Postoperative chemoradiotherapy after curative ...

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related Castleman's disease following the administration of highly active antiretroviral therapy. (HAART). The use of highly active antiretroviral therapy (HAART) ...
356 M. Colleoni1*, N. Rotmensz2, G. Martinelli3, R. D. Gelber4, A. Coates5, A. Goldhirsch6 1

Department of Medicine, 2Department of Epidemiology and Biostatistics, and 3Division of Hemato-oncology, Department of Medicine, European Institute of Oncology, Milan, Italy; 4Department of Biostatistical Science, Dana-Farber Cancer Institute, Boston, USA; 5The Cancer Council Australia, Sydney, NSW, Australia; 6Oncology Institute of Southern Switzerland, Lugano, Switzerland, and Department of Medicine, European Institute of Oncology, Milan, Italy (*E-mail: [email protected])

References

DOI: 10.1093/annonc/mdh054

Postoperative chemoradiotherapy after curative gastrectomy for cancer I read with interest the paper by Park et al. on postoperative chemoradiotherapy for gastric cancer, published in a recent issue of Annals of Oncology [1] and I fully agree with the conclusions they report in the Discussion. In particular, I share the perplexity of the authors in extrapolating the benefit of chemoradiotherapy achieved in the patients undergoing a limited lymphadenectomy in the Intergroup trial INT-0116 [2] also to those undergoing D2 lymph node dissection. In fact, patients in the American trial would be considered undertreated according to the surgical standard of many centers in Europe and Japan and this could account for the success of the subsequent chemoradiotherapy. In support to this thesis, it is interesting to note that the 5-year survival of the 290 patients in the Korean study [1] who received adjuvant chemoradiotherapy is quite comparable, stage by stage, to that of 618 patients enrolled in an Italian randomised study comparing subtotal versus total gastrectomy alone, both the procedures being associated with D2 lymph node dissection [3]. Namely, the 5-year survival for stages IB, II, III and IV were 93%,

F. Bozzetti* Istituto Nazionale Tumori, Milan, Italy (*E-mail: [email protected])

References 1. Park SH, Kim DY, Heo JS et al. Postoperative chemoradiotherapy for gastric cancer. Ann Oncol 2003; 14: 1373–1377. 2. MacDonald JS, Smalley SR, Benedetti J et al. Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 2001; 345: 725–730. 3. Bozzetti F, Marubini E, Bonfanti G et al. Subtotal versus total gastrectomy for gastric cancer: five-year survival rates in a multicenter randomized Italian trial. Italian Gastrointestinal Tumor Study Group. Ann Surg 1999; 230: 170–178. 4. Marubini E, Bozzetti F, Miceli R et al. Lymphadenectomy in gastric cancer: prognostic role and therapeutic implications. Eur J Surg Oncol 2002; 28: 406–412.

DOI: 10.1093/annonc/mdh055

Successful treatment of AIDSrelated Castleman’s disease following the administration of highly active antiretroviral therapy (HAART) The use of highly active antiretroviral therapy (HAART) was associated with a dramatic improvement in the outcome of patients with human immunodeficiency virus (HIV) infection [1, 2]. In this report, we would like to describe the case of a patient with AIDS-related multicentric Castleman’s disease who has also enjoyed a long-lasting complete clinical and pathological remission following the use of HAART alone. Castleman’s disease belongs to the group of atypical lymphoid proliferations, which are usually confused with the diagnosis of malignant lymphoma. First described in 1956, the typical patient presents with either localized mediastinal lymphadenopathy or a

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1. Rodenhuis S, Bontenbal M, Beex LV et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 2003; 349: 7–16. 2. Coates AS, Gelber RD, Goldhirsch A. Subsets within the chemotherapy overview. International Breast Cancer Study Group. Lancet 1998; 352: 1783–1784. 3. Goldhirsch A, Wood WC, Gelber RD et al. Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer. J Clin Oncol 2003; 21: 3357–3365. 4. Rose DP, Davis TE. Effects of adjuvant chemohormonal therapy on the ovarian and adrenal function of breast cancer patients. Cancer Res 1980; 40: 4043–4047. 5. Basser R, O’Neill A, Martinelli G et al. Randomized trial comparing upfront, multi-cycle dose-intensive chemotherapy (CT) versus standard dose CT in women with high-risk stage 2 or 3 breast cancer (BC): first results from IBCSG Trial 15-95. Proc Am Soc Clin Oncol 2003; 22: 6 (Abstr 20).

75%, 53% and 13% in the Korean study versus 86%, 75%, 61% and 13% in the Italian study, respectively. Although such comparisons should always be viewed with caution, I am asking whether it is ethically correct to compare, in a randomized fashion, a D2 gastrectomy with a D2 gastrectomy plus adjuvant chemotherapy if the expected clinical benefit is so limited and this adjuvant treatment appears to be a demanding procedure and is sometimes toxic for the patient. Moreover, I wonder how big the sample size should be if the difference to be detected between the two groups is very small! I acknowledge that randomized clinical trials are the best way to proceed on the road of evidence-based medicine; nevertheless, surgeons and medical oncologists should realistically consider that the extent of lymphadenectomy makes some difference to the outcome of patients who undergo surgical treatment for cancer of the stomach [4].

357

more aggressive form of the disease characterized by diffuse lymphadenopathy and systemic symptoms [3]. The differential diagnosis of Castleman’s disease should include malignant lymphoma, as well as other causes of lymphoma-like syndromes, such as adverse reactions to drugs, autoimmune disorders and viral or bacterial infections. Until recently, Castleman’s disease was not considered an AIDS-related event, being managed with local surgery, irradiation and cortisteroids. Cytotoxic therapy was reserved only for highly symptomatic patients with refractory disease. Over the past years, however, a newly described AIDS-related multicentric form of Castleman’s disease (MCD) has been recognized. In this aggressive form of the disease, patients develop progressive lymphadenopathy, B symptoms and usually a fatal course [4]. Our patient was a 46 year-old HIV-positive black man who presented with dyspnea, cough, hemoptysis and severe weight loss. He had fever, bibasilar rales and widespread lymphadenopathy. The blood tests were normal, except for a hemoglobin level of 10.7 g/dl. The chest X-ray showed bilateral reticulonodular infiltrates and the computed tomography (CT) scan revealed multiple mediastinal lymph nodes (Figure 1a). The CD4 count was 54 cells/mm3 and the CD4/CD8 ratio was 0.06. A supraclavicular and submandibular lymph node biopsy confirmed MCD. The additional medical work-up ruled out malignant lymphoma, catch-scratch fever, autoimmune or infectious diseases. Due to the aggressiveness of the disease, combination chemotherapy was offered to the patient, which he refused due to fear of infectious complications. HAART (lamivudine/zidovudine plus indinavir/ritonavir) alone was started and, surprisingly, the patient showed a rapid clinical improvement, with the disappearance of B symptoms within days. By the end of an 18-month follow-up period, the CT scan showed a complete disappearance of the mediastinal lymph nodes (Figure 1b) and a new lymph node biopsy revealed only reactive changes. The CD4 count was

135 cells/mm3 and the viral load was less than 50 copies/ml. The patient remains completely asymptomatic with no evidence of Castleman’s disease following a 24 month follow-up period on HAART alone. Our report comes as the first in which a complete histologicallyproven response for a prolonged period of follow-up is clearly documented in AIDS-related MCD with the use of HAART alone. There are other reports on the clinical outcome of AIDS-related MCD, using a variety of combined therapeutic approaches including antiviral drugs, interferon-α, anti-interleukin-6 and chemotherapeutic agents along with HAART. In general, tumor responses are partial and short-lasting, sometimes at the cost of significant clinical toxicity [5–8]. It should be noted that our patient did not develop a clear neoplastic transformation of the disease into a malignant lymphoma after such a long-term followup period. Considering the poor treatment results and high risk of infectious complications following cytotoxic therapy in the AIDS population, we postulate that patients with AIDS-related MCD should be first managed with HAART, leaving more aggressive therapeutic approaches for patients at relapse. E. Sprinz*, M. Jeffman, P. Liedke, A. Putten & G. Schwartsmann Hospital de Clinicas de Porto Alegre (HCPA), Federal University of Rio Grande do Sul (UFRGS), Rua Ramiro Barcelos 2350/7, Porto Alegre, CP 90.030-003, Brazil (*E-mail: [email protected])

References 1. Palella FJ Jr, Delaney KM, Moorman AC et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 1998; 338: 853–860. 2. Miller V, Staszewski S, Nisius G et al. Risk of new AIDS diseases in people on triple therapy. Lancet 1999; 353: 463–464. 3. Castleman B, Iverson L, Menendez VP. Localized mediastinal lymphnode hyperplasia resembling thymoma. Cancer 1956; 9: 822–830.

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Figure 1. (a) Computerized tomography with multiple enlarged mediastinal lymph nodes. (b) After 18 months, computerized tomography showing regression of the mediastinal lymph nodes.

358 4. Oksenhendler E, Duarte M, Soulier J et al. Multicentric Castleman’s disease in HIV infection: a clinical and pathological study of 20 patients. AIDS 1996; 10: 61–67. 5. Lanzafame M, Carretta G, Trevenzoli M et al. Successful treatment of Castleman’s disease with HAART in two HIV-infected patients. J Infect Dis 2000; 40: 90–91. 6. Revuelta MP, Nord JA. Successful treatment of multicentric Castleman’s disease in a patient with human immunodeficiency virus. Clin Infect Dis 1998; 26: 527. 7. Scott D, Cabral L, Harrington WJ Jr. Treatment of HIV-associated multicentric Castleman’s disease with oral etoposide. Am J Hematol 2001; 66: 148–150. 8. Dupin N, Krivine A, Calvez V et al. No effect of protease inhibitor on clinical and virological evolution of Castleman’s disease in an HIV-1 infected patient. AIDS 1997; 11: 1400–1401.

DOI: 10.1093/annonc/mdh066

The tyrosine kinase inhibitor imatinib mesylate (STI-571, Gleevec®) has led to a paradigm shift in our approach to the treatment of chronic myeloid leukemia (CML). Clinical studies carried out in all disease phases have revealed excellent hematological and cytogenetic responses, and hence it has recently been approved as the first-line treatment in CML patients who are not the ideal candidates for allogenic bone marrow transplantation [1]. All recent studies have shown that imatinib is well tolerated. Although most patients experience side effects, these are generally mild (grade I/II). The common non-hematological side effects include nausea, superficial edema, muscle cramps, musculoskeletal pain and skin rashes [1]. Of these, the cutaneous reactions are the most common side effects, which primarily include superficial edema, and skin rash and related events seen in 50% and 34% of patients, respectively [1]. The exact pathophysiology of the cutaneous reactions is unclear. The high prevalence of these adverse events and their relationship with dose suggests that these reactions are probably due to the direct pharmacological effect of imatinib [2]. We enrolled and followed 118 patients with CML between January 2001 and June 2003 in chronic phase (n = 79; 400 mg/ day), accelerated phase (n = 22; 600 mg/day) and blast crisis (n = 17; 600 mg/day). At a median follow up of 6 months in this study group, commonly reported cutaneous adverse effects, i.e. superficial edema and rash, were seen in 48% and 12.7% of patients, respectively. A striking event was the high prevalence of pigmentary disturbances in these patients, which included depigmentation (localized or generalized) in 40.9% of cases and hyperpigmentation in 3.6% of cases. The median time of onset of pigmentary changes was 4 weeks (range 2–14) after the start of therapy. At the onset the changes were generally localized, generally becoming diffuse over the next few weeks.

B. Arora, L. Kumar*, A. Sharma, J. Wadhwa & V. Kochupillai India Institute of Medical Sciences, 236, RDHMM, 110049 New Delhi, India (*E-mail: [email protected])

References 1. O’Brien SG, Guilhot F, Larson RA et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic phase chronic myeloid leukemia. N Engl J Med 2003; 348: 994–1004. 2. Valeyrie L, Bastuji-Garin S, Revuz J et al. Adverse cutaneous reactions to Imatinib (STI-571) in Philadelphia chromosome positive leukemias: A prospective study of 54 patients. J Am Acad Dermatol 2003; 48: 201– 206. 3. Etienne G, Cony-Makhoul P, Mahon FX. Imatinib mesylate and grey hair. N Engl J Med 2000; 347: 446. 4. Lammie A, Dronjak M, Gerald W et al. Expression of c-kit and kit ligands proteins in normal human tissues. J Histochem Cytochem 1994; 42: 1417–1425. 5. Grichnik JM, Burch JA, Burchette J, Shea CR. The SCF/KIT pathway plays a critical role in the control of normal human melanocyte homeostasis. J Invest Dermatol 1999; 113: 139–140.

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Pigmentary changes in chronic myeloid leukemia patients treated with imatinib mesylate

In the literature there are few data on pigmentary changes during imatinib therapy. There are a few reports of depigmentation (localized or diffuse) of skin [2], but hyperpigmentation of skin has not been reported so far. A recent report described repigmentation of hair in nine of 133 patients taking imatinib [3]. The frequency of pigmentary changes is much higher in our population. A common factor in our report and the previous reports is the occurrence of these events only in ethnically pigmented patients; this probably explains the difference in reported frequency of pigmentary changes, as our study population was ethnically pigmented. The molecular basis of these cutaneous changes is unknown at present. Imatinib targets the ATP binding site of BCR-ABL tyrosine kinase, as well as the tyrosine kinases of platelet-derived growth factor receptor-β, C-kit and ABL. C-kit is normally expressed in skin basal cells, melanocytes, epithelial cells of the breast, tissue mast cells and other cells [4]. There are recent data suggesting that C-kit and its ligand stem-cell factor have a major role in melanogenesis, melanocyte homeostasis and UVBinduced pigmentation [5]. The stimulation of C-kit leads to activation followed by rapid degradation of microphthalmia transcription factor (Mi), which transactivates the tyrosinase pigmentation gene promoter in melanocytes [6]. Hence the pigmentary changes, skin rash and related events are likely to be due to imatinibinduced C-kit inhibition in skin. In a recent series of 54 patients, all seven patients who developed hypopigmentation of the skin also had associated skin rash in the area of hypopigmentation, suggesting a common etiology [2]; however, in our series only six (5.4%) patients had associated skin rash, indicating that complex molecular events may be involved. Imatinib is presently the paradigm of a new class of oral molecular-targeted drugs. Inhibition of multiple tyrosine kinases with varied, but as yet unknown, functional consequences stresses the fact that a clear understanding of these events will definitely be useful in the future treatment of patients.