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`
`REVIEWING THE LITERATURE
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`Nonprostate Urologic Oncology
`
`Therapeutic Strategies, Predicting Outcomes in
`Patients With Renal Cell and
`Transitional Cell Carcinomas
`
`Allan Pantuck, MD, Amnon Zisman, MD, Arie Belldegrun, MD, FACS
`University of California, Los Angeles, School of Medicine
`
`[Rev Urol. 2000;2(1):22-24]
`
`The search continues for more effective treatments for
`
`patients with renal cell carcinoma (RCC), with im-
`munotherapy currently showing promise. For
`patients with advanced RCC, survival predictors can help
`clinicians to stratify patients. Postchemotherapy surgery to
`resect residual cancer in patients with transitional cell car-
`cinoma (TCC) may be an option for carefully selected
`patients.
`
`Up-Regulation of Retinoic Acid Receptor ß
`Expression in Renal Cancers In Vivo Correlates
`With Response to 13-cis-Retinoic Acid and
`Interferon-␣-2a.
`Berg WJ, Nanus DM, Leung A, et al.
`Clin Cancer Res. 1999;5:1671-1675.
`
`The inefficacy of surgery, radiation therapy, hormonal
`therapy, and chemotherapy in altering the dismal natural
`history of advanced and metastatic RCC has stimulated the
`search for more effective approaches. Biologic strategies
`using immunotherapy are the only current treatments that
`have produced promising therapeutic results. The authors
`of this study from Memorial Sloan-Kettering Cancer Center
`(MSKCC) have published their results previously using the
`combination of 13-cis-retinoic acid (13-CRA) and interfer-
`on alpha (IFN-␣), which demonstrated improved response
`rates, suggesting that 13-CRA potentiates the antitumor
`effects of IFN-␣. The mediators of retinoic acid biologic
`activity include a family of several retinoic acid receptors
`(RAR) isoforms, and expression of specific retinoid recep-
`tor messenger RNA (mRNA) has been shown to suppress
`the growth of malignant leukemia, breast cancer, lung
`cancer, and teratocarcinoma lines. The authors have also
`shown previously that the only known retinoid-sensitive
`RCC cell line, SK-RC-06, basally expressed RAR-ß and
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`22 REVIEWS IN UROLOGY WINTER 2000
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`that RAR-ß mRNA expression was up-regulated by 13-
`CRA treatment. In the current study, the authors sought to
`determine whether RAR-ß mRNA expression in vivo could
`predict response to retinoid-based therapy in patients
`studied in a phase II trial of 13-CRA and IFN-␣.
`Forty-five patients with advanced RCC were treated with
`both oral 13-CRA at a dosage of 1 mg/kg/d and subcuta-
`neous injections of IFN-␣ with dose escalation to 9 million
`units daily. Response criterion for a major response was
`defined as a greater than 50% decrease in the summed
`products of the perpendicular diameters of all measured
`lesions for a minimum of 4 weeks. Renal cancer specimens
`were obtained from 23 patients prior to the clinical trial;
`then, 10 specimens were obtained from patients on active
`therapy or within 1 month of discontinuing treatment.
`RAR-ß mRNA expression was then determined using
`nonradioactive in situ hybridization. Specimens were cat-
`egorized by the pretreatment level of RAR-ß mRNA ex-
`pression and by the change in relative staining of the
`expression with treatment. The relationship between ex-
`pression and treatment response was assessed using the
`two-sided Fisher’s exact test.
`RAR-ß expression was present in 22 (96%) of 23 pre-
`treatment specimens and in 9 (90%) of 10 specimens from
`treated patients. Pretreatment levels of expression were not
`predictive of major clinical response to RA plus IFN-␣
`therapy. However, an increase in the intensity of RAR-ß
`mRNA expression was detected in 4 (80%) of 5 patients
`who achieved a major response but in 0 of 5 patients
`whose disease progressed and for whom sequential tissue
`specimens were available.
`Although this study involves a small number of patients
`and is limited by having to compare pre- and post-treat-
`ment RAR-ß mRNA expression from different tumor sites
`in the same patients, the data presented have interesting
`implications regarding the possible mechanisms of coop-
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`eration between 13-CRA and INF. First, pretreatment lev-
`els of RAR-ß cannot be used as a marker to select patients
`with advanced RCC for retinoid-based therapies. Second,
`patients whose tumor cells were able to increase their ex-
`pression of RAR-ß experienced a clinical response, while
`those whose tumor cells were unable to do this did not.
`This supports the concept that RAR-ß is a mediator for the
`antitumor effect of RA on RCC. Taken together, this study
`provides the rationale for the concept that further studies
`of agents that can induce RAR-ß expression should be
`performed and that these agents may hold some promise
`for the future of immunotherapy in the management of
`advanced or metastatic RCC.
`
`Survival and Prognostic Stratification of 670
`Patients With Advanced Renal Cell Carcinoma
`Motzer RJ, Mazumdar M, Bacik J, et al.
`J Clin Oncol. 1999;17:2530-2541.
`
`Prognosis of RCC is primarily determined by tumor size,
`nuclear grade, and stage.1 During the last decade, tumors
`have been discovered earlier, and innovative, immune-
`based treatments have become available for advanced dis-
`ease. Updated information on prognostic factors for ad-
`vanced cancer is clearly needed to better select patients
`for therapy. The authors of this paper reviewed 670 pa-
`tients treated in 24 clinical trials at MSKCC between 1975
`and 1996. The results provide important and interesting
`information regarding biology, diagnosis, and prognosis
`of advanced disease.
`The patients were identified through registration for 24
`consecutive MSKCC clinical trial programs. All patients
`had histologic confirmation of RCC and measurable met-
`astatic lesions. Routine studies at the time of clinical trial
`entry included detailed history and physical examination,
`Karnofsky performance status, complete blood evaluation,
`and imaging studies for staging. The response to treatment,
`time to progression after systemic therapy, and survival
`were recorded. A stepwise statistical model was created to
`define possible prognostic factors.
`Univariate and multivariate analyses were performed.
`Five variables were found to be significant: hemoglobin
`lower than the normal limit, lactate dehydrogenase higher
`than 300 U/L, corrected calcium higher than 10 mg/dL, ab-
`sence of prior nephrectomy, and Karnofsky performance
`status lower than 80%. These were found to be indepen-
`dent risk factors for predicting survival. The highest risk
`ratio for mortality (⫻ 2.52) was found to be lactate dehy-
`drogenase at 1.5 times the upper limit or higher; the low-
`est risk ratio (⫻ 1.35) was absence of prior nephrectomy.
`Survival was expressed as a function of the number of
`
`Nonprostate Urologic Oncology
`
`~ i, k: f<ie:-1:ois:
`i:EI Nor,e:
`D Oroe: or two
`D Thre:e:ormore:
`
`Figure. In patients with metastatic renal cell carcinoma (RCC), certain risk
`factors, such as hemoglobin lower than normal, were predictive of survival.
`
`risk factors each patient had (Figure). Patients with meta-
`static RCC who had no risk factors (25% of the study
`group) had 1- or 2-year survival rates of 71% and 31%,
`respectively. Patients with one or two risk factors (53% of
`the group) had 1- or 2-year survival rates of 42% and 7%,
`respectively. Patients with three or more risk factors (22%
`of the group) had a 1-year survival rate of 12%; no patient
`lived for 3 years.
`Overall, 59% of the group received immune-based ther-
`apy for RCC, which resulted in improved survival. For each
`of the three risk groups, median survival was better for
`patients treated recently than for those treated during the
`early years of the study period. Furthermore, median sur-
`vival time was greater for patients treated with immuno-
`therapy than for those treated with conventional chemo-
`therapy. For patients treated with immunotherapy (IFN-␣
`and/or interleukin-2), the median survival times for favor-
`able-, intermediate-, and poor-risk patients were 26, 12,
`and 6 months, respectively. Moreover, when the authors
`applied their statistical tool to external data,2 identical re-
`sults were obtained: the median survival times of favor-
`able-, intermediate-, and poor-risk patients were 29, 14,
`and 4 months, respectively.
`Although lacking the uniformity of a prospective study,
`the results in this study are based on a solid statistical
`foundation. The authors supply the clinician with very
`simple survival predictors, based on only five clinical
`variables. This tool enables the physician to stratify
`patients. In the future, these parameters likely will be
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`WINTER 2000 REVIEWS IN UROLOGY 23
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`Nonprostate Urologic Oncology continued
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`combined with a panel of molecular markers that will bet-
`ter predict outcomes.
`
`References
`1. Maldazys JD, deKernion JB. Prognostic factors in metastatic renal cell carci-
`noma. J Urol. 1986;136:376-379.
`2. Motzer PJ, Murphy BA, Mazumdar M, et al. Randomized phase III trial of
`interferon alfa-2␣ (IFN) versus IFN plus 13-cis-retinoic acid (CRA) in patient
`(pts) with advanced renal cell carcinoma (RCC). Proc Am Soc Clin Oncol.
`1999;18:330A. Abstract 1271.
`
`Outcome of Postchemotherapy Surgery After
`Treatment With Methotrexate, Vinblastine,
`Doxorubicin, and Cisplatin in Patients
`With Unresectable or Metastatic Transitional
`Cell Carcinoma
`Dodd PM, McCaffrey JA, Herr H, et al.
`J Clin Oncol. 1999;17:2546-2552.
`
`TCC is the most common histologic type of urothelial can-
`cer. The sensitivity of TCC to the combination of metho-
`trexate, vinblastine, doxorubicin, and cisplatin (M-VAC) is
`well documented, and combination chemotherapy is the
`mainstay of treatment for patients with metastatic or unre-
`sectable TCC. The use of postchemotherapy surgery to
`resect viable residual cancer to achieve a multimodality
`complete response to treatment is well defined in other
`genitourinary malignancies. Although several studies have
`emphasized its value for patients in terms of improved sur-
`vival and palliation of symptoms, the role of postchemo-
`therapy surgery for TCC is not well defined. In this inter-
`esting study from MSKCC, the authors have appraised their
`experience with postchemotherapy surgery after M-VAC to
`assess its impact on survival and to better define optimal
`candidates for this aggressive approach.
`This report is based on the retrospective analysis of 203
`patients with metastatic or unresectable TCC who were treat-
`ed at MSKCC with M-VAC chemotherapy as part of five tri-
`als whose results have already been reported. These trials
`include patients treated with standard-dose M-VAC in a
`phase II setting, with recombinant human granulocyte
`colony-stimulating factor (rh-G-CSF), with standard dose
`M-VAC, with dose-intense M-VAC with rh-G-CSF (phase I
`trial), with intermediate-dose methotrexate and standard
`VAC, and with dose-intense M-VAC with rh-G-CSF versus
`gallium nitrate plus fluorouracil (randomized trial). In-
`clusion criteria for these studies were similar and included
`the absence of brain metastasis and the documentation of
`adequate renal, hepatic, and cardiac function. Patients re-
`ceived from 1 to 12 cycles of M-VAC, and their response to
`
`chemotherapy was evaluated after every 2 cycles. Using
`criteria that this report does not define (“multidisciplinary
`evaluation of suitability was performed on a case-by-case
`basis”), 50 patients were selected to undergo postchemother-
`apy surgery after their maximum response to M-VAC was
`determined.
`Compared with the overall cohort, the 50 patients cho-
`sen for surgery had a higher Karnofsky performance status,
`lower levels of alkaline phosphatase and lactate dehydro-
`genase, lower rates of visceral or osseous metastasis, and
`similar rates of lymph node involvement. They also repre-
`sented a larger number of patients with unresectable pri-
`mary tumors only. Furthermore, no patient with more than
`one anatomic site of visceral metastatic disease at baseline
`underwent surgery postchemotherapy. In 30 patients, a
`complete response was achieved using the combination of
`surgery and chemotherapy; of these, 10 patients (33%) are
`alive at 5 years, giving them a Kaplan-Meier survival esti-
`mation similar to that of the patients who achieved com-
`plete response to chemotherapy alone (41%). Subgroup
`analysis based on disease extent revealed that patients with
`unresectable primary tumors alone or with primary tumors
`and metastatic regional lymph nodes only responded best
`to multimodal therapy, with 5-year survival rates of 66%
`(2 of 3 patients) and 33% (3 of 9), respectively. Patients
`with metastases in distant lymph nodes, with visceral
`metastases, and with metastatic disease only responded less
`well. The median survival for the 30 patients with complete
`response was 37 months. None of the patients with lymph
`node involvement at the time of surgery, without a major
`response to chemotherapy, or without a disease-free status
`were alive at 5 years.
`There are a number of criticisms of this study. The small
`size of the patient population, the retrospective nature of
`the analysis, the variety of chemotherapy protocols used,
`the variety of primary tumor sites included (bladder, renal
`pelvis, ureter, and urethra), and the potential selection bias
`inherent in the lack of prospective criteria to determine
`which patients would undergo postchemotherapy surgery
`all decrease the power of the study’s findings. However, the
`conclusion that aggressive use of combination therapy can
`improve disease-free survival for carefully selected patients,
`particularly those with disease restricted to the primary
`tumor or regional lymph node sites who have achieved a
`major response to chemotherapy, is an important observa-
`tion. The findings of this study regarding this promising
`therapeutic approach should be verified—via randomized,
`prospective trials—in terms of long-term survival, efficacy,
`and safety.
`I
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