Concomitant chemoradiotherapy: rationale and clinical experience in patients with solid tumors.

REVIEW ARTICLE

Concomitant Chemoradiotherapy: Rationale and Clinical Experience in Patients With Solid Tumors By Everett E. Vokes and Ralph R. Weichselbaum Concomitant chemoradiotherapy can be used in order to increase both the local and systemic control of solid tumors. The rationale for its use and experimental data for selected chemotherapy drugs are reviewed. Clinical trials have focused on increasing complete response (CR) and survival rates; in addition, improved quality of life by decreasing the use of conventional surgical procedures is being pursued. Both of these goals may have been achieved for some tumors, most

C

URE RATES for patients with advanced

solid tumors remain low and improvements in locoregional and systemic tumor control remain a clinical necessity. The concomitant administration of chemotherapy and radiotherapy holds promise in approaching these goals; in addition, it may reduce the long-term morbidity of cancer therapy by either reducing the need for radical surgery or by allowing for the use of lower radiotherapy doses. The purpose of this article is to review the rationale for concomitant chemoradiotherapy, present experimental data, and summarize the clinical experience for selected types of solid tumors. RATIONALE

The use of combined chemotherapy and radiation therapy in patients with locally advanced solid tumors aims at overcoming radioresistance as a cause of local treatment failure and at early eradication of distant micrometastases as a cause of systemic treatment failure. Four theoretic types of interaction between radiation and chemotherapy can occur, as formulated by Steel and Peckham.' First is "spatial cooperation," a term describing the independent activity of each treatment modality-for radiotherapy within the radiation treatment field against the primary site of disease, and for chemotherapy outside of the radiotherapy field against presumed or documented metastatic disease. Second is "toxicity independence," which allows for administration of each treatment modality at full or near full dose without a significant increase in normal tissue damage. Steel and Peckham1 point out that for these two mecha-

notably for anal cell carcinoma. Improved survival with concomitant chemoradiotherapy has also been shown for patients treated on randomized studies for pancreatic, colorectal, small-cell lung, head and neck, and cervical cancer. These results call for the continued investigation of this approach in the laboratory and in the clinic. J Clin Oncol 8:911-934. o 1990 by American Society of ClinicalOncology.

nisms no interaction between the two therapy modalities is required and that additive activity would be the expected clinical outcome. Third is the protection of normal tissues from radiation by a systemic agent, allowing for the administration of higher doses of radiation. However, increased efficacy will result only if the tumor is exempted from the protective action of the drug, and metastases do not already exist. The fourth mechanism, finally, postulates increased activity within the radiation field as a direct result of the interaction of chemotherapy with radiation. In this situation, the drug has been called a "sensitizer," "enhancer," or "potentiator" of radiation. Steel has further proposed a precise terminology to characterize the type and extent of interaction between two agents in the laboratory.2 This terminology is based on the availability of a dose-response curve for each of the singletreatment modality agents and an isobologram analysis of their combined response. Where the drug is inactive by itself, a positive interaction with radiation is referred to as "sensitization" and a negative interaction as "protection." Where the drug has activity by itself and dose-response From the Section of Hematology/Oncology, Department of Medicine, and the Department of Radiation and Cellular Oncology, The University of Chicago Pritzker School of Medicine, Chicago,IL. Submitted December 27, 1989; accepted January 17, 1990. Address reprintrequests to Everett E. Vokes, MD, Section of Hematology/Oncology, University of Chicago, 5841 S MarylandAve, Box 420, Chicago, IL 60637. © 1990 by American Society of Clinical Oncology. 0732-183X/90/0805-0020$3.00/0

Journalof Clinical Oncology, Vol 8, No 5 (May), 1990: pp 911-934

Downloaded from ascopubs.org by UNIVERSITY of OTAGO on April 20, 2019 from 139.080.135.089 Copyright © 2019 American Society of Clinical Oncology. All rights reserved.

911

912

VOKES AND WEICHSELBAUM

curves are available for both the drug and radiation, the interaction can be described as supraadditive (synergistic), additive, or subadditive. However, detailed dose-response curves may be available for only one or none of the two agents; in these cases, a positive interaction is described as "enhancement" or "cooperation," and a negative interaction as "inhibition" or "antagonism," respectively. While this terminology is helpful in the laboratory, its use requires detailed information about each of the agents, more than is usually available in the clinic. In this review we will, therefore, use the term enhancement to describe an increase in the activity of radiation in the presence of chemotherapy, while not attempting, specifically, to distinguish between additivity and synergy. The extent of positive interaction between two agents may not be the truly critical factor determining their efficacy when administered in combination. Tannock and Rotin 3 have pointed out that synergistic or additive interaction per se will not result in improved clinical antitumor efficacy; rather, a decrease in the relation between normal tissue effects to antitumor effects is required. According to this theory, the combination must result in a proportionately greater increase in antitumor efficacy than in toxicity. However, even in the absence of a decreased ratio between normal tissue to antitumor effects, concomitant chemoradiotherapy can increase tumor control provided that increased acute toxicity does not preclude the administration of both agents at optimal doses. Thus, where increased acute toxicity is clinically tolerable, improved tumor control may be achieved through treatment intensification; in that case, chronic toxicities may become dose-limiting. THEORETICAL MECHANISMS OF INTERACTION BETWEEN CHEMOTHERAPY AND RADIATION Ionizing radiation is cytotoxic to cells as a direct consequence of DNA damage.4 Several types of DNA damage can be observed following radiation exposure; among these, DNA double strand breaks are considered to be the initial molecular lesions leading to cell death. Radiation resistance may occur as a result of several factors. When multiple fractions of radiation are administered, cellular recovery from sublethal radiation damage may occur between

fractions; this recovery is referred to as sublethal or potentially lethal damage repair.5-7 In addition, repopulation of tumor cells between radiation fractions may occur, 4 and inherent tumor cell radioresistance has been described.8 1- Radiation resistance may also occur as a consequence of amplification of DNA repair genes, increased cellular production of radical scavengers, predominance of cells in a radioresistant cell cycle phase (S-phase), or as a result of activation of certain protooncogenes. 4'1 -14 Finally, factors in the tumor microenvironment such as hypoxia may limit radiocurability.15 Clinically, the most important factor limiting radiotherapy is tumor cell burden; small solid tumors are frequently cured, whereas large tumors are not. Resistance due to a large tumor cell burden may reflect all the above mentioned factors, which are more likely to apply to large masses than to smaller tumors. Possible mechanisms of interaction between chemotherapeutic drugs and radiation have been reviewed in detail 3','5 9 and include those listed in Table 1. These interactions may be based on differential activity of drug and radiation against specific tumor cell subpopulations, eg, tumor cell hypoxia, 20 a lower pH in tumor cells,21- 23 cell

cycle phase distribution patterns, 24,25 or on mechanical factors such as reduced tumor bulk leading to improved drug delivery to malignant cells and reoxygenation of hypoxic cells. Other mechanisms will require a direct interaction between drug and radiation and include inhibition of repair of radiation damage, cell cycle synchronization, or the elimination of inherent resistance to drug or radiation as single agents. Table 1. Interaction of Chemotherapy and Radiotherapy Drug and radiation active against different tumor cell subpopulations based on hypoxia, cell cycle specificity, and pH Decreased tumor cell repopulation following fractionated radiation due to effects of chemotherapy Increased tumor cell recruitment from Go into a therapy-responsive cell cycle phase Increased tumor cell oxygenation following radiation with improved drug or radiation activity Improved drug delivery with shrinkage of tumor Early eradication of tumor cells preventing emergence of drug and/or radiation resistance Irradication of cells resistant to one treatment modality by the other Cell cycle synchronization Inhibition of repair of sublethal radiation damage or inhibition of recovery from potentially lethal radiation damage


CONCOMITANT CHEMORADIOTHERAPY: A REVIEW While possible interactions exceed those listed in Table 1, it is likely that all of them will have limited applicability in vivo. First, a high degree 3 26 of tumor heterogeneity is found in solid tumors ' and is likely to limit potentially additive or synergistic effects of concomitant chemoradiotherapy to certain tumor cell subpopulations rather than apply to the tumor as a whole. Second, adverse interactions may occur, including the emergence of drug resistance following resolution of hypoxia due to DNA overreplication; gene amplification of dihydrofolate reductase following hypoxia has already been described, a mechanism that could lead to methotrexate resistance.7 A third example is the emergence of cross-resistance, as described by Ozols et a128 for melphalan or cisplatin and radiation; clinically, cross-resistance has been implied in trials involving sequential chemotherapy and radiation. 29 Finally, it has been suggested that chemotherapy administered concomitantly with radiotherapy could increase rather than decrease the incidence of distant metastases. 30 More specific information on the interaction of chemotherapy and radiation is available for certain specific drugs. Cisplatin Cisplatin interacts with nucleophilic sites on DNA, RNA, or proteins to form intra- and interstrand cross-links as its major cytotoxic lesions.31 Therefore, DNA is the principal cellular target of both cisplatin and radiation. Cisplatin has been frequently studied as a radiation enhancer." Zak and Drobnik3 6 first described enhanced radiation cytotoxicity in the presence of cisplatin in a murine tumor. Wodinsky et a137 subsequently reported an increase in life span in the murine P388 lymphocytic leukemia model, followed by quantitative observations demonstrating that cisplatin enhanced the cytotoxicity of radiation in bacterial spores3 8 '39 and

mammalian cells.40 '4 ' Radiation enhancement by cisplatin may occur as a direct result of cisplatin effects that are active at the actual time of radiation. This "preradiation enhancement" is postulated to include the intracellular formation of reactive free radicals by cisplatin or altered binding of platinum complexes to DNA during radiation 38 '39 and has been observed both in hypoxic and in oxygen-

913 ated cells. 40,41 Another possible mechanism,

"postradiation enhancement," describes enhanced cytotoxicity when cisplatin is administered following fractionated radiation. 42' 43 Inhibition of repair of potentially lethal damage or of recovery from sublethal radiation damage may 31 be mechanisms involved in this process. ,42,43 Postradiation enhancement has been speculated to be the more important mechanism clinically." Larger degrees of enhancement have been observed in cells that are sensitive to cisplatin as a single agent 43'44 and following the administration of larger doses of cisplatin.3 1 Therefore, enhancement of radiation by cisplatin is likely to be most successful in tumors that are responsive to cisplatin; independent activity of cisplatin and, with it, "spatial cooperation" also would be expected to occur only in cisplatin-sensitive tumors. Cell culture experiments may provide some help in the design of clinical treatment schedules. One important consideration in schedule design concerns the cisplatin concentrations necessary to achieve enhancement. Tissue platinum concentrations of 2 to 6 ag/g have been measured in patients with head and neck cancer 2 to 10 hours following a dose of 100 mg/m2 of cisplatin.45 These tissue concentrations are equivalent to 38 4 those used in some laboratory experiments. ' 1,42 Therefore, administration of the drug at a high dose shortly before radiation may be most likely to allow for enhancement, as the highest concentration of drug would be present at the actual time of radiation. However, if postradiation enhancement is the predominant mechanism, there may be a range of timing before and after radiation during which radiation enhancement by cisplatin can occur. 46,47 Studies by Lelieveld et a146 demonstrated the highest degree of enhancement when administering the drug in a divided daily schedule before radiation. That schedule also showed less enhancement of normal tissue toxicity,46,48 an important consideration, since enhanced normal tissue radiation effects by cisplatin have also been described. 49"5 Carboplatin has also been investigated as a radiation enhancer.5 254 1 While to date less information is available about this drug, it may be more effective than cisplatin in this role, since higher concentrations of the drug in free solution are achieved5 2; thus, chemical radiation enhance-


914


ment, which is concentration-dependent, might be induced more rapidly with carboplatin than with cisplatin. Laboratory studies testing this compound have been published, and a clinical trial in patients with head and neck cancer has been completed.5 4 Fluorouracil Fluorouracil (5-FU) is a uracil analog that can either undergo sequential phosphorylation and integration into RNA, or bind to the enzyme thymidylate synthase as 5-fluorodeoxyuridine monophosphate (5-FdUMP). Heidelberger et a155 and Vermund et a156 demonstrated that doses of radiation and 5-FU that by themselves are not sufficient to induce tumor cell death can effectively eradicate a mouse sarcoma system if administered in combination. Subsequent in vitro studies by Bagshaw 57 and Berry 58 also demonstrated increased cytotoxicity of radiation in the presence of 5-FU. Vietti et a159 studied the combination of radiation and 5-FU in a mouse leukemia model and noted a marked increase in cytotoxicity when 5-FU was administered within 8 hours following radiation; this effect was larger than that observed if the drug was administered before radiation. Byfield et al60 expanded on these observations in tissue culture studies. For 5-FU alone, increased cytotoxicity was seen with increased exposure time of the cells to the drug. For irradiated cells, 5-FU markedly increased cytotoxicity when present in the postirradiation period for up to 48 hours (as opposed to its presence only before radiation); cell-kill enhancement was more pronounced at higher 5-FU concentrations. Looney et al also noted maximal tumor growth delay when radiation was administered before 5-FU.6 1 Due to the short half-life of 5-FU in vivo, 62 only continuous infusion schedules of 5-FU can reproduce this prolonged exposure to the drug in humans and could be expected to result in the most pronounced radiation enhancement, particularly if given in the postirradiation period. Since increased cytotoxicity also depends on the level of cell kill achieved by 5-FU alone, tumors that have at least partial sensitivity to 5-FU would be expected to most likely benefit from the combined use of 5-FU and radiation. Conflicting results have been published by Beaupain and Dionet,63 who reported 5-FU pre-

ceding radiation to be most effective and by Weinberg and Rauth,64 who did report a doserelated increase in 5-FU efficacy when administered as continuous infusion, but found no schedule dependency of radiation enhancement. The cellular mechanisms of 5-FU interaction with radiation have not been clearly identified. While a decrease in repair of radiation damage has been postulated, Berry 58 and Byfield et a160 found no effect on the repair of sublethal radiation damage in vitro. Similarly, Weinberg and Rauth64 and Nakajima et a165 reported only additive activity of the two agents. These results suggest that independent activity of both agents may be responsible for the observed radiation enhancement. Mitomycin Mitomycin is a bioreductive alkylating agent 20,66'67 that is activated intracellularly to form reactive metabolites resulting in interstrand DNA cross-links. 6 6-6 9 There is evidence that

mitomycin is preferentially activated in hypoxic cells, 68 ,70 although this has not been uniformly

reported.71'72 Since hypoxic cells are resistant to radiotherapy, 73 7 5 the combination of mitomycin and radiation is attractive allowing for the two agents to attack different subpopulations of malignant cells. Rockwell 76 has indeed demonstrated additive cytotoxicity of radiation and mitomycin in EMT 6 mouse mammary tumor cells. The schedule of drug administration had no effect on the survival curves in these experiments suggesting that no direct interaction between the two agents took place. In other studies, it was demonstrated that mitomycin could kill hypoxic cellls that had survived radiation.7 7 Hydroxyurea Hydroxyurea is an S-phase specific agent that inhibits ribonucleotide reductase. Therefore, it may have additive effects with radiation since it is toxic to S-phase cells that are considered radioresistant.24,25 It has also been shown to synchronize cells by inhibiting the entry of cells from the radiosensitive G 1-phase into the radioresistant S-phase. 24 '2 5 Finally, Phillips and Tolmach7 8 reported inhibition of repair of potentially lethal radiation damage when administering hydroxyurea to radiated cells. Few additional drugs have been studied with


915

CONCOMITANT CHEMORADIOTHERAPY: A REVIEW

radiation, among these dactinomycin7 9 and bleomycin, which have been shown to enhance radiation in vitro and in animal models, 46,80 -82 although little information exists on possible underlying mechanisms. CLINICAL GOALS OF CONCOMITANT CHEMORADIOTHERAPY

The primary treatment goal for concomitant chemotherapy must be an increased complete remission and cure rate. This may be achieved through spatial cooperation leading to the early elimination of micrometastases; alternatively, locoregional enhancement may result in increased locoregional tumor control.83 An alternative end point is treatment morbidity and quality of life.84 Here, survival may not be improved, but, by decreasing the incidence of a standard surgical procedure, the extent of surgery, or the total radiotherapy dose, the quality of life may be improved. This may also represent a major therapeutic achievement as exemplified by the possibility of larynx, anal sphincter, or bladder conservation. CONSIDERATIONS IN CLINICAL TREATMENT DESIGN

Several factors will influence the specific design of a treatment schedule for a given disease.1 5 These include the availability of active cytotoxic drugs and whether any of them are thought to enhance the activity of radiation. The normal tissue that will be included in the radiotherapy field will also require consideration. It may be difficult to administer drugs that have mucositis as their dose-limiting toxicity to patients requiring radiotherapy to the head and neck; similar considerations would apply to cisplatin and renal radiation, bleomycin and pulmonary radiation, or cyclophosphamide and bladder radiation. The choice of a specific treatment schedule and the exact timing of drugs and fractionated radiation has so far occurred largely empirically; however, a rational schedule design based on laboratory experiments may be also feasible, as outlined above for cisplatin and 5-FU. Decisions on whether to use continuous radiotherapy with single-agent chemotherapy, or split course radiotherapy with single or combination chemotherapy, however, are likely to be based on the

clinical experiences in a given disease rather than experimental data. An alternative schedule of combining radiation with chemotherapy has been described by Looney and is based on experimental studies in the hepatoma 392A model.8 5 It consists of alternating courses of chemotherapy with radiotherapy and aims at decreasing the acute toxicities frequently encountered with concomitant chemoradiotherapy while administering each treatment modality at optimal dose. The latter is accomplished by using hyperfractionated radiotherapy (multiple daily fractions) alternating with a full course of combination chemotherapy. This concept is also under clinical evaluation8 6 and, where applicable, has been included in this review. The evaluation of clinical toxicities is another issue of clinical concern. Generally these can be divided into three types: acute systemic, acute within the radiation treatment field, and chronic. The first two types of acute toxicities are readily assessed, and in quality usually are similar to toxicities seen with each treatment modality by itself, although their severity may be increased. However, if these acute toxicities can be managed, the long-term toxicities of radiation may limit the feasibility of concomitant chemotherapy. These chronic toxicities require special attention, since many concomitant chemoradiotherapy regimens are administered with curative intent or in an attempt to decrease the need for radical surgical procedures. Therefore, an assessment of long-term morbidity from concomitant chemoradiotherapy is essential and, in final evaluation, must be balanced against the efficacy of a given regimen. The following discussion will be about the clinical applications of concomitant chemoradiotherapy for several specific disease areas. Carcinomaof the Anus Carcinoma of the anus has become an important example for the pursuit of both major goals of concomitant chemoradiotherapy: improved survival, and improved quality of life through organ preservation.87-90

Anal cancer is a locoregionally invasive disease, eventually invading neighboring structures and regional lymph nodes. 89' 91, 92 Standard therapy has consisted of abdominoperineal resection and permanent colostomy, frequently resulting


916


in 5-year survival rates of _ 50%, although higher survival rates have been reported. 91 -96 Radiotherapy as a single-treatment modality (external radiation and/or brachytherapy) has often been reserved for patients with unresectable or recurrent lesions.91 It has also been shown to be effective when used with curative intent at doses exceeding 5,000 or 6,000 cGy. 91,97 Cantril et a197 reported on 39 patients treated with high-dose radiotherapy alone (:< 6,500 cGy) achieving an 80% local control rate and a 79% 5-year survival. At these radiation doses, chronic complications of proctitis, cystitis, and anal strictures or radionecrosis can occur, although the incidence of these severe complications was low in this series. Trials using concomitant chemoradiotherapy are summarized in Table 2. Nigro et al were the first to publish on the use of mitomycin, 5-FU, and concomitant radiotherapy. 98 This study has been updated repeatedly 98-10 2 and, most recently, included 44 patients treated between 1971 and 1983.102 In this study, radiotherapy consisted of only 3,000 cGy and chemotherapy was initiated on the first day of radiation. Initially, abdominoperineal resection was performed 4 to 6 weeks following completion of radiotherapy; however, after 1975, this procedure was performed only on patients with residual disease following chemoradiotherapy. As shown in Table 2, 40 of 44 patients (91%) had a clinical complete response (CR); residual microscopic disease was documented in only one of these 40 patients. However, five of nine patients with large initial lesions (6 to 8 cm) had residual disease after chemoradiotherapy and died of their disease, compared with only two deaths in 35 patients with tumors of < 5 cm. This study clearly demonstrated the feasibility of using chemoradiotherapy in patients with anal carcinoma resulting in a prolonged disease-free survival and organ preservation for the great majority of patients. However, patients with large lesions achieved less favorable results. al, 98 Following the original report by Nigro et 03 -114 studies. similar initiated other investigators Investigators at Memorial Sloan-Kettering Cancer Center used a schedule in which a single cycle of preoperative mitomycin and 5-FU was followed by radiotherapy to 3,000 cGy (not concomitant).' 0 3 015 In their latest report'0 5 on 44

previously untreated patients, the histologic CR rate was 59% and, thus, lower than reported by Nigro et al. 02 The 5-year actuarial survival, however, was 80%. Ten patients developed recurrence, all locoregionally. Comparison with a nonrandomized group of patients treated surgically only suggested a survival benefit from the addition of chemotherapy to radiation. Others have attempted to completely eliminate the routine use of surgery by investigating the use of higher doses of radiation with chemotherapy.106 110 Sischy'08 reported on 29 patients treated with chemoradiotherapy to 5,500 cGy and no surgery. Twenty-six of these (90%) achieved local control, and only three died of local disease. Distant disease was observed in two patients. The Radiation Therapy Oncology Group followed up on this report with a group-wide pilot study' 0 9 on 79 patients and achieved similar good results. Overall survival rates were 97% at 1 year and 73% at 3 years (median follow-up, 32 months). John et a1"0 also reported on a regimen containing higher radiation doses (3,000 to 4,500 cGy) with two cycles of mitomycin and 5-FU. In this study only two patients died (of other causes) and 20 continue alive with no evidence of disease at a median follow-up of 45 months. These and other studies98 114 all suggest that surgery can be avoided in an overwhelming number of patients with anal carcinoma and should no longer be considered standard therapy. In the absence of randomized studies, this conclusion is based on the cumulative survival data presented in Table 2, all indicating that longterm survival following concomitant therapy is at least equal to that observed in surgical series and all indicating a sharply reduced need to use conventional surgical approaches despite the frequently used low doses of radiation. Some of these studies also suggest that higher radiation doses and possibly larger radiation fields may be needed for patients with larger tumors or involvement of inguinal nodes,102 while radiotherapy alone may be sufficient treatment for patients with smaller lesions. 97 Questions regarding the optimal chemoradiotherapy doses, schedule, and radiation field remain to be answered. Randomized studies are currently in progress that will help to define those patients most likely to benefit from the use of chemotherapy in this disease.


917

CONCOMITANT CHEMORADIOTHERAPY: A REVIEW Table 2. Chemoradiotherapy for Anal Carcinoma Authors

Surgery

Schedule

Nigro et al'"

No. of Patients

Response

44

cCR 40/44, pCR 34/35

79% alive at 5 years

Outcome

Mito 15 mg/m2 d 1,5-FU 1,000 mg/m2/d d 1-4, 28-31; 3,000 cGy (200 cGy/fx) d 1-21 to pelvis and inguinal nodes

17 patients, 4-6 weeks after chemoradiother-

Enker et al'o

Mito 10-15 mg/m' d 1, 2 5-FU 750 mg/m /d d 1-5; 3,000 cGy in 3 weeks to whole pelvis (after chemotherapy)

Local excision 20 patients Surgery: 24 patients (after 2-4 wks)

"44

cCR N/A, pCR 26/44

80% alive at 5 yrs

Cummings et al"'

Mito 10 mg/m' d 1, 5-FU 1,000 mg/m2/d d 1-4; 5,000 cGy in 20 fx to pelvis and inguinal nodes (d 1-28)

No

13

cCR 13/13, pCR N/A

N/A

Sischy'•

Mito 10 mg/m d 2, 5-FU 2 1,000 mg/m /d d 2-5, 28-31,4,500 cGy at 180 cGy/fx d 1-35 to anus and nodes, 1,000 cGy boost to anus

Four patients only

33

cCR: 30/33, pCR: 4/4

81% alive at minimum follow-up of 1 year

Sischy et ao1' (RTOG)

Mito and 5-FU as above, 4,080 cGy in 4-5 weeks to perineum, pelvis and inguinal nodes

Biopsy followed by resection for residual disease (eight patients)

79

cCR N/A, pCR 57/65

73% alive at 3 years

John et al"

Mito 12-15 mg/m2 d 1, 28; 5-FU 1,000 mg/m'/d d 1-4, 28-31; s 4,500 cGy (180 cGy/fx) to pelvis and perineum, starting day 1

None

22

cCR N/A, pCR 10/13

91% alive at median follow-up of 45 months

Meeker et aln"

Mito 15 mg/m2 d 1, 5-FU 1,000 mg/m'/d d 1-4, 29-32; 3,000 cGy (200 cGy/fx) d 1-21 to pelvis and perineum

Nine patients

19

cCR N/A, pCR 14/16

87% alive at 40 months

Secco et al"'

Mito 15 mg/m2 d 1,5-FU 2 750 mg/m over 12 hr d 1-5; 3,000 cGy (200 cGY/fx) d 8-28 to pelvis and perineum

One patient

16

cCR N/A, pCR N/A

63% alive at 42 months

1

2

0

apy

Abbreviations: Mito, mitomycin; fx, radiotherapy fraction; d, day; wk, week; cCR, clinical complete response; pCR, pathologic complete response; N/A, not available; RTOG, Radiation Therapy Oncology Group.

Rectal Cancer Adjuvant chemotherapy, radiotherapy, and concomitant chemoradiotherapy have been investigated in rectal cancer."'• The Gastrointestinal Tumor Study Group (GITSG) randomized 227 patients with rectal adenocarcinoma to surgery

alone, surgery followed by radiation, surgery followed by adjuvant chemotherapy, or surgery followed by concomitant chemoradiotherapy with 5-FU and subsequent adjuvant chemotherapy with 5-FU and semustine." 16 Time to recurrence was statistically significantly prolonged by com-



918 bined postoperative concomitant therapy compared with surgery alone. Survival was also statistically significantly prolonged" 7 (median survival, 4.3 years for surgery, while median not reached for combined treatment group [P = .01], although for the covariate adjusted analysis, the P value was only .16). Acute toxicities were more severe with combined treatment,"118 while chronic complications were observed infrequently on all arms. The major benefit from postoperative therapy included a decreased local recurrence rate, although a decreased incidence of distant metastases was also seen. A different strategy was investigated in a pilot study by Fabian et al," 9 who postoperatively administered 3,000 cGy of whole abdominal radiation with concomitant 5-FU at two different dose levels (300 mg/m 2 days 1 to 5 and 28 to 32, or on days 1 to 3 and 28 to 31) to 38 patients with stage B and C colon cancer. For patients receiving the higher dose of 5-FU, the overall survival was 73% at 44 months of median follow-up, and for those receiving the lower 5-FU dose, 100% at median follow-up of 23 months. Another study using whole abdominal radiation (2,200 cGy) and weekly bolus 5-FU was reported by Brenner et al'12 who reported a 5-year overall survival of 65% in patients with stage C2 disease. Shehata et al' 21 also reported a high local control rate in 21 patients with cecal carcinoma treated with postoperative radiotherapy and concomitant 5-FU. Related to the treatment of colorectal cancer have been attempts at decreasing the incidence of hepatic metastases or improving the palliative therapy of documented hepatic metastases. Rotman et a1' 22 treated 23 patients with continuous infusion 5-FU and concomitant radiotherapy to the liver. Three cycles were administered every other week. Fifteen patients had a partial response, 19 had subjective palliation and toxicity was minimal; the median survival for all patients completing therapy was 30 weeks. This high rate of palliation is unlikely to be achieved with chemotherapy alone, and additional studies of this approach are warranted. The use of intraarterial iododeoxyuridine in patients with liver metastases is also being investigated.123 PancreaticCarcinoma The prognosis for patients with adenocarcinoma of the pancreas is very poor with few

long-term survivors reported, even following initial complete resection of the disease. A primary goal of any experimental treatment in this disease, therefore, must be to improve survival. A palliative role for radiotherapy has long been suggested.124 Moertel et al attempted to increase the local activity of radiation and were the first to report on the use of concomitant chemoradiotherapy in patients with unresectable disease.125 ,126 Randomized studies conducted since

then are summarized in Table 3. In 1969, Moer tel et al reported a statistically significantly improved survival in 187 patients with unresectable pancreatic, gastric, and colorectal cancer treated with 5-FU and moderate-dose radiation (3,500 to 4,000 cGy) compared with placebo and radiation.' 26 This observation was subsequently confirmed for pancreatic cancer in a randomized study by the GITSG.127 The addition of 5-FU to radiation (6,000 cGy) significantly increased the time to progression and survival, while the dose of radiotherapy (4,000 v 6,000 cGy) did not by itself significantly alter the treatment outcome. Despite this significant impact on survival, the pattern of failure remained unchanged with no difference in relative control of distant or local disease among the three study arms. Similar data supporting the use of radiotherapy with concomitant 5-FU in the adjuvant setting for patients with resectable tumors also exist, although the number of patients in that GITSG study was small.128 The GITSG subsequently tried to determine whether concomitant chemoradiotherapy with 5-FU was not only superior to single-modality radiotherapy but also superior to single-modality combination chemotherapy with 5-FU, mitomycin, and streptozocin.' 29 This study also demonstrated a statistically significant survival advantage for concomitant therapy; however, the number of patients studied was small and a similar study by the Eastern Cooperative Oncology Group comparing concomitant radiotherapy and 5-FU with 5-FU alone showed an equally poor survival of 8 months (median) on both study arms.13

0

Other trials have compared radiotherapy with concomitant 5-FU to a lower radiotherapy dose with concomitant doxorubicin' 3 1 or focused on the addition of intraoperative radiotherapy to a concomitant treatment schedule'

32 33

,1 ; none of


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these trials have demonstrated a noticeable improvement in survival. These studies demonstrate a consistently improved survival for patients with resectable and unresectable pancreatic carcinoma treated with 5-FU and concomitant radiotherapy compared with radiotherapy or chemotherapy alone. However, while statistically significant, the survival data achieved with 5-FU are still very unsatisfying. Therefore, 5-FU and radiotherapy might be recommended as standard therapy for patients who are unable to participate in clinical trials. For the majority of patients, however, these results should merely be taken as a lead in the design of future studies that continue the investigation of concomitant chemoradiotherapy in pancreatic carcinoma. Head and Neck Cancer Disease progression in patients with head and neck cancer occurs predominantly locoregionally, with only about 20% of patients developing clinically detectable distant disease, although recent autopsy series have indicated a much higher incidence of systemic tumor dissemination.134,135 Concomitant chemoradiotherapy

represents an interesting concept in the treatment of this disease, since improved local control beyond that achieved with standard surgical and/or radiotherapeutic techniques is needed. With improved local control, it would be reasonable to expect distant metastases to become a clinically more important site of treatment failure, requiring active systemic therapy. Both improved local and distant disease control are theoretically addressed by concomitant chemoradiotherapy through the principles of direct radiation enhancement and spatial cooperation. In addition to disease control, organ preservation may be an important therapeutic goal in head and neck cancer. Clinical trials testing concomitant chemoradiotherapy in head and neck cancer have been conducted since the 1960s.136,137 All major drugs potentially enhancing radiotherapy have been used in patients with locally advanced unresectable disease, and positive randomized clinical trials are summarized in Table 4. Methotrexate was used with concomitant radiotherapy based on its high single-agent activity in the disease.13 8'13 9 However, randomized and nonrandomized studies' 40 ,141 failed to show a benefi-

Table 4. Positive Randomized Trials in Head and Neck Cancer Survival No. of Patients

Author Shanta and Krishnamurthi'46

1 47

Fu et a

107

104

Chemotherapy Bleo IA and IV, 10-15 mg, 2-3 x per wk (total dose, 150-250 mg); IM, 30 mg, 2 x per wk before XRT, 1 dose during XRT

Radiotherapy Dose 5,500-6,000 cGy

During XRT; Bleo 5 mg IV 7,000 cGy 2 x per wk; maintenance: Bleo 15 mg IV;

Chemotherapy

Control

59% 23% (at 5 yrs)

43% 24% (at 3 yrs, P = .112)

Disease-Free Survival Chemotherapy

Control

Comments

72%

17%

Survival significantly improved with IA or IV bleo (P = .05); no survival curves presented, large number of patients unaccounted for

(at 5 years)

31% 15% (at 3 yrs, P = .024)

methotrexate 25 mg/ 2 m IV weekly x 16 Eschwege et a1148

199

Bleo 15 mg IM or IV 2 x per wk for 5 wks

6,400 cGY

6,000-7,000 cGy in 6-10 wks

Lo et al's

136

5-FU 10 mg/kg, d 1-3, then 5 mg/kg 3 x per wk

Weissberg et all56

117

Mito 15 mg/m d 5 (repeated 6 wks later for gross disease or postop residual)

2

> 5,000 cGy (preop or postop) >5,600 cGy (gross disease or postop residual)

12 mos 12 mos (median) 22% 23%

22%

22%

(at 5 yrs)

(at 5 years) 32% 14% (at 5 yrs, P < .05)

49% 18% (at 2 yrs, P < .5)

48% 40% (at 5 yrs, P > .3)

75% 55% (at 5 yrs, P < .01)

Heterogeneous study group includes surgical and nonsurgical patients

Abbreviations: Bleo, bleomycin; 5-FU, fluorouracil; mito, mitomycin; d, day; wk, week; yr, year; IA, intraarterial; IV, intravenous; IM, intramuscular; postop, postoperative; preop, preoperative.


921


cial impact on survival, while toxicity was increased. Bleomycin, another frequently used drug in head and neck cancer, has been investigated more frequently in randomized studies,142-148 including three studies each with over 100 patients. 146-14 Shanta and Krishnamurthi' 46 reported increased disease-free survival and overall survival with bleomycin, although bleomycin was administered at a variety of doses and schedules, and survival curves were not reported. Fu et al147 also reported improved disease-free survival in patients receiving concomitant bleomycin; a similar trend for survival was not statistically significant, possibly due to low patient accrual. While these two studies suggest a small but statistically significantly improved control rate with radiotherapy and concomitant bleomycin, a third large randomized study found no difference in the treatment outcome. 14 Hydroxyurea has been used infrequently as a single cytotoxic agent in head and neck cancer, although activity has been demonstrated.1 38 ' 13 9 Stefani et a1' 49 reported on a placebo controlled randomized trial in 126 patients. There was no significant difference in locoregional response rates or survival, while mucositis in the hydroxyurea group was increased. In addition, the incidence of distant metastases also seemed increased. Richards and Chambers1 50 reported a second placebo controlled randomized study with 40 patients and found a higher histologic CR rate at subsequent surgery in patients treated with concomitant hydroxyurea (six of 11 patients v two of 12 patients). These patient numbers are too small to allow for definitive conclusions, although favorable survival data on these and additional patients treated with concomitant hydroxyurea were presented in a subsequent report.' 51 Additional pilot studies using concomitant hydroxyurea have also reported favorable impressions. 152-154 A randomized study comparing radiotherapy alone with radiotherapy plus intravenous 5-FU 55 was reported by Lo et al.ss Local control and survival were improved for all patients in the concomitant therapy group. This difference in survival was statistically significant in patients with lesions in the oral cavity. The same trend for improved survival was seen in all anatomic sub-

groups included in the study (oral cavity, base of tongue, oropharynx). Weissberg et al' 56 recently reported on a randomized comparison of radiotherapy alone to radiotherapy and concomitant mitomycin in 117 patients. While this was a heterogeneous study population, including surgical and nonsurgical patients, the actuarial disease-free survival at 5 years was statistically significantly higher in the combined treatment group. Overall survival was also higher in the mitomycin group; however, no statistical significance was reached. A high incidence of pulmonary complications on the experimental arm was also noted. In summary, randomized trials showing improved survival in patients with head and neck cancer treated with concomitant chemoradiotherapy have been published for 5-FU,'5 5 and bleomycin,' 4 6 and studies showing improved dis46 47 55 ease-free survival for 5-FU,s bleomycin, 1 ,1 and mitomycin.s 56 In each of these studies, statistical significance was reached. However, since the differences involved fairly small percentages, and long-term survival was still poor, none of these concomitant programs have been adopted as standard therapy. The role of cisplatin as a radiation enhancer in head and neck cancer remains to be established. 57 '61 Positive pilot data using large doses of cisplatin administered every 3 weeks during radiotherapy have been published by Al-Sarraf et al.' 5 7 Additional pilot studies using cisplatin at lower doses administered in shorter intervals have been less promising,'16 and in a preliminary presentation of a randomized trial comparing weekly low-dose cisplatin and radiotherapy with radiotherapy alone, the combination failed to significantly increase the disease-free or overall survival.162 Therefore, additional randomized studies testing cisplatin administered in a schedule that is more likely to enhance the efficacy of radiation are needed. This also applies to carboplatin, which to date has been investigated in only one pilot study. 54 More recently, pilot studies have used splitcourse radiotherapy schedules with intensified concomitant chemotherapy. 63-170 Several of these

regimens are based on 5-day infusional 5-FU administered with or without additional chemotherapy drugs every other week with concomitant radiotherapy, as initially described by Byfield et


922


al.' 63 While the local control and survival data of several of these studies are impressive,i 63 -i68 they still require confirmation in large randomized studies to truly assess their impact on local and distant control rates and their acute and chronic toxicities. Studies investigating the rapid alternation of chemotherapy and radiation as suggested by Looney 85 are also in progress. 171' 172 Merlano et al'71 have compared a schedule of radiotherapy alternating with vinblastine, bleomycin, and methotrexate with the sequential administration of four cycles of the same chemotherapy drugs followed by radiation and reported a statistically significantly improved local control and progression-free survival rate for the alternating arm; survival, however, was poor on both study arms. In summary, the focus of concomitant chemoradiotherapy in head and neck cancer to date has been on survival. The concept is supported by positive single-agent randomized trials and the more recent pilot trials using intensified regimens, although no regimen has replaced singlemodality radiotherapy as the standard of care. Its relative value compared with other investigational therapies (eg, induction chemotherapy) also remains unsettled. Furthermore, the potential for organ preservation when using these regimens 84,164 deserves more attention, analogous to studies testing organ preservation with induction chemotherapy.173

271 days, P < .01); however, since there was no control group, the CAP regimen can only be considered the more successful experimental arm but not superior to standard therapy. Soresi et al'7 7 treated 29 patients with weekly doses of cisplatin at 12 mg/m 2 and concomitant radiotherapy to only 5,000 cGy. Only 16 patients responded, and the median survival was 9 months. A subsequent randomized study by these investigators compared this regimen with radiation only in 95 patients; in view of their pilot data it is not surprising, that this study failed to show any significant differences in progression-free or overall survival.178

The use of split-course radiotherapy with concomitant infusional 5-FU in NSCLC was investigated by Byfield et a1' 79 and Taylor et al.' 80 In the latter study, cisplatin and 5-FU were administered with radiotherapy in an alternate week schedule. Following four cycles (4,000 cGy), a high clinical CR rate of 56% was seen in 64 patients, and residual clinical disease was frequently not confirmed at surgery. The 12- and 18-month survival figures were 61% and 47%, respectively.' 80 The further addition of etoposide to the regimen has been presented in a preliminary report.i18 These and additional studies in patients with NSCLC'8 2-188 show the feasibility of concomitant chemoradiotherapy in this disease, including its use in the preoperative setting. However, a true therapeutic gain remains to be shown in a randomized study.

Nonsmall-Cell Lung Cancer Nonsmall-cell lung cancer (NSCLC) is only marginally responsive to chemotherapy174 and not frequently cured with radiation therapy used as single-treatment modality."17 Since both locoregional and systemic treatment failures occur frequently in patients with regionally confined disease, concomitant chemoradiotherapy has been investigated in that setting with the goal of improving survival. Eagan et al' 76 compared cyclophosphamide, doxorubicin, and cisplatin (CAP) with cyclophosphamide, doxorubicin, and dacarbazine (CAD), each administered for a total of 10 cycles in 72 patients with unresectable regionally advanced NSCLC. The first two cycles were each administered during a course of radiotherapy. Median time to progression was longer in patients treated with CAP than those treated with CAD (303 v

Small-Cell Lung Cancer In limited-stage small-cell lung cancer (SCLC), radiotherapy has been used to intensify the treatment delivered to the primary disease. This is justified by the high local relapse rate seen in patients with limited disease as well as a high response rate to radiotherapy. Several fully published randomized trials have addressed the addition of thoracic radiotherapy to chemotherapy.189-196 These trials vary in regard to the chemotherapy and radiation schedules (Table 5). In three trials, thoracic radiation was administered with concomitant chemotherapy.' 8 9 '191All three demonstrated improved local control with the combined treatment compared to chemotherapy alone; in addition, two trials also demonstrated statistically significantly improved survival'8 9,190 ; in both of these trials radiation was


923

CONCOMITANT CHEMORADIOTHERAPY: A REVIEW 6

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administered early in the overall treatment plan. In other trials the administration of chemotherapy was interrupted to administer radiothera92 py' 9 2 -19 6 ; of these, only the trial by Perez et al,1 in which chemotherapy and radiotherapy were alternated, demonstrated improved survival for the combined modality therapy. It seems that the addition of thoracic radiotherapy to systemic chemotherapy for limited SCLC can increase the local control rate and offer a survival advantage, particularly if the two treatment modalities are administered concomitantly or in rapid alternation early in the treatment plan.' 97"' 98 This is 99 2 further supported by recent pilot studies,1 ' 00 including a study by Turrisi et al,199 who used chemotherapy with concomitant hyperfractionated radiotherapy initiated on day 1 of chemotherapy; at a median follow-up of 22 months the projected 2-year survival was 56%. EsophagealCancer A large number of pilot studies have investigated concomitant chemoradiotherapy in regionally advanced esophageal cancer including resectable and unresectable patients. 1210 As shown in Table 6, the regimens used are most frequently based on the use of mitomycin and infusional 5-FU, analogous to those used in anal cancer. In addition, cisplatin-containing regimens and splitcourse radiotherapy regimens have been used. These pilot studies clearly show that preoperative concomitant chemoradiotherapy is feasible. However, only a minority of patients will achieve pathologic complete remission. Whether surgery is a necessary component of these treatment programs is not clear, since the survival figures in surgical series202,206,207 are quite similar to those 05 This suggests that of nonsurgical trials. 20 1,20 3-2 organ preservation as a secondary treatment goal should be vigorously investigated. Infusional 5-FU is a component of all published programs and must be considered a vital component in this approach. Which, if any, of the other drugs significantly increase the efficacy of these programs remains to be investigated; so far, pilot studies do not show a noticeable difference

between mitomycin-201-204 and cisplatin-contain07

205 ing regimens. -2 Most importantly, it remains unclear at present whether any of these programs are superior to standard therapy alone on account of either

survival or organ preservation. Carefully designed randomized studies addressing these questions are in progress and their results should allow a more accurate assessment of the indications for concomitant chemoradiotherapy in esophageal cancer. Bladder Cancer Locally advanced bladder cancer has a poor prognosis when treated with surgery or radiotherapy, with patients failing both locally and distantly. Among investigational approaches are induction chemotherapy and concomitant chemoradiotherapy, the latter frequently using cisplatin as a single agent. Initial trials reported by Jakse et al21' and Soloway et al, 212 each including less than 10 patients, were followed by a larger study conducted by the National Bladder Cancer Group.21 3 Seventy patients with T2 to T 4 bladder cancer who were considered inoperable or unresectable received 70 mg/m 2 of cisplatin intravenously every 3 weeks for a total of eight cycles. Cycles 1 to 3 were administered during a full course of continuous radiotherapy to a total tumor dose of 6,500 cGy. Seventy of the patients achieved a CR, although for patients with T 4 tumors, the CR rate was only 50%. The median survival for all 70 patients was 30 months; patients with T 2 disease survived significantly longer than those with T 3 or T 4 disease (64% v 24% at 4 years). Information on local versus distant disease control was not reported. Similar positive pilot results were reported by Jaske et al on 22 patients.214 A different strategy was investigated by Eapen et a1215 who treated 25 patients with locally advanced bladder cancer with three cycles of intraarterial cisplatin. Ninety-six percent of the patients achieved a CR including eight of nine patients with T 4 lesions; at a median follow-up of 18 months the projected 2-year survival is 90%. A high incidence of sensory sacral root neuropathy was noted (48%). This study is remarkable for its high initial control rate in advanced cases, which may be superior to control rates achieved with intravenous cisplatin, possibly as a result of a higher cisplatin concentration at the tumor site following its intraarterial administration leading to either increased radiation enhancement and/


925

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or increased single-agent cytotoxicity of cisplatin. A single study using continuous infusion 5-FU (25 mg/kg/day) during weeks 1, 4, and 7 of a course of radiotherapy to 6,000 to 6,500 rad was reported by Rotman et al.2 16 Eleven of 18 assessable patients (61%) achieved a CR. Disease recurrence was regional in one patient and distant in six (follow-up time not given). These studies, particularly that by Eapen et al, 215 achieve the goal of organ preservation and suggest improved survival. No randomized studies comparing this approach with standard therapy or with sequential multimodality therapy (induction chemotherapy followed by radiotherapy) are available to date. However, given these promising results, additional research with concomitant chemoradiotherapy in bladder cancer seems highly warranted. Cancer of the Cervix Studies on concomitant chemoradiotherapy in cervical cancer have focused on the use of hydroxyurea; randomized trials in this disease are summarized in Table 7. After a report by Hreshchyshyn2 17 suggested improved efficacy with the administration of hydroxyurea during radiotherapy, the Gynecologic Oncology Group conducted a placebocontrolled randomized study in 190 patients with 218 nonsurgically staged III B and IV disease. While the study was conducted poorly (26 patients were ineligible, and 60 patients nonassessable), the median survival and progression-free survival were statistically significantly prolonged with hydroxyurea. A subsequent study comparing hydroxyurea with misonidazole219 showed a trend for a longer progression-free interval with hydroxyurea (P - .08), but no difference in survival between the two study arms (P - .25). Piver et al have conducted a series of randomized and nonrandomized studies at Roswell Park Memorial Institute.220-225 Two initial placebo-

controlled studies demonstrated a statistically significant increase in survival for nonsurgically staged patients with regionally advanced disease 1 22 22 with hydroxyurea. 0,

A subsequent study confirmed these results in 40 surgically staged patients with stage II B disease, 222 and a similar 5-year survival of 92%

was reported in a pilot study of 20 patients with 223 stage II B disease staged by lymphangiogram. Two additional randomized trials have compared hydroxyurea with placebo in patients with stage III B disease. 2 24' 225 These studies again

indicate a superior outcome with hydroxyurea, although both studies suffer from inconsistencies in the radiotherapy schedule and a small patient cohort. While each of these studies by itself is open to some criticism, taken as an entity, they do suggest a role for hydroxyurea with radiotherapy as standard therapy for patients with cervical cancer. Additional drugs have been tested in cervical cancer, although to date only in small pilot trials.226 228 CONCLUSIONS In conclusion, a theoretic rationale suggests that local and systemic tumor control might be improved through the simultaneous use of chemotherapy and radiation. A large body of experimental data exists, which to date has largely focused on the use of cisplatin, 5-FU, and mitomycin with concomitant radiation. While these and other drugs can clearly enhance the effects of radiation in experimental settings, data derived from these experiments cannot routinely be translated into the clinical setting, in which repeated fractions of radiotherapy are the rule and cyclic combination chemotherapy is more likely to be beneficial than single-agent chemotherapy. Also, experimental data provide little insight into the differential activity of a given regimen to the tumor compared with normal tissues. In general, experimental data suggest that drugs that are active by themselves in a given disease should be used preferentially; in addition, some recommendations for scheduling can be made, eg, cisplatin should be used in intermittent high-dose schedules rather than daily low doses; 5-FU is best used as a continuous infusion at maximally tolerated dose. Clinical trials testing concomitant chemoradiotherapy have been conducted for many years. Improved survival has been demonstrated in randomized studies in patients with pancreatic, rectal, head and neck, small-cell lung, and cervical cancer. In addition, pilot studies in anal carcinoma suggest a high failure-free survival rate and the possibility of avoiding routine surgi-


927

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cal procedures. Concomitant chemoradiotherapy could, therefore, be considered as standard care for several of these tumors. At the same time, continued investigation of this approach in clinical trials is necessary. End points in these trials should be CR and survival rates as well as quality of life assessment and the feasibility of organ preservation. It is hoped that increased inter-

change between basic scientists and clinical investigators will facilitate the rational design of these studies. ACKNOWLEDGMENT We wish to thank Margaret Caldwell for preparation of the manuscript, and Richard L. Schilsky for his critical suggestions.

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Experience with GM-CSF in the treatment of solid tumors.

Experience with "second-look" operations in pediatric solid tumors.

Safety of Onartuzumab in Patients with Solid Tumors: Experience to Date from the Onartuzumab Clinical Trial Program.

Bloodstream infections in patients with solid tumors.

Combining Bevacizumab with Radiation or Chemoradiation for Solid Tumors: A Review of the Scientific Rationale, and Clinical Trials.

Monitoring tumor-derived cell-free DNA in patients with solid tumors: clinical perspectives and research opportunities.

Phase I Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors.

Concomitant-chemoradiotherapy-associated oral lesions in patients with oral squamous-cell carcinoma.

Predicting clinical benefit from everolimus in patients with advanced solid tumors, the CPCT-03 study.

Introducing iron isomaltoside 1000 (Monofer®)-development rationale and clinical experience.

Primary venous thromboembolism prophylaxis in patients with solid tumors.

Constitutional balanced translocations in patients with solid tumors.

Prognostic significance of HER3 in patients with malignant solid tumors.

Serum lysozyme levels in patients with solid tumors.

Single institutional experience of prevalence and risk factors of thromboembolic events in children with solid tumors.

Experience in clinical diagnosis and treatment of duodenal tumors.

Concomitant chemoradiotherapy with cisplatin, 5-fluorouracil and hydroxyurea in poor-prognosis head and neck cancer.

Clinical trials of bestatin for leukemia and solid tumors.

Suppression of mTOR pathway in solid tumors: lessons learned from clinical experience in renal cell carcinoma and neuroendocrine tumors and new perspectives.

Phase I clinical trial of ifosfamide, oxaliplatin, and etoposide (IOE) in pediatric patients with refractory solid tumors.

Clinical and pharmacologic evaluation of two dosing schedules of indotecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors.

Clinical application of adoptive T cell therapy in solid tumors.

Adjuvant temozolomide-based chemoradiotherapy versus radiotherapy alone in patients with WHO III astrocytoma: The Mainz experience.

Laparoscopic central pancreatectomy for solid pseudopapillary tumors of the pancreas: our experience with ten cases.