8. Fabbri A, Cencini E, Rigacci L, et al. Efficacy and safety of rituxi-mab plus low-dose oral fludarabine and cyclophosphamide asfirst-line treatment of elderly patients with indolent non-Hodgkinlymphomas [published online ahead of print July 22, 2013]. LeukLymphoma.

Alessandro Gozzetti, MDMarzia Defina, MD

Alberto Fabbri, MDDivision of Hematology

University Medical Center of SienaSiena, Italy

DOI: 10.1002/cncr.28443, Published online October 22, 2013in Wiley Online Library (wileyonlinelibrary.com)

Reply to Myelosuppression AfterFrontline Fludarabine,Cyclophosphamide, andRituximab in Patients WithChronic Lymphocytic Leukemia

Analysis of Persistent and New-OnsetCytopenia

Myelosuppression can persist after the completion offrontline therapy with fludarabine, cyclophosphamide,and rituximab (FCR) in patients with chronic lympho-cytic leukemia (CLL), mostly among elderly patients withbaseline cytopenia. Its frequency decreases over time, withno association noted with disease progression, secondmyeloid malignancies, or infections (unless persisting upto 9 months).1 The data shown by Gozzetti et al describegrade 3 to 4 hematological toxicity (rather than grade 2to 4) during treatment (rather than after) in elderlypatients with CLL receiving frontline oral FC with rituxi-mab. The observed complete response (CR) rate was 78%and the rate of grade 3 to 4 cytopenia was 15%. In our ini-tial phase 2 study of FCR among patients with a medianage of 58 years, the reported CR rate was 70% and grade 3to 4 neutropenia (the most common hematological toxic-ity) complicated 52% of courses.2 During the CLL8 trial(among patients with a median age of 61 years), the CRrate was 44% and grade 3 to 4 neutropenia was observedin 34% of patients.3 Either calculated per person or cycle,the toxicity reported by Gozzetti et al is lower. It is notclear how many patients had baseline cytopenia, anotherfactor that is significantly associated with myelosuppres-sion in our analysis, and how many received support withgrowth factor. It is interesting to note that the addition ofgranulocyte-macrophage–colony-stimulating factor to

FCR among patients with a median age of 55 yearsproduced a significant reduction in the rate of severe

infections, albeit comparable rates of CR and grade 3 to 4

neutropenia per cycle and per patient.4 Together with the

fact that the addition of rituximab to FCR did not

increase the frequency of infections despite a higher rate

of neutropenia,3 these data raise the question of whether

limiting hematological toxicity will translate into an

actual clinical benefit.

CONFLICT OF INTEREST DISCLOSURESThe authors made no disclosures.

REFERENCES1. Strati P, Wierda W, Burger J, et al. Myelosuppression after frontline

fludarabine, cyclophosphamide, and rituximab in patients withchronic lymphocytic leukemia: analysis of persistent and new-onsetcytopenia [published online ahead of print August 13, 2013]. Cancer.doi: 10.1002/cncr.28318.

2. Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoim-munotherapy regimen of fludarabine, cyclophosphamide, and rituxi-mab as initial therapy for chronic lymphocytic leukemia. J ClinOncol. 2005;23:4079-4088.

3. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituxi-mab to fludarabine and cyclophosphamide in patients with chroniclymphocytic leukaemia: a randomised, open-label, phase 3 trial.Lancet. 2010;376:1164-1174.

4. Strati P, Ferrajoli A, Lerner S, et al. Fludarabine, cyclophosphamideand rituximab plus granulocyte macrophage colony-stimulatingfactor as frontline treatment for patients with chronic lymphocyticleukemia [published online ahead of print July 29, 2013]. LeukLymphoma.

Paolo Strati, MDSusan O’Brien, MD

Department of LeukemiaThe University of Texas MD Anderson Cancer Center

Houston, Texas

DOI: 10.1002/cncr.28442, Published online October 22, 2013in Wiley Online Library (wileyonlinelibrary.com)

Margin Assessment in OralSquamous Cell Carcinoma

We have read with great interest the study by Ch’ng et alin which the authors attempt to show that surgical treat-ment alone achieves an “acceptable” local control amongpatients with close margins.1 This study appears to rea-sonably show that increase in the number of adverse pa-rameters is associated with higher rates of local andregional failure. However, we are concerned by theauthors’ methods for characterization of margins, hetero-geneity of studied cases (in terms of anatomic subsites and

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452 Cancer February 1, 2014

pT, pN), and the lack of direct comparison of local con-trol among patients with positive, close, and negative mar-gins. In our opinion, the above caveats limit theconclusions by Ch’ng et al.

For instance, the authors chose not to take intoaccount revision of surgical margins or assessment of anysupplemental tissue, most likely obtained from the tumorbed. Such an approach precludes meaningful comparisonof this study to others. For example, authors claim thatthe exceptional local control of 91% at 5 years is compara-ble to that previously reported by Brandwein-Gensler

et al.2 However, in the latter study, cases with supplemen-

tal margins were grouped separately from those with close

margins. Parenthetically, comparison to the report by

Weijers et al is also suboptimal, because the latter study

excluded cases with epithelial dysplasia, focused only on

carcinomas involving tongue and floor of mouth, and

aimed to study the deep margin only.3

On a more conceptual level, although the value ofmargin revision is disputed, many consider even the needfor margin revision as an adverse prognostic factor, espe-cially when the revised margin contains residual tumor.4

Although it is not clear how to account for “supplementalmargins,” one may add the width of supplemental tissueto the margin clearance as assessed from the resectionspecimen (especially if the true surface of the supplemen-tal margin is indicated).5 An extra cuff of tissue obtainedat the time of margin revision may actually “convert”some of the “close” margins into “negative.”

Ch’ng et al use the 2-cm cutoff to separate local re-currence from the second primary. It is unclear, however,how local and regional recurrences were distinguished.For example, for carcinomas involving the oral tongueand/or floor of mouth, differentiating local failure fromregional recurrence in level I can be quite challenging,especially in patients with prior neck dissection. If therecurrent carcinoma is located in the soft tissue, withoutany adjacent lymphoid tissue, it may represent local ratherthan regional recurrence. These details are especially rele-vant in a study that: 1) combines pN0 and pNX patients,2) is limited to the outcome analysis based on 9 local and14 regional recurrences, and 3) is perhaps better suited tostudy the value of elective neck dissection.

The oral cavity subsite also affects technical aspectsof the margin assessment. Therefore, the value of marginstatus is difficult to judge in this heterogeneous cohortthat includes 26 patients with carcinomas involving gin-giva, retromolar trigon, or palate. From a practical stand-point, bony margins are routinely processed as “shave,”

precluding any measurements from the invasive tumorfront to the bone margin and making it impossible to cat-egorize a bone margin as “close.” The problem is evenmore cumbersome when dealing with tumors that abutthe periosteum. Complete excision of these tumors mayrequire the resection of bone or may be accomplished bydrilling the bone, as opposed to an en bloc resection. Thisthen further complicates the assessment of the bony mar-gin. Because none of these technical aspects are addressed,the report by Ch’ng et al appears to be limited to the “softtissue” margin (without specifying whether it is mucosalor deep).

Finally, the authors arbitrarily preset the acceptablelocal failure rate as 15% at 5 years. A direct comparison oflocal control among patients with positive or negativemargins may provide a more informative context. In fact,based on authors’ own review of the relevant literature,the direct comparison of “close” and “positive” marginsseems to be the standard approach.

Although these points may appear rather granular,we feel that this degree of scrutiny and attention to routineissues of margin assessment are necessary before acceptingthe notion that close margins should not be treated withadjuvant therapy.

CONFLICT OF INTEREST DISCLOSUREThe authors made no disclosures.

REFERENCES1. Ch’ng S, Corbett-Burns S, Stanton N, et al. Close margin alone does

not warrant postoperative adjuvant radiotherapy in oral squamous cellcarcinoma. Cancer. 2013;119:2427-2437.

2. Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squamouscell carcinoma: histologic risk assessment, but not margin status, isstrongly predictive of local disease-free and overall survival. Am J SurgPathol. 2005;29:167-178.

3. Weijers M, Snow GB, Bezemer DP, van der Wal JE, van der Waal I.The status of the deep surgical margins in tongue and floor of mouthsquamous cell carcinoma and risk of local recurrence; an analysis of68 patients. Int J Oral Maxillofac Surg. 2004;33:146-149.

4. Jackel MC, Ambrosch P, Martin A, Steiner W. Impact of re-resectionfor inadequate margins on the prognosis of upper aerodigestive tractcancer treated by laser microsurgery. Laryngoscope. 2007;117:350-356.

5. Black C, Marotti J, Zarovnaya E, Paydarfar J. Critical evaluation offrozen section margins in head and neck cancer resections. Cancer.2006;107:2792-2800.

Uma Duvvuri, MD, PhD1

Raja R. Seethala, MD2

Simion I. Chiosea, MD2

1Department of Otolaryngology, University of Pittsburgh Medical Center,Pittsburgh, Pennsylvania

2Department of Pathology, University of Pittsburgh Medical Center,Pittsburgh, Pennsylvania

DOI: 10.1002/cncr.28432, Published online November 5, 2013in Wiley Online Library (wileyonlinelibrary.com)

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Cancer February 1, 2014 453