Multiple drug chemotherapy combined with multiple fractions per day (MFD) radiotherapy in an experimental solid tumor model.

A series of multi-drug chemotherapy studies combined with multi fractions per day (MFD) radiotherapy have been carried out in an experimental solid tumor model to provide information on how drugs contribute in combinations, both for effect on tumor and with regard to host toxicity. Twenty-five different combinations of cyclophosphamide (CP) and 5-fluorouracil (FU) were evaluated in this initial study. All tumors received a total dose of 6000 cGy of radiation given in multiple fractions per day for three courses one week after combined chemotherapy. Doses of each drug in the combinations ranged from 25 to 100% of the LD10 (150 mg/kg or .9 mg/m2) of each drug when given as a single agent. Proportional hazards analysis of the survival data yielded optimal doses of 132.8 mg/kg FU and 115.0 mg/kg CP, that is, approximately 3/4 of the LD10 of each drug in the combination. The group close to the optimum combination had a median GD of 295.3 days. Among the 5 rats in this group there were 4 partial responses and 1 cure for a 100% response rate. Excessive toxicity occurred in the group given the highest doses of FU and CP along with the 6000 cGy radiotherapy. These experimental cancer treatment studies in well defined solid tumor models demonstrate how the quantitative inter-relationship between anti-tumor effects and host toxicity to tumor burden and total therapeutic dose chemotherapy (single or multiple combinations) and radiotherapy alone or in combination can be obtained. These major determinants on treatment outcome are difficult or impossible to determine in clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Relationship of tumor regrowth to tumor cell survival, tumor cure rates and host survival in a solid tumor model following combined chemotherapy and radiotherapy.

Endpoints available for comparison of two or more treatment arms in a clinical cancer trial include response rates (complete and partial), time to progression, and patient survival. In experimental systems, similar endpoints are available (tumor cell survival, tumor regrowth, tumor cure rates, and host survival), but there is opportunity for more precise measurements and a wider range for varying the independent variables. Radiotherapy alone was compared with an alternating schedule in which both radiotherapy and cyclophosphamide (CP) were given intermittently for a total of 3 courses of each. Radiotherapy was given as multiple, 250 cGy fractions per day (MFD) in 2-day courses. Cyclophosphamide alone (3 x 150 mg/kg) was equivalent in tumor effect to 3600 cGy of irradiation given with the MFD schedule. The experimental points for the combined modality treatments fell along the lower edge of the zone of additivity. Exprapolation of the plots of log surviving fraction vs. total radiation for the combined treatment predicted a 37% cure rate at 6000 cGy + CP. There was a high probability for long term control and tumor cures only with the highest total doses of radiation (6000, 7000 and 8000 cGy) when combined with CP. The results obtained in well defined experimental tumor models provide quantitative information of the interrelationship of the major determinants on end results of the effectiveness of treatment and acceptable host toxicity of combined chemotherapy and radiotherapy. The quantitative evaluation of these major determinants on treatment outcome in relationship to host toxicity is often difficult or impossible to obtain in clinical host toxicity is often difficult or impossible to obtain in clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Rationale for different chemotherapeutic and radiation therapy strategies in cancer management.

The two primary therapeutic strategies in cancer have been to give either chemotherapy and radiation therapy together or give a complete course of one treatment modality before starting the second. Clinical studies show that toxicity has been one of the major deterrents to substantial improvements in cancer management when the two modalities are administered together. On the other hand, the prolonged time necessary to administer all of one modality followed by the other makes it likely that repopulation of the tumor during sequential treatment will diminish therapeutic effectiveness. A third strategy of giving chemotherapy and radiation therapy has been developed. This new regimen was designed to give chemotherapy initially, maintain the chemotherapy schedule to avoid any reduction in its effectiveness, and add radiation therapy as early as possible in between courses of chemotherapy to minimize the development of cross resistance. One of the primary objectives of alternating chemotherapy and radiation therapy is to increase the therapeutic index by reducing toxicity without a significant reduction in therapeutic effectiveness. Recent clinical, experimental, and theoretic results with radiation therapy and chemotherapy for cancer management emphasize the necessity of giving both modalities with the greatest intensity possible in the initial phase of induction therapy. Cancer treatment scheduling determines the toxicity and thereby limits the dose intensity that can be tolerated. Scheduling may also govern the antitumor effect directly; however, normal host tissue makes the determination of the direct effects on the tumor difficult, if not impossible, in clinical studies. Well-defined experimental solid-tumor systems provide the means for determining directly the relationship between toxicity and antitumor effects in relation to tumor burden and total therapeutic dose. In addition, its relationship to dose intensity and scheduling can be determined by the using more sophisticated research techniques, such as response surface methods. Well-defined clinical protocols to determine how to interact chemotherapy with radiation therapy more effectively hold considerable potential for rapid improvement in treatment of radiosensitive and chemosensitive cancers.

Integration of chemotherapy in an MFD--radiotherapy plan for advanced inoperable squamous cell carcinoma of the head and neck.

From January 1987 to May 1988, 16 patients with advanced squamous cell carcinoma of the head and neck received combined treatment, based on an alternating schedule of chemotherapy and multiple fractions per day (MFD)-radiotherapy. The chemotherapy regimen consisted of cisplatin, 20 mg/m2, followed by 5-fluorouracil (5-FU), 200 mg/m2 i.v. push, from days 1 to 5 during weeks 1, 5, and 9. Radiotherapy was administered in two courses of 32 Gy each (total dose, 64 Gy) during weeks 2 and 3 and 6 and 7. Each course was given in two fractions per day, 5 days per week. The 16 patients were evaluated for toxicity and response. We observed 7 complete responders, 6 partial responders, and 3 nonresponders. The overall response rate was 81%. Toxicity was heavy: 44% of the patients developed grade III-IV mucositis. Our results suggest that cisplatin and 5-fluorouracil alternating with MFD-radiotherapy is effective; however, a new less toxic scheduling must be determined.

Experimental and clinical studies alternating chemotherapy and radiotherapy.

Clinical and experimental results with radiotherapy and chemotherapy for the treatment of cancer emphasize the necessity of giving treatment with both modalities with the greatest intensity possible in the initial phase of induction therapy. This can best be accomplished by utilizing new approaches, such as alternating the chemotherapy with newer methods of delivery of radiotherapy, which has the potential for greater destruction of tumor within acceptable limits of host toxicity. The clinical data from Institut Gustave Roussy, Villejuif, shows that alternating chemotherapy and radiotherapy produced an excellent complete response rate of 79% and a 4 year relapse-free survival rate of 22% in 109 patients with limited small cell lung cancer. Based on 5 year survival criteria, approximately one-fourth of the patients can be considered cured in 1 more year if no further change occurs. The results of the University of Virginia experimental studies have also demonstrated the superiority of alternating cyclophosphamide and radiotherapy in three courses of induction therapy over conventional methods of delivery of the two modalities. Using the experimental solid tumor 3924A, a cure rate of 50% or greater was obtained with this protocol with acceptable toxicity to the host, as opposed to no cures from three or more courses of either modality alone. One of the major deterrents to tumor cure with concomitant chemotherapy and radiotherapy has been excessive toxicity, which can be avoided by temporal separation (+/- 7 days) of the delivery of the two modalities without a significant loss of therapeutic effectiveness. Well-defined clinical protocols to determine how to more effectively interact chemotherapy with radiotherapy offer some of the greatest potential for a more rapid improvement in treatment.

Administration of radiation or cyclophosphamide versus alternated radiation and cyclophosphamide treatment of primary tumor and pulmonary metastases.

The experimental tumor 3924A in ACI rats metastasizes to the lungs, but this is rarely apparent unless the life span of the animal is increased by treatment of the tumor. Pulmonary metastases were prevalent among animals given radiation daily or in multiple fractions per day over periods of 3-4 weeks at total doses ranging from 3,000 to 11,250 rad. Multiple doses of cyclophosphamide, each at the level that was lethal to 10% of the animals, did not cure the primary tumor but appeared to delay the appearance of metastases. Treatment schedules that alternated the delivery of multiple 250-rad fractions of radiation during 2-day periods with cyclophosphamide at a dose of 150 mg/kg for a total of three courses were effective in curing the primary tumor and eliminating pulmonary metastases.

Alternating chemotherapy and radiotherapy.

The more effective utilization of well-established chemotherapeutic agents with radiotherapy can be brought to clinical use more rapidly and with greater efficiency than can new agents. New therapeutic approaches to improving cancer treatment will most likely be coordinated with either chemotherapy or radiotherapy or combined chemotherapy and radiotherapy. The results of experimental, theoretical, and clinical studies suggest that the potential for the greatest progress over the shortest period of time in the clinical management of tumors responsive to both treatment modalities lies in the more effective interaction of well-established chemotherapeutic agents with newer radiotherapy schedules in which large amounts of radiation can be delivered between the courses of chemotherapy and temporally separated to minimize toxicity without loss of therapeutic effectiveness. The experimental and theoretical studies reinforce the basic tenets first demonstrated in the clinical management of Hodgkin's disease. This provides the medical framework for more rapidly exploiting the concepts of alternating chemotherapy and radiotherapy in tumors responsive to both treatment modalities and brings options into sharper focus. 1) Either the doses given in radiotherapy or chemotherapy can be increased or the time between treatment modalities or between courses can be decreased. 2) Experimental, theoretical, and clinical results to date provide a rational basis for clinical protocols designed to determine the most effective utilization of these two primary means of cancer management.

Solid tumor models for the assessment of different treatment modalities: XXVI. Estimates of cell survival from tumor growth delay after alternating radiotherapy and chemotherapy.

The doubling time (Td) for hepatoma 3924A in ACI rats is relatively constant between different treatments when growth resumes after treatment with either chemotherapy or radiotherapy. Advantage was taken of this to estimate the fraction of surviving cells (SF) from in vivo growth delay (GD) data using the expression SF = 1/2GD/Td. Survival curves were constructed for several recently published treatment schedules which employed alternating radiotherapy and chemotherapy, and for both daily and multiple fractions per day (MFD) radiation schedules. A doubling time of 5.2 days was assumed, in the range observed for control and regrowing treated tumors, which yields one surviving cell at the TCD37 (3650 cGy single dose). The single fraction, multi-target, single hit model, SF = 1 - (1 - e-D/D0)n with D0 = 406 cGy and n = 1.63 is a reasonable representation of the data over the dose range 375-2250 cGy. The D0 of 406 cGy should be considered as a relative, not absolute value which is dependent on the radiosensitivity of the tumor cells and the accuracy of the doubling time, but is useful in relating the single dose data to more complex radiation schedules. Using D0 = 406 cGy, n = 1.63, and f = number of fractions, the multi-fraction, multi-target, single hit model SF = (1 - [1 - e-D/D0]n)f closely fits our data for 30 daily fractions given at 100 to 375 cGy/day for total radiation doses of 3000 to 11,250 cGy. The fraction of surviving cells for daily radiation alternated with three courses of cyclophosphamide (CP) was in good agreement with an additive effect of the two modalities at radiation doses of 3000 to 5640 cGy. Multiple fractions per day radiation given as 250 cGy fractions was more effective than predicted by the model both when given alone or alternately with cyclophosphamide.

Solid tumor models for the assessment of different treatment modalities: XXV. Comparison of the effect of one radiation fraction per day with multiple fractions per day (MFD) given either continuously or intermittently on tumor response and normal tissue reaction.

A series of experimental studies has been carried out to assess the relationship between the effectiveness of tumor control, normal tissue reaction and median survival following different radiation fractionation schedules on the solid tumor model 3924A in the ACI rat. The total radiation dose of 7500 rad and the dose per fraction of 250 rad were held constant. Tumor control and life expectancy improved with 250 rad given continuously as multiple fractions per day (MFD) (1, 2 and 3 fractions per day over 30-, 15- and 10-day periods, respectively). However, the maximum acute skin reaction surrounding the tumor was greater for MFD given continuously than for single daily fractions. We have also completed studies of the therapeutic effectiveness of MFD given intermittently at 11-day intervals. Tumor control following MFD given intermittently was comparable to that following the daily fraction schedule given continuously, and the normal tissue reaction was acceptable at a total radiation dose of 7500 rad. Experimental and clinical results in head and neck cancer indicate that large total radiation doses in the order of 7000 rad given as continuous MFD are associated with unacceptable normal tissue reaction. However, these clinical and experimental results also indicate that large total radiation doses can be given as MFD intermittently and effectively used in cancer management. The marked superiority of alternating chemotherapy and radiotherapy in obtaining a tumor cure rate of greater than or equal to 50% in our experimental system and the superiority of alternating chemotherapy and radiotherapy in extensive Hodgkin's disease (complete response rate--87%) over chemotherapy alone, radiotherapy alone, or the two modalities given together or as split course provides the clinical and experimental basis for the development of more effective protocols in the treatment of tumors responsive to chemotherapy and radiotherapy. A complete response rate of 78% in patients with head and neck cancer, and a complete response rate of 89% in patients with limited small cell carcinoma of the lung using alternating chemotherapy and radiotherapy indicate that it is now possible to proceed rapidly in clinical protocol design for these two additional tumors responsive to both chemotherapy and radiotherapy.

Solid tumor models for the assessment of different treatment modalities: XXIII. A new approach to the more effective utilization of radiotherapy alternated with chemotherapy.

This study with the rat hepatoma 3924A demonstrated the marked improvement in tumor cure rates and control of tumor growth that can be achieved by the addition of cyclophosphamide (CP) to multiple fractions of radiation per day (MFD) schedules given intermittently. MFD radiation was delivered over a 2-day period followed by CP (150 mg/kg or 0.9 g/m2) 1 day later; this combined course was repeated at 11-day intervals (to allow for gastrointestinal tract and bone marrow recovery) for a total of 3 courses over a 23-day period. Cure rates of 30, 50 and 60% were achieved with total radiation doses of 4500, 6000 and 7500 rad, respectively, when the MFD radiation was given with CP. No cures and no complete responses were realized when the same intermittent MFD schedules for radiation were employed up to 9000 rad without CP. Other groups of 10 animals each were treated with daily fractions of 100, 150, 188, 250 and 375 rad given on days 0-9, 11-20 and 22-31. A 150 mg/kg or 0.9 g/m2 dose of CP was given after each course of daily radiation on days 10, 21 and 32 in the combined treatment groups. No complete responses or tumor cures occurred with radiation alone given daily for total radiation doses, which were increased from 3000 to 11,250 rad. Only the highest radiation dose given, 375 rad per day to a total of 11,250 rad, resulted in a complete response rate and tumor cure rate of 50% when CP was added. The addition of CP to the daily fractionation schedules reduced the total dose needed to give a growth delay of 100 days by 39% (5600 rad versus 9200 rad). The addition of CP to the intermittent MFD schedules further reduced the total dose needed to give a growth delay of 100 days to 4200 rad. Major improvements in some types of cancer treatment may be realized if we can develop clinical protocols for the alternate use of chemotherapy and radiotherapy as we have done successfully in our experimental program. The finding that intermittent MFD radiation schedules are as effective as daily schedules when given alone suggests that greater flexibility of patient management in clinical radiotherapy may be possible without a major loss of therapeutic effectiveness. These alternated fractionated schedules offer the possibility of optimizing treatment in terms of patient convenience and economy as well as the potential for improving the effectiveness of the interaction of radiotherapy with radiosensitizers, radioprotectors, and hyperthermia in addition to chemotherapy.

Solid tumor models for the assessment of different treatment modalities. XXII. The alternate utilization of radiotherapy and chemotherapy.

Major increases in the time between administration of two modalities, radiation and cyclophosphamide (CP), from 1 to 7 days and in the overall time of delivery of 3 courses of combined therapy from 24 to 35 days were carried out in rats with hepatoma 3924A without major loss of therapeutic effectiveness. Cure rates of 50% or greater could be maintained even though treatment was given over much longer time periods. The radiation was given as hyperfractionated, split-course schedules which were devised by increasing the number of 250 rad fractions over a 2-day period. In one series of experiments these 2-day schedules were given at 11-day intervals for 3 courses on days 0 and 1, 11 and 12, 22 and 23; and CP (150 mg/kg) was given 1 day after each of the 3 radiation courses on days 2, 13, and 24. In the second series of experiments radiation was given on days 0 and 1, 14 and 15, 28 and 29; and this was alternated with 3 single doses of CP given 1 week after each of the 3 courses of radiation, on days 7, 21 and 35. Increasing the total radiation dose from 6000 to 7500 rad in the series given CP 1 day after each of three courses of radiation results in an increase in total tumor cure rates from 50% to 60%. The tumor cure rate in the series given CP 7 days after radiation increased from 10% to 70% when the total radiation dose was increased from 6000 to 7500 rad. Increasing the total radiation dose from 6000 to 7500 rad increased the magnitude of the acute skin reaction as well as the duration of recovery. However, the skin reactions for both the 6000 and 7500 rad were acceptable. Host toxicity and normal tissue reaction were within acceptable limits for both modalities. The results of these studies, therefore, indicate that excessive toxicity, one of the major deterrents to the effective combined utilization of these two primary means of cancer management, may be avoided by temporal separation of delivery while maintaining tumor cure rates of 50% or greater.

Tumour-cord parameters in two rat hepatomas that differ in their radiobiological oxygenation status.

Tumour cords have been examined quantitatively in two rat hepatomas, 3924A and H-4-II-E, that differ in their radiobiological oxygenation status (oxygen enhancement ratio for growth delay [tumour clamped: tumor 'in air'] was 1.35 for 3924A and only 1.08 for H-4-II-E). The average thickness of tumour cords in 3924A was 118 microns and only 69 microns in H-4-II-E. The migration rates across the cords of the two tumours were approximately the same (1.7 and 1.4 micron X h-1) but for any given distance from the subtending blood vessel, the proportion of histologically-dead cells within the cord was always higher for H-4-II-E. Volume for volume, H-4-II-E contained four times as much vascular space as 3924A but it is suggested that the poor quality of this vasculature in H-4-II-E contributed to its relative radioresistance.

Solid tumor models for the assessment of different treatment modalities. XXI. Comparison of different radiation dose schedules alone or in combination with cyclophosphamide.

Total radiation (4500 rad) and cyclophosphamide doses (450 mg/kg or 2.7 g/m2) were held constant over a 24-day period in rat hepatoma 3924A using radiation schedules in which 1500 rad were given over a 1- to 2-day period in 1-8 fractions, repeated at 11-day intervals, with or without cyclophosphamide. Reducing the rad per fraction resulted in a reduced incidence of complete tumor response and tumor cures, and a reduction in the magnitude of skin response. Cure rates were 40, 10, 0, and 0%, respectively, for the 1500, 750, 500, and 250 rad per fraction groups without cyclophosphamide. When the 1500, 750, 500, 375, 250, and 188 rad per fraction groups were given 150 mg/kg cyclophosphamide day 1 after radiation, major increases occurred in tumor cures, with the cure rates being 80, 80, 80, 70, 60, and 50%, respectively. The addition of cyclophosphamide did not significantly alter skin reaction to radiation. The higher rad per fraction schedules were more effective in controlling metastatic dissemination when radiation was used alone. The addition of cyclophosphamide markedly reduced metastatic dissemination in both high and low-dose per fraction schedules. Optimal treatment levels were estimated from analysis of fitted response surfaces, and the quantitative interrelationship between normal tissue reaction, probability of tumor cure, and associated relative hazard to the host estimated from the results of these analytical methods. Hyperfractionated radiation dose schedules with dose/fraction in the clinical range combined with cyclophosphamide can significantly increase the therapeutic ratio and prevent metastatic dissemination compared with radiation alone as a result of the increased effectiveness of combined modality therapy on the tumor, without a concomitant increase in normal tissue reaction.