Correspondence 8. Fabbri A, Cencini E, Rigacci L, et al. Efficacy and safety of rituximab plus low-dose oral fludarabine and cyclophosphamide as first-line treatment of elderly patients with indolent non-Hodgkin lymphomas [published online ahead of print July 22, 2013]. Leuk Lymphoma.

Alessandro Gozzetti, MD Marzia Defina, MD Alberto Fabbri, MD Division of Hematology University Medical Center of Siena Siena, Italy DOI: 10.1002/cncr.28443, Published online October 22, 2013 in Wiley Online Library (

FCR among patients with a median age of 55 years produced 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 DISCLOSURES The authors made no disclosures.

Reply to Myelosuppression After Frontline Fludarabine, Cyclophosphamide, and Rituximab in Patients With Chronic Lymphocytic Leukemia Analysis of Persistent and New-Onset Cytopenia Myelosuppression can persist after the completion of frontline therapy with fludarabine, cyclophosphamide, and rituximab (FCR) in patients with chronic lymphocytic leukemia (CLL), mostly among elderly patients with baseline cytopenia. Its frequency decreases over time, with no association noted with disease progression, second myeloid malignancies, or infections (unless persisting up to 9 months).1 The data shown by Gozzetti et al describe grade 3 to 4 hematological toxicity (rather than grade 2 to 4) during treatment (rather than after) in elderly patients with CLL receiving frontline oral FC with rituximab. The observed complete response (CR) rate was 78% and the rate of grade 3 to 4 cytopenia was 15%. In our initial phase 2 study of FCR among patients with a median age of 58 years, the reported CR rate was 70% and grade 3 to 4 neutropenia (the most common hematological toxicity) complicated 52% of courses.2 During the CLL8 trial (among patients with a median age of 61 years), the CR rate was 44% and grade 3 to 4 neutropenia was observed in 34% of patients.3 Either calculated per person or cycle, the toxicity reported by Gozzetti et al is lower. It is not clear how many patients had baseline cytopenia, another factor that is significantly associated with myelosuppression in our analysis, and how many received support with growth factor. It is interesting to note that the addition of granulocyte-macrophage–colony-stimulating factor to 452

REFERENCES 1. Strati P, Wierda W, Burger J, et al. Myelosuppression after frontline fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: analysis of persistent and new-onset cytopenia [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 chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079-4088. 3. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164-1174. 4. Strati P, Ferrajoli A, Lerner S, et al. Fludarabine, cyclophosphamide and rituximab plus granulocyte macrophage colony-stimulating factor as frontline treatment for patients with chronic lymphocytic leukemia [published online ahead of print July 29, 2013]. Leuk Lymphoma.

Paolo Strati, MD Susan O’Brien, MD Department of Leukemia The University of Texas MD Anderson Cancer Center Houston, Texas DOI: 10.1002/cncr.28442, Published online October 22, 2013 in Wiley Online Library (

Margin Assessment in Oral Squamous Cell Carcinoma We have read with great interest the study by Ch’ng et al in which the authors attempt to show that surgical treatment alone achieves an “acceptable” local control among patients with close margins.1 This study appears to reasonably show that increase in the number of adverse parameters is associated with higher rates of local and regional failure. However, we are concerned by the authors’ methods for characterization of margins, heterogeneity of studied cases (in terms of anatomic subsites and Cancer

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pT, pN), and the lack of direct comparison of local control among patients with positive, close, and negative margins. In our opinion, the above caveats limit the conclusions by Ch’ng et al. For instance, the authors chose not to take into account revision of surgical margins or assessment of any supplemental tissue, most likely obtained from the tumor bed. Such an approach precludes meaningful comparison of this study to others. For example, authors claim that the exceptional local control of 91% at 5 years is comparable to that previously reported by Brandwein-Gensler et al.2 However, in the latter study, cases with supplemental 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 of margin revision is disputed, many consider even the need for margin revision as an adverse prognostic factor, especially when the revised margin contains residual tumor.4 Although it is not clear how to account for “supplemental margins,” one may add the width of supplemental tissue to the margin clearance as assessed from the resection specimen (especially if the true surface of the supplemental margin is indicated).5 An extra cuff of tissue obtained at 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 recurrence from the second primary. It is unclear, however, how local and regional recurrences were distinguished. For example, for carcinomas involving the oral tongue and/or floor of mouth, differentiating local failure from regional recurrence in level I can be quite challenging, especially in patients with prior neck dissection. If the recurrent carcinoma is located in the soft tissue, without any adjacent lymphoid tissue, it may represent local rather than regional recurrence. These details are especially relevant in a study that: 1) combines pN0 and pNX patients, 2) is limited to the outcome analysis based on 9 local and 14 regional recurrences, and 3) is perhaps better suited to study the value of elective neck dissection. The oral cavity subsite also affects technical aspects of the margin assessment. Therefore, the value of margin status is difficult to judge in this heterogeneous cohort that includes 26 patients with carcinomas involving gingiva, retromolar trigon, or palate. From a practical standpoint, bony margins are routinely processed as “shave,” Cancer

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precluding any measurements from the invasive tumor front to the bone margin and making it impossible to categorize a bone margin as “close.” The problem is even more cumbersome when dealing with tumors that abut the periosteum. Complete excision of these tumors may require the resection of bone or may be accomplished by drilling the bone, as opposed to an en bloc resection. This then further complicates the assessment of the bony margin. Because none of these technical aspects are addressed, the report by Ch’ng et al appears to be limited to the “soft tissue” margin (without specifying whether it is mucosal or deep). Finally, the authors arbitrarily preset the acceptable local failure rate as 15% at 5 years. A direct comparison of local control among patients with positive or negative margins may provide a more informative context. In fact, based on authors’ own review of the relevant literature, the direct comparison of “close” and “positive” margins seems to be the standard approach. Although these points may appear rather granular, we feel that this degree of scrutiny and attention to routine issues of margin assessment are necessary before accepting the notion that close margins should not be treated with adjuvant therapy. CONFLICT OF INTEREST DISCLOSURE The authors made no disclosures. REFERENCES 1. Ch’ng S, Corbett-Burns S, Stanton N, et al. Close margin alone does not warrant postoperative adjuvant radiotherapy in oral squamous cell carcinoma. Cancer. 2013;119:2427-2437. 2. Brandwein-Gensler M, Teixeira MS, Lewis CM, et al. Oral squamous cell carcinoma: histologic risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol. 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 mouth squamous cell carcinoma and risk of local recurrence; an analysis of 68 patients. Int J Oral Maxillofac Surg. 2004;33:146-149. 4. Jackel MC, Ambrosch P, Martin A, Steiner W. Impact of re-resection for inadequate margins on the prognosis of upper aerodigestive tract cancer treated by laser microsurgery. Laryngoscope. 2007;117:350-356. 5. Black C, Marotti J, Zarovnaya E, Paydarfar J. Critical evaluation of frozen 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 1

Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 2 Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania DOI: 10.1002/cncr.28432, Published online November 5, 2013 in Wiley Online Library (


Margin assessment in oral squamous cell carcinoma.

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