The hazard of accelerated tumor clonogen repopulation during radiotherapy

Withers, H. Rodney; Taylor, Jeremy M. G.; Maciejewski, B.

doi:10.3109/02841868809090333

Cited by 1,458 publications

(615 citation statements)

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“…Thus, a shortening of overall treatment times might increase the chance of local control in properly selected patients. Recent studies (4-6,37,38) indicate a striking similarity between these effective tumor doubling times during treatment (14,18,19,21,39) and a quantity called the tumor potential doubling time, Tpot, measured prior to treatment. Tpot is the minimum time for tumor volume doubling, taking growth fraction into account but ignoring cell loss.…”

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confidence: 96%

“…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. 0 1994 Wiley-Liss, Inc.Key terms: Cell kinetics, bromodeoxyuridine, iododeoxyuridine, human tumors Analyses of both experimental and clinical data indicate decreased local tumor control with prolongation of overall radiation therapy treatment times (4,13, 18,31,39). Such an effect is likely to be due, at least in part, to tumor clonogenic proliferation during treatment.…”

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confidence: 99%

“…Key terms: Cell kinetics, bromodeoxyuridine, iododeoxyuridine, human tumors Analyses of both experimental and clinical data indicate decreased local tumor control with prolongation of overall radiation therapy treatment times (4,13, 18,31,39). Such an effect is likely to be due, at least in part, to tumor clonogenic proliferation during treatment.…”

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Tumor cell kinetics using two labels and flow cytometry

et al. 1994

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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 does 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. 0 1994 Wiley-Liss, Inc.Key terms: Cell kinetics, bromodeoxyuridine, iododeoxyuridine, human tumors Analyses of both experimental and clinical data indicate decreased local tumor control with prolongation of overall radiation therapy treatment times (4,13, 18,31,39). Such an effect is likely to be due, at least in part, to tumor clonogenic proliferation during treatment. Thus, a shortening of overall treatment times might increase the chance of local control in properly selected patients. Recent studies (4-6,37,38) indicate a striking similarity between these effective tumor doubling times during treatment (14,18,19,21,39) and a quantity called the tumor potential doubling time, Tpot, measured prior to treatment. Tpot is the minimum time for tumor volume doubling, taking growth fraction into account but ignoring cell loss. These data indicate that many human tumors-about one-half of all head and neck tumors, for example (371-have the potential to double their cell number in as short a time as five or fewer days. Such considerations have stimulated much interest in the in situ measurement of rates of tumor cell proliferation.The delayed biopsy, relative movement technique (7) permits the estimation of Tpot from a single biopsy without the use of radioisotopes required by previous cell cycle analysis methods (31). It employs bromodeoxyuridine (BrdUrd) or iododeoxyuridine (IdUrd) pulse labeling of the DNA of established tumor cell lines in vitro or of tumors in situ, followed, after a delay of several hours, by a single biopsy. Halogenated pyrimidine-specific monoclonal antibodies and propidium iodide staining of DNA are then employed with flow cytometry to determine the labeling index (LI) and a parameter called the relative movement that monitors the progression of labeled cells through the cell cycle. The length of S phase (T,) and the potential doubling time can then be ...

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Tumor cell kinetics using two labels and flow cytometry

et al. 1994

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“…A strong association of nuclear p53 protein accumulation with local relapse in breast cancer patients receiving or not postoperative radiotherapy has been recently reported by Zellars et al (2000). The association of a high proliferation index with local relapse may be explained by a possible role of rapidly proliferating cells in the so-called 'accelerated clonogen repopulation' phenomenon during radiotherapy (Withers et al, 1998). An increased rate of locoregional and distant relapse has been reported in patients with breast cancer bearing a high thymidine labelling index (Amadori and Silvestrini, 1998).…”

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confidence: 79%

Molecular analysis of local relapse in high-risk breast cancer patients: can radiotherapy fractionation and time factors make a difference?

et al. 2003

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Large primary breast tumours and extensive lymph node involvement are linked to a high rate of local recurrence after surgery. In 10 -20% of such high-risk breast cancer patients, local relapse will occur despite postoperative radiotherapy. In the present study, we investigated whether molecular features, such as angiogenesis, cancer cell proliferation, steroid receptor expression, c-erbB-2 oncoprotein overexpression, p53 protein nuclear accumulation or bcl-2 antiapoptotic protein expression, can predict failure of local therapy. We further examined as to which subgroups of patients could benefit from altered fractionation schemes of radiotherapy. In univariate analysis, high intratumoural angiogenesis, c-erbB overxpression and mutant-p53 nuclear accumulation were significantly associated with increased relapse rate (P ¼ 0.0002, 0.009 and 0.05, respectively). In multivariate analysis, the microvessel density and the c-erbB-2 status were independent and significant factors related to local relapse (P ¼ 0.001, t-ratio 3.36 and P ¼ 0.02, t-ratio 2.26, respectively). Hypofractionated and accelerated radiotherapy supported with amifostine (HypoARC regimen) was significantly more effective than standard radiotherapy in cases with high cancer cell proliferation index, c-erbB-2 and p53 overexpression. High angiogenesis, however, was linked with local relapse regardless of the radiotherapy regimen.

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“…Repopulation of surviving clonogenic tumour cells during fractionated radiotherapy has been identified as an important factor associated with clinical failure in squamous cell carcinoma of the head and neck (Withers et al, 1988;Fowler and Lindstrom, 1992). According to the results of randomized clinical trials (Dische et al, 1997;Dobrowsky and Naude, 2000) the dose needed to counteract tumour cell repopulation accounts for approximately 0.4 Gy per day longer overall treatment time.…”

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Mitomycin C in combination with radiotherapy as a potent inhibitor of tumour cell repopulation in a human squamous cell carcinoma

et al. 2002

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The potential of Mitomycin C in combination with fractionated irradiation to inhibit tumour cell repopulation of a fast growing squamous cell carcinoma after fractionated radiotherapy was investigated in vivo. A rapidly growing human squamous cell carcinoma (FaDu dd ) was used for the study. For experiments, NMRI (nu/nu) mice with subcutaneously growing tumours were randomly allocated to no treatment, Mitomycin C, fractionated irradiation (ambient: 11x4.5 Gy in 15 days), or fractionated irradiation combined with Mitomycin C. Graded top up doses (clamped blood flow: 0 -57 Gy) were given at day 16, 23, 30 or 37. End point of the study was the time to local tumour progression. Data were examined by multiple regression analysis (Cox). Mitomycin C alone resulted in a median time to local tumour progression of 23 (95% confidence limits: 17 -43) days, fractionated irradiation in 31 (25 -35) days and combined Mitomycin C plus fractionated irradiation in 65 (58 -73) days (P=0.02). Mitomycin C decreased the relative risk of local recurrence by 94% (P550.001) equivalent to 31.7 Gy top up dose. Repopulation accounted for 1.33 (0.95 -1.72) Gy per day top up dose after fractionated irradiation alone and for 0.68 (0.13 -1.22) Gy per day after fractionated irradiation+Mitomycin C (P=0.018). Mitomycin C significantly reduces the risk of local recurrence and inhibits tumour cell repopulation in combination with fractionated irradiation in vivo in the tested tumour model.

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The hazard of accelerated tumor clonogen repopulation during radiotherapy

Cited by 1,458 publications

References 59 publications

Tumor cell kinetics using two labels and flow cytometry

Tumor cell kinetics using two labels and flow cytometry

Molecular analysis of local relapse in high-risk breast cancer patients: can radiotherapy fractionation and time factors make a difference?

Mitomycin C in combination with radiotherapy as a potent inhibitor of tumour cell repopulation in a human squamous cell carcinoma

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