumor cells labeled was 94 +/- 1%. Immunohistochemical staining of IdUrd labeled tumor tissues showed an exposure dependent gradient of cellular labeling that was initially highest in regions close to blood vessels. After 4 days of exposure at 100 mg/kg/day, there was an increase in the fraction of cells in G(0) + G1 and a decrease in the S phase population, suggesting a block between G1 and S phase. CONCLUSION: We conclude that the in vivo kinetics of IdUrd thymidine replacement and fraction of cells labeled after continuous exposure followed exponential saturation kinetics with a halflife of approximately the potential doubling time of the tumor cell population. Simple modeling suggests that some form of prolonged, or briefly interrupted, continuous infusion should be considered for clinical administration because such schedules would leave fewer cells unsensitized than shorter infusions would. Even 10% of unlabeled clonogenic cells could explain the lack of dramatic clinical successes with IdUrd or BrdUrd sensitization.

Animals↗