Drug Profile

10.1586/14737140.6.7.973 © 2006 Future Drugs Ltd ISSN 1473-7140 973www.future-drugs.com

Satraplatin: an orally available platinum analog for the treatment of cancerHak Choy

University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, TX 75390–9183, USATel.: +1 214 645 7600Fax: +1 214 645 7622hak.choy@utsouthwestern.edu

KEYWORDS: cisplatin, head and neck cancer, prostate cancer, radiation, satraplatin

Satraplatin is a novel, orally bioavailable, platinum anticancer drug. Platinum analogs form the mainstay of treatment for a number of cancers, including lung, ovarian, colorectal and head and neck cancer. A disadvantage of the currently marketed platinum analogs is that they must all be administered via intravenous infusion. In addition, their utility is often limited by toxicity, particularly neurotoxicity, ototoxicity and renal toxicity. Satraplatin has preclinical antitumor activity comparable with that of cisplatin and, clinically, has a more manageable side-effect profile. Satraplatin is active in lung, ovarian and prostate cancer, and appears to have good efficacy in combination with radiation for lung and head and neck cancer. Preclinical data suggest it may also be effective for the treatment of certain cisplatin-refractory tumors. A large, randomized Phase III trial is currently evaluating satraplatin in combination with prednisone for the treatment of patients with hormone-refractory prostate cancer whose disease has progressed following prior systemic therapy. Positive results from this trial would support regulatory approval for satraplatin for this indication. The availability of an active oral platinum agent, such as satraplatin, with few of the serious toxicities associated with traditional intravenous platinum compounds makes satraplatin an alternative to other platinum agents and a new treatment option in the oncologist’s armamentarium.

Expert Rev. Anticancer Ther. 6(7), 973–982 (2006)

Platinum-based chemotherapy continues to bean integral part of many currently used regi-mens for a variety of tumor types. Cisplatin,and to a lesser extent carboplatin, are widelyused both as single agents and, more com-monly, in combination regimens with othercytotoxics and with radiotherapy (RT) for thetreatment of various solid tumors. However,these platinum compounds, which are admin-istered intravenously (i.v.), often result insevere, dose-limiting adverse effects, such asrenal toxicity, neurotoxicity, ototoxicity, nauseaand vomiting. Similarly, i.v. administration ofoxaliplatin, another platinum derivative, caninduce hematological and gastrointestinal (GI)tract toxicity, as well as a unique neuropathy. Insome patients, these agents can trigger hyper-sensitivity and anaphylactic or anaphylactoidreactions. Moreover, de novo or acquired resist-ance to cisplatin is commonly observed inovarian cancer and other malignancies, which

often necessitates a change in therapy. Conse-quently, recent studies have focused on devel-oping new, superior platinum analogs that havean improved toxicity profile and reducedcross-resistance to cisplatin [1].

There has also been increasing interest in,and development of, oral anticancer agents fortreatment of many solid tumors. Over the past10 years, oral chemotherapy agents, such ascapecitabine [2] and oral etoposide [3], and tar-geted therapies, such as the epidermal growthfactor receptor tyrosine kinase inhibitor erlo-tinib [4], have been evaluated in a largenumber of clinical trials and were generallyfound to be effective, with low to moderatetoxicity. For hematological malignancies, oralchemotherapeutics have been used in treat-ment regimens for several years [5]. Some oralchemotherapeutics appear to be as efficaciousas their i.v. counterparts, and all offer theadvantages of greater convenience and ease of

CONTENTS

Satraplatin

Clinical trials with satraplatin

Satraplatin & radiation therapy

Conclusion

Expert commentary

Five-year view

Key issues

References

Affiliation

For reprint orders, please contact reprints@future-drugs.com

Choy

974 Expert Rev. Anticancer Ther. 6(7), (2006)

administration, reduced need for patient office visits, elimina-tion of venous access devices and associated complications andreduced healthcare costs [6–10]. The platinum analog satraplatinwas synthesized in order to address both the toxicity and resist-ance issues. Satraplatin is an orally administered platinumderivative that has a milder toxicity profile than cisplatin (i.e.,closer to carboplatin) but with activity comparable with theseparenterally administered platinums.

SatraplatinSatraplatin (formerly known as JM-216) is a fourth-generationplatinum analog originally synthesized by Johnson Matthey. Incontrast to other marketed platinum derivatives that must beadministered intravenously (i.e., cisplatin, carboplatin andoxaliplatin), satraplatin is orally bioavailable. Therefore, admin-istration is easier for healthcare professionals and more conven-ient for patients. Satraplatin was identified through an intensiveresearch program designed to identify potential oral platinumderivatives with a milder toxicity profile than cisplatin. Thecompound was selected for clinical development based on itsactivity profile observed in preclinical studies, including cispla-tin-resistant tumor cell lines, and its oral availability and toxic-ity profile. In this review, preclinical, pharmacokinetic and clin-ical data on satraplatin in the treatment of various types of solidtumors are summarized, as are the future prospects for its use incombination with RT.

Satraplatin chemistrySatraplatin, or bis-(acetato)-ammine dichloro-(cyclohexylamine)platinum(IV), shares some structural similarities with cisplatinsince both have two chlorine atoms attached to the platinum(FIGURE 1) [11]. However, satraplatin is a platinum(IV) complexwith two acetate groups attached and a cyclohexyl moiety sub-stituted on one of the amine groups. Therefore, satraplatin ismore lipophilic than cisplatin, which reduces its solubility inwater but increases its oral bioavailability.

Preclinical activitySimilar to cisplatin, satraplatin acts through formation of DNAadducts and inter- and intrastrand crosslinks [12]. These producearrest at the G2 stage of the cell cycle, with subsequent induc-tion of apoptosis, although some studies have also demonstratedan S-phase delay [13]. Platinum–DNA adducts are induced bysatraplatin at similar levels in tumor cell lines sensitive or resist-ant to cisplatin, suggesting that tolerance or DNA repair mech-anisms, rather than the level of adduct formation, play a role incisplatin resistance [13,14]. Similarly, DNA adducts induced bysatraplatin are repaired by the nucleotide excision repair (NER)pathway with kinetics similar to that of other platinum analogs[15]. Consequently, cross-resistance to cisplatin is not likelyrelated to differences in excision repair. In contrast to cisplatinand carboplatin, satraplatin-induced adducts are not recognizedby DNA mismatch repair proteins [16]. This difference may pro-vide a mechanism by which satraplatin can overcome drugresistance owing to loss of DNA mismatch repair. Other studies

point to the relative resistance of satraplatin–DNA adducts tobinding by high mobility group (HMG)1 protein (known torecognize cisplatin-damaged DNA) and to replicative bypass bycertain DNA polymerases, compared with adducts formed byother platinum agents [17].

Satraplatin demonstrated potent antitumor activity in vitroand in vivo against cancer cells that are sensitive or resistant tocisplatin. In cervical and ovarian cancer cell lines, 50% inhibi-tory concentration (IC50) values for satraplatin were0.6–1.7 µM, comparable with those observed for cisplatin [18].Similar results were noted in small cell lung cancer (SCLC) celllines [19]. Satraplatin also has antitumor activity against prostatecancer, with micromolar concentrations producing cytotoxicityin androgen-sensitive and -insensitive human prostate cancercell lines [20]. Its cytotoxicity was comparable with that of cispl-atin when evaluated against a panel of ovarian cancer cell linesand was also active against selected cisplatin-resistant lines [21].In four ovarian cancer cell lines with varying sensitivity to cispl-atin and carboplatin, satraplatin had comparable activity andwas superior to another platinum analog, tetraplatin. In vivo,satraplatin had greater tumor selectivity against the cisplatin-sensitive murine ADJ/PC6 plasmacytoma, compared with cis-platin, carboplatin or tetraplatin. Preclinical experiments havedemonstrated that satraplatin retains activity against tumor celllines that are resistant to taxanes due to tubulin mutations orP-glycoprotein expression [19,20].

Importantly, satraplatin exhibited additive or synergistictumor inhibition when combined with other therapeuticmodalities. Satraplatin plus the topoisomerase II inhibitoretoposide produced synergistic inhibition of the P388 murineleukemia [22].

Other preclinical data suggest that satraplatin has an additiveeffect when combined with RT. Mice implanted with H460human lung cancer xenografts were treated with 30 mg/kg sat-raplatin then, 1 h later, with 2 Gy radiation, for 5 consecutivedays [23]. The combination regimen produced greater inhibi-tion of tumor growth than either agent alone, results that weresupported by in vitro clonogenic assays using the same cell line.

Taken together, these preclinical findings indicate satraplatinhas potent antitumor activity across a number of tumor types.They also suggest its potential for combination therapy withother commonly used treatments, such as chemotherapy andRT, providing the rationale for exploring the clinical activity ofsatraplatin as a single agent and in combination regimensagainst various human malignancies.

Figure 1. Structures of satraplatin (JM-216; bis-[acetato]-amminedichloro-[cyclohexylamine]platinum[IV]) and cisplatin.

PtCl

Cl

NH3

NH3

Pt

OCOCH3

OCOCH3NH3

NH2

Cl

Cl

Satraplatin Cisplatin

Satraplatin

www.future-drugs.com 975

PharmacokineticsAbsorption of satraplatin is rapid, with peak plasma levels gener-ally attained within 2 h. The half-life (t½) was determined to beapproximately 12 h when assayed 5 days after oral administra-tion of a dose of 100 mg/m2 [24,25]. Little drug is detectable asfree platinum in the plasma ultrafiltrate since satraplatin and itsmetabolites are largely bound to plasma proteins and other bloodcomponents. Within 3 h of administration, satraplatin is rapidlyconverted to its major metabolite, cis-amine dichloro (cyclohexy-lamine) platinum(II), also known as JM118 [18]. When incu-bated in whole blood in vitro, satraplatin undergoes rapidbiotransformation to JM118; this reductive activation dependson dihydronicotinamide adenine dinucleotide (NADH) and,possibly, the presence of heme proteins that may act as reducingagents [26,27]. Other metabolites have been identified, some ofwhich are biologically active [28].

McKeage and colleagues conducted a Phase I pharmacokineticstudy of satraplatin administered at doses of up to150 mg/m2/day for 5 days [24,25]. These investigators observed alinear correlation between plasma ultrafiltrate area under thecurve (AUC) and doses up to 120 mg/m2/day. At higher doses(single doses >200 mg/m2/day), this relationship became nonlin-ear owing to saturable GI absorption of satraplatin. Plasma ultra-filtrate AUC on days 1 and 5 was also found to correlate with thelevel of thrombocytopenia [28]. Studies in small animal tumormodels suggested that the daily 5-day schedule was associatedwith optimal antitumor activity and pharmacokinetics [29],results that were confirmed in Phase I trials.

Another pharmacokinetic study evaluated daily oral adminis-tration of satraplatin in 19 cancer patients enrolled in Phase Iand II trials [30]. Satraplatin was administered at doses of10–50 mg/m2/day for 14 days (dose-escalation Phase I study) or120 mg/m2/day for 5 days (fixed-dose Phase II study). Linearpharmacokinetics were observed across the Phase I dose range;total platinum levels on day 14 correlated with satraplatin doseper body surface area (BSA) of ultrafilterable platinum levels.Following administration of the last dose, prolonged t½ valueswere noted for both total and ultrafilterable platinum (mean:216 ± 37 h and 107 ± 89 h, respectively). The cumulative satra-platin dose and AUC of total platinum on day 14 correlatedwith the thrombocytopenia nadir, although no relationships toneutropenia or leukopenia were found. These data suggest thatsatraplatin has predictable pharmacokinetics and that the drugaccumulates in the plasma following repeated administration.

Preclinical data suggest that satraplatin may inhibit certain cyto-chrome P450 isozymes [31], necessitating dose reductions whenused in combination regimens, such as with oral etoposide [22].

Satraplatin is formulated as 10- and 5-mg capsules. The drugis typically administered once daily on an empty stomach.

Clinical trials with satraplatinSatraplatin has been investigated in numerous clinical trials for avariety of human malignancies. To date, more than 600 patientshave been enrolled in these trials, which include trials in prostate,ovarian, cervical, head and neck and lung cancer.

Phase I studiesMultiple Phase I trials have been conducted to evaluate the dos-ing and safety of satraplatin. A variety of dosing schedules werestudied, ranging from a single dose every 3 weeks to daily dos-ing (for up to 14 days) [24,25,29,31–34]. The daily 5-day dosingschedule, repeated every 4–5 weeks, was deemed optimal andwas selected for further clinical development.

The primary dose-limiting toxicity (DLT) of satraplatin wasmyelosuppression (primarily neutropenia and thrombocytope-nia), although these were not cumulative and recovered byday 28 [25]. The incidence of grade 3/4 GI toxicity was low andconsisted of nausea (11% of courses), vomiting (13%) anddiarrhea (7%). Emesis could be managed through premedica-tion with 5-hydroxytryptamine (5-HT3) antagonists. A poten-tially important clinical benefit is that no nephrotoxicity, periph-eral neurotoxicity or ototoxicity was observed with satraplatintherapy. The recommended dose schedule for chemonaivepatients was 100–120 mg/m2/day for 5 consecutive days,repeated every 4–5 weeks. Using a similar dose and schedule ofsatraplatin in chemonaive lung cancer patients, Fokkema andcolleagues found no evidence of drug-related nephrotoxicity [35].

In light of the efficacy and widespread use of platinum/tax-ane combination chemotherapy regimens in lung cancer andother tumor types, a Phase I study was conducted to evaluatethe combination of satraplatin and paclitaxel [36]. In thisstudy, 43 patients received a total of 146 courses of the com-bination regimen. These patients, most having colorectal (19)or lung (10) cancer, had received a median of two prior chem-otherapy regimens. The combination of satraplatin and pacli-taxel was generally well tolerated; myelosuppression was themost common serious adverse event. These authors recom-mended a regimen consisting of satraplatin 60 mg/m2/day for5 days and paclitaxel 200 mg/m2, repeated every 3–4 weeks,for Phase II studies.

Phase II & III studiesA number of Phase II and III trials have been conducted to inves-tigate the efficacy and safety of satraplatin for the treatment ofvarious cancers. These studies are now summarized.

Prostate cancer

Androgen-deprivation therapy is the most common treatmentfor men with prostate cancer who experience disease progres-sion. However, a significant proportion of patients subse-quently develop hormone-resistant prostate cancer (HRPC)and become refractory to such treatment [37]. Until the recentdevelopment of taxane-based regimens, there was no effectivetreatment for HRPC. Previously approved drugs for the treat-ment of HRPC include mitoxantrone and estramustine,which have palliative benefit. Results from two randomizedPhase III trials (TAX 327 and Southwest Oncology Group[SWOG] 9916) conclusively demonstrated that first-linetreatment with docetaxel could prolong survival in this set-ting. In these trials, the combination of mitoxantrone plusprednisone was compared with docetaxel plus estramustine or

Choy

976 Expert Rev. Anticancer Ther. 6(7), (2006)

docetaxel plus prednisone [38,39]. Docetaxel-based therapyimproved survival, increased prostate-specific antigen (PSA)response, decreased pain scores and improved quality of life,leading the US FDA to approve i.v. docetaxel in combinationwith prednisone as first-line therapy in metastatic HRPC.Current treatment guidelines support the use of a docetaxel-based regimen with prednisone or oral estramustine asfirst-line therapy for this patient population [101].

However, the benefit of docetaxel is limited since manypatients subsequently progress and become resistant to this agent(median time to PSA progression following taxane-based therapyis approximately 6 months) [40]. No standard treatment exists forsecond-line therapy of metastatic HRPC. Thus, there is a signifi-cant unmet need for effective therapies in the second-line settingfor patients with metastatic HRPC.

Early studies evaluating cisplatin-based therapy for advancedprostate cancer have produced unimpressive results [41,42].Moreover, the severe toxicities associated with cisplatin canresult in missed doses and/or dose reductions that compromisethe efficacy of therapy. The availability of a less toxic oral plati-num analog, such as satraplatin, coupled with its preclinicalactivity in hormone-sensitive and -resistant prostate cancer celllines [43], prompted investigation of satraplatin for the treatmentof prostate cancer.

Five Phase II or III trials of satraplatin for the treatment ofprostate cancer have been completed or are ongoing. Three ofthe completed trials were terminated by the pharmaceuticalsponsor at the time (Bristol-Myers Squibb) prior to achievingtarget accrual, owing to an internal decision not to pursuedevelopment of this drug. Preliminary activity and a manage-able toxicity profile were observed in an open-label Phase IItrial in 39 chemonaive patients with HRPC who received satra-platin 120 mg/m2/day for 5 days, every 28 days [44]. A partialPSA response was observed in 26% of patients, stable disease in36% and PSA progression in 21%. Documented partial tumorresponses were noted in two out of 20 patients with measurabledisease. The most common grade 3/4 adverse events includedanemia (24%), neutropenia (52%), thrombocytopenia (54%),diarrhea (28%), nausea (13%) and vomiting (16%).

The largest completed study was a randomized Phase III trialconducted by the European Organization for Cancer Research(EORTC 30972) that compared satraplatin plus prednisonewith prednisone alone as first-line therapy for patients withHRPC [45]. Satraplatin was administered orally at a dose of100 mg/m2/day for 5 days, repeated every 35 days. The pred-nisone dose in both arms was 10 mg/m2, which was adminis-tered twice daily. Target accrual was 380 patients; however, thestudy was terminated early by the sponsor after 50 patientswere enrolled. Analysis of these data demonstrated that thecombination of satraplatin and prednisone significantlyincreased progression-free survival (PFS) compared with theprednisone arm (5.2 vs 2.5 months; p = 0.023) (FIGURE 2). Addi-tionally, the combination produced a statistically significantincrease in PSA response compared with prednisone alone(33.3 vs 8.7%; p = 0.046) (TABLE 1). Median overall survival was

3 months longer with satraplatin (14.9 vs 11.9 months); thisdifference was not statistically significant (p = 0.579), probablyowing to the small sample size. Toxicity with satraplatin/pred-nisone was acceptable (TABLE 2). Serious hematological toxicitiesincluded leukopenia (25.9%, grade 3), thrombocytopenia(29.6%, grade 3) and absolute neutrophil count (14.8%, grade3/4) [46]. Serious nonhematological toxicities consisted of vom-iting, diarrhea, infection, cardiovascular and hyperglycemia (all7.4%, grade 3). These data suggest that the combination of sat-raplatin and prednisone is an active and tolerable first-line regi-men in patients with HRPC. While the conclusions of this trialmust be tempered in light of the small patient size as a result ofearly study closure, the data support an increase in PSAresponse and PFS with satraplatin.

To extend the results observed in the EORTC trial anddetermine the possible impact on survival, a Phase III trial ofsatraplatin plus prednisone in HRPC was initiated. The Satra-platin and Prednisone Against Refractory Cancer (SPARC)trial is an ongoing multinational, multicenter, double-blind,placebo-controlled study designed to compare satraplatin andprednisone with prednisone alone as second-line therapy inpatients with HRPC [47]. Treatment consists of prednisone5 mg twice daily on days 1–35, plus either placebo or oral sat-raplatin 80 mg/m2 twice daily on days 1–5 of a 35-day cycle(FIGURE 3). Patients are randomized to either of the two treat-ment groups in a 2:1 ratio in favor of the satraplatin arm. Sat-raplatin therapy is continued for a maximum of eight cycles.Patients on the satraplatin arm are administered oral graniset-ron (1 mg twice daily on days 1–5) as an antiemetic, whilethose on the prednisone-only arm receive a placebo antiemetic.Major inclusion criteria include: patients with metastatic

Figure 2. Progression-free survival curves for two treatment arms (prednisone alone and prednisone plus satraplatin) in the Phase II European Organization for the Research and Treatment of Cancer trial for hormone-refractory prostate cancer. Median: Pred: 2.5 months (95% CI: 2.1–4.7); Pred + satraplatin: 5.2 months (95% CI: 2.8–13.7); Hazard ratio: 0.50 (95% CI: 0.28–0.92); p = 0.023. Adapted with permission from [45].Pred: Prednisone; CI: Confidence interval.

1009080706050403020100

0 3 6 9 12 15 18 21 24 27

PredPred + satraplatin

O N Number of patients at risk:23 23 10 5 3 3 1 1 0 025 27 18 11 11 11 6 5 5 3

Months

Su

rviv

al (

%)

Satraplatin

www.future-drugs.com 977

prostate cancer and disease progression following one line ofchemotherapy; hormone-refractory disease; Eastern Coopera-tive Oncology Group performance status of 2 or less; lifeexpectancy 3 months or greater; and adequate hematological,renal and hepatic function. Primary exclusion criteria include:more than one prior chemotherapy treatment or prior therapywith a platinum analog; significant prior RT; presence of brainmetastases; contraindication to steroids; and inability to ade-quately absorb satraplatin orally. End points are PFS, overallsurvival and time to progression for pain. Enrollment of912 patients into the SPARC trial was recently completed.Results of this trial, if positive, will serve as the basis for sub-mission for regulatory approval of satraplatin combined withprednisone as second-line therapy for HRPC.

Other tumor types

Satraplatin was evaluated in a Phase II trial as first-line therapyfor patients with advanced non-small cell lung cancer(NSCLC) [48]. The dose schedule consisted of oral satraplatin120 mg/m2/day for 5 days every 3 weeks. Five out of 13 evalua-ble patients had stable disease as best response. However, itshould be noted that single-agent response rates for cisplatin orcarboplatin are also poor, generally 10% or less [49]. Addition-ally, a Phase II trial evaluated satraplatin in 27 chemonaivepatients with limited or extensive SCLC [50]. Satraplatin was ini-tially dosed at 120 mg/m2/day for 5 days, repeated every21 days; this was subsequently escalated to 140 mg/m2/day in13 patients. Objective responses occurred in ten out of 26 eval-uable patients with a response rate of 38%, similar to thatobserved with cisplatin monotherapy in SCLC [51]. Of note, nonephrotoxicity or neurotoxicity occurred with satraplatin.

A multicenter Phase II trial investigated the activity of oralsatraplatin (30 mg/m2/day × 14 every 5 weeks) in patientswith advanced or recurrent squamous cell carcinoma of thecervix who had previously been treated with RT (includingfour who also had received prior cisplatin) [52]. One out of 18patients treated achieved a partial response (PR) and 12 had a

best response of stable disease. These data suggest satraplatin isactive in recurrent cervical cancer, although patient numberswere small and a low drug dose was used in this study.

Satraplatin & radiation therapyPlatinum anticancer agents are often used in combination withRT for the treatment of several cancers. Since the marketedplatinum analogs have to be administered by i.v. infusion, theyare usually given either weekly or every 3 weeks in multimodal-ity regimens. A number of clinical studies suggest that dailyadministration of a platinum analog may be superior to peri-odic administration. For example, patients with nonmetastaticinoperable NSCLC who received RT plus daily cisplatin had asignificantly longer survival compared with those treated withRT and a less frequent cisplatin dosing schedule [53]. In locallyadvanced squamous cell head and neck cancer (SCCHN), Jere-mic and colleagues found that the combination of hyperfrac-tionated RT and daily cisplatin was superior to hyperfraction-ated RT alone, resulting in higher overall survival, locoregionalPFS and distant metastasis-free survival at 5 years [54]. A pro-spective randomized trial by these investigators in a similarpatient population revealed improved outcomes using dailyadministration of cisplatin or carboplatin with standard frac-tion RT, compared with RT alone. Patients receiving dailychemotherapy had higher overall response rates, longer mediansurvival time and higher 5-year survival rates [55]. These resultssuggest that daily administration of a platinum in combinationwith RT is effective for the treatment of several advancedmalignancies, although randomized Phase III trials are requiredto confirm this idea.

Since satraplatin is orally bioavailable, it can be convenientlyadministered on a daily basis in combination with RT. Preclinicalstudies suggested that the combination of satraplatin and RT pro-duced at least additive inhibition of lung cancer cell growth [23].Therefore, two Phase I trials were conducted to explore the clini-cal potential of this combined-modality approach. In the firststudy, patients with NSCLC or esophageal cancer were treated

Table 1. European Organization for the Research and Treatment of Cancer 30972 trial of satraplatin and prednisone versus prednisone in hormone-resistant prostate cancer.

Prednisone plus satraplatin N (%)(n = 27)

Prednisone N (%)(n = 23)

p-value

Prostate-specific antigen response

Response 9 (33.3) 2 (8.7) 0.046

Stable disease 5 (18.5) 3 (13.0)

Progression 12 (44.4) 17 (73.9)

Not evaluable 1 (3.7) 1 (4.3)

Progression-free survival (months) 5.2 2.5 0.023

Median overall survival (months) 14.9 11.9 0.579

Efficacy data from [45].

Choy

978 Expert Rev. Anticancer Ther. 6(7), (2006)

with 30–60 mg/m2 satraplatin daily for 5 days, every 3 weeks [56].Radiation was delivered to the chest in single daily fractions of200 cGy for 5 consecutive days each week. The major dose-limit-ing toxicity (DLT) was myelosuppression. These authors recom-mended a satraplatin dose of 30 mg/m2/day every 3 weeks withconcurrent radiation. In another Phase I trial, Choy and col-leagues evaluated satraplatin and RT in 20 patients with NSCLCor locally advanced SCCHN. [57]. Those with prior malignancy,previous radiotherapy or systemic chemotherapy or distantmetastases were excluded from the study. Satraplatin 10–30 mgwas administered three times per week (Monday, Wednesday andFriday) 1–3 h prior to radiation (60 Gy/6 weeks for NSCLC;70 Gy/7 weeks for SCCHN). This regimen was better toleratedthan the previous Phase I radiation trial; nausea and vomitingwere the major DLTs. It should be noted that, in this Phase Istudy, prophylactic antiemetics were not used. Efficacy resultswere encouraging: seven out of eight SCCHN patients achieved acomplete response (CR) and one CR and six PRs were observedin 15 NSCLC patients. The recommended dose of satraplatin forfuture trials was 20 mg administered three times a week duringthe course of radiotherapy. Although the small number ofpatients in this trial does not allow definitive conclusions, thesehigh response rates were encouraging and warrant further studyof this regimen.

A modification of this combined modality regimen is currentlybeing evaluated in an ongoing Phase I trial for locally advanced,unresectable NSCLC (Choy H, principal investigator). In the

dose-escalation Phase I study, satraplatin is administered daily for5 days continuously through the entire 7-week course of RT(TABLE 3). Escalating doses of satraplatin (from 10 to 50 mg/day)will be administered daily five times per week for 7 weeks, incombination with RT (total dose of 63 Gy, administered in1.8-Gy daily fractions), as shown in TABLE 3. Upon completion ofradiotherapy, consolidation therapy consisting of docetaxel75 mg/m2 will be administered every 21 days for three cycles.Patients with histologically confirmed NSCLC who have notreceived chest radiotherapy are eligible for this study. Once theoptimal dose has been established, a Phase II study of this regi-men will be initiated in this patient population. Of note, to date,no DLT has been observed with this schedule.

ConclusionData from clinical trials support the efficacy of satraplatin for thetreatment of multiple tumor types. This novel platinum analogis orally administered, has antitumor activity that appears to becomparable with that of cisplatin and has a more tolerable safetyprofile than other platinum agents. Preclinical findings suggestits potential for treatment of cisplatin-resistant tumors, whichwarrants evaluation in clinical trials of cisplatin-resistant ovariancancer and other malignancies.

Data from the EORTC Phase II study make satraplatin theonly platinum to demonstrate activity against prostate cancer in amulticenter randomized trial. Results of the SPARC trial areawaited with interest to determine the impact of the regimen of

Table 2. European Organization for the Research and Treatment of Cancer 30972 trial of satraplatin/prednisone versus prednisone in hormone-resistant prostate cancer.

PrednisoneN (%)(n = 23)

Prednisone plus satraplatinN (%)(n = 27)

WBC (grade 3) NA 7 (25.9)

Platelets (grade 3) NA 8 (29.6)

ANC (grade 3/4) NA 4 (14.8)

Hemoglobin (grade 3/4) NA 0 (0.0)

Serum creatinine (grade 4)* 1 (4.3) 0 (0.0)

SGOT (grade 3) 2 (8.7) 0 (0.0)

Alkaline phosphatase (grade 3/4) 7 (30.4) 3 (11.1)

Diarrhea (grade 3) 0 (0.0) 2 (7.4)

Vomiting (grade 3) 0 2 (7.4)

Infection (grade 3) 1 (4.3) 2 (7.4)

Cardiovascular (grade 3) 2 (8.7) 2 (7.4)

Hyperglycemia (grade 3) 4 (17.0) 2 (7.4)

Renal (grade 3) 1 (4.3) 0 (0.0)

ANC: Absolute neutrophil count; NA: Data not available; SGOT: Glutamic-oxaloacetic transaminase; WBC: White blood cells.Safety data from [45,46].

Satraplatin

www.future-drugs.com 979

satraplatin and prednisone as second-line therapy for the treat-ment of patients with HRPC. Since the EORTC trial was haltedprematurely, data from the SPARC trial are needed to confirmthe activity of satraplatin in this setting.

Since combined modality therapy with radiation and platinum-based chemotherapy is now the standard of care for locallyadvanced NSCLC and is also commonly used for other malignan-cies, substitution of cisplatin with satraplatin has the potential toimprove outcomes and reduce toxicities. Its dosing and administra-tion favor its use in combined-modality regimens with radiation.In contrast to infusional agents, such as cisplatin, that are adminis-tered weekly or every 3 weeks, satraplatin can be administered dailywith radiation – in essence simulating a continuous infusion. Thiswould ensure that adequate drug levels are maintained duringirradiation to allow for the maximum synergistic effect.

Expert commentaryToxicities observed with satraplatin appear to be less than thoseseen with other platinums. Cisplatin is associated with signifi-cant toxicities that can limit its use, such as nephrotoxicity, oto-toxicity and neurotoxicity. Similarly, oxaliplatin can result indose-limiting peripheral sensory neuropathy. These adverse

effects are not observed with satraplatin. Myelosuppression isthe DLT with satraplatin; GI toxicities are generally of lowgrade and manageable with standard treatment. The mild tox-icity profile of satraplatin, including absence of significant oto-toxicity and neurotoxicity, will foster its use with concurrentRT for SCCHN and lung cancer regimens requiring protracteddrug administration [36]. Satraplatin does not require the i.v.hydration that is necessary with cisplatin. Furthermore, the lackof nephrotoxicity and neurotoxicity make satraplatin an optionfor patients unable to tolerate such adverse effects.

In SCCHN, cisplatin combined with infusional 5-fluorour-acil has been the standard of care for chemonaive patients withrecurrent and/or metastatic disease and good performance sta-tus [58]. The addition of other agents, such as paclitaxel, hasincreased response rates but not improved survival [59]. Thus,there is a significant need for newer agents that can improveupon these results for patients with advanced SCCHN. Satrapl-atin used in combination with radiation has the potential tosignificantly improve outcomes in the advanced disease setting,both as adjuvant therapy and in patients with metastatic/recur-rent disease. Results from the Phase I/II trial may demonstratethe efficacy, safety and convenience of the daily 5-day scheduleof satraplatin and radiotherapy, which must be substantiatedthrough subsequent Phase II trials.

Oral chemotherapeutics, such as satraplatin, have obviousadvantages over i.v. approaches, although certain issues must beaddressed. Patients should realize that oral agents are ‘real’chemotherapy and can be just as effective as i.v. formulations.The effectiveness of oral agents is highly dependent on patientcompliance, therefore it is incumbent on healthcare providers toeducate patients on the importance of adherence and monitortherapy on an ongoing basis.

Five-year viewOver the next 5 years, satraplatin in combination with pred-nisone will likely be approved in the USA for second-line treat-ment of HRPC, assuming a survival advantage over prednisonealone is demonstrated in the SPARC trial. It should also continueto be explored as an option in the first-line hormone-refractory

Figure 3. Schema for the Phase III Satraplatin and Prednisone Against Refractory Cancer trial of satraplatin plus prednisone versus placebo plus prednisone as second-line therapy for metastatic HRPC. Satraplatin was continued for a maximum of eight cycles.HRPC: Hormone-resistant prostate cancer.

ProgressivemetastaticHRPC

Satraplatin80 mg/m2/day × 5, every 5 weeks +Prednisone5 mg twice daily, every 35 days

Placebo +Prednisone5 mg twice daily, every 35 days

Ran

dom

ize

Table 3. Dose escalation for an ongoing Phase I trial of satraplatin and radiation therapy in advanced non-small cell lung cancer.

Dose level Satraplatin dose (mg/day) Treatment days or a radiotherapy Total satraplatin dose over 7 weeks (mg)

-1 10 M, W, F 210

1 10 M, Tu, W, Th, F 340

2 20 M, Tu, W, Th, F 680

3 30 M, Tu, W, Th, F 1020

4 40 M, Tu, W, Th, F 1360

5 50 M, Tu, W, Th, F 1700

M: Monday, Tu: Tuesday, W: Wednesday; Th: Thursday; F: Friday.

Choy

980 Expert Rev. Anticancer Ther. 6(7), (2006)

setting, given the encouraging results from the EORTC study.Satraplatin-based regimens may prove to extend survival and pro-vide pain palliation equal to that observed with first-linedocetaxel regimens in this disease.

Initial Phase I results suggest that satraplatin plus RT hassignificant activity and a good tolerability profile, particularlyin patients with SCCHN. Further Phase II trials of this regi-men should be conducted in both SCCHN and NSCLC toconfirm these data and determine the impact on survival.Given its efficacy against selected cisplatin-resistant cell lines,it is possible that satraplatin may add to the effects of radia-tion for the treatment of malignancies that exhibit cisplatinresistance. Continued study of satraplatin-based combinationregimens in the treatment of platinum-sensitive ovarian can-cer is warranted, based on initial Phase II data. Its activity in

platinum-resistant and/or refractory ovarian cancer is an areathat could also be explored. Pharmacogenomic studies mayhelp to identify specific tumor types and individual patientswith greater sensitivity to satraplatin compared with cisplatinand identify surrogate markers for satraplatin response.

It is evident that the use of oral chemotherapy will continueto increase as more agents become available with efficacy com-parable with that of i.v. drugs and equivalent or reduced toxic-ity. Greater patient convenience, lower cost and simplifiedadministration schedules all argue in favor of the expanded useof oral agents. The availability of an oral platinum, such as sat-raplatin, if proven to be effective in randomized Phase II andIII trials, will facilitate the development of all-oral regimens,either used in combination with other oral cytotoxics or oraltargeted therapies.

ReferencesPapers of special note have been highlighted as:• of interest•• of considerable interest

1 Ho YP, Au-Yeung SC, To KK. Platinum-based anticancer agents: innovative design strategies and biological perspectives. Med. Res. Rev. 23, 633–655 (2003).

2 O’Shaughnessy J, Miles D, Vukelja S et al. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J. Clin. Oncol. 20, 2812–2823 (2002).

3 Alici S, Saip P, Eralp Y et al. Oral etoposide (VP16) in platinum-resistant epithelial ovarian cancer (EOC). Am. J. Clin. Oncol. 26, 358–362 (2003).

4 Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353, 123–132 (2005).

5 Geller RB, Dix SP. Oral chemotherapy agents in the treatment of leukaemia. Drugs 58(Suppl. 3), 109–118 (1999).

6 Greco FA. Evolving role of oral chemotherapy for the treatment of patients with neoplasms. Oncology 12(Suppl. 4), 43–50 (1998).

7 O'Neill VJ, Twelves CJ. Oral cancer treatment: developments in chemotherapy and beyond. Br. J. Cancer 87, 933–937 (2002).

8 Hwang JJ, Marshall JL. Capecitabine: fulfilling the promise of oral chemotherapy. Expert Opin. Pharmacother. 3, 733–743 (2002).

9 Cunningham D, Coleman R. New options for outpatient chemotherapy – the role of oral fluoropyrimidines. Cancer Treat. Rev. 27, 211–220 (2001).

10 Ajani JA, Takiuchi H. Recent developments in oral chemotherapy options for gastric carcinoma. Drugs 58(Suppl. 3), 85–90 (1999).

11 Scher HI, Leibel SA, Fuks Z, Cordon-Cardo C, Scardino PT. Cancer of the prostate. Cancer: Principles and Practice of Oncology (7th Edition). DeVita VT Jr, Hellman S, Rosenberg SA (Eds). Lippincott Williams & Wilkins, PA, USA (2005).

12 Mellish KJ, Barnard CF, Murrer BA et al. DNA-binding properties of novel cis- and trans platinum-based anticancer agents in 2 human ovarian carcinoma cell lines. Int. J. Cancer 62, 717–723 (1995).

13 O'Neill CF, Koberle B, Masters JR, Kelland LR. Gene-specific repair of Pt/DNA lesions and induction of apoptosis by the oral platinum drug JM216 in three human ovarian carcinoma cell lines sensitive and resistant to cisplatin. Br. J. Cancer 81, 1294–1303 (1999).

14 Fokkema E, Groen HJ, Helder MN, de Vries EG, Meijer C. JM216-, JM118-, and cisplatin-induced cytotoxicity in relation to platinum-DNA adduct

Key issues

• Satraplatin is an oral platinum analog with antitumor activity similar to that of cisplatin.

• In vitro, satraplatin is active against selected tumors resistant to cisplatin and taxanes, and may synergize with other chemotherapeutics and radiation.

• Both cisplatin and satraplatin induce formation of DNA adducts and crosslinks. However, satraplatin adducts are not recognized by DNA mismatch repair proteins, which may play a role in overcoming resistance to other platinum compounds.

• The combination of satraplatin and prednisone is superior to prednisone alone in patients with hormone-refractory prostate cancer in the first-line setting, and may also have efficacy as second-line therapy.

• Preliminary results suggest that satraplatin with concurrent radiation is highly active in patients with squamous cell carcinoma of the head and neck.

• Satraplatin is also being evaluated for the treatment of non-small cell lung, ovarian and cervical cancer as a single agent, and in combination regimens.

• In contrast with other platinums, satraplatin has a generally mild toxicity profile, with myelosuppression as the dose-limiting toxicity. The nephrotoxicity, ototoxicity and neurotoxicity observed with cisplatin and the peripheral neuropathy common with oxaliplatin are rare with satraplatin.

Satraplatin

www.future-drugs.com 981

formation, glutathione levels and p53 status in human tumour cell lines with different sensitivities to cisplatin. Biochem. Pharmacol. 63, 1989–1996 (2002).

15 Reardon JT, Vaisman A, Chaney SG, Sancar A. Efficient nucleotide excision repair of cisplatin, oxaliplatin, and bis-aceto-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) platinum intrastrand DNA diadducts. Cancer Res. 59, 3968–3971 (1999).

16 Fink D, Nebel S, Aebi S et al. The role of DNA mismatch repair in platinum drug resistance. Cancer Res. 56, 4881–4886 (1996).

17 Vaisman A, Lim SE, Patrick SM et al. Effect of DNA polymerases and high mobility group protein 1 on the carrier ligand specificity for translesion synthesis past platinum-DNA adducts. Biochemistry 38, 11026–11039 (1999).

18 Kelland LR. An update on satraplatin: the first orally available platinum anticancer drug. Expert Opin. Investig. Drugs 9, 1373–1382 (2000).

•• Review of the chemistry, pharmacodynamics and pharmacokinetics of satraplatin, and of early Phase I studies.

19 Twentyman PR, Wright KA, Mistry P et al. Sensitivity to novel platinum compounds of panels of human lung cancer cell lines with acquired and inherent resistance to cisplatin. Cancer Res. 52, 5674–5680 (1992).

20 Wosikowski K, Caligiuri M, Rattel B et al. Efficacy of satraplatin (JM216) and its metabolites is maintained in taxane-resistant tumors. Proceedings of the First International Conference on Cancer Therapeutics: Molecular Targets, Pharmacology and Clinical Applications. Florence, Italy, 19–21 February 2004.

21 Kelland LR, Abel G, McKeage MJ et al. Preclinical antitumor evaluation of bis-acetato-ammine-dichloro-cyclohexylamine platinum(IV): an orally active platinum drug. Cancer Res. 53, 2581–2586 (1993).

22 Rose WC. Combination chemotherapy involving orally administered etoposide and JM-216 in murine tumor models. Cancer Chemother. Pharmacol. 40, 51–56 (1997).

23 Amorino GP, Mohr PJ, Hercules SK et al. Combined effects of the orally active cisplatin analogue, JM216, and radiation therapy in antitumor therapy. Cancer Chemother. Pharmacol. 46, 423–426 (2000).

24 McKeage MJ, Mistry P, Ward J et al. Phase I and pharmacology study of an oral platinum complex, JM216: dose-dependent pharmacokinetics with single-dose administration. Cancer Chemother. Pharmacol. 36, 451–458 (1995).

25 McKeage MJ, Raynaud F, Ward J et al. Phase I and pharmacokinetic study of an oral platinum complex given daily for 5 days in patients with cancer. J. Clin. Oncol. 15, 2691–2700 (1997).

26 Carr JL, Tingle MD, McKeage MJ. Rapid biotransformation of satraplatin by human red blood cells in vitro. Cancer Chemother. Pharmacol. 50, 9–15 (2002).

27 Carr JL, Tingle MD, McKeage MJ. Satraplatin activation by haemoglobin, cytochrome C and liver microsomes in vitro. Cancer Chemother. Pharmacol. 57, 483–490 (2006).

28 Poon GK, Mistry P, Raynaud FI et al. Determination of metabolites of a novel platinum anticancer drug JM216 in human plasma ultrafiltrates. J. Pharm. Biomed. Anal. 13, 1493–1498 (1995).

29 McKeage MJ, Kelland LR, Boxall FE et al. Schedule dependency of orally administered bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) in vivo. Cancer Res. 54, 4118–4122 (1994).

30 Vouillamoz-Lorenz S, Buclin T, Lejeune F, Bauer J, Leyvraz S, Decosterd LA. Pharmacokinetics of satraplatin (JM216), an oral platinum (IV) complex under daily oral administration for 5 or 14 days. Anticancer Res. 23, 2757–2765 (2003).

31 Ando Y, Shimizu T, Nakamura K et al. Potent and non-specific inhibition of cytochrome P450 by JM216, a new oral platinum agent. Br. J. Cancer 78, 1170–1174 (1998).

32 Beale P, Raynaud F, Hanwell J et al. Phase I study of oral JM216 given twice daily. Cancer Chemother. Pharmacol. 42, 142–148 (1998).

33 Kurata T, Tamura T, Sasaki Y et al. Pharmacokinetic and pharmacodynamic analysis of bis-acetato-ammine-dichloro-cyclohexylamine-platinum(IV) (JM216) administered once a day for five consecutive days: a phase I study. Jpn. J. Clin. Oncol. 30, 377–384 (2000).

34 Sessa C, Minoia C, Ronchi A et al. Phase I clinical and pharmacokinetic study of the oral platinum analogue JM216 given daily for 14 days. Annals Oncol. 9, 1315–1322 (1998).

35 Fokkema E, de Vries EG, Meijer S, Groen HJ. Lack of nephrotoxicity of new oral platinum drug JM216 in lung cancer patients. Cancer Chemother. Pharmacol. 45, 89–92 (2000).

36 Jones S, Hainsworth J, Burris HA et al. Phase I study of JM-216 (an oral platinum analogue) in combination with paclitaxel in patients with advanced malignancies. Invest. New Drugs 20, 55–61 (2002).

• Useful summary of the toxicity profile observed in a Phase I trial.

37 Muthuramalingam SR, Patel K, Protheroe A. Management of patients with hormone refractory prostate cancer. Clin. Oncol. (R. Coll. Radiol.) 16, 505–516 (2004).

38 Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N. Engl. J. Med. 351, 1513–1520 (2004).

• Survival advantage with docetaxel-based regimens in advanced, hormone-refractory prostate cancer.

39 Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 351, 1502–1512 (2004).

• Survival advantage with docetaxel-based regimens in advanced, hormone-refractory prostate cancer.

40 Savarese DM, Halabi S, Hars V et al. Phase II study of docetaxel, estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: a final report of CALGB 9780. Cancer and Leukemia Group B. J. Clin. Oncol. 19, 2509–2516 (2001).

41 Soloway MS, Beckley S, Brady MF et al. A comparison of estramustine phosphate versus cis-platinum alone versus estramustine phosphate plus cis-platinum in patients with advanced hormone refractory prostate cancer who had had extensive irradiation to the pelvis or lumbosacral area. J. Urol. 129, 56–61 (1983).

42 Osborne CK, Blumenstein BA, Crawford ED et al. Phase II study of platinum and mitoxantrone in metastatic prostate cancer: a Southwest Oncology Group Study. Eur. J. Cancer 28(2–3), 477–478 (1992).

43 Wosikowski K, Rattel B, Caligiuri M et al. Cytotoxic activity of satraplatin (JM216) and its metabolites in human prostate carcinoma cell lines. Proceedings of the 95th Annual Meeting of the American Association for Cancer Research. FL, USA, 27–31 March 2004 (Abstract 4614).

44 Latif T, Wood L, Connell C, Smith DC et al. Phase II study of oral bis (aceto) ammine dichloro (cyclohexamine) platinum (IV) (JM-216, BMS-182751) given daily × 5 in hormone refractory prostate cancer (HRPC). Invest. New Drugs 23, 79–84 (2005).

45 Sternberg CN, Whelan P, Hetherington J et al. Phase III trial of satraplatin, an oral platinum plus prednisone vs. prednisone

Choy

982 Expert Rev. Anticancer Ther. 6(7), (2006)

alone in patients with hormone-refractory prostate cancer. Oncology 68, 2–9 (2005).

•• European Organization for the Research and Treatment of Cancer study demonstrating superior response rate and survival with satraplatin plus prednisone compared with prednisone alone.

46 Sternberg CN, Hetherington J, Paluchowska B et al. Randomized phase III trial of a new oral platinum, satraplatin (JM-216) plus prednisone or prednisone alone in patients with hormone refractory prostate cancer. Proc. Am. Soc. Clin. Oncol. 22(395) (2003) (Abstract 1586).

47 Nathan FE, Sternberg C, Sartor O et al. Satraplatin: a new treatment option for patients with hormone refractory prostate cancer. Proc. Am. Soc. Clin. Oncol. (2005) (Abstract 48020).

48 Judson I, Cerny T, Epelbaum R et al. Phase II trial of the oral platinum complex JM216 in non-small-cell lung cancer: an EORTC early clinical studies group investigation. Ann. Oncol. 8, 604–606 (1997).

49 Schrump DS, Altorki NK, Henschke CL et al. Non–small cell lung cancer. Cancer: Principles and Practice of Oncology (7th Edition). DeVita VT, Jr, Hellman S, Rosenberg SA (Eds). Lippincott Williams & Wilkins, PA, USA (2005).

50 Fokkema E, Groen HJ, Bauer J et al. Phase II study of oral platinum drug JM216 as first-line treatment in patients with small-cell lung cancer. J. Clin. Oncol. 17, 3822–3827 (1999).

51 Grant SC, Gralla RJ, Kris MG et al. Single-agent chemotherapy trials in small-cell lung cancer, 1970 to 1990: the case for studies in previously treated patients. J. Clin. Oncol. 10, 484–498 (1992).

52 Trudeau M, Stuart G, Hirte H et al. A phase II trial of JM-216 in cervical cancer: an NCIC CTG study. Gynecol. Oncol. 84, 327–331 (2002).

53 Schaake-Koning C, van den Bogaert W, Dalesio O et al. Effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer. N. Engl. J. Med. 326, 524–530 (1992).

54 Jeremic B, Shibamoto Y, Milicic B et al. Hyperfractionated radiation therapy with or without concurrent low-dose daily cisplatin in locally advanced squamous cell carcinoma of the head and neck: a prospective randomized trial. J. Clin. Oncol. 18, 1458–1464 (2000).

55 Jeremic B, Shibamoto Y, Stanisavljevic B et al. Radiation therapy alone or with concurrent low-dose daily either cisplatin or carboplatin in locally advanced unresectable squamous cell carcinoma of the head and neck: a prospective randomized trial. Radiother. Oncol. 43, 29–37 (1997).

56 George CM, Haraf DJ, Mauer AM et al. A phase I trial of the oral platinum analogue JM216 with concomitant radiotherapy in advanced malignancies of the chest. Invest. New Drugs 19, 303–310 (2001).

57 Cmelak A, Choy H, Murphy B et al. Phase I study of JM-216 with concurrent radiation in non-small cell lung cancer and squamous cell head and neck cancer. Proc. Am. Soc. Clin. Oncol. 18 (1999) (Abstract 1520).

• Initial indication of high response rate with radiation in non-small cell lung cancer and squamous cell carcinoma of the head and neck.

58 Fanucchi M, Khuri FR. Chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck. Semin. Oncol. 31, 809–815 (2004).

59 Khuri FR, Shin DM, Glisson BS et al. Treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck: current status and future directions. Semin. Oncol. 27(Suppl. 8), 25–33 (2000).

Websites

101 National Comprehensive Cancer Network Clinical Practice Guidelines in Oncologywww.nccn.org/

Affiliation

• Hak Choy, MD

University of Texas Southwestern Medical Center, Department of Radiation Oncology, Dallas, TX 75390–9183, USATel.: +1 214 645 7600Fax: +1 214 645 7622hak.choy@utsouthwestern.edu