Complications of combined radiotherapy and chemotherapy

Complications of Combined Radiotherapy and Chemotherapy Hans vonder Maase The radiation-modifying effect of cancer chemotherapeutic drugs is reviewed based on experimental studies covering skin, esophagus, intestinal tract, lungs, kidney, bladder, testis, and hematopoietic tissue. The results obtained in experimental studies have, whenever possible, been compared with observations of normal tissue reactions in clinical practice. Such a comparison of experimental and clinical data is difficult and should be cautiously interpreted. However, where comparable data are available there seems to be a reasonable agreement between experimental and clinical data. It appears that drugs with an effect on the tissue by itself should especially be expected to enhance the radiation re-

sponse in that specific tissue. Concerning the importance of the intervals and sequence of the two treatment modalities, experimental data seem to indicate the effect of timing in clinical practice, The best way to avoid enhanced reactions in normal tissues is to separate the two treatment modalities in time and, possibly, to administer chemotherapy before radiotherapy. Experimental data should be cautiously considered, together with clinical experience, in planning of drug-radiation combinations to avoid unacceptable reactions in critical normal tissues. Guidelines for the clinical use of combined radiotherapy and chemotherapy are proposed. Copyright 9 1994 by W.B. Saunders Company

he objective of combining radiation treatment and cancer chemotherapeutic drugs is to obtain a therapeutic gain either by an improved tumor response with less or no enhancement of the toxicity or by a reduced toxicity with less or no diminution of the tumor response. Such a therapeutic gain may be achieved by one of four potentially exploitable modes of actionl,2: (1) Enhancement of tumor response. A therapeutic gain by enhancement of tumor response in excess of the enhancement of normal tissue damage has been shown in experimental studies but this is not a common observation in the clinical application of combined radiotherapy and chemotherapy. (2) Normal tissue protection. Normal tissue protection has been observed in a few experimental studies but has, so far, had no clinical implications. It should be emphasized that a therapeutic gain obtained by normal tissue protection would require that the tumor cells are not similarly protected. (3) Independent cell kill. A therapeutic gain can only be achieved if the toxicities of the drugs and the radiation treatment do not overlap. There are examples of a therapeutic gain obtained by independent cell kill but, generally, toxicity independence should not be expected. (4) Spatial cooperation. This mode of action indicates that the two treatment modalities affect different tumor sites and represents the most

common mode to achieve a therapeutic gain in the clinical use of combined radiotherapy and chemotherapy. Thus, spatial cooperation and, to a lesser degree, independent cell kill rather than the true interactive mechanisms are the modes of action that are most likely to lead to a therapeutic gain in clinical practice. However, this is only attainable if critical normal tissue damage is not enhanced. Otherwise, it is impossible to apply an optimal radiation treatment and an optimal cancer chemotherapeutic regimen for the disease in question. Therefore, knowledge about critical normal tissue reactions is essential for a rational application of combined radiotherapy and chemotherapy. Normal tissue reactions following combinations of radiotherapy and chemotherapy depend on several factors such as the specific drug and drug dose, the radiation dose, dose rate and fractionation regimen, the time intervals and sequence of the two modalities, and the specific tissue in question. Thus, the possible modes of interaction are numerous and difficult to evaluate in clinical studies and, therefore, most detailed knowledge about the combined effects of radiotherapy and chemotherapy is derived from experimental studies. These studies most often use single doses of drugs and radiation in mice and may seem far removed from clinical practice. On the other hand, the qualitative implications of these experimental studies on normal tissue reactions are likely to apply also in fractionated clinical therapy. The normal tissue reactions in humans will of course not be quantitatively similar to the results from experimental studies. However, it seems possible, qualitatively, to point to combined schedules bearing a risk of increased toxic-

T

From the Department of Oncology, and the Danish Cancer Society, DepartmentofExperimental ClinicalOncology,Aarhus UniversityHospital, Aarhus, Denmark. AdAre~ reprint requeststo Hans vonder Maase, MD, Department of Oncologv,Aarhus UniversityHospital, 8000Aarhus C, Denmark. Copyright 9 1994 by W.B. Saunders Company 1053-4296/93 / 0402-0004$05.00/ 0

Seminars in Radiation Oncology, Vol 4, No 2 (April), 1994:pp 81-94

81

82

Hans yon der Maase

ity in humans based on reactions in experimental studies. In this article, experimental data in selected normal tissues are reviewed and evaluated with respect to the clinical implications to deduce general guidelines regarding the clinical use of combined radiotherapy and chemotherapy.

Experimental Studies The effect of chemotherapy in combination with radiotherapy was evaluated as enhancement, no effect, or protection. The term enhancement indicates that the combined effect was significantly more pronounced and the term protection indicates that the combined effect was less pronounced than that of radiation alone. It has not been attempted to evaluate whether the combined effects were supraaddirive, additive, or subadditive because these terms require analysis of data by the isobologram approach} ,3 which is not possible in most studies of normal tissue reactions. The degree of enhancement was evaluated as minor (+), moderate ( + + ) or pronounced (+ + +), whereas the degree of protection has not been quantified. The conclusion as to whether the effect of a drug was classified as enhancement, no effect, or protection, and the degree of enhancement was based on an overall evaluation of all available experimental data. Admittedly, it is difficult to compare different studies using different animal strains or even different species, ie, mice, rats or, in few studies, pigs, different drug-radiation regimens, and different endpoints, even when assessing injuries in the same normal tissue. This means that an overall evaluation necessarily involves a subjective interpretation and priority of results from different studies. This has been done as cautiously as possible and important contradictory results have been indicated. The degree of enhancement was, whenever possible, evaluated from the dose effect factor (DEF) defined as the radiation dose required to produce a specific effect when given alone relative to the radiation dose required to produce the same effect when combined with a drug. Generally, minor enhancement (+) indicates DEF values below 1.2, moderate enhancement ( + + ) indicates DEF values between 1.2 and 1.4, and pronounced enhancement (+ + +) indicates DEF values above 1.4. Concerning the importance of the sequence and intervals between the two treatment modalities, simultaneous treatment was defined as drug administration within 24 hours before or after irradiation

and nonsimultaneous treatment as 3 or more days before or after irradiation. It should be noted that the radiation-modifying effect of drugs within the interval of 24 hours before to 24 hours after irradiation may vary considerably (an example is shown in Fig [). Such an extreme time dependency is of obvious interest from an experimental point of view and may suggest different mechanisms responsible for the drug-radiation interactions. From a clinical point of view, such variations within a few hours of drug administration may be responsible for differences in the observed toxicity among patients but are virtually impossible to evaluate in clinical practice. The variations at longer drug-radiation intervals seem to be less pronounced (Fig 1) although studies

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CombinedRadiotherapy and Chemotherapy

on drug-radiation intervals beyond 3 and especially beyond 7 days are sparse. Most of the referred experimental studies were done on mice. The drug doses used in these studies generally represented the maximum tolerated dose (MTD) which, although defined in different ways, normally was the dose that would kill approximately 1% of the mice within the assay time. These drug doses are not necessarily relevant for clinical use. However, for comparison of the drug-modifying effect in studies using different drug doses, priority has been given to results obtained at the MTD. The radiation treatment has been applied as single doses in most studies, which is not particularly relevant for clinical practice. Fractionated experimental studies may elucidate factors of importance for drugradiation interactions. However, it is not clear whether fractionated regimens are superior to single dose studies for the qualitative prediction of combined effects in clinical therapy. Nearly all investigations have used high dose rate irradiation but a few data on drugs combined with low dose rate irradiation, which may be of great clinical importance, are presented here. The review of experimental studies on normal tissues covers skin, esophagus, intestinal tract, lungs, kidney, bladder, testis, and hematopoietic tissue. Previous reviews of experimental normal tissue data include the articles by Phillips and Fu, 4 Steel, 2 and v o n d e r Maase. 5,6 Two recent reviews on experimental tumor data, a topic not covered here, are by Steel 2 and Hill] Skin Early normal skin tissue reactions are most often evaluated by use of the mouse foot skin scoring system based on the degree of erythema and moist desquamation as first described by Fowler et a l / A s indicated in Table 1, many drugs have been shown to enhance radiation-induced skin reactions. The radiation-modifying effect has in most cases been minor or moderate and, if so, generally been observed with drug administration simultaneously with or a few hours before radiation. Actinomycin D and doxorubicin have also been shown to enhance the radiation response when administered 72 hours after fractionated irradiation.U Cyclophosphamide has resulted in a protective effect when administered immediately before or after irradiation in one study 12or from 1 to 2 days before irradiation in another study. 2~ On the other hand, cyclophosphamide had no effect on the radiation response in two other studies} ~ The

83

Table 1. Effects on the Radiation Response in Normal Skin of Drugs Administered Before, Simultaneously With, or After Irradiation

OverallEffect*for Drug Administrationi" Drug

Before With After

Actinomycin D 0 Doxorubicin 0 BCNU Bleomycin 0 C/s-platinum 0 Cyclophosphamide - / 0 5-fluorouracil 0 Hydroxyurea Melphalan Methotrexate 0 Mitomycin C 0

+ + + ++ + -/0 0 + 0 + +

+ 0/+ 0 0 0 0 0 0

References 9-11 5, 9-12 13 5, 10, 12, 14-16 5, 12, 17-19 5, 10, 12,20,21 5, 12 15 22 5, 10, 12, 15, 23 5, 12

*0, no effecton radiation response; +, enhancement, ie, combined effect more pronounced than that of radiation alone, + minor, ++ moderate, + + + pronounced; - , protection, ie, combined effect less pronouncedthan that of radiation alone. %imultaneous treatment is defined as drug administration within 24 hours before or after irradiation and nonsimultaneous treatment as 3 or more daysbefore or after irradiation. Important contradictory results are indicated in the table and specifiedin the text. possible radioprotective effect of cyclophosphamide is interesting with respect to underlying mechanisms of the drug-radiation interactions but overall this is probably of no major clinical significance.

Esophagus Phillips et a124 have investigated a series of drugs administered 2 hours before irradiation using the esophageal lethality endpoint. Most drugs resulted in a pronounced enhancement of the radiation response (Table 2). The conflicting results concerning the effect of actinomycin D were obtained by use of

Table 2. Effects on the Radiation Response in Esophagus of Drugs Administered Before, Simultaneously With, or After Irradiation

OverallEffectfor Drug Administration Drug Actinomycin D Doxorubicin BCNU Bleomycin C/s-platinum Cyclophosphamide Vincristine

Before 0

With 0/+ + + +++ ++ + +++ -/0 0

After References 24, 25 26 25 24, 25 25 24, 25 25

NOTE. For definitionofoveralleffectand time ofdrug administration, see Table 1.

Hans vonderMaase

84

different drug doses. Actinomycin D resulted in a DEF of 1.6 at a dose exceeding the MTD, 25whereas the MTD had no effect on the radiation response. 24 Cyclophosphamide had a radioprotective effect in one study')4 but no significant effect in another. 25 Again, the possible radioprotective effect ofcyclophosphamide is probably of no clinical relevance. Sherman et a126observed that esophageal toxicity after doxorubicin combined with radiation depended on the dose rate. Thus, the DEF value was 1.5 at a dose rate of 70 rad/minute and 1.7 at a dose rate of 5 tad/minute. This enhancement of the radiation response was observed with drug administration 1 day before irradiation, whereas no effect was observed with drug administration 1 week before the radiation treatment. 26 Intestinal Tract Injuries to the gastrointestinal tract have been evaluated by the microcolony survival assay first described by Withers and Elkind 27 or by determining lethality within 5 to 7 days of total or partial body irradiation. 2s,29As shown in Table 3, nearly all investigated drugs enhanced the radiation response. The effect was generally most pronounced for simultaneous treatment. Enhancement of the radiation response for drug administration before or after irradiation was only observed in a few cases. Actinomycin D administered 2 days after irradiation resulted in a radiation-modifying effect similar to that for drug T a b l e $. Effects on the Radiation Response in the Intestinal Tract of Drugs Administered Before, Simultaneously With, or After Irradiation

OverallEffect for Drug Administration Drug Actinomycin D Doxorubicin BCNU Bleomycin C/s-platinum Cyclophosphamide Cytosine Arabinoside 5-fluorouracil Hydroxyurea Methotrexate Mitomycin C Vincristine

Before With A f t e r

References

0 + + 0 0

+ + ++ ++ + ++ 0 +++ 0 ++ +

24,30 5, 24, 30-37 24, 30, 32, 38 5, 24, 30, 37, 39 5, 18, 37, 40-43

0

0/+

0

5, 24, 30, 32, 44-46

0

0

0

++ + ++

0

+

0/+

0 0

47, 48 5, 30, 46, 49 50 5,32,46,51 5,37 30, 52

NOTE. For definition of overall effect and time of drug administration, see Table 1.

administration 2 hours before irradiation? 4 The effect of doxorubicin has been shown to disappear when the drug was given either 3 days before or 3 days after irradiation 5,37 and 7 days before irradiation? 4 On the other hand, Dethlefsen and Rileya4 and Schenken et a135 have shown that doxorubicin still enhanced intestinal tract toxicity evaluated by the lethality endpoint with drug administration 2 to 14 days34 and 14 to 49 days~5 before irradiation. This apparent discrepancy may be attributable to the use of different endpoints, ie, microcolony survival assay and lethality. Most studies with c/s-platinum have shown that the drug only enhanced the radiation response with simultaneous drug-radiation treatment. However, in one study, the effect of c/s-platinum was found to be nearly constant in the interval from 1 day before to 3 days after irradiation. 42 The reason for this different time dependency is not clear. Cyclophosphamide seems to be one of the few drugs with no or only minor influence on the radiation response. The contradictory results for vincristine represent a minor enhancement for drug administration 7 hours before irradiation 52and no effect for drug administration 2 hours 3~ or 1 minute before irradiation. 52 This may reflect different modes of action, but the difference is probably not important from a clinical point of view. Cytosine arabinoside is the only cancer chemotherapeutic drug that has been shown to protect against intestinal damage when given 12 hours before irradiation. 47,48 Pearson and Steel ~3 observed a totally different time dependency. They investigated several drugs in combination with pelvic irradiation evaluated by animal lethality within 30 days. However, lethality within 30 days is not a normal endpoint for injuries to the intestinal tract, and the results may represent a combination of toxicities. On the other hand, involvement of different normal tissues do simulate common clinical situations and the results are likely to be clinically relevant. The study showed that doxorubicin, CCNU (lomustine), c/s-platinum, cyclophosphamide, cytosine arabinoside, 5-fluorouracil, methotrexate, and VP-16 (etoposide) all enhanced the radiation response with the most pronounced effect for drug administration 3 days after irradiation. 5~The differences between our microcolony survival data 5,a7,46 and these lethality data ~3 are clearly shown and discussed in the review article by Steel. 2 The data are not included in Table 3 because the results may represent more than just intestinal tract toxicity.2,53

CombinedRadiotherapyand Chemotherapy

Nevertheless, these results are of obvious clinical importance. All the above mentioned studies have concentrated on acute toxicity, whereas only a few studies have investigated the effect of drugs on late radiation damage. The most throughly investigated drug in this respect is c/s-platinum. Dewit et a154and Julia et a155,56 have found no enhanced delayed radiation on late intestinal tract toxicity. 54-56 It is obvious that more studies of delayed toxicity are warranted. Lungs

Lung damage has been evaluated by either the lethality of mice following thoracic irradiation 28,57 or by the ventilation rate. 58~ As shown in Table 4, some drugs resulted in a pronounced enhancement of radiation-induced lung reactions, whereas other drugs had no effect at all. In cases where drugs enhanced the radiation response, this was generally most pronounced for drugs administered simultaneously with, and to a lesser degree, after irradiation. However, there are contradictory results. Thus, we found the most pronounced effect when bleomycin was administered near the time of the radiation treatment, still a moderate enhancement 3 days after irradiation but no effect 7 days before or after irradiation. 65 However, Collis et a166 found the radiation-modifying effect of bleomycin to be similar with drug administration 28 days before, simultaneously with and 28 days after irradiation. The reason for this discrepancy is not clear. Clinically, the most serious reacT a b l e 1. Effect on the Radiation Response in Lungs of Drugs Administered Before, Simultaneously With, or After Whole Thoracic Irradiation

OverallEffectfor DrugAdministration Drug

Berate With A3qer

0 ++ ++ Actinomycin D ++ +++ ++ Doxorubicin -BCNU 0/++ +++ 0/++ Bleomycin 0 / + + 0/+ 0 / + + C~-platinum ++ +++ + Cyclophosphamide Cytosine Arabinoside 0 5-fluorouracil 0 0 0 Hydroxyurea 0 0 0 0 Methotrexate 0 + 0 Mitomycin C + + + Vincristine

References 10,24,25,61,62 10,26,61,63-65 24 20,24,61,65,66 43,61,65 10, 24, 61, 65, 67, 68 61 65 24 10,61,65 65 24, 61

NOTE. Fordefinitionofoveralleffectand time ofdrug administration, see Table I.

85

tions have been observed for simultaneous administration of bleomycin and radiation. The time dependency of cyclophosphamide seems also to be more complex than shown in Table 4. 65,67 The results for doxorubicin administered before irradiation is not necessarily contradictory. We found a declining effect of doxorubicin when given before irradiation but still a moderate enhancement 3 days before irradiation, 65 and Peckham and Collis6z found no effect for drug administration 28 days before irradiation. C/s-platinum had no effect on radiation-induced lung reactions in two studies using single doses, 6~,~5 whereas Tanabe et al,43 using a fractionated schedule, found c/s-platinum to enhance the radiation response especially with drug administration 3 days before or after irradiation. This may be an example of the radiation-modifying effect of drugs being more pronounced when applied in fractionated regimens than in single dose studies. Sherman et aF 6 found that the radiation-modifying effect of doxorubicin in the lungs depended on the dose rate in the same way as for esophageal toxicity. Thus, the DEF value was about 1.6 at a dose rate of 70 rad/minute and about 2 at a dose rate of 5 rad/minute. 26 The results in Table 4 are based on whole thoracic irradiation, which from a clinical point of view is not that relevant. Therefore, Lockhart et a169have investigated a series of drugs in combination with right or left hemithoraeic irradiation with experiments capable of detecting a DEF value of 1.3 or more. All drugs were administered 45 minutes before irradiation. Cyclophosphamide enhanced the radiation response, whereas, in contrast to the whole thoracic irradiation data, doxorubicin had no effect when combined with hemithoracic irradiation. BCNU (carmustine) delayed the appearance of the ventilation rate response compared with radiation alone, whereas earboplatin, vincristine and vinblastine had no significant effect on the radiation-induced lung reactions. This use of hemithoracic irradiation may be clinically more relevant but may on the other hand overlook a drug-induced minor or moderate enhancement (DEF values below 1.3) of the radiation response in the lungs. Kidney The effect on renal function of radiation alone and drug-radiation combinations has been investigated following either renal irradiation or total body irradiation. BCNU 7~and c/s-platinum 7~ have been shown

Hans yon derMaase

86

to enhance renal damage when administered before, simultaneously with, and after renal irradiation compared with the effect of radiation alone (Table 5). Other investigated drugs have not been shown to enhance the radiation response (Table 5). Moulder and Fish 7~ investigated the effect of BCNU, c/s-platinum, and mitomycin C administered 3 months before total body irradiation followed by bone marrow transplantation. Both BCNU and c/splatinum decreased the renal tolerance of the drug compared with that following total body irradiation alone, whereas mitomycin C had no effect. 7~It should also be mentioned that BCNU and c/s-platinum in these experiments also decreased the gastrointestinal tolerance dose. 7~ C/s-platinum has also been investigated at long intervals of 3 to 12 months after irradiation. 77-79In these three studies, the renal tolerance to c/splatinum after previous renal irradiation was markedly reduced. This was shown both by a decreased LDso for c/s-platinum and by more severe late renal function damage. It was also shown that renal damage became more severe with increasing radiationdrug intervals. 77,78

Bladder Changes in bladder function after either radiation alone or drug-radiation combinations can be assessed by urination frequencs~~ or by cystometric analysis of the bladder volume capacity,re,s2 C/s-platinum has been shown to enhance both early83,84 and late response in the bladder. 83-85The minor enhancement of the early response was present with simultaneous treatment and for drug administration after irradiation, whereas the enhancement of the late response was more pronounced for drug administration before, simultaneouslywith, and after irradiation (Table 6). Cyclophosphamide enhanced both early84 and late radiation response, s4~ The effect of cyclophos-

Table 5. Effects on the Radiation Response in Kidney of Drugs Administered Before, Simultaneously With, or After Irradiation OverallEffectfor DrugAdministration Drug BCNU C/s-platinum Cyclophosphamide Cytosine Arabinoside Mitomycin C

Before With After References ++ ++ 0 0 0

++ ++

++ +++

0

0

70 70-76 76 76 70

NOTE.For definitionof overalleffectand timeofdrug administration, see Table 1.

Table 6. Effects on the Radiation in Bladder of Drugs Administered Before, Simultaneously With, or After Irradiation OverallEffectfor DrugAdministration Drug Cis-platinum (early response) C/s-platinum (late response) Cyclophosphamide (early response) Cyclophosphamide (late response)

Before W i t h After References 0

+

+

83, 84

++

++

++

83-85

+++

+++

+++

84

+++

+++

+++

84-88

NOTE.For definitionofoveralleffectand timeofdrug administration, see Table 1.

phamide was pronounced and independent of the timing of the drug-radiation combination (Table 6). From a clinical point of view, it is important that cyclophosphamide enhanced bladder damage even when administered 9 months before or after irradiation. 88 Lundbeck et a184 have investigated the relation between two different functional assays, ie, urination frequency and cystometry. Both assays were found suitable for investigation of early as well as late bladder damage. However, the DEF values obtained on the two assays were rather different for some combinations, showing the difficulties in comparing DEF values based on different endpoints. Furthermore, Lundbeck and Stewart 89 showed that the evaluation of acute bladder damage was significantly different in two strains of mice receiving drug alone, radiation alone, and following drug-radiation combinations. Such an animal-strain--dependent response has also been shown following radiation alone in three other studies on lung damage, 9~ testis, 91 and heart failure. 92

Testis The effects on testis have been assessed by the survival of spermatogoneal stem cells by the colony assay first described by Withers et al.93 Delic et a194 have studied the effect ofBCNU, cyclophosphamide, and procarbazine administered at intervals from 14 days before to 14 days after irradiation. Cyclophosphamide and procarbazine enhanced the radiation response for all intervals with the most pronounced effect when the drug was given 1 day before irradiation. 94 BCNU enhanced the radiation response to a lesser degree and the effect was less time dependent, although the effect, as for the two other drugs, was

CombinedRadiotherapyand Chemotherapy

most pronounced for drug administration close to the radiation treatment. 94 Hansen and Sorensen 95 have investigated the effect of bleomycin and vincristine administered from 21 days before to 21 days after irradiation. Vincristine enhanced the radiation response for all drug-radiation intervals, the most pronounced effect being with drug administration 6 and 12 hours after irradiation. % Bleomycin enhanced the radiation response when administered before and simultaneously with irradiation. 95The radiationmodifying effects in the testis of the various drugs are summarized in Table 7.

Hematopoietic Tissue Injuries to the hematopoietic tissue in rodents can be evaluated by lethality within 1 month of whole body irradiation 28,97or more directly by an analysis of the effect on the hematopoietic stem cells (colony forming units), which may be assessed by assays such as the spleen colony assay. 98 As indicated in Table 8, the effect of drugradiation combinations in hematopoietic tissue is extremely time-dependent. Thus, enhancement of the radiation response was most pronounced for drug administration simultaneously with and after irradiation in contrast to drug administration before irradiation where drugs may even have a radioprotective effect. We found that injuries to the hematopoietic tissue assessed by the lethality endpoint was, in all cases, more pronounced for drug administration 1 to 3 days after irradiation compared with drug administration 1 to 3 days before irradiation. 5'~m Most remarkably, methotrexate had a radioprotectire effect when administered 1 to 3 days before irradiation, had no effect at simultaneous treatment, and resulted in a pronounced enhancement of the radiation response when administered 1 to 3 days after irradiation. Millar et al 1~ have also shown a T a b l e 7. Effects on the Radiation in Testis of Drugs Administered Before, Simultaneously With, or After Irradiation

OverallEffectfor DrugAdministration Drug

Before

BCNU Bleomycin Cyclophosphamide Hydroxyurea Procarbazine Vincristine

+ + + + +

W i t h After References ++ + +++ +++ +++ ++

+ 0 + ++ + +

94 95 94 96 94 95

NOTE. For definitionofoveralleffectand time ofdrug administration, see Table 1.

87

T a b l e 8. Effects on the Radiation Response in Hematopoietic Tissue of Drugs Administered Before, Simultaneously With, or After Irradiation

OverallEffectfor Drug Administration Drug

Before With

Doxorubicin + Bleomycin C/s-platinum + Cyclophosphamide - / + Cytosine Arabinoside 5-fluorouracil + Hydroxyurea Methotrexate Mitomycin C + Vincristine

After

0/++ 0 +++

++

++

+++

++ +++ ++ 0 +++ 0

++

+++ +++ +

References 5, 99-10! 100, 10i 5, 101 5,68, 101-103 100, 103 5, 100, 101, I04 100 5, 100, 101,103 5, 101 I00

NOTE.For definitionofoveralleffectand timeofdrug administration, see Table 1. radioprotective effect of methotrexate administered 1 to 3 days before irradiation. A similar effect has also been shown for cyclophosphamide and cytosine arabinoside) ~176 This radioprotective effect seems to be mediated by a drug-induced enhancement of the recovery ofhematopoietic stein cells after whole body irradiation) ~176176176 We found no radioprotective effect of cyclophosphamide. On the other hand, the effect was much less pronounced when the drug was given before irradiation (DEF about 1.2) compared with simultaneous treatment (DEF about 1.4) and with drug administration after irradiation (DEF about 1.7).5 This time dependency for cyclophosphamide and total body irradiation has been confirmed byYan et al. 68 Assessed by the survival of colony forming units, doxorubicin had no effect in one study J~176 and resulted in a minor enhancement of the radiation response with simultaneous treatment in another. 99 Assessed by the lethality endpoint, we found doxorubicin to induce a moderate enhancement of the radiation response. 5,wj There may be a general tendency for the degree of the radiation-modifying effect of the drugs to be less pronounced when assessed by survival of colony forming units than by lethalityA 5 This may be attributable to the lethality endpoint representing toxicity to multiple normal tissues.

Drugs Combined With Low Dose-Rate Irradiation Knowledge of normal tissue reactions following combinations of drugs and low dose-rate irradiation is important as the main rationale of using low dose-

88

Hans yon der Maase

rate irradiation is to reduce toxicity. Unfortunately, only a few studies are available investigating this issue. As mentioned, Sherman et al26 have shown that the radiation-modifying effect of doxorubicin on esophageal and lung toxicity was dose rate--dependent. In both cases, the DEF values markedly increased when the dose rate was decreased. Lochhart et a1107observed that the effect ofcyclophosphamide and thoracic irradiation depended on dose rate. The sparing effect of low dose-rate was abolished when cyclophosphamide was administered 30 to 60 minutes before irradiation. Similarly, Varekamp et al 1~ observed that cyclophosphamide enhanced radiationinduced lung damage when administered 1 day before low dose-rate irradiation followed by bone marrow transplantation but had no effect in combination with high dose-rate irradiation. In two other studies, I~,t~ enhancement of the radiation response was apparently not increased when using low doserate irradiation. Fu et al m9found bleomycin to be the only one of six investigated drugs that showed an enhanced effect on intestinal tract toxicity when administered as a continuous infusion in combination with low dose-rate irradiation. The study did not include a control group receiving high dose-rate irradiation, but the toxicity of the combined treatments was less than one would expect (Table 3) and the sparing effect of low dose-rate irradiation seemed to be maintained. In the other study, 19c/s-platinum had no significant radiation-modifying effect on the skin when combined with high or low dose-rate irradiation. Thus, the question whether drugs may reduce the sparing effect of low dose-rate irradiation is unresolved but the possibility should induce caution.

Clinical Implications Drug-radiation interactions in normal tissues are extremely complex and it is obvious that all the different factors of importance for the outcome of combined treatments are difficult to evaluate in clinical studies. Therefore, knowledge based on experimental studies have to be taken into consideration in the planning of drug-radiation regimens. On the other hand, this is only appropriate if it is possible to document an acceptable agreement between experimental data and available clinical observations. In the following, the clinical relevance of the observed radiation-modifying effects of specific drugs in specific normal tissues and the effect of timing are

elucidated by a comparison of experimental and clinical data in selected normal tissues in which sufficient valid data are present.

Skin and Mucous Membranes Actinomycin D and doxorubicin have both been found to enhance skin reactions in humans including induction of the so-called recall phenomenon?,lt~ Similarly, bleomycin is known to enhance skin reactions and mucositis. ~12'113Bachaud et al ~14have shown in a randomized study that c/s-platinum administered concurrently with radiotherapy for head and neck cancer enhanced the frequency of severe mucositis compared with radiation alone. These results are in accordance with those obtained in experimental studies (Table 1). It is more difficult to evaluate the clinical relevance of the results obtained with cyclophosphamide, 5-fluorouracil, and methotrexate. Experimentally, methotrexate enhanced radiation induced skin reactions, whereas cyclophosphamide and 5-fluorouracil did not (Table 1). Clinically, Bentzen et al ll5 have investigated cyclophosphamide and a combination of cyclophosphamide, methotrexate and 5-fluorouracil in combination with postmastectomy radiotherapy. Cyclophosphamide had no significant effect on the radiation response, whereas the three-drug regimen enhanced acute skin reactions as well as late fibrosis, tl5 It is not possible to evaluate whether methotrexate or 5-fluorouracil was responsible for the radiation-modifying effect in this study. However, in a review on combined treatments in breast cancer by Fowbl@ 16 an increased risk of moist desquamation was found when radiation treatment was combined with drug regimens using methotrexate or doxorubicin, but not specifically 5-fluorouracil. Nor did 5-fluorouracil enhance the skin reactions in randomized studies of adjuvant postoperative treatment for adenocarcinoma of the rectum tIT and treatment of locally recurrent or inoperable colorectal carcinoma, t 18Thus, the experimental results seem to be qualitatively in accordance with the observed skin reactions in clinical practice.

Esophagus Actinomycin D, doxorubicin, and bleomycin have all been shown to enhance the radiation response in the esophagus in both experimental (Table 2) and clinical studies. 4,113,119 Recently, it has also been shown that esophagitis was more frequent when c/s-platinum was given together with radiation treatment in a randomized study for non-small cell lung cancer compared with radiation aloneY ~ For comparison

CombinedRadiotherapyand Chemotherapy

with the experimental results, it is especially important that c/s-platinum did not enhance lung toxicity 12~in accordance with experimental studies showing enhancement in esophagus (Table 2) and no effect in lungs (Table 4).

Intestinal Tract Experimentally, many drugs have been shown to enhance the radiation response in the intestinal tract, especially when administered simultaneously with irradiation (Table 3). Clinically, actinomycin D, doxorubicin, bleomycin and 5-fluorouracil have been reported to enhance gastrointestinal toxicity especially when administered concurrently with irradiation4,113,119 in accordance with the experimental results (Table 3). For 5-fluorouracil, enhanced toxicity for concurrent drug administration and pelvic irradiation has been confirmed in two randomized studies. 117,~18Valid comparisons between experimental and clinical data for the other drugs in Table 3 are not available. This is not because of a lack of studies using these drugs in combination with abdominal irradiation, but because toxicity is not always fully reported. Another problem is the use of multidrug combinations that complicate the evaluation of the single drug components.

Lung Actinomycin D, doxorubicin, bleomycin, and cyclophosphamide have resulted in the most pronounced enhancement of the radiation-induced lung reactions in experimental studies (Table 4). Actinomycin D ~21and bleomycin ~i3,1z2have, in accordance with the experimental data, been shown to increase pulmonary toxicity when combined with thoracic radiation. A high incidence of fatal complications has been caused by these drug-radiation combinations, especially with simultaneous administration. High dose cyclophosphamide has also been reported to enhance radiation-induced lung fibrosis, 123 whereas clinical data on doxorubicin are more difficult to evaluate. The combination of cyclophosphamide and 5-fluorouracil plus either methotrexate or doxorubicin administered concurrently with radiation for patients with breast cancer has been shown to increase the risk of symptomatic pneumonitis.~16 It is difficult to evaluate which drugs or combinations of drugs that are responsible for the enhanced radiation response. One would expect the enhancement to be attributable to cyclophosphamide and doxorubicin but it may be due to cyclophosphamide alone. There have been no reports on radiation pneumonitis enhanced by

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methotrexate or 5-fluorouracil alone. 4,119 C/s-platinum had no effect in experimental studies using whole thoracic irradiation 61,65and, similarly, carboplatin had no effect when administered in combination with hemithoracic irradiation. 69 These results seem to be in accordance with clinical practice. Thus, c/s-platinum did not influence lung toxicity in combination with irradiation evaluated in a randomized studyJ 2~It should be mentioned that, in one experimental study,43 c/s-platinum was shown to enhance the radiation induced lung reactions in contrast to clinical experience. Effect o f Timing The most pronounced radiation-modifying effect of drugs in experimental studies has been observed for simultaneous treatment. This time dependency is in accordance with most clinical reports. 4,61,lzHI3,1~6,124 Experimentally, drug-radiation effects in hematopoietic tissue showed a different time dependency with the most pronounced enhancement of the radiation response being with drug administration after irradiation (Table 8). This time dependency is in accordance with the clinical experience that doses of chemotherapy often have to be reduced in patients who have previously received radiation treatment to portions of the bone marrow, t~5,126 The experimental results obtained by Pearson and Steel53indicate that the effect of drugs in combination with pelvic irradiation may be most pronounced for drug administration after irradiation. This seems to be in accordance with the clinical observations by Yarnold et alJ 97 They observed that the risk of subcutaneous fibrosis, gastrointestinal damage, and hematologic toxicity was most pronounced when chemotherapy was administered after irradiation for testicular cancer compared with the risk following the reverse drugradiation sequence.

Clinical Implications Comparisons of experimental and clinical data are difficult and should be cautiously interpreted. However, where comparable data are available, there seems to be a reasonable agreement between experimental and clinical data. It appears that drugs with an effect on the tissue by itself should especially be expected to enhance the radiation response in that specifc tissue. Regarding the timing of the two treatment modalities, experimental data seem to be consistent with the effects noted in clinical practice. The best way to avoid enhanced reactions in critical

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normal tissues is to separate the two treatment modalities in time and, possibly, to administer chemotherapy before radiotherapy. The choice of this sequence is also supported by reports of the so-called "recall" phenomenon)10,128-130 It has also been proposed to use an integrated alternating regimen. 131,~32 However, such a regimen may be very complex and has the potential risk of diminishing the effect of both modalities. A better understanding of the underlying mechanisms of drug-radiation interactions is critical for a rational application of combined modality therapy. However, these mechanisms are seldom known in detail. Possible mechanisms may include effects on repair processes, modification of the radiation doseresponse curve, perturbation of cell kinetics, and influence on environmental factors/~3-~36 These possible interactive mechanisms may primarily be dominating in normal tissues, whereas effects in tumors most often seem to be purely additive. Thus, evidence for a therapeutic gain by use of drug-radiation combinations has only been documented in few studies and, if so, generally achieved by spatial cooperation.6~,~32,137

Conclusions Drug-radiation interactions in normal tissues are extremely complex. The reactions depend on the tissue, the drug regimen, the radiation treatment, and the time intervals and sequence of the two treatment modalities. The reactions observed in a particular tissue following a specific drug-radiation combination are, therefore, not predictive of reactions in other tissues or of alternative drug-radiation combinations. The most serious reactions in normal tissues generally occur with simultaneous treatment or, for some tissues, with drug administration after irradiation. Experimental data should be considered cautiously, together with clinical experience, in planning drug-radiation combinations to avoid unacceptable reactions in critical normal tissues. The following guidelines are proposed: 1. Combinations of radiation and cancer chemotherapeutic drugs should only be applied for tumors that are sensitive to both treatment modalities. 2. The main rationale for combining radiotherapy and chemotherapy is the achievement of a therapeutic gain by spatial cooperation. The strategy that best serves this purpose is independent application of the most effective radiation and chemotherapeutic regimens considering the imperative of avoiding critical normal tissue toxicity.

3. A therapeutic gain may also be achieved from an additive effect of the two treatment modalities by independent cell kill within the radiation fields. However, this is only possible if critical normal tissue reactions are avoided. Otherwise, a reduction of the radiation dose is required. A combined treatment may, therefore, only affect local tumor control equivalent to what is obtained by radiation alone administered at the conventional dose, so the only gain is sparing of radiation doses. A simultaneous eradication of tumor cells outside the radiation field is the only warrant for such a situation, ie, a therapeutic gain is obtained by spatial cooperation. 4. Enhanced normal tissue reactions may be avoided by separation of the two treatment modalities in time and the best sequence may be chemotherapy followed by radiotherapy. The possibility that such a sequential treatment will result in a decreased local tumor control due to tumor regrowth before institution of radiotherapy is primarily a problem if the chemotherapeutic regimen in question is ineffective, and such a regimen should not be applied. 5. Both early and late normal tissue reactions should always be recorded.

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