8. Matsui T, Yokoyama A, Matsushita S et al. Effect of a comprehensive lifestyle

modification program on the bone density of male heavy drinkers. Alcohol

Clin Exp Res 2010 Feb 24. [Epub ahead of print].

9. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly:

Consequences for bone loss and fractures and therapeutic implications. En-

docr Rev 2001;22:477–501.

10. Bikle DD. Effects of alcohol abuse on bone. Compr Ther 1988;14:16–20.

METRONOMIC CYCLOPHOSPHAMIDE IN ELDERLYPATIENTS WITH ADVANCED, CASTRATION-RESISTANT PROSTATE CANCER

To the Editor: Metronomic chemotherapyFlow-dose,long-term, frequently administered chemotherapyFhasbeen found to have an important effect on the stabilizationof cancer, including prostate cancer,1,2 without any high-grade toxicity. However, no data from prospective metro-nomic clinical trials are available in elderly patients withcancer. Anecdotal case reports3 and a small retrospectiveclinical study on metastatic melanoma4 have suggestedmetronomic chemotherapy as an alternative therapy in el-derly patients requiring palliation.

The present study was a retrospective review of 29consecutive elderly patients (aged � 78) with advancedcastration-resistant prostate cancer (CRPC) who had beentreated with metronomic cyclophosphamide (50 mg per dayby mouth) plus celecoxib (200 mg twice a day bymouth) and dexamethasone (1 mg once daily by mouth)at Pisa University Hospital and Livorno General Hospital.The treatment was given for at least 12 weeks.

Median age was 83 (range 78–92); six patients (20%)had an Eastern Cooperative Oncology Group PerformanceStatus (PS) of 0 and 23 (80%) of 1 or more; the mediannumber of comorbidities was 2 (range 0–6), and 19 patients(65%) were deemed frail.5 Median baseline serum prostatespecific antigen (PSA) level was 49.4 ng/mL (range 6.7–567.8 ng/mL); bone was the most frequent metastatic site(72.4%); two patients had measurable disease (7%). Tenpatients (34.5%) received one or more previous chemother-apeutic lines, including docetaxel (9 patients, 31%), mitox-antrone (5 patients, 10%), estramustine phosphate (7 patients,24%), and vinorelbine and etoposide (1 patient, 3.4%).Zoledronic acid was administered to 19 patients (65.5%).

No Grade 3 or 4 hematological or nonhematologicaltoxicities were observed in the 29 assessable patients. Fourpatients (14%) developed National Cancer InstituteFCommon Toxicity Criteria Grade 2 anemia, and twopatients (7%) developed Grade 2 thrombocytopenia (one ofthese patients required cyclophosphamide discontinuation).Neither major cardiovascular events nor toxicity-relateddeaths were observed.

Overall, 18 patients (62%) experienced any reductionin PSA level (a decrease of 2% to 99%); 13 (45%) had aconfirmed PSA decrease of 50% or greater. Of the 13responders (77%), 10 had not received any prior chemo-therapy, whereas the remaining three had previously re-ceived chemotherapy (median 2 lines of chemotherapy).Moreover, nine of the 16 nonresponders had previouslybeen received chemotherapy, and seven had not. Based onthese results, there was not any statistical difference in theclinical activity in this metronomic combination between

patients previously treated or untreated (P 5.43; Fisherexact test).

One of two patients (7%) with measurable disease ac-cording to the Response Evaluation Criteria In Solid Tu-mors obtained a partial response, and the other showeddisease stabilization.

Median duration of response of the 18 patients withany reduction in PSA levels was 8.6 months (95% confi-dence interval (CI) 5 7.6–9.6 months).

After a median follow-up of 27.3 months (95%CI 5 18.8–35.8 months), median progression-free survivaland median overall survival were 7.7 months (95%CI 5 2.3–13.1 months) and 19.7 months (95% CI 5 12.8–26.6 months), respectively (Figure 1).

Palliative docetaxel plus low-dose prednisone every 3weeks is the standard treatment for CRPC.6,7 The clinicalefficacy and tolerability of first-line docetaxel was recentlyreported on in 175 patients aged 75 and older. The authorsobserved a favorable safety and efficacy profile of 3 weeksof docetaxel only in ‘‘fit’’ elderly patients with prostatecancer (PS � 1).8 Conversely, 46% of patients received anadapted docetaxel regimen (delivered on a weekly schedulein nearly 90% of the cases) because of their vulnerablecondition: aged 80 and older or a PS of 2 or greater. How-ever, this subgroup of patients also experienced severe non-hematological toxicity in approximately 40% of the cases.Such results lead the authors to consider the weekly regimenless safe than reported previously in elderly patients withprostate cancer.8

Despite the known limitations of a retrospective studywith a small sample size, the regimen in the current study wasfeasible and demonstrated a favorable toxicity profile evenin elderly and ‘‘unfit’’ patients with prostate cancer. A goodtoxicity profile was also seen in patients treated for longer

Figure 1. Actuarial progression free survival and overall sur-vival curves calculated using the Kaplan–Meier method from thefirst day of the combined metronomic cyclophosphamide,celecoxib, and dexamethasone regimen.

986 LETTERS TO THE EDITOR MAY 2010–VOL. 58, NO. 5 JAGS

than 1 year. This is also because of the primarily noncyto-toxic mechanism of action of this combination. The anti-angiogenic action of the metronomic cyclophosphamide hasbeen demonstrated in preclinical studies9 and confirmed inpatients with prostate cancer using pharmacodynamic mark-ers (vascular endothelial-cadherin expression and plasmavascular endothelial growth factor).1 The observed activityand toxicity profiles in the present study were consistent withprevious reports1,2 and seems to be well tolerated, safe, andactive in elderly, unfit patients with CRPC.

Andrea Fontana, MDUnit of Medical Oncology 2

Azienda-Ospedaliero Universitaria PisanaIstituto Toscano Tumori and Department of Oncology,

Transplants, and New Technologies in MedicineUniversity of Pisa

Pisa, Italy

Guido Bocci, MD, PhDDivision of Pharmacology and Chemotherapy

Department of Internal MedicineUniversity of Pisa

Pisa, Italy

Luca Galli, MDUnit of Medical Oncology 2

Azienda-Ospedaliero Universitaria PisanaIstituto Toscano Tumori and Department of Oncology

Transplantes and New Technologies in MedicineUniversity of Pisa

Pisa, Italy

Manolo D’Arcangelo, MDDivision of Medical Oncology

Azienda USL 6 of LivornoIstituto Toscano Tumori

Italy

Lisa Derosa, MDUnit of Medical Oncology 2

Azienda-Ospedaliero Universitaria PisanaIstituto Toscano Tumori and Department of Oncology

Transplantes and New Technologies in MedicineUniversity of Pisa

Pisa, Italy

Anna Fioravanti, PhDPaola Orlandi, PhD

Division of Pharmacology and ChemotherapyDepartment of Internal Medicine

University of PisaPisa, Italy

Maria Teresa Barletta, MDLorenza Landi, MD

Simona Bursi, MDGabriele Minuti, MD

Division of Medical OncologyAzienda USL 6 of Livorno

Istituto Toscano TumoriItaly

Eleonora Bona, MDIlaria Grazzini, MD

Unit of Medical Oncology 2Azienda-Ospedaliero Universitaria Pisana

Istituto Toscano Tumori and Department of OncologyTransplantes and New Technologies in Medicine

University of PisaPisa, Italy

Romano Danesi, MD, PhDDivision of Pharmacology and Chemotherapy

Department of Internal MedicineUniversity of Pisa

Pisa, Italy

Alfredo Falcone, MDUnit of Medical Oncology 2

Azienda-Ospedaliero Universitaria PisanaIstituto Toscano Tumori and Department of Oncology

Transplantes and New Technologies in MedicineUniversity of Pisa

Pisa, Italy

ACNOWLEDGEMENTS

The authors thank Dr. Urban Emmenegger for critical re-view of the manuscript and Michele Andreuccetti for datamanagement. The present work was supported by a re-search grant from the Fondazione Cassa di Risparmio diLucca to G. Bocci and, in part, from the Associazione Ital-iana per la Ricerca sul Cancro to A. Falcone and G. Bocci.

Conflict of Interest: The authors have no financial orany other kind of personal conflicts of interest with thispaper.

Author Contributions: AF, GB, LG, and AF: study con-cept and design and overall supervision of the project. MD,LD, AF, PO, MTB, LL, SB, GM, EB, and IG: coordinationof the project and patient recruitment. GB: statistical anal-ysis. AF and GB: drafting of the manuscript. All partici-pated in the revision of the manuscript.

Sponsor’s Role: Neither sponsor had any role in thedesign, conduct, analysis, or reporting of the trial.

REFERENCES

1. Fontana A, Galli L, Fioravanti A et al. Clinical and pharmacodynamic eval-

uation of metronomic cyclophosphamide, celecoxib and dexamethasone in ad-

vanced hormone-refractory prostate cancer. Clin Can Res 2009;15:4954–4962.

2. Glode LM, Barqawi A, Crighton F et al. Metronomic therapy with

cyclophosphamide and dexamethasone for prostate carcinoma. Cancer

2003;98:1643–1648.

3. Borne E, Desmedt E, Duhamel A et al. Oral metronomic cyclophosphamide in

elderly with metastatic melanoma. Invest New Drugs 2009 Aug 12. [Epub

ahead of print].

4. Sung CC, Chang PY, Cheng MF et al. Successful metronomic low-dose

cyclophosphamide therapy in an older patient with advanced mucosa-associ-

ated lymphoid tissue lymphoma. Ann Hematol 2009;88:1257–1259.

5. Falci C, Morello E, Droz JP Treatment of prostate cancer in unfit senior adult

patients. Cancer Treat Rev 2009;35:522–527.

6. Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine com-

pared with mitoxantrone and prednisone for advanced refractory prostate can-

cer. N Engl J Med 2004;351:1513–1520.

7. Tannock IF, de Wit R, Berry WR et al. Docetaxel plus prednisone or mitox-

antrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;

351:1502–1512.

LETTERS TO THE EDITOR 987JAGS MAY 2010–VOL. 58, NO. 5

8. Italiano A, Ortholan C, Oudard S et al. Docetaxel-based chemotherapy in el-

derly patients (age 75 and older) with castraction-resistant prostate cancer. Eur

Urol 2009;55:1368–1375.

9. Man S, Bocci G, Francia G et al. Antitumor effects in mice of low-dose (met-

ronomic) cyclophosphamide administered continuously through the drinking

water. Cancer Res 2002;62:2731–2735.

LEIOMYOSARCOMA OF THE SPERMATIC CORD:AN UNUSUAL TUMOR MISDIAGNOSED ASINGUINAL HERNIA IN A GERIATRIC PATIENT

To the Editor: Tumors of the spermatic cord and parates-ticular tissue are rare.1,2 The spermatic cord is the mostcommon site of extratesticular neoplasia. Only 30% of ex-tratesticular neoplasms are malignant, 90% of which aresarcomas. Radical inguinal orchiectomy and high ligationof the cord is the standard primary surgical procedure, butthe extent of surrounding soft tissue excision required androle of adjuvant radiotherapy remains controversial. A caseof leiomyosarcoma arising from the spermatic cord thatwas treated using transinguinal radical orchiectomy andlocal adjuvant radiation is reported. The management ofleiomyosarcoma of the spermatic cord is also discussed byreviewing the literature.

CASE

An 80-year-old man was referred to the hospital with acomplaint of a painful mass in the left groin. Physicalexamination showed a tender, irreducible left inguinalmass. On ultrasound examination, a hernia sac containingbowel segments herniating through a fascial defect was de-tected. The patient was taken to surgery with a diagnosis ofleft inguinal hernia.

Inguinal exploration was performed, and a 5- � 4-cm-diameter heterogenous solid mass was found in the sper-matic cord detached from the testis (Figure 1). A left radicalorchiectomy was performed. Definite histology revealed alow-grade spermatic cord leiomyosarcoma. All resectionmargins were negative. Comprehensive studies did notshow any metastasis in the lungs, liver, or lymphatic system.

The patient was referred for adjuvant therapy. He is freefrom disease after 12 months of follow-up.

DISCUSSION

Paratesticular sarcomas are uncommon tumors, and mostof the available information derives from small series orcase reports. Spermatic cord sarcoma is a rarely encoun-tered malignancy that may be mistakenly diagnosed asmore common processes, such as inguinal hernia or cordlipoma. The unexpected discovery of a sarcoma in the in-guinal region often poses a surgical dilemma when optionsfor surgical treatment have not been discussed with the pa-tient before surgery.

The sarcomas are divided in two groups according toclinical and histological features: sarcomas of children andteenagers (rhabdomyosarcoma) and sarcomas of adults(liposarcoma, leiomyosarcoma, and fibrosarcoma). Mostparatesticular tumors have a mesenchymal origin, and themajority (70%) are benign; the rest (30%) are malignant.The most frequent age incidence is in the 60s and 70s.3

Most patients present with a paratesticular mass. In theclinical examination, it is possible to define the size, mo-bility, consistency, and relation to testis and epididymis. Inthis case, the neoplasia affected neither the testis nor theepididymis.

In case of paratesticular masses, the local examinationis completed with the preoperative scrotal ultrasound andtumoral markers.3 In the current case, because the initialdiagnosis was inguinal hernia, an inguinal ultrasound wasperformed. The tumor markers were studied after thehistopathological examination and were found to be withinnormal ranges.

Most reports advocate radical inguinal orchiectomywith wide excision of surrounding soft tissue as the stan-dard treatment.4,5 Factors that can affect local control ratesinclude tumor biology, adequacy of surgical resection, andadjuvant treatment. The importance of adequate surgicalmargins has been well documented.6 In cases of positivemargins, a second surgical procedure must be performed toremove adjacent structures. Distant metastases of spermaticcord leiomyosarcomas most commonly occurs in a hema-togenous way, and the lungs or liver is often affected. Iflymphatic spread occurs, para-aortic lymph nodes arefound to be affected. Hematogenous metastasis seem tobe more frequent than lymphatic spread. Therefore, retro-peritoneal lymph node dissection is not a regular treatmentoption for spermatic cord leiomyosarcoma patients. Thedefinite roles of adjuvant therapy, including chemotherapyand radiation therapy, are unknown, but most physiciansrecommend radical surgery followed by adjuvant therapy toachieve complete tumor regression. The risk of recurrence ishigh, which underscores the need for through radiographicevaluation and intensive long-term follow-up.3,7 Few pa-tients receive adequate perioperative radiographic stagingbefore their initial surgical treatment, which emphasizes therarity of the lesion and the difficulties with misdiagnosis. It isadequate to perform a computerized tomography scan ormagnetic resonance imaging to evaluate lymph node staging.

A 75% local recurrence rate in cases treated only usingtransinguinal orchiectomy has been reported, and the needfor strong adjuvant therapies was emphasized.8 Definite

Figure 1. The solid mass in the spermatic cord (on the left side ofthe photograph, divided horizontally) is the leiomyosarcoma.The testis is on the right side of the photograph.

988 LETTERS TO THE EDITOR MAY 2010–VOL. 58, NO. 5 JAGS