Accelerated repopulation

Radiation treatment schemes that accelerate the dose delivery, i.e., attempt to deliver it in a shorter overall time, endeavor to compensate for any accelerated repopulation of the tumor that may be occurring. These schemes are often accompanied by increased morbidity. Ultimately abetter understanding of the molecular and cellular events involved may give rise to measures that will allow us to compensate for accelerated repopulation in tumors or to induce repopulation in normal tissues earlier in a course of therapy in order to minimize treatment related morbidity. 

Dorr W, Kummermehr J. Accelerated repopulation of mouse tongue epithelium during fractionated irradiations or following single doses. Radiother Oncol 1990 17(3) 249-259. 

Unfortunately, none of the seven randomized trials that have compared radiation therapy alone vs neoadjuvant cisplatin-containing chemotherapy plus radiation therapy demonstrated an improvement in overall or disease-free survival with combined-modality therapy (Table 2). Two studies actually demonstrated poorer survival with neoadjuvant chemotherapy. Souhami et al. (15) reported a significantly poorer survival rate with neoadjuvant chemotherapy in a small trial of patients with stage IIIB disease. This outcome was partly due to increased toxicity and poor compliance in patients who received chemotherapy. Another trial of neoadjuvant epirubicin and cisplatin was closed early when interim analysis revealed a significantly higher recurrence rate in the chemotherapy arm (16). These trials fail to provide any evidence that sequential cisplatin-containing chemotherapy and radiation therapy are of benefit. Possible explanations for the disappointing results include the effects of chemotoxicity, altered compliance, and possible accelerated repopulation of resistant clones after neoadjuvant chemotherapy. 

Under such conditions, despite a response to chemotherapy, cell survival after radiotherapy is no better than after the same course of radiotherapy alone (yet toxicity results from both modalities). Accelerated repopulation has also been described after treatment of murine breast tumors with sequential, weekly cycles of 5-fluorouracil and cyclophosphamide (Wu and Tannock 2003). 

Tumour Microenvironment and Accelerated Repopulation of Tumour Stem Cells 294... 

The effective cell doubhng time is determined by the rate of cell production and cell loss. Therefore, accelerated repopulation of tumour stem cells during radiotherapy could result from an increased production rate or reduced stem cell loss. 

While changes in microenvironment appear to passively affect repopulation, it has been postulated that an active regulatory element is involved in triggering accelerated repopulation in tumours. This view is supported by similar repopulation kinetics in squamous cell carcinomas and normal epithelium where reoxygenation is unlikely to contribute to accelerated repopulation. Several studies indicate a role of signalling via epidermal growth factor receptor (EGFR). 

In experimental studies, inhibition of EGFR by monoclonal antibodies has been shown to inhibit accelerated repopulation during fractionated irradiation. 

In a large variety of advanced carcinomas curative radiotherapy is combined with chemotherapy. Experimental observations and some clinical studies indicate that chemotherapy as a single modality can induce accelerated repopulation in tumours (reviewed in Davis and Tannock 2000 Kim and Tannock 2005). Induced repopulation by induction chemotherapy may possibly explain the inferior results of induction chemotherapy before radiotherapy compared with concurrent chemo-radiation in patients with non-small cell lung cancer (Fournel et al. 2005 Furuse et al. 1999 Zatloukal et al. 2004). 

Prolongation of overall treatment time has an adverse effect on outcome after fractionated radiotherapy. Accelerated repopulation of tumour stem cells during therapy, as the most likely explanation of this so-called time factor, is an established mechanism of treatment resistance. Understanding the underlying mechanisms and molecular regulation of accelerated repopulation resulted in successful therapeutic interventions. However, further investigations into accelerated repopulation in the context of combined treatments and into the clinical benefits of dose-dense chemotherapy without irradiation are necessary. 

Kummermehr J, Dorr W, Trott KR (1992) Kinetics of accelerated repopulation in normal and malignant sqimmous epithelia during fractionated radiotherapy. BJR Suppl 24 193-199... 

Suwinski R, Bankowska-Wozniak M, Majewski W, et al (2008) Randomized clinical trial on 7-days-a-week postoperative radiotherapy for high-risk squamous cell head and neck cancer. Radiother Oncol 87 155-163 Thames HD, Ruifrok AC, Milas L, et al (1996) Accelerated repopulation during fractionated irradiation of a murine ovarian carcinoma downregulation of apoptosis as a possible mechanism. Int J Radial Oncol Biol Phys 35 951-962 Trott KR, Kummermehr J (1991) Rapid repopulation in radiotherapy a debate on mechanism. Accelerated repopulation in tumours and normal tissues. Radiother Oncol 22 159-160... 

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