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  • 1. Ovarian Sex Cord–Stromal Tumors in Children and Adolescents By D.T. Schneider, G. Calaminus, R. Wessalowksi, R. Pathmanathan, B. Selle, W. Sternschulte, D. Harms, and U. Gobel ¨ Purpose: To develop diagnostic standards and a risk- overall survival was 0.89 ؎ 0.05 (49 of 54 patients). Prog-adapted therapeutic strategy for ovarian sex cord–stromal nosis correlated with stage (event-free survival ؎ SD: IA, 1.0tumors (OSCST). [27 of 27 patients]; IC, 0.76 ؎ 0.09 [16 of 21 patients]; and Patients and Methods: Fifty-four patients were prospec- II/III, 0.67 ؎ 0.19 [four of six patients]; P ‫ .)20. ؍‬Ten of 15tively enrolled as follow-up patients onto the German Ma- patients treated with chemotherapy, including four of sixligne Keimzelltumoren protocols. Surgical protocols and stage II to III patients, are alive after a median follow-up ofhistopathology were reviewed centrally (53 patients with 33 months. Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission.complete data). Surgery included ovariectomy in 18 pa- Conclusion: On the basis of a standardized clinical andtients, salpingo-ovariectomy in 34 patients, and hysterec- histopathologic assessment, risk-adapted therapeutic strate-tomy in one patient. Patients with stage IA tumors were gies for OSCST can be evaluated. Considering our experience,followed-up at regular intervals, whereas nine patients we would recommend that stage IA tumors be followed up atwith stage IC and six patients with stage II to III tumors were regular intervals, whereas we would recommend cisplatin-treated with cisplatin-based chemotherapy. based chemotherapy in stage IC tumors with preoperative Results: International Federation of Gynecology and Ob- rupture or malignant ascites, especially those with high mitotic Copyright © 2003 American Society of Clinical Oncology. All rights reserved.stetrics stage was IA in 27 patients, IC in 21 patients, II in activity. Finally, cisplatin-based chemotherapy also seems tothree patients, and III in three patients. After a median be effective in advanced-stage tumors.follow-up of 59 months (range, 6 to 193 months), event-free J Clin Oncol 21:2357-2363. © 2003 by Americansurvival ؎ SD was 0.86 ؎ 0.05 (47 of 54 patients) and Society of Clinical Oncology. VARIAN SEX cord–stromal tumors (OSCST) constitute a logic assessment that may allow more valid conclusions withO heterogeneous group of rare tumors that develop from thegonadal nongerminative component, such as granulosa, Sertoli, regard to meaningful treatment strategies in these tumors.or Leydig cells. Histologic evaluation and modern immunohis- PATIENTS AND METHODStochemical techniques allow for an accurate classification of Between 1985 and 2000, 54 patients with OSCST were reported asOSCST that distinguishes them from the more frequent malig- follow-up patients to the consecutive protocols for nontesticular germ cellnant germ cell tumors or the rare ovarian small-cell carcinoma of tumors Maligne Keimzelltumoren (MAKEI) of the German Society ofthe hypercalcemic type, which, in most patients, is associated Pediatric Oncology and Hematology. Patients gave informed consent to datawith fatal outcome. collection and evaluation. Data have been prospectively recorded according to the standards of the MAKEI protocols.7 The MAKEI protocols have been Unfortunately, the advances in diagnosis have not yet trans- approved by the responsible Ethics Committee at the Heinrich-Heine-lated into standardized therapeutic strategies. The conclusions University in Dusseldorf, Germany. ¨derived from the first study1 of juvenile granulosa cell tumors Radiographic assessment included abdominal ultrasound and computer-(JGCTs) still hold true that the vast majority of JGCT present as ized tomography. Serum alpha1-fetoprotein and human chorionic gonadotro-localized disease confined to the ovary and that these tumors pin were measured to exclude secreting germ cell tumors. Because there was no recommendation for the evaluation of inhibin as a serologic tumorusually behave in a benign manner despite having histopatho- marker, inhibin was not assessed on a regular basis.logic features of malignancy. Conversely, advanced JGCT andpoorly differentiated Sertoli-Leydig cell tumors (SLCTs) areconsidered prognostically poor, and the impact of chemotherapyin such tumors is a controversial issue.1-3 The current literature provides only a few case reports about From the Department of Pediatric Hematology and Oncology, Children’s Hospital, Heinrich-Heine-University Medical Center, Dusseldorf; Depart- ¨successfully treated patients with advanced or recurrent ment of Pediatric Hematology and Oncology, Children’s Hospital, Univer-OSCST.4-6 In these reports, a broad range of chemotherapeutic sity of Heidelberg; Children’s Hospital Koln, Koln; and Institute for ¨ ¨agents has been applied in different combinations. However, no Pediatric Pathology, Christian-Albrechts-University, Kiel, Germany.meaningful conclusions can be drawn from these case reports Submitted May 2, 2002; accepted February 28, 2003. Supported by the Deutsche Krebshilfe, Bonn, Germany.with regard to the respective efficacy of the different regimens. Address reprint requests to D.T. Schneider, MD, Clinic of Pediatric Therefore, we have prospectively evaluated a large series of Oncology, Hematology, and Immunology, Children’s Hospital, Universitychildren with OSCST diagnosed and treated according to uni- Hospital Dusseldorf, Heinrich-Heine-University, Moorenstr 5, D-40225 ¨form standards. The objective of this study is to define prognos- Dusseldorf, Germany; email: dominik.schneider@uni-duesseldorf.de. ¨ © 2003 by American Society of Clinical Oncology.tic parameters on the basis of a thorough clinical and histopatho- 0732-183X/03/2112-2357/$20.00Journal of Clinical Oncology, Vol 21, No 12 (June 15), 2003: pp 2357-2363 2357DOI: 10.1200/JCO.2003.05.038
  • 2. 2358 SCHNEIDER ET AL Table 1. Synopsis of the Clinical and Thorapeutic Data of All Patients Treated With Adjuvant Chemotherapy Age Maximum Patient (years/ Diameters Completeness of Mitoses/ Second-Look Irrediation Follow-Up No. months) FIGO Stage (cm) Histology Surgery Reaction 10 HPF Chemotherapy Reaction (day) Status (months) 1 15/2 IC 20 SLCT-pd Hysterectomy Microscopic residues ND 3 ϫ BEP No No DOD 7 2 16 IC/IIIC 9 SLCT-pd Adnectomy Microscopic residues 23 Delayed† Yes No DOD 19 6 ϫ PEI 3 6/6 IC Bilateral 10 SLCT-id Adnectomy Microscopic residues 19 2 ϫ PE No No CR1 47 4 13/3 IC Bilateral 17 JGCT Adnectomy Microscopic residues 8 3 ϫ BEP No No CR1 82 5 13/3 IC Bilateral 26 JGCT Adnectomy Microscopic residues 33 6 ϫ PEI No No CR1 33 6 12/11 IC* 10 JGCT Adnectomy Microscopic residues 25 4 ϫ BEP No No DOD 22 1 ϫ VIP Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission. 7 9/10 IC* 6 JGCT Ovariectomy Microscopic residues 29 4 ϫ PEI No No CR1 59 8 3 IC* 10 JGCT Ovariectomy Microscopic residues 30 7 ϫ EVAIA No No DOD 28 9 16/9 IC/IIIC 11 JGCT Partial Microscopic residues 40 Delayed‡ Yes No AWD 22 ovariectomy 6 ϫ PEI 10 6/1 IIC 11 JGCT Adnectomy Complete 6 3 ϫ BEP No No CR§ 138 3 ϫ VIP 11 10/11 IIC 10 JGCT Adnectomy Microscopic residues 47 5 ϫ PEI No No DOD 16 Copyright © 2003 American Society of Clinical Oncology. All rights reserved. 1 ϫ PE 12 14/8 IIC 15 JGCT Adnectomy Microscopic residues 1 3 ϫ BEP No No CR1 106 3 ϫ VIP 13 17/0 IIIA 7 JGCT Adnectomy Microscopic residues 7 4 ϫ PEI Yes࿣ No CR1 15 14 18/11 IIIC 8 JGCT Partial Microscopic residues 20 Delayed¶ Yes No CR3 47 ovariectomy 6 ϫ PEI 15 4/2 IIIC 30 JGCT Adnectomy; Complete 9 6 ϫ PEI ϩ No 40 CR1 111 omentectomy mitoxantrone Abbreviations: SLCT-pd, poorly differentiated Sertoli-Leydig cell tumor; SLCT-id, intermediately differentiated SLCT; JGCT, juvenile granulosa cell tumor; CR, completeremission; CR1 first CR; CR3, third CR; DOD, dead of disease; AWD, alive with disease; HPF, high-power field; FIGO, International Federation of Gynecology and Obstetrics;ND, not determined; BEP, bleomycin; etoposide, cisplatin; PEI, cisplatin, etoposide, ifosfamide; PE, cisplatin, etoposide; VIP, vincristine, ifosfamide, cisplatin; EVAIA,etoposide, vincristine, doxorubicin, ifosfamide, dactinomycin. *Spontaneous preoperative tumor rupture. †At diagnosis, this patient underwent adnectomy, during which a preoperative tumor rupture was observed. After 1 month, this patient developed a massive recurrencewith diffuse peritoneal spread, and chemotherapy was started. ‡At diagnosis, this patient underwent laparoscopic incomplete ovariectomy, during which the situation was interpreted as a stage T1 tumor. After 5 months, the patientpresented with a diffuse peritoneal relapse, underwent hysterectomy with tumor debulking, and was referred for start of chemotherapy. §After 126 months of follow-up, this patient developed a contralateral juvenile granulosa cell tumor, which was interpreted as metachronous tumor. ࿣Second-look surgery with lymph-node sampling and omentectomy (revealing peritoneal metastases) before start of chemotherapy. ¶Surgical procedures at diagnosis: laparoscopic partial ovariectomy; 2 weeks later hysterectomy and bilateral adnectomy, lymph-node dissection, and rectosigmoidac-tomy; another 5 weeks later, third-look resection with tumor debulking and partial resection of the small bowel followed by referral for start of chemotherapy.Surgical and Pathologic Data Statistical Analysis The surgical protocols were evaluated centrally. Tumor resection was Statistical analysis was performed with the SPSS program, Version 9.0considered complete when the intact tumor and the ovary were removed in (SPSS Inc, Chicago, IL). For categorical data, the two-sided Pearson ␹2 testone piece and without rupture or puncture of the capsule. On microscopic was applied. Numerical data were calculated with the Mann-Whitney U test.examination, tumor margins had to be free of tumor cells. Staging was Overall and event-free survival (EFS) was estimated according to theperformed according to the International Federation of Gynecology and Kaplan-Meier method, and the influence of suspected prognostic factors wasObstetrics (FIGO) staging system, and classification was based on both analyzed with the log-rank test. EFS was defined as the time from diagnosissurgical and pathologic report.8 To delineate the impact of tumor rupture to the first relapse or death, and in this analysis, 10-year EFS and overallduring surgery, we also distinguished between accidental stage IC (violation survival rates are provided. Patients lost to follow-up were censored at theof tumor capsule during surgery) and natural stage IC tumors (preoperative time of their last reported follow-up examination. Follow-up data untilrupture or malignant ascites). March 2002 were included. Because of the limited numbers of patients, no In 47 patients, a histologic review by an experienced pediatric multivariate analysis was performed.pathologist (Institute of Pathology in Kiel or Munich, Germany, orHarvard Medical School, Boston, MA) was obtained, and 43 patients RESULTSwere documented in Kiel. Mitotic rate was assessed by counting mitosesin at least 10 high-power fields (HPF) and was categorized as low, Clinical and Histologic Dataintermediate, or high when less than 10, 10 to 19, or more than 19 Median age was 6 years and 10 months (range, 5 months to 19mitoses/10 HPF were found, respectively. Whenever necessary, conven- years and 4 months). Twenty-one patients showed clinical signstional histology was supplemented by immunohistochemistry, includingstaining for inhibin. Fifteen patients received up to six cycles of of isosexual pseudoprecocity, and among these patients, ninechemotherapy in concordance with the respective MAKEI protocol suffered from prepubertal vaginal bleeding. Secondary amenor-opened at the time of diagnosis (Table 1).7 rhea was reported in eight patients and virilization was reported
  • 3. OVARIAN SEX CORD–STROMAL TUMORS 2359 Table 2. Histologic Subtypes cisplatin, etoposide, and ifosfamide (PEI) chemotherapy (patient JGCT SLCT Sclerosing Annular Total 13, Table 1). The second patient developed massive peritonealAge (years) (no.) (no.) (no.) (no.) (no.) metastases 2 weeks after initial surgery (patient 14, Table 1). InϽ5 17 1 — — 18 the third patient, a 19-year-old girl with a JGCT, the tumor was5-9 14 2 — 1 17 removed in pieces and remnants of the ovary were left in situ10-14 9 — 1 — 1015-19 5 3 1 — 9 (accidental stage Ic). Histologically, this tumor showed lowTotal 45 6 2 1 54 mitotic activity (seven mitoses/10 HPF) and foci with Sertoli cell Abbreviations: JGCT, juvenile granulosa cell-tumor; SLCT, Sertoli-Leydig cell differentiation. This patient did not receive adjuvant treatmenttumor; Sclerosing, sclerosing stromal tumor; Annular, sex cord tumor with annular and is currently in first complete remission (46 months).tubules. Sixteen patients (14 with JGCT, one with SLCT, and one with Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission. sclerosing stromal tumor) underwent laparotomy with ovariec- tomy, which was complete in 11 patients and microscopicallyin one patient. The frequency of endocrinologic symptoms was incomplete in five patients. Eleven patients had stage IA tumors,comparable for all histologic types (65% in JGCT v 50% in all and five patients had stage IC tumors. One of the patients withother types). However, endocrinologic symptoms were particu- stage IC tumor relapsed with peritoneal and liver metastaseslarly frequent in children younger than 5 years (14 of 17 despite adjuvant chemotherapy (patient 8, Table 1). Copyright © 2003 American Society of Clinical Oncology. All rights reserved.patients Ͻ 5 years v 16 of 31 patients Ն 5 years; P ϭ .035; 48 Thirty-three patients underwent adnectomy (salpingo-ovariec-patients with complete clinical data). Notably, patients with tomy), which was complete in 18 and incomplete in 15 patients.endocrinologic symptoms were diagnosed at earlier stages (for Sixteen patients had stage IA tumors, 13 had stage IC tumors,stage IA, 19 of 28 patients with endocrinologic symptoms v five three had stage II tumors, and one had a stage III tumor. Fourof 20 patients without endocrinologic symptoms; P ϭ .022). patients suffered recurrences after incomplete resection, whereas Twenty-three patients reported abdominal pain, and 13 all completely resected patients are remaining disease-free.showed abdominal distension with palpable tumor masses and/or Finally, one patient with a large poorly differentiated SLCTfatigue. The mean maximal tumor diameter was 11.8 cm (range, underwent hysterectomy but developed a relapse despite adju-2 to 30 cm) with no significant difference between the different vant chemotherapy (patient 1, Table 1).histologic subtypes. Thirty-five tumors were right-sided and 16were left-sided. Three tumors developed synchronously in both Adjuvant Therapyovaries (two JGCTs and one SLCT). Tumor stage was IA in 27 Fifteen patients received adjuvant chemotherapy. By clini-patients, IC in 21 patients (including three bilateral tumors), IIC cian’s choice, one patient received etoposide, vincristine, doxo-in three patients, IIIA in one patient, and IIIC in two patients. In rubicin, ifosfamide, and dactinomycin in analogy to the proto-12 of 21 stage IC patients, the tumor was classified as stage IC cols for advanced sarcomas (patient 8, Table 1). The remainingbecause of intraoperative tumor rupture or puncture of tumor patients were treated with cisplatin- and etoposide-based three-cysts (accidental IC), whereas in nine patients, the tumor was agent chemotherapy regimens according to the guidelines forruptured preoperatively or malignant ascites was diagnosed by advanced malignant germ cell tumors outlined in the MAKEIcytologic examination (natural IC). Lymph node or hematogenic protocol opened at the time of diagnosis (Table 1).7metastases were not observed at diagnosis. Among these fifteen patients who received adjuvant chemo- The histologic diagnoses are listed in Table 2. JGCT was the therapy, three (patients 2, 9, and 14) were treated after recurrencemost frequent diagnosis (n ϭ 45), followed by SLCT (n ϭ 6), and after microscopically incomplete second-look resection. Insclerosing stromal tumor (n ϭ 2), and one sex-cord tumor with the remaining patients, decision for adjuvant chemotherapy wasannular tubules (n ϭ 1). based on advanced stage in patients 2 and 9 through 15 (Table According to the criteria previously defined, 27 patients 1), incompletely resected bilateral tumors (patients 3 to 5), orshowed low, eight patients showed moderate, and 13 patients spontaneous preoperative tumor rupture of rapidly proliferat-showed high mitotic activity (48 patients with complete data). ing tumor with more than 19 mitoses/10 HPF (patients 1 andThe two sclerosing stromal tumors (one and three mitoses/10 6 to 8). One patient with multiple peritoneal metastases alsoHPF, respectively) and the sex cord tumor with annular tubules received 40 Gy of abdominal irradiation. In patients 2 and 8,(one mitosis/10 HPF) showed low mitotic activity, compared resection of residual tumor was performed after two and threewith SLCTs (mean, 10 mitoses/10 HPF) and JGCTs (mean, 15 cycles of chemotherapy, respectively. Histology revealedmitoses/10 HPF). complete necrosis.Surgical Therapy Outcome In 53 of 54 patients, data were available from surgical All patients achieved complete clinical remission. During aprotocols. Three patients underwent resection through laparo- median follow-up of 59 months (range, 6 to 193 months),scopic surgery. One of these patients underwent second-look eight patients suffered a recurrence. Notably, after 126laparotomy with adnectomy and omentectomy 2 weeks after months, one patient with a JGCT (patient 9, Table 1)diagnosis. On this occasion, previously undetected peritoneal developed a tumor in the contralateral ovary. As is the casespread was found (stage IIIA) and the patient received adjuvant with ovarian germ cell tumors, this event was categorized as
  • 4. 2360 SCHNEIDER ET AL among the two sclerosing stromal tumors and the sex cord tumor with annular tubules (all stage IC). Prognosis significantly correlated with stage (Fig 2). We observed no recurrences of stage IA tumors, whereas five of 21 patients with stage IC tumors and two of six patients with stage II to III tumors relapsed. We saw no relapses among 12 patients who were categorized as having accidental stage IC tumors because of intraoperative penetration of the tumor capsule. Among these were three bilateral tumors treated with adjuvant chemotherapy. In contrast, five of nine patients with natural stage IC tumors who experi- Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission. enced preoperative tumor rupture or malignant ascites relapsed (P ϭ .001). This group includes four patients (patients 1, 6, 7, and 8) treated with adjuvant chemotherapy, among whom, three developed a recurrence. Two of the remaining five patients who were not treated with adjuvant chemotherapy at diagno- Copyright © 2003 American Society of Clinical Oncology. All rights reserved. sis relapsed. Age significantly correlated with outcome. Pa- Fig 1. Event-free and overall survival, according to Kaplan-Meier, of 54 tients younger than 10 years had a better EFS (Ϯ SD) thanpatients with ovarian sex cord-stromal tumors. older patients (0.97 Ϯ 0.03 [34 of 35 patients] v 0.68 Ϯ 0.11 [13 of 19 patients], respectively; P ϭ .0035; Fig 3). Ina metachronous contralateral tumor and not as a relapse, and addition, there was a correlation of endocrinologic symptomsthis patient was censored at 126 months of follow-up. As a at diagnosis with outcome (EFS Ϯ SD, no symptoms 0.7 Ϯresult, seven relapses (seven events) were observed. 0.1 [14 of 20 patients] v symptoms 0.96 Ϯ 0.04 [27 of 28 Two patients with stage IC tumors (patients 2 and 9, Table 1) patients]; P ϭ .014; 48 patients with complete data). Thisand one patient with a stage IIIC tumor (patient 14) were not might be explained by the association of endocrinologicinitially treated with adjuvant chemotherapy and relapsed. One symptoms with low tumor stage (clinical and histologic data).of these patients had a poorly differentiated SLCT (patient 2), Among the histopathologic features, we found a significantdeveloped massive peritoneal relapse 2 months after diagnosis, correlation between mitotic activity and prognosis (Fig 4). Weand subsequently was treated with six cycles of chemotherapy. observed no relapses in 35 patients with low or moderate mitoticSecond remission lasted for 12 months, and the patient ulti- activity, whereas six of 13 tumors with high mitotic activitymately died as a result of tumor progression. The second patient recurred (P Ͻ .0001). Most importantly, the analysis of stage IC(patient 9) suffered from a highly proliferative JGCT and tumors revealed a correlation between risk of relapse and mitoticrelapsed 5 months after initial resection; the patient achieved a activity (low or moderate mitotic activity, 1.0 [11 of 11 patients];second remission after surgery and chemotherapy but developed high mitotic activity, 0.33 Ϯ 0.19 [two of six patients]; P ϭ .006;a second relapse. At present, she is receiving chemotherapy, and 17 patients with complete data).radiographic examination indicates complete third remission.The third patient was initially treated with laparoscopicovariectomy, which was macroscopically incomplete. Within2 weeks, this patient developed a massive peritoneal tumorprogression and was treated with two attempts of tumorresection, six cycles of PEI chemotherapy, and second-lookresection. At present, this patient is remaining in completesecond remission after 47 months. Four patients (patients 1, 6, 8, and 11; Table 1) sufferedrecurrences despite chemotherapy, and all four patients died as aresult of further tumor progression, although in three patients, atemporary second complete remission was achieved. In sum-mary, EFS (Ϯ SD), according to the Kaplan-Meier method, was0.86 Ϯ 0.05 (47 of 54 patients), and overall survival (Ϯ SD) was0.89 Ϯ 0.05 (49 of 54 patients; Fig 1).Prognostic Factors We observed no prognostic difference with regard to thehistologic subtypes. However, apart from JGCT, the numbers oftumors within each histologic subgroup were too small for Fig 2. Event-free survival of 54 patients with ovarian sex cord-stromal tumorsmeaningful statistical analysis. Nevertheless, we saw no relapses correlated with International Federation of Gynecology and Obstetrics stage.
  • 5. OVARIAN SEX CORD–STROMAL TUMORS 2361 DISCUSSION The literature provides limited data on risk-adapted therapeu- tic strategies in OSCST, and most of the current experience is derived from case reports or retrospective studies of heteroge- neous cohorts of patients. Therefore, we believe that this study might provide important information with regard to mandatory diagnostic standards and meaningful therapeutic concepts in OSCST. Our analysis of 54 prospectively documented patients indicates that risk groups can be defined with respect to the parameters of stage; completeness of resection; histologic ap- Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission. pearance, such as differentiation (eg, undifferentiated SLCT); and proliferative activity of the tumor. Furthermore, our data on advanced-stage tumors reveal that cisplatin-based chemo- therapy constitutes a promising concept in the adjuvant therapy of these otherwise fatal tumors. The extent to which Copyright © 2003 American Society of Clinical Oncology. All rights reserved. chemotherapy improves the outcome of patients within de- Fig 3. Event-free survival of 54 patients with ovarian sex cord-stromal tumors fined risk groups has to be addressed in a future trial,correlated with age at diagnosis. preferably with a randomized design. The overall clinical and pathologic data obtained in our series correlate well with other series on OSCST.1,3 During the sameToxicity of Chemotherapy observation period, an additional 31 patients with OSCST were reported to the Kiel Pediatric Tumor Registry but not to the In 10 of 15 patients treated with chemotherapy, toxicity was MAKEI. Notably, 100% of stage II and III tumors, 95% of stagedocumented according to MAKEI standards. Acute toxicity was IC tumors, but only 64% of stage IA tumors diagnosed at themainly attributed to myelotoxicity and nausea. In 19 of 51 docu- Kiel Tumor Registry were also reported to MAKEI. In conclu-mented cycles, World Health Organization (WHO) grade 3 to 4 sion, there seems to be a slight selection toward higher-stagesevere nausea was observed. WHO grade 3 to 4 neutropenia was tumors in the MAKEI series. Unfortunately, these patients couldreported after 35 of 51 cycles. No patient suffered septic infections, not be included in the analysis reported here because noand WHO grade 2 moderate infections were seen after 10 cycles. informed consent was obtained and no follow-up data wereWe observed neither therapy-related deaths nor secondary tumors. collected. However, the data indicate that the real incidence ofFour patients experienced a WHO grade 1 objective hearing loss. OSCST is higher than can be assumed from the data of theHowever, no patient experienced a subjective hearing impairment. MAKEI studies alone.Nephrotoxicity was reversible in all patients. Six patients, including The largest series of JGCT published to date analyzed 125two patients with bilateral tumors, are infertile after hysterectomy patients, with follow-up data in 83 patients.1 In this series, onlyand/or bilateral adnectomy. two of 80 stage I tumors were fatal, but all three stage II tumors were fatal. Additional clinical and histologic parameters did not contribute to the prognostic assessment. The largest series of SLCT has been reported by the same study group and included 207 patients, among whom follow-up information was available in 164 patients.3 Outcome correlated with both stage and histologic differentiation, and both parameters closely correlated with each other. All well-differentiated SLCT behaved in a clinically benign manner, whereas 11% of SLCT with interme- diate differentiation and 59% of poorly differentiated SLCT (all stage II to III) showed a malignant course. These data correlate with our observation that two of three patients with poorly differentiated SLCT (patients 1 and 2, Table 1) but none of the patients with SLCT of intermediate (patient 3) or high differen- tiation relapsed. The most recent significant study of JGCT reports on 40 patients treated in France between 1965 and 1990.2 When our study is compared with the French study, the different staging systems (FIGO v Wollner classification, respectively) must be Fig 4. Event-free survival of 54 patients with ovarian sex cord-stromal tumors considered. In the French series, six patients treated withcorrelated with mitotic activity of the tumor. HPF, high-power field. chemotherapy were classified as stage III because of tumor
  • 6. 2362 SCHNEIDER ET ALrupture (n ϭ 5) or positive ascites (n ϭ 1), and these patients symptoms less frequently, may present at advanced stage, and issurvived. According to FIGO, these would have been stage IC relatively refractory to treatment.patients. However, only one of four patients with peritoneal or Several issues remain to be critically addressed. The indica-lymph node metastases survived despite chemotherapy (n ϭ 2), tion for chemotherapy and the minimum amount of chemother-radiotherapy (n ϭ 1), or combined chemotherapy and radiother- apy necessary in stage IC tumors are ill defined. Despite a certainapy (n ϭ 1). variation of treatment strategy throughout the 15-year observa- In contrast to this discouraging data, there are case reports that tion period, chemotherapy was administered only to patientssupport the use of adjuvant chemotherapy in advanced-stage with natural stage IC (ie, preoperative tumor rupture) or higherJGCT. Colombo et al9 reported on a girl with a stage III JGCT stage tumors or who experienced recurrence. Our data indicatewho achieved complete remission for at least 7 months after that, among stage IC patients, a subgroup of patients at high risk Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission.cisplatin, vinblastine, bleomycin chemotherapy. Powell et al10 can be identified through histologic assessment. These patientsreported on a 13-year-old primigravida with a stage IIIB JGCT may be suitable for adjuvant chemotherapy. However, thewho was successfully treated with a combination of methotrex- limited data available from our analysis do not allow the requiredate, dactinomycin, and chlorambucil. The patient has remained minimum chemotherapy for tumors at stage IC or higher to bein complete remission for 7 years, during which she gave birth defined. In our study, all patients with stage II to III tumorsto additional children. The same authors reported on two stage received at least four cycles. Considering other studies with less Copyright © 2003 American Society of Clinical Oncology. All rights reserved. favorable outcome,1-3 we would not advocate less chemother-III tumors successfully treated with surgical debulking and apy, but rather argue for an extension to six cycles. Although, tochemotherapy with carboplatin and etoposide, and on a a certain extent, chemotherapeutic regimens varied with therecurrent JGCT with liver metastases that achieved complete consecutive MAKEI protocols, all but one patient receivedremission for 44 months after surgery and six cycles of chemotherapy that included cisplatin and etoposide, mostly asbleomycin and paclitaxel.4,5 part of three-agent regimens. Therefore, it seems meaningful to Although case reports certainly represent a selection of en- include these two drugs into a three-agent combination regimencouraging experience and exclude discouraging experience from such as PEI.other patients, these reports are in line with our data in advanced- Finally, alternative strategies must be developed for refractorystage tumors (Table 1). Our previous analysis on JGCT demon- tumors. Thermochemotherapy may present a promising conceptstrated that adjuvant multimodal chemotherapy may help to because preliminary clinical data and a case report show signif-achieve lasting complete remissions in advanced-stage tumors.11 icant efficacy of thermochemotherapy in refractory tumors.12That analysis is further substantiated by this updated and The limited data on patients with recurrent disease indicate thatexpanded evaluation, which reveals that, regardless of initial PEI chemotherapy may help to achieve a second remission.stage, all patients achieved complete clinical remission after However, in the majority of patients, the second remission wassurgery and adjuvant cisplatin- and etoposide-based three-agent not durable.chemotherapy. Most importantly, complete responses also trans- In conclusion, our data allow the development and prospectivelate into durable remissions. Despite the pronounced therapeutic evaluation of risk-adapted therapeutic strategies in OSCST onefficacy, acute toxicity was tolerable, and chronic side effects the basis of a standardized clinical and histopathologic assess-were mainly related to surgery (eg, with bilateral adnectomy or ment. Considering our experience, we recommend that patientshysterectomy) in advanced tumors. with stage IA and accidental IC tumors be followed up at regular The histologic work-up demonstrates that patients with intervals, whereas we would recommend that patients withhigh mitotic activity have a poorer long-lasting response to natural stage IC tumors with preoperative rupture or malignantadjuvant chemotherapy (Fig 4). Notably, the analysis of those ascites be treated with adjuvant cisplatin-based chemotherapy,patients who were treated with chemotherapy also reflects the especially patients with tumors with high mitotic activity.impact of high mitotic activity because all refractory, ulti- Finally, we recommend that advanced-stage tumors be treatedmately fatal tumors showed high mitotic activity (Table 1). with at least four to six cycles of cisplatin-based chemotherapy.One may argue that this finding might correlate with induction However, it has to be considered that the data presented in thisof resistance to chemotherapy. analysis are limited and need to be validated in a larger In this context, the finding of the prognostic impact of age prospective and preferably randomized trial. If one considers thatseems intriguing (Fig 3). Summarizing the clinical data, we the incidence of OSCST is probably underestimated because ofpropose that two biologically and clinically distinct types of incomplete patient recruitment, this study reveals encouragingtumors might exist. One type occurs in young children, com- perspectives that merit further investigation.monly results in isosexual precocity, is diagnosed at early stages, ACKNOWLEDGMENTand is prognostically favorable, which is in line with the French We thank all medical centers that contributed patients to the Malignedata that isosexual precocity correlates with favorable outcome.2 Keimzelltumoren studies and gratefully acknowledge Susanne Koch for dataThe other type of tumor appears later, causes endocrinologic management.
  • 7. OVARIAN SEX CORD–STROMAL TUMORS 2363 REFERENCES 1. Young RH, Dickersin GR, Scully RE: Juvenile granulosa cell tumor of 8. Benedet JL, Bender H, Jones H III, et al: FIGO staging classificationsthe ovary: A clinicopathological analysis of 125 cases. Am J Surg Pathol and clinical practice guidelines in the management of gynecologic cancers:8:575-596, 1984 FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet 70:209- 2. Plantaz D, Flamant F, Vassal G, et al: Granulosa cell tumors of the 262, 2000ovary in children and adolescents: Multicenter retrospective study in 40 9. Colombo N, Sessa C, Landoni F, et al: Cisplatin, vinblastine, andpatients aged 7 months to 22 years. Arch Fr Pediatr 49:793-798, 1992 bleomycin combination chemotherapy in metastatic granulosa cell tumor of 3. Young RH, Scully RE: Ovarian Sertoli-Leydig cell tumors: A clinico- the ovary. Obstet Gynecol 67:265-268, 1986pathological analysis of 207 cases. Am J Surg Pathol 9:543-569, 1985 10. Powell JL, Johnson NA, Bailey CL, et al: Management of advanced 4. Powell JL, Connor GP, Henderson GS: Management of recurrent juvenile granulosa cell tumor of the ovary. Gynecol Oncol 48:119-123, 1993juvenile granulosa cell tumor of the ovary. Gynecol Oncol 81:113-116, 2001 11. Calaminus G, Wessalowski R, Harms D, et al: Juvenile granulosa cell 5. Powell JL, Otis CN: Management of advanced juvenile granulosa cell tumors of the ovary in children and adolescents: Results from 33 patients Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission.tumor of the ovary. Gynecol Oncol 64:282-284, 1997 registered in a prospective cooperative study. Gynecol Oncol 65:447-452, 6. Vassal G, Flamant F, Caillaud JM, et al: Juvenile granulosa cell tumor 1997of the ovary in children: A clinical study of 15 cases. J Clin Oncol 6:990-995, 12. Wessalowski R, Spaar HJ, Pape H, et al: Successful liver treatment of1988 a juvenile granulosa cell tumor in a 4-year-old child by regional deep 7. Gobel U, Schneider DT, Calaminus G, et al: Germ-cell tumors in ¨ hyperthermia, systemic chemotherapy, and irradiation. Gynecol Oncol 57:childhood and adolescence. Ann Oncol 11:263-271, 2000 417-422, 1995 Copyright © 2003 American Society of Clinical Oncology. All rights reserved.
  • 8. CORRESPONDENCEIt’s the Poison That Killed Him, You Say! I urge that we require reporting the any-cause death rate at the time units given above in all therapeutic phase III studies and important therapeutic To the Editor: A learned medical oncologist said, “Seventy-four-year-old phase II studies (especially randomized studies). The Journal of ClinicalMr Doe, who died on day 27 of his second cycle of the MENACE regimen, Oncology should be the first to require reporting this way.must be considered a toxic death on this study.” He added, “I know he hada carotid endarterectomy performed 1 year ago and had a history of coronary Jaffer A. Ajaniartery disease and died of a hemorrhagic CVA [cerebrovascular accident], Department of Gastrointestinal Medical Oncologybut I still believe had he not received this chemotherapy, he would still be The University of Texas M.D. Anderson Cancer Centeralive today, so it’s a toxic death. Period.” In disagreement with him, the other Houston, TXmedical oncologist on the safety monitoring committee of the MENACEphase II trial said, “Listen everyone, this is a clear case of treatment- AUTHOR’S DISCLOSURES OF POTENTIALexaggerated death. What more information do you need to make that CONFLICTS OF INTEREST Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission.judgment? The patient was predisposed to having a stroke, and MENACE The author indicated no potential conflicts of interest.triggered it.” The discussion continued. Members, using facial expressionsand body language, started seeking out others who would align with them.By this time, another medical oncologist had teamed with a statistician on the DOI: 10.1200/JCO.2003.99.159committee and said, “This patient was at high risk for developing a CVAirrespective of this treatment, and there were no lingering treatment effects, Copyright © 2003 American Society of Clinical Oncology. All rights reserved.such as thrombocytopenia, coagulation abnormalities, dehydration, or car-diac arrhythmias, that might have facilitated the CVA. Therefore, this is not c-Kit Proto-Oncogene Product Is Rarely Detected ina toxic death.” He added, “Toxic deaths usually occur after the first cycle of Colorectal Adenocarcinomatreatment.” Now the range of facial expressions was taken to another level bythe six members of the committee, mostly reflecting disagreement at To the Editor: c-kit (CD117) is a growth factor receptor of the tyrosine kinase subclass III family, normally expressed in a variety of human tissuesdiffering levels. Something had to be done about the case. Finally, the including hematopoietic stem cells, mast cells, gametocytes, melanocytes,committee classified the cause of death as “treatment exacerbated.” and the interstitial cells of Cajal.1 Binding of the c-kit ligand (stem cell So, what did we learn from this? I have sat on a few safety monitoring factor) leads to activation of the c-kit tyrosine kinase via receptor ho-committees and deliberated on a number of cases like this one where there modimerization and auto-phosphorylation of specific tyrosine residues on thewas little agreement and a high level of subjectivity pervaded throughout the intracellular domain of the receptor. c-kit signaling promotes cell survival,process. Some individuals dominate the discussion, whereas others feel proliferation, differentiation, adhesion, and migration.2 Several gain-of-reduced. The discomfort level is often on the high side in meetings like these. function mutations of the c-kit gene have been identified that produceAm I saying there is usually no agreement? Not at all. Obvious cases are not ligand-independent activation of c-kit and cell proliferation.3 Some of thesedisputed and I certainly do not question the case that constitutes toxic death. mutations appear causative in the pathogenesis of adult mastocytosis3 andThere are instances where it is clear to all that a patient dies as a result of most gastrointestinal stromal tumors (GISTs).4,5 c-kit mutations have beentherapy, but thankfully, this is no longer common because of improved identified in hematolymphoid malignancies, melanomas, seminomas, neuro-awareness and better supportive care across the board. The larger fraction of blastomas, endometrial carcinoma, and small-cell carcinoma of the lung.6-9patients determined to have died as a result of a toxic death is due to the use Recent therapeutic breakthroughs in the treatment of GISTs involve STI571of personal interpretation of data, biases, and the level of experience of the (imatinib mesylate [Gleevec]; Novartis Pharmaceuticals, East Hanover, NJ),individuals deliberating. In addition, anecdotes are often thrown around. This a drug that targets mutated c-kit by inhibiting its tyrosine kinase activity.10,11is an extremely important issue in evaluating the safety of treatments Several other c-kit tyrosine kinase inhibitors are under investigation.6 Theseemerging from phase III studies. The current standards for evaluating cases developments have increased interest in identifying other tumors with c-kitdo vary; however, generally three elements are embraced in most formats: activating mutations for potential targeted therapy.11-13 c-kit receptor and itsthe investigators weigh in and classify a serious adverse event as it might ligand have been demonstrated in human colon cancer cell lines.14-17 On therelate to therapy, the sponsor (when applicable) weighs in and classifies the basis of experiments on colon cancer cell lines, it was suggested that the c-kitevents, and an independent safety monitoring committee is asked to classify tyrosine kinase inhibitor STI571 be considered for clinical trials as chemo-or define the safety of the regimen(s). This system is flawed, because none therapeutic agent for the prevention and treatment of colon cancer.18of these processes can overcome personal bias and subjective interpretation However, a recent study failed to demonstrate c-kit expression in aof data. significant number of colorectal cancers.19 Should we simply throw away this process? No, but we should have a Because of the clinical interest in c-kit expression in colon cancer by ourmore objective process that would gain more general acceptance by the oncologists, and lack of such information in the literature at that time, wemedical community and be viewed with more confidence than the current previously undertook a study to determine the extent of c-kit expression inprocess. Specifically, in all phase III therapeutic studies, the authors must human colorectal adenocarcinoma (CRC) tissues. We performed immuno-report the rate of any-cause death in all treatment and nontreatment arms at peroxidase staining for c-kit on sections of formalin-fixed and paraffin-30, 60, 90, 120, and 365 days. Needless to say, interpretation is not required embedded tissue from 62 consecutive unselected CRCs using standardfor the cause of death when looking for events at these landmarks. By methodology, after steam-heat antigen retrieval, and using a polyclonaladhering to the reporting of any-cause death, we will remove all biases and rabbit antibody at 1/200 dilution (sc-168; Santa Cruz Biotechnology Inc,subjectivity in data interpretation. Such built-in landmarks would reveal the Santa Cruz, CA). Positive controls were GISTs, and mast cells and/ortreatment effects (in terms of activity and safety). This process would not interstitial cells of Cajal present in all sections of the tumors served asreplace the current one for safety assessment, but would rather complement internal positive controls. Negative controls consisted of sections immuno-it, although it may supersede the current process in the future. An objective stained with nonrelevant rabbit polyclonal antibody or without antibody. Themethod might give us a better understanding of treatment as a whole and percentage of positive cancer cells was recorded. Only two cases (3%)more effective therapy would result in fewer deaths per time unit. Therefore, showed faint cytoplasmic c-kit immunoreactivity in 1% to 10% of the cancerJournal of Clinical Oncology, Vol 21, No 20 (October 15), 2003: pp 3885-3889 3885
  • 9. 3886 CORRESPONDENCEcells. The remaining cases (60 samples, 97%) were completely negative for 10. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al: Effect of the tyrosinec-kit. Occasional nonspecific (artifact) staining was noted in luminal debris, kinase inhibitor ST1571 in a patient with metastatic gastrointestinal stromalapoptotic cancer cells, and intracytoplasmic mucin in cancer cells. Internal tumor. N Engl J Med 344:1052-1056, 2001positive controls were always positive. Our immunohistochemistry labora- 11. Demetri GD: Targeting c-kit mutations in solid tumors: Scientifictory has been receiving requests from oncologists to perform immunostain- rationale and novel therapeutic options. Semin Oncol 28:19-29, 2001 (5ing for c-kit on sections of colon cancer patient samples. Of 10 prospective suppl 17)patient samples that we stained on the basis of such requests, nine were 12. Longley BJ, Ma Y, Carter E, et al: New approaches to therapy forcompletely negative and one had c-kit immunoreactivity in 10% to 25% of mastocytosis: A case for treatment with kit kinase inhibitors. Hematol Oncolthe cancer cells. Our combined data (from the study and the prospective Clin North Am 14:689-695, 2000patient samples) indicate that c-kit protein is rarely detected in CRC. These 13. Longley BJ, Metcalfe DD: A proposed classification for mastocytosisresults are in agreement with a report by Reed et al.19 incorporating molecular genetics. Hematol Oncol Clin North Am 14:697- A feature of the tyrosine kinase inhibitors currently being developed is 701, 2000 Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission.their lack of absolute specificity for a subtype of tyrosine kinase. All tyrosine 14. Toyota M, Hinoda Y, Takaoka A, et al: Expression of c-kit and kitkinase inhibitors that cause c-kit inhibition also inhibit two or more related ligand in human colon carcinoma cells. Tumour Biol 14:295-302, 1993receptors, including the fusion gene product BCR-ABL (the intended target 15. Lahm H, Amstad P, Yilmaz A, et al: Interleukin 4 down-regulatesfor which STI571 was developed), platelet-derived growth factor receptor, expression of c-kit and autocrine stem cell factor in human colorectalkinase insert domain receptor, insulin receptor, fibroblast growth factor carcinoma cells. Cell Growth Differ 6:1111-1118, 1995receptor, and macrophage colony-stimulating factor receptor.6 Although our 16. Bellone G, Silvestri S, Artusio E, et al: Growth stimulation offindings suggest that c-kit kinase activation is not a prominent pathogenetic colorectal carcinoma cells via the c-kit receptor is inhibited by TGF-beta-1. Copyright © 2003 American Society of Clinical Oncology. All rights reserved.feature of CRC, some of the tyrosine kinase inhibitors may nonetheless be J Cell Physiol 172:1-11, 1997beneficial in treatment of CRC as a result of inhibition of related tyrosine 17. Bellone G, Carbone A, Sibona N, et al: Aberrant activation of c-kitkinases.6,20 Therefore, negative c-kit immunostaining in CRC should not be protects colon carcinoma cells against apoptosis and enhances their invasiveinterpreted as evidence that the patient will not respond to treatment with potential. Cancer Res 61:2200-2206, 2001tyrosine kinase inhibitors. On the other hand, our findings strongly suggest 18. Attoub S, Rivat C, Rodrigues S, et al: The c-kit tyrosine kinasethat c-kit immunostaining is not a cost-effective, and perhaps not a sensitive, inhibitor STI571 for colorectal cancer therapy. Cancer Res 62:4879-4883,method of identifying patients with CRC who may benefit from treatment 2002with tyrosine kinase inhibitors 19. Reed J, Ouban A, Schickor FK, et al: Immunohistochemical staining for c-kit (CD117) is a rare event in human colorectal carcinoma. Clin Rebecca Yorke Colorectal Cancer 2:119-122, 2002 Minnie Chirala 20. Shaheen RM, Tseng WW, Davis DW, et al: Tyrosine kinase inhibition Mamoun Younes of multiple angiogenic growth factor receptors improves survival in mice Department of Pathology bearing colon cancer liver metastases by inhibition of endothelial cell Baylor College of Medicine and The Methodist Hospital survival mechanisms. Cancer Res 61:1464-1468, 2001 Houston, TX AUTHORS’ DISCLOSURES OF POTENTIAL DOI: 10.1200/JCO.2003.99.213 CONFLICTS OF INTEREST The authors indicated no potential conflicts of interest. In Reply: Dr Yorke et al have demonstrated that KIT tyrosine kinase is rarely detected in colorectal adenocarcinoma by immunohistochemistry, and REFERENCES this is consistent with a recent report by Reed et al.1 Enthusiasm for staining 1. Ashman LK: The biology of stem cell factor and its receptor C-kit. Int a variety of human malignancies for KIT is widespread in the wake of theJ Biochem Cell Biol 31:1037-1051, 1999 successful use of imatinib for the treatment of gastrointestinal stromal tumors 2. Vliagoftis H, Worobec AS, Metcalfe DD: The protooncogene c-kit and (GISTs). The hope is that a positive signal will predict for drug sensitivity,c-kit ligand in human disease. J Allergy Clin Immunol 100:435-440, 1997 regardless of tumor origin. Although this approach is well intended, it has 3. Longley BJ, Reguera MJ, Yongsheng MA: Classes of c-KIT activating two major problems. First, immunohistochemistry can lead to false-positivemutations: Proposed mechanisms of action and implications for disease staining when the antibody is not properly titered, and this is particularly trueclassification and therapy. Leuk Res 25:571-576, 2001 for KIT. When the staining is performed with care, KIT expression is, in fact, 4. Hirota S, Isozaki K, Moriyama Y, et al: Gain-of-function mutations of uncommon in most human malignancies.2 Second—and more important—c-kit in human gastrointestinal stromal tumors. Science 279:577-580, 1998 the premise that expression of KIT in a tumor implies that it has a critical role 5. Lux ML, Rubin BP, Biase TL, et al: KIT extracellular and kinase in supporting tumor cell growth and survival is not supported by recentdomain mutations in gastrointestinal stromal tumors. Am J Pathol 156:791- studies. Clinical responses to imatinib therapy have been observed almost795, 2000 exclusively in malignancies known to harbor a genomic alteration that 6. Heinrich MC, Blanke CD, Druker BJ, et al: Inhibition of KIT tyrosine accounts for activation of the targeted kinase. For example, mutations of KITkinase activity: A novel molecular approach to the treatment of KIT-positive are present in 80% to 85% of GISTs, and it is the type of KIT mutation, rathermalignancies. J Clin Oncol 20:1692-1703, 2002 than the level of KIT expression, that best correlates with imatinib response 7. Natali PG, Nicortra MR, Sures I, et al: Expression of c-kit receptor in in GIST patients.3 Similarly, the impressive clinical responses to imatinibnormal and transformed human nonlymphoid tissues. Cancer Res 52:6139- observed in patients with chronic myelogenous leukemia, chronic my-6143, 1992 elomonocytic leukemia, and dermatofibrosarcoma protuberans all correlate 8. Tsuura Y, Hiraki H, Watanabe K, et al: Preferential localization of c-kit with the presence of specific chromosomal translocations that activate otherproduct in tissue mast cells, basal cells of skin, epithelial cells of breast, imatinib-sensitive kinases.4-7 In contrast, attempts to target tumors solely onsmall cell lung carcinoma and seminoma/dysgerminoma in human: Immu- the basis of KIT positivity, without evidence of kinase activation, have beennohistochemical study on formalin-fixed, paraffin-embedded tissues. Vir- much less effective.8chows Arch 424:135-141, 1994 It also should be noted that standard immunohistochemistry may not be 9. Elmore LW, Domson K, Moore JR, et al: Expression of c-kit (CD117) sufficiently sensitive to detect biologically relevant levels of kinase expres-in benign and malignant human endometrial epithelium. Arch Pathol Lab sion in all tumors. We recently reported a case of a malignant GIST that,Med 125:146-151, 2001 despite nearly undetectable levels of KIT expression, contained a typical KIT
  • 10. CORRESPONDENCE 3887exon 11 deletion and responded well to imatinib therapy.9 In conclusion, contrast with the 50% complete response and 13.8 months median survivalimmunohistochemistry for KIT is useful to pathologists in confirming the of the present study.diagnosis of GIST and a limited number of other tumors, but it should not be Nevertheless, despite the poor results in patients receiving arm C chemo-regarded as a predictor of imatinib sensitivity. radiotherapy regimen in the phase III study, it must be emphasized that complete response rate in arm C patients was statistically better than that for Michael C. Heinrich control patients, and higher than that in arm B patients. Christopher L. Corless Consequently, it could be suggested that the poor results in arm C were OHSU Cancer Institute due to a more complex schedule rather than a real low efficacy of this Departments of Medicine and Pathology chemoradiotherapy regimen. This interpretation could also explain the Oregon Health & Science University and VA Medical Center significantly higher proportion of patients who did not complete the Portland, OR treatment in this arm. Furthermore, it would be of interest to know if patients who did not complete the treatment in arm C had been treated AUTHORS’ DISCLOSURES OF POTENTIAL Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission. mainly in community hospitals participating in the study rather than in CONFLICTS OF INTEREST major medical centers, and to know if the authors analyzed the complete The authors indicated no potential conflicts of interest. response and survival rates in the arm C patients who completed the treatment. Indeed, considering the good results of the phase II study and the higher REFERENCES complete response rate in arm C than in arm B of the present phase III study, improving the feasibility of this schedule would be a promising target for 1. Reed J, Ouban A, Schickor FK, et al: Immunohistochemical staining Copyright © 2003 American Society of Clinical Oncology. All rights reserved. patients with unresectable head and neck cancer.for c-Kit (CD117) is a rare event in human colorectal carcinoma. ClinColorectal Cancer 2:119-122, 2002 Emmanuel Blot 2. Hornick JL, Fletcher CD: Immunohistochemical staining for KIT Elsie Staub(CD117) in soft tissue sarcomas is very limited in distribution. Am J Clin Department of Medical OncologyPathol 117:188-193, 2002 Henri Becquerel Center 3. Heinrich MC, Corless C L, Blanke CD, et al: KIT mutational status Rouen, Francepredicts clinical response to STI571 in patients with metastatic gastrointes-tinal stromal tumors (GISTs). Proc Am Soc Clin Oncol 21:2a, 2002 (abstr 6) AUTHORS’ DISCLOSURES OF POTENTIAL 4. Apperley JF, Gardembas M, Melo JV, et al: Response to imatinib CONFLICTS OF INTERESTmesylate in patients with chronic myeloproliferative diseases with rearrange-ments of the platelet-derived growth factor receptor beta. N Engl J Med The authors indicated no potential conflicts of interest.347:481-487, 2002 5. Druker BJ, Talpaz M, Resta DJ, et al: Efficacy and safety of a specific REFERENCESinhibitor of the bcr-abl tyrosine kinase in chronic myeloid leukemia. N EnglJ Med 344:1031-1037, 2001 1. Adelstein DJ, Li Y, Adams GL, et al: An Intergroup phase III 6. Maki RG, Awan RA, Dixon RH, et al: Differential sensitivity to comparison of standard radiation therapy and two schedules of concurrentimatinib of 2 patients with metastatic sarcoma arising from dermatofibrosar- chemoradiotherapy in patients with unresectable squamous cell head andcoma protuberans. Int J Cancer 100:623-626, 2002 neck cancer. J Clin Oncol 21:92-98, 2003 7. Rubin BP, Schuetze SM, Eary JF, et al: Molecular targeting of 2. Adelstein DJ, Kalish LA, Adams GL, et al: Concurrent radiationplatelet-derived growth factor B by imatinib mesylate in a patient with therapy and chemotherapy for locally unresectable squamous cell head andmetastatic dermatofibrosarcoma protuberans. J Clin Oncol 20:3586-3591, neck cancer: An Eastern Cooperative Oncology Group pilot study. J Clin2002 Oncol 11:2136-2142, 1993 8. Apperley JF: A rationally designed, targeted tumor treatment approach:A phase II study of imatinib mesylate (Gleevec) in patients with lifethreatening diseases known to be associated with imatinib-sensitive tyrosine DOI: 10.1200/JCO.2003.99.017kinases. Proc Am Soc Clin Oncol 21:2a, 2002 (abstr 7) 9. Bauer S, Corless CL, Heinrich MC, et al: Response to imatinibmesylate of a gastrointestinal stromal tumor with very low expression of In Reply: This phase III randomized trial in patients with unresectableKIT. Cancer Chemother Pharmacol 51:261-265, 2003 squamous cell head and neck cancer compared three treatments: standard, once-daily, continuous-course radiation therapy (arm A); continuous-course radiation therapy and concurrent high-dose, single-agent cisplatin (arm B); DOI: 10.1200/JCO.2003.99.004 and a third arm using multiagent chemotherapy (fluorouracil and cisplatin) and a split-course of radiation therapy (arm C).1 Blot and Staub have asked why the arm C results in this study were inferior to the results achieved by the Eastern Cooperative Oncology Group in their pilot study of this sameChemoradiotherapy in Unresectable Squamous Cell regimen,2 particularly when the complete response rate for arm C was higher than that for the other treatment arms. They have asked if these results reflectHead and Neck Cancer inferior efficacy for the arm C treatment schedule or merely the impact of the To the Editor: We have read with interest the report of Adelstein et al1 in significantly greater number of arm C patients who did not complete theirthe January 1 issue of the Journal of Clinical Oncology, which provided treatment because of the more difficult schedule.evidence for the benefits of concomitant chemoradiotherapy in patients with We think that both explanations are true. This treatment arm wasadvanced unresectable head and neck squamous cell cancer. Nevertheless, originally designed with the hope that after a partial course of radiationthe authors mentioned the difference between the results of treatment in arm therapy and concurrent chemotherapy, surgery would be possible in patientsC of the present study and the previous report of this chemoradiotherapy initially deemed unresectable, and that this surgery would offset theregimen.2 In fact, midcourse surgical treatment had been performed in only well-recognized disadvantages of a split-course of radiation therapy.3 Be-14 of 89 (16%) patients, whereas it was possible in 18 of 50 (36%) patients cause midcourse surgery was only infrequently accomplished in the arm Cin the previous phase II study.2 Moreover, the complete response rate was patients on this study, however, the suboptimal radiotherapy schedule77% and the median survival was 37 months in the initial phase II study, in became a disadvantage. Furthermore, the arm C schedule was more compli-
  • 11. 3888 CORRESPONDENCEcated and required a longer period of time to complete. Treatment could not associated psychologic dysfunction, including anxiety,4,5 and that an ele-be completed in more arm C patients than for the other treatment arms; vated level of chronic anxiety exists among a significant proportion ofanother design feature that inadvertently led to inferior results. long-term survivors of testicular cancer.6 Thus, in the study by Huddart et al, It also should not be surprising that both the frequency of midcourse it is unclear what proportion of patients with cardiovascular events definedsurgery and the survival were superior in our initial limited institution phase by chest pain actually had noncardiac chest pain, with or without associatedII pilot study, as opposed to this large multi-institutional phase III trial. The psychologic dysfunction. Nonetheless, this work attests to the ongoing needpatients on this phase III study were treated in both community hospitals and for long-term follow-up of such patients, and for continued attention tomajor medical centers. Completion of the arm C treatment schedule was a minimizing the toxicity of therapy.problem in both settings. Among the complete responders on arm C were patients undergoing Cyrus P. Tambolimidcourse surgery, an option not available to those patients on arm A or B. Department of HepatogastroenterologieThus, the complete response rate for that treatment arm should be higher than CHRU, Hoptial Claude Huriez ˆ Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission.that for the other arms. Lille, France David J. Adelstein Department of Hematology and Medical Oncology AUTHOR’S DISCLOSURES OF POTENTIAL Cleveland Clinic Foundation CONFLICTS OF INTEREST Cleveland, OH The author indicated no potential conflicts of interest. AUTHOR’S DISCLOSURES OF POTENTIAL Copyright © 2003 American Society of Clinical Oncology. All rights reserved. CONFLICTS OF INTEREST REFERENCES The author indicated no potential conflicts of interest. 1. Huddart RA, Norman A, Shahidi M, et al: Cardiovascular disease as a REFERENCES long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513-1523, 2003 1. Adelstein DJ, Li Y, Adams GL, et al: An Intergroup phase III 2. Botoman VA: Noncardiac chest pain. J Clin Gastroenterol 34:6-14,comparison of standard radiation therapy and two schedules of concurrent 2002chemoradiotherapy in patients with unresectable squamous cell head and 3. Nevens F, Janssens J, Piessens J, et al: Prospective study onneck cancer. J Clin Oncol 21:92-98, 2003 prevalence of esophageal chest pain in patients referred on an elective 2. Adelstein DJ, Kalish LA, Adams GL, et al: Concurrent radiation basis to a cardiac unit for suspected myocardial ischemia. Dig Dis Scitherapy and chemotherapy for locally unresectable squamous cell head and 36:229-235, 1991neck cancer: An Eastern Cooperative Oncology Group pilot study. J Clin 4. Kane FJ, Stronhlein J, Harper RG: Noncardiac chest pain in patientsOncol 11:2136-2142, 1993 with heart disease. South Med J 84:847-852, 1991 3. Parsons JT, Bova FJ, Million RR: A re-evaluation of split-course 5. Richter JE, Obrecht WF, Bradley LA, et al: Psychologic comparison oftechnique for squamous cell carcinoma of the head and neck. Int J Radiat patients with nutcracker esophagus and irritable bowel syndrome. Dig DisOncol Biol Phys 6:1645-1652, 1980 Sci 31:131-138, 1986 6. Fosså SD, Dahl AA, Loge JH: Fatigue, anxiety, and depression in DOI: 10.1200/JCO.2003.99.069 long-term survivors of testicular cancer. J Clin Oncol 21:1249-1254, 2003 DOI: 10.1200/JCO.2003.99.110Long-Term Survivors of Testicular Cancer To the Editor: Huddart et al1 have recently presented an interesting studyin this journal on cardiovascular events in long-term survivors of testicular In Reply: We read with interest the comments of Cyrus P. Tamboli, MD,cancer. In that study, the authors documented an increased risk in patients regarding our article on the risk of developing cardiovascular disease aftertreated previously with radiotherapy, chemotherapy, or both, when compared treatment for testicular cancer.1 His points about the possibility of includingwith surveillance-only patients. The study included a large cohort of patients, patients with noncardiac chest pain in this series are well made. Because we,and the physiologic mechanisms proposed for cardiovascular disease that to date, have not undertaken detailed cardiac assessment of these patients, wemay follow cancer therapy are entirely plausible. Importantly, this studydocuments one of the highest rates of long-term cardiovascular events in cannot absolutely refute these assertions.testicular cancer survivors so far. However, it is possible that some of the However there is a clear imbalance in the risk of a cardiac event (asincluded criteria for defining cardiovascular disease may have inflated the defined in our study) between the different treatment groups, with a clearoverall magnitude of risk. increased risk in those patients receiving chemotherapy or radiotherapy. We The authors document that out of the 68 patients having a cardiac event, do not believe that such an imbalance would be seen if a substantial portion41 patients (60%) were defined by the symptoms of angina or chest pain of the effect was due to physiologic chest pain. In parallel studies of thealone, as determined by patient questionnaires or retrospective general quality of life, including study of psychologic well-being of these patients,practitioner or physician records. Verification of a cardiovascular etiology we could detect no major differences in the treatment groups.2 Therefore, wefor these symptoms is not presented for this subgroup. It is known that even do not think that psychologic factors could account for our findings. Inangina-like chest pain is sometimes noncardiac in origin, and that differen- addition, in a smaller group of patients who had received chemotherapy,tiating chest pain of cardiac versus noncardiac origin may be difficult or Meinardi et al3 noted a 6% risk of a major cardiac event after a medianimpossible on the basis of history alone.2 Up to 30% of unselected patients follow-up of 14 years. In this series, all patients had either a myocardialpresenting with angina-like chest pain have normal coronary arteries docu- infarction or documented angina requiring revascularization.3 These data aremented at subsequent angiography.3 In general, the prognosis of such entirely consistent with our quoted risk of a cardiac event, which includespatients (who are often young) is good. Of additional significance are the patients with angina, of 6.8% for chemotherapy-treated patients after adual observations that many patients with noncardiac chest pain have slightly shorter median follow-up of 9.7 years.
  • 12. CORRESPONDENCE 3889 Thus, we continue to believe that our data are most consistent with a real REFERENCESand significant increased risk in cardiac morbidity after treatment for 1. Huddart RA, Norman AR, Shahidi M, et al: Cardiovascular disease astesticular cancer. This risk should be confirmed and studied in more detail in a long term complication of treatment for testicular cancer. J Clin Oncoladditional well-designed studies of this issue. 21:1513-1523, 2003 R.A. Huddart 2. Huddart RA, Norman A, Moynihan C, et al: Quality of life of long term A. Norman survivors of testicular cancer. Proc Am Soc Clin Oncol 20:176b, 2001 (abstr The Academic Unit of Radiotherapy and Oncology 2456) The Royal Marsden NHS Trust 3. Meinardi MT, Gietema JA, van der Graaf WT, et al: Cardiovascular Sutton, Surrey, United Kingdom morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725-1732, 2000 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission. DOI: 10.1200/JCO.2003.99.158 The authors indicated no potential conflicts of interest. Copyright © 2003 American Society of Clinical Oncology. All rights reserved.
  • 13. ERRATUM The June 15, 2003, article by Schneider et al, entitled “Ovarian Sex Cord—Stromal Tumors in Children and Adolescents” (J ClinOncol 21:2357-2363, 2003) contained an error. The correct spelling of the third author’s name is R. Wessalowski. DOI: 10.1200/JCO.2003.08.903 Downloaded from jco.ascopubs.org on February 25, 2013. For personal use only. No other uses without permission. Copyright © 2003 American Society of Clinical Oncology. All rights reserved.3890