Sequencing of drugs and radiation. The integrated alternating regimen

Abstract

The association of radiotherapy (RT) and chemotherapy (CT) constitutes one of the main avenues for research in therapeutic oncology. This association has two aims: (1) increase in control rate of primary tumor (this requires either the potentiation of one of the two modalities by the other or the additivity of their effect on tumor cells without a parallel increase in the toxic effects on critical normal tissues); (2) spatial cooperation (RT being used for the control of the primary tumor or of the sanctuaries, and CT for the control of the disseminated disease). In these two strategies, RT and CT should be given up to full doses in order to be effective. The main risk is an increase in the number and severity of the early and late side effects. To circumvent this problem, two possibilities are being explored: (1) use of drugs without serious toxic effects on those critical tissues which are included in the irradiated volume; and (2) avoidance of concomitant administration and introduction of a sufficiently long‐time gap between the completion of one modality and initiation of the other. However, in such sequential treatment, a delay of CT until after the completion of RT, or an interruption of CT cycle during the course of RT, allows the occult metastases to increase in size; a similar delay in initiation of RT is also detrimental, as drugs are often not effective on bulky tumors. Moreover, under CT, the cells which are resistant to the cytotoxic drugs may disseminate and initiate chemoresistant metastases. Taking these disadvantages into account, a treatment protocol was proposed in 1980 in which CT and RT are given alternately, without undue delay. Chemotherapy is started with the usual scheduling of one cycle every month. Radiotherapy courses are interdigitated between CT cycles. Each course is initiated 1 week after interrupting CT and continued until 1 week before beginning the subsequent cycle of chemotherapy, and so on until completion of RT. Such split‐course RT should have an effect on a tumor comparable to that of a conventional fractionation. This protocol has been used on 24 patients with non‐Hodgkin's lymphoma (NHL) of diffuse histology, and 63 patients with small cell carcinoma of the lung. The 2‐year relapse‐free survivals are promising (in clinical stage II NHL of diffuse histology, 75%; and in small cell lung carcinomas, 33%). The early and late tolerances are satisfactory and no untoward complications have been observed.

Analysis and comparison of multimodal cancer treatments

“…Furthermore, under the additional condition that vascularization of dormant metastatic tumors does not occur within the first R ( 40) days after surgery, then SRCR is optimal over all possible schedules that employ surgery, R days of radiotherapy and C days of chemotherapy. A noteworthy feature of of this result is its simplicity: one only needs to split radiotherapy into two disjoint segments to attain optimality, and more sophisticated strategies, such as the integrated alternating regimen in [63], need not be considered. A second interesting aspect of this result is that SRCR has the same cure probability in our model as a SR 1 C policy that employs R 1 < R time units of radiotherapy.…”

Experimental and clinical studies alternating chemotherapy and radiotherapy

“…In order to reconcile the needs for early administration of both agents and for delivery, without a long interruption of one of the two modalities, an alternating treatment schedule was developed in which CT and RT are inter-digitated [2,3]. CT is initiated without any delay, and the interval between the successive cycles is, as usual, about 4 weeks.…”

“…The clinical investigations at the lnstitut Gustavc Roussy at Villejuif were developed simultaneously but independently from the experimental studies [1][2][3][4][5][6][7][8][9][10]. Alternating RT and CT was based on two clinical observations.…”