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`Current Management of Renal Cell Carcinoma
`
`Mitchell H. Sokoloff, MD
`Jean B. deKernion, MD
`Robert A. Figlin, MD
`Arie Belldegrun, MD
`
`Introduction
`Renal cell carcinoma (also called renal
`adenocarcinoma, hypernephroma, or
`Grawitz tumor) is the most common ma-
`lignancy of the kidney and accounts for
`about three percent of all adult neo-
`plasms.1 The number of new cases in the
`United States in 1996 is projected to be
`30,600 with an estimated 12,000 deaths.1
`The incidence of renal cell carcinoma is
`expected to increase slightly, primarily
`due to enhanced detection of tumors by
`expanded use of imaging techniques such
`as computed tomography and ultrasound.
`The early detection of these tumors,
`which are generally incurable except by
`surgical means, should ultimately trans-
`
`Dr. Sokoloff is Chief Resident in the Department of
`Urology at the University of California, Los
`Angeles, School of Medicine in Los Angeles,
`California.
`Dr. deKernion is a Professor of Surgery and
`Urology and Chief of the Department of Urology at
`the University of California, Los Angeles, School of
`Medicine in Los Angeles, California.
`Dr. Figlin is a Professor of Medicine (Hema-
`tology/Oncology) at the University of California,
`Los Angeles, School of Medicine in Los Angeles,
`California.
`Dr. Belldegrun is a Professor of Surgery and
`Urology and Director of the Cancer Immuno-
`therapy Program at the University of California,
`Los Angeles, School of Medicine and Chief of the
`Division of Urology at Olive View/UCLA Medical
`Center in Los Angeles, California.
`Supported in part by the Leslie and Susan Gonda
`Foundation.
`
`late into slight improvements in survival
`due to application of operative interven-
`tion at an earlier, potentially curable stage.
`
`Clinical Presentation
`Symptoms from renal cell carcinoma are
`generally caused by either invasion of the
`tumor beyond the confines of the kidney,
`causing pain, hematuria, or a flank mass,
`or from the manifestations of metastatic
`spread, which include weight loss, fever,
`hypertension, night sweats, and the sud-
`den onset of a varicocele in a male pa-
`tient.2 The classic triad of pain, hema-
`turia, and a flank mass is seen in only 10
`percent of patients, and usually only
`those with advanced disease.
`About one third of patients with re-
`nal cell carcinoma have metastasis at the
`time of diagnosis,3 although this number
`should fall with the increased incidental
`detection of small renal masses.4 Para-
`neoplastic syndromes occur in about 30
`percent of patients with renal cell carci-
`noma and account for such presenting
`symptoms as hypertension, hypercal-
`cemia, pyrexia, and hepatic dysfunc-
`tion.5,6 The last entity, known as Staufer
`syndrome, can occur in up to 40 percent
`of patients with renal cell carcinoma and
`is characterized by hepatosplenomegaly,
`elevated alkaline phosphatase and serum
`haptoglobin, and prolonged prothrombin
`time.7 After nephrectomy, liver function
`may return to normal and hepatomegaly
`may disappear, yet most patients with this
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`syndrome die within five years.8 Clearly,
`renal cell carcinoma patients presenting
`with any symptoms are at a high risk for
`having either local extension or metasta-
`sis, and those whose tumors are discov-
`ered incidentally while still asymptomatic
`are most likely to be cured.
`
`Staging and Prognostic Factors
`Renal cell carcinomas can grow locally
`into very large masses and invade through
`the surrounding fascia into adjacent or-
`gans. They also metastasize through lym-
`phatic channels to regional and mediasti-
`nal nodes or by hematogenous routes
`primarily to the lungs, bone, and brain, al-
`though metastasis has been described in
`virtually every part of the body.9 Other
`than metastasis, the factors that are asso-
`ciated with poor prognosis include tumor
`size, extension through Gerota’s fascia,
`involvement of contiguous organs, spread
`to regional or distant lymph nodes, and
`vena caval involvement.9-11
`Although the prognostic importance
`of tumor size is often debated, the pro-
`pensity for metastasis increases with larg-
`er lesions. Metastasis may occur from
`very small tumors, but the incidence of
`this is low.12 Microscopic features (includ-
`ing histologic pattern, cell type, aneu-
`ploidy, and nuclear grade) and genetic
`factors (such as p53 suppressor gene ac-
`cumulation) also impact on the risk of
`metastasis and are useful in predicting
`long-term survival.13-15 Of special note is
`chromophobe cell carcinoma, a rare tu-
`mor with very low malignant potential
`despite histologic similarities to renal cell
`carcinoma.16
`Two systems have been developed
`to stage renal cell carcinoma. Historical-
`ly, Robson’s modification of the Flocks
`and Kadesky system was used.17 Current-
`ly, however, the most commonly em-
`ployed method is the American Joint
`Committee on Cancer Staging and End
`Results Reporting classification (Table
`1).18 This method has advantages over
`
`the Robson system in that it more clearly
`separates the various components of lo-
`cally invasive tumors and quantifies the
`extent of lymph node involvement,
`thereby more explicitly defining the
`anatomic extent of disease. Regardless of
`the system used, pathologic stage is the
`most consistent single prognostic vari-
`able that influences survival.
`For clinical staging, CT scanning re-
`mains the radiologic procedure of choice.
`For equivocal lesions, angiography can
`occasionally differentiate pathognomonic
`malignant and nonmalignant vascular
`features. If further clarification of venous
`involvement is necessary, magnetic reso-
`nance imaging is extremely sensitive,
`making venography a seldomly used pro-
`cedure for documenting and measuring
`tumor thrombus burden.
`
`Diagnosis
`The diagnosis of renal cell carcinoma is
`usually apparent with modern imaging
`techniques. As seen on CT, the typical re-
`nal cell carcinoma is generally greater
`than 4 cm in diameter, has a heteroge-
`neous density, and enhances with con-
`trast injection (Fig. 1). Some benign tu-
`mors, however, also present as solid renal
`lesions and may be misdiagnosed as renal
`cell cancers. The most common of these
`rare lesions are angiomyolipomas (renal
`hamartoma) and oncocytomas. Unless
`very small, angiomyolipomas are usually
`readily distinguishable from renal cell
`cancer by the finding of a distinctive fat
`density on CT scan.19 Several reports,
`however, have shown that macroscopic
`fat can be detected within renal cell carci-
`nomas, and it may no longer be reason-
`able to dismiss all fat-containing lesions
`as benign.20 Unlike angiomyolipomas,
`oncocytomas do not have a distinct radio-
`logic characteristic. Although they are of-
`ten solid and are usually without evidence
`of extensive vascularity or hemorrhage,
`frequently the diagnosis cannot be made
`except by surgical excision.21 Other rare
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`
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`
`Table 1
`America Joint Committee on Cancer
`Staging Classification System for Renal Cell Carcinoma
`
`TNM Clinical Classification
`
`Primary Tumor (T)
`TX
`Primary tumor cannot be assessed
`T0
`No evidence of primary tumor
`T1
`Tumor 2.5 cm or less in greatest dimension limited to the kidney
`T2
`Tumor more than 2.5 cm in greatest dimension limited to the kidney
`T3
`Tumor extends into major veins or adrenal gland or perinephric tissue
`but not beyond Gerota’s fascia
`Tumor extends into adrenal gland or perinephric tissue but not
`beyond Gerota’s fascia
`Tumor grossly extends into renal vein or vena cava
`Tumor extends beyond Gerota’s fascia
`
`T3a
`
`T3b
`
`T4
`
`Regional Lymph Nodes (N)
`NX
`Regional nodes cannot be assessed
`NO
`No regional node metastasis
`N1
`Metastasis in a single node, 2 cm or less in greatest dimension
`N2
`Metastasis in a single node, more than 2 cm but not more than 5 cm
`in greatest dimension, or multiple nodes, none more than 5 cm
`in greatest dimension
`Metastasis in a node more than 5 cm in greatest dimension
`
`N3
`
`Distant Metastasis (M)
`MX
`Presence of distant metastasis cannot be assessed
`M0
`No distant metastasis
`M1
`Distant metastasis
`
`Adapted with permission from American Joint Committee on Cancer.18
`
`benign and malignant lesions occur in the
`kidney, but these are seldom distinguish-
`able from renal cell carcinoma preop-
`eratively. The kidney is also a frequent
`site of metastatic deposits from a variety
`of solid and hematologic malignancies.
`
`Most are discovered at autopsy and are
`clinically inconsequential. Metastatic or
`secondary lesions within the kidney rarely
`produce symptoms, although hematuria
`and flank pain may occur. The most com-
`mon metastatic lesions in the kidney oc-
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`cur from primary lung and breast cancers
`and should be suspected in patients with
`these neoplasms.22
`
`Management of Clinically Localized
`Lesions
`The mainstay of treatment for primary
`renal cell carcinoma is surgical excision.
`It is the only currently known curative
`therapeutic modality. In the past, the
`simple nephrectomy had been advocat-
`ed as adequate treatment. Over the past
`two decades, however, increases in sur-
`vival have been documented with the
`radical nephrectomy, and it is now the
`surgical procedure of choice for renal
`cell carcinoma.23,24 Although defined in
`various ways, the radical nephrectomy
`involves complete removal of Gerota’s
`fascia and its contents, including the
`adrenal glands, kidney, perinephric fat,
`and, at times, hilar lymph nodes. Implicit
`in the term radical nephrectomy in many
`institutions is the inclusion of a regional
`lymph node dissection.
`While the superiority of radical ne-
`phrectomy over simple nephrectomy has
`never been proven in a formal study, the
`rationale for the complete removal of
`Gerota’s fascia appears sound. Renal tu-
`mors frequently impinge on the renal
`capsule and often may invade into the
`perinephric fat. A rich plexus of lym-
`phatics drains this area and can poten-
`tially diffuse neoplasm throughout Gero-
`ta’s fascia. Invasion of the perinephric fat
`is an important determinant of survival,
`which may be seriously compromised if
`either microscopic or gross tumor re-
`mains.25 The removal of the adrenal has
`been advocated not only because it is en-
`closed within Gerota’s fascia, but also be-
`cause ipsilateral adrenal metastasis oc-
`curs in two to 10 percent of most
`reported series.26,27 The risk of adrenal
`metastasis is related to the malignant po-
`tential of the primary tumor as well as its
`size and position. The need for routine
`ipsilateral adrenalectomy is currently a
`
`A
`
`B
`Fig. 1. (A) Computed tomographic scan of large,
`left renal cell carcinoma. (B) Intraoperative speci-
`men of large, left renal cell carcinoma.
`
`topic of debate, but certainly patients
`with large tumors or tumors high in the
`upper pole are probably better served by
`a standard radical nephrectomy that in-
`cludes adrenalectomy.
`Regional lymph node extension is
`an important prognostic factor in renal
`cell carcinoma. Increased survival attrib-
`uted to removal of involved lymph nodes
`has prompted the incorporation of re-
`gional lymphadenectomy as part of the
`surgical procedure.25,28 This too, howev-
`er, is controversial for several reasons.
`Even with lymphadenectomy, the sur-
`vival rate of patients with positive nodes
`is extremely poor. Likewise, these favor-
`able studies include primarily patients
`with small-volume metastasis in close
`proximity to the kidney.
`A number of studies have shown
`that the lymphatic drainage from kidney
`tumors is not always consistent and may
`occur anywhere in the retroperitoneum.
`Furthermore, bloodborne metastasis oc-
`curs with at least equal incidence to lym-
`phatic spread, and most patients with
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`positive lymph nodes eventually acquire
`bloodborne metastasis. Finally, many pa-
`tients without metastasis to regional
`lymph nodes develop disseminated dis-
`ease.29 No good randomized study has
`conclusively demonstrated a benefit of
`extensive lymphadenectomy in patients
`with renal cell carcinoma. Nonetheless, it
`is a valuable staging device, and most
`urologists now advocate a limited unilat-
`eral lymphadenectomy, except for those
`patients with very small and well-differ-
`entiated lesions.
`Surgical techniques for radical ne-
`phrectomy are well established and are
`guided more by individual preference
`than by necessity. Because outcome de-
`pends on tumor stage, grade, and his-
`tology and because multiple staging
`systems are used, data comparison is dif-
`ficult and only broad conclusions on
`
`life. A study of 16,249 autopsies in Swe-
`den revealed that 350 patients had renal
`cell carcinoma, 235 of which had been
`previously undetected.32 In a review of
`the Greater Los Angeles Tumor Regis-
`try, the number of incidental renal masses
`detected has increased significantly as the
`use of imaging techniques has expanded.3
`Another series noted that only four per-
`cent of asymptomatic tumors were diag-
`nosed in 1976. By 1991, 61 percent were
`detected.33 This number continues to in-
`crease. In 1988 Smith et al34 reported that
`94 percent of the operable tumors at their
`institution were discovered incidentally.
`This is primarily attributed to increased
`detection by ultrasound and CT imaging.
`Incidentally identified renal masses
`present a significant clinical problem, as
`the nature of a renal lesion less than 3 cm
`in diameter is often difficult to determine
`
`About one third of patients already have metastatic
`lesions when diagnosed with renal cell carcinoma.
`
`prognosis can be made.30 After radical
`nephrectomy for T1 and T2 disease, five-
`year survival ranges from 60 to 82 per-
`cent. This is increased to over 90 percent
`for incidentally diagnosed tumors.31 For
`T3 disease, five-year survival averages
`50 percent, although the surgical out-
`come
`improves with regional
`lym-
`phadenectomy.25
`
`MANAGEMENT OF INCIDENTALLY
`DIAGNOSED RENAL TUMORS
`Asymptomatic renal cell carcinoma may
`be incidentally diagnosed on routine phys-
`ical exam or by abdominal imaging stud-
`ies obtained for unrelated problems. Tu-
`mors identified by CT are often low stage
`and associated with an excellent progno-
`sis. Careful postmortem studies have doc-
`umented that a significant number of re-
`nal cell tumors are not diagnosed during
`
`with current imaging modalities. They
`are most commonly either early renal
`cell carcinomas, angiomyolipomas, onco-
`cytomas, or complex cysts. Although CT
`can often detect small renal cell carcino-
`mas and ultrasound can differentiate sol-
`id from cystic components, the diagnosis
`of these lesions frequently eludes all
`tests.35 Likewise, size by itself is not a re-
`liable indicator of malignancy. Our expe-
`rience suggests that about 50 to 60 per-
`cent of these lesions are early renal cell
`carcinomas, and the others are distrib-
`uted among the benign lesions men-
`tioned above.
`Therefore, the management of these
`small lesions is problematic. Bell36 demon-
`strated a direct correlation between tumor
`size and malignant potential and noted
`that lesions less than 3 cm had little
`propensity for metastasis. In a series of 62
`renal tumors less than 3 cm in size, Mur-
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`phy and Mostofi12 showed that three had
`already metastasized when the lesion was
`diagnosed. Tsukamoto et al37 demon-
`strated that 10 percent of tumors measur-
`ing less than 6 cm had associated distant
`metastasis at time of diagnosis. As a gen-
`eral rule, therefore, solid lesions less than
`3 cm that are clearly not angiomyolipo-
`mas should be excised. In view of their
`low metastatic potential, however, they
`can be observed in selected high-risk or
`elderly patients.
`
`NEPHRON-SPARING SURGERY
`
`The surgical management of small lesions
`is currently being debated. Although
`standard treatment with radical nephrec-
`tomy has produced good results, at issue
`is whether a more conservative, nephron-
`sparing operation would be more appro-
`priate. This procedure was developed for
`patients who developed tumors in a soli-
`tary kidney. The goal is to excise the le-
`sion completely while leaving sufficient
`renal parenchyma to obviate the need for
`dialysis. This can almost always be ac-
`complished in situ, but occasionally exci-
`sion of the kidney for ex vivo workbench
`surgery followed by autotransplantation
`is necessary.
`The excision of renal cell tumors in
`solitary kidneys has produced encourag-
`ing results. Several series have demon-
`strated that five-year survival depends on
`the reason for removal of the contralater-
`al kidney, with improved prognosis when
`the kidney was excised for benign condi-
`tions (70 percent) as compared with
`neoplasm (50 percent).38 Currently, par-
`tial nephrectomy for tumor in a solitary
`kidney is associated with a five-year sur-
`vival of about 80 percent. The local recur-
`rence rate is about five percent, but it is
`almost zero for small, well-differentiated
`tumors.39,40 The patient whose tumor is
`not amenable to nephron-sparing surgery
`should be offered a radical nephrectomy
`followed by dialysis for 18 to 24 months.
`If no evidence of recurrence or metastasis
`
`is present at that time, transplantation
`should be considered.
`Nephron-sparing surgery is gradual-
`ly becoming an accepted method of ther-
`apy for the primary treatment of small
`renal cell carcinomas (less than 3 cm) in
`patients with a normal contralateral kid-
`ney. Licht and Novick40 reviewed 241 pa-
`tients treated in this fashion. The mean
`cancer-specific survival rate was 95 per-
`cent at about three years, and there were
`only two cases of postoperative local tu-
`mor recurrence. At Memorial Sloan-Ket-
`tering Cancer Center, partial nephrec-
`tomies for renal cell carcinoma with a
`normal opposite kidney resulted in a re-
`currence rate of 2.4 percent and a sur-
`vival rate of 95 percent at three years of
`follow-up.41
`Those who argue against nephron-
`sparing surgery cite studies that demon-
`strate the multifocality of renal lesions in
`tumor-bearing kidneys.42 These are usu-
`ally microscopic foci, however, and are
`uncommon except in patients with large
`tumors. Furthermore, follow-up studies
`after excision of tumors from a solitary
`kidney, as mentioned earlier, document
`an amazing lack of recurrent disease
`within the involved kidney. For these rea-
`sons, most urologists now agree that le-
`sions measuring less than 3 cm in size may
`be treated by partial nephrectomy or
`wedge enucleation of the tumor with a
`rim of normal tissue. Lesions that are cen-
`trally located, however, still require a rad-
`ical nephrectomy.
`After radical nephrectomy, follow-
`up includes laboratory studies, chest radi-
`ographs, and physical examinations every
`six months for up to two years, then an-
`nually thereafter.43 Abdominal CT scans
`are taken every 12 months for two years
`and every 24 months after that. Recom-
`mendations after partial nephrectomy
`differ by including an additional laborato-
`ry and physical examination three months
`postoperatively and by obtaining abdom-
`inal CT scans at one, six, 12, 18, and 24
`months and then every year thereafter.
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`At the University of California, Los An-
`geles (UCLA), we often substitute ultra-
`sound for CT scans, especially after par-
`tial nephrectomy.
`
`Management of Locally Invasive
`Lesions
`Renal cell tumors, even when very large,
`seldom invade contiguous organs. In-
`stead, they have a tendency to compress
`and displace adjacent tissues. Nonethe-
`less, occasional direct invasion of the liv-
`er, duodenum, large bowel, and peri-
`nephric muscle does occur. Such patients
`usually present with pain, generally from
`involvement of nerve roots, the abdomi-
`nal wall, or paraspinous muscles. The out-
`look for these patients is dismal. Yet
`when surgical excision is feasible, it
`should be attempted because no alterna-
`tive treatment modalities exist. Partial ex-
`cision (debulking) of a primary lesion is
`seldom indicated.
`Although postoperative adjuvant ra-
`diotherapy has been proposed for pa-
`tients with T3 tumors, no study has
`demonstrated a distinct survival advan-
`tage.44 The role of radiotherapy as a pri-
`mary treatment for locally extensive re-
`nal cell carcinoma has failed to show a
`beneficial effect, although a possible pre-
`operative role to decrease the size of the
`primary tumor and delay local recurrence
`after resection does exist.44,45
`Renal cell carcinoma has an unusual
`propensity to extend into the renal vein
`and vena cava. The extent of the tumor
`thrombus influences prognosis, and pa-
`tients with minimal extension to a point
`below the hepatic veins have a better out-
`look than those with supradiaphragmatic
`or atrial extension.46 In the absence of
`any effective alternative therapy, the indi-
`cations for surgery include patients with
`vena caval extension at any level, includ-
`ing those with thrombus extending into
`the right atrium. The results of surgical
`excision in these patients have been good
`enough to warrant continued aggressive
`
`surgery, although patients with extension
`to or above the diaphragm seldom are ul-
`timately cured.46,47 Patients with extensive
`caval tumor thrombus must be placed on
`vascular bypass and in extreme cases may
`require cardiopulmonary bypass and hy-
`pothermic arrest. For tumors invading
`into the vena cava wall, resection of the
`involved vessel is possible with preserva-
`tion of a sleeve of tissue to accommodate
`venous drainage.
`
`Management of Metastatic Disease
`THE ROLE FOR SURGICAL
`MANAGEMENT
`About one third of patients already have
`metastatic lesions when diagnosed with
`renal cell carcinoma. For these patients,
`five-year survival is less than 20 percent.48
`Metastasis from renal cell carcinoma is
`usually multifocal, either within the same
`organ or to multiple sites. Occasionally
`(one to three percent of cases) patients
`will present with solitary metastasis. The
`five-year survival after excision of such le-
`sions is about 25 percent.49
`In a study at our institution, aggres-
`sive therapy of solitary lesions of the
`skeleton, central nervous system, and soft
`tissue produced significant palliation of
`symptoms and occasionally prolonged
`survival.48 This is a select group of pa-
`tients, however, and only those with a
`definite solitary lesion and no lymphatic
`involvement have any prospect of bene-
`fiting from surgical management.
`The most favorable lesions for resec-
`tion are solitary pulmonary masses, which
`occasionally appear more than one year
`after removal of the primary tumor.9 Un-
`fortunately, a metastatic lesion identified
`at the time of diagnosis of renal cell carci-
`noma is seldom an isolated lesion, and
`more clinically evident lesions invariably
`appear shortly after surgical excision.
`In the past, nephrectomy was advo-
`cated in the treatment of metastatic dis-
`ease as a method of both reducing the
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`Table 2
`Phase II Trials of Interleukin-2 for the Treatment
`of Metastatic Renal Cell Cancer
`
`Reference
`
`West et al86
`Fisher et al87
`Rosenberg et al88
`Bukowski et al89
`Geertsen et al90
`Weiss et al91
`Rosenberg et al83
`Atkins et al92
`Rosenberg et al85
`
`Totals
`
`Year
`
`1987
`1988
`1989
`1990
`1992
`1992
`1992
`1993
`1994
`
`Number of
`Patients
`
`Response
`(percent)
`
`40
`35
`54
`41
`30
`94
`60
`71
`143
`
`568
`
`32
`16
`22
`12
`20
`18
`18
`17
`20
`
`19.4
`
`growth of the primary lesion and possibly
`triggering a spontaneous regression of
`metastatic disease. Unfortunately, this
`can be expected to occur in less than one
`percent of cases, the remissions are ex-
`tremely short-lived, and the mortality
`rate from surgery can approach 15 per-
`cent, depending on patient selection.10
`This concept has been abandoned as it is
`now clear that nephrectomy itself seldom,
`if ever, has any influence on metastatic
`disease. Therefore, the routine use of ad-
`junctive nephrectomy is unwarranted.
`Palliation of symptoms is, however, a rea-
`sonable rationale for nephrectomy in the
`face of metastasis, provided the primary
`tumor can be completely removed with-
`out undue morbidity. Patients with peri-
`neoplastic syndromes will sometimes
`benefit from palliative nephrectomy, es-
`pecially if metastatic sites are not large.
`Repeated hemorrhage and tumor pain
`can also frequently be ameliorated by
`nephrectomy.
`
`The advent of immunotherapy for
`renal cell carcinoma has once again raised
`the issue of the role of surgery in patients
`with metastatic disease. Studies at our in-
`stitution49,50 and elsewhere51,52 have docu-
`mented improved response rates to im-
`munotherapy when given in conjunction
`with removal of the diseased kidney. Our
`data indicate that even when considering
`all the various prognostic factors, patients
`who receive immunotherapy have a bet-
`ter response rate when nephrectomy is
`performed prior to treatment. Nonethe-
`less, it is debatable as to whether ne-
`phrectomy is best performed before or
`after immunotherapy, and a randomized
`study is being performed that will hope-
`fully resolve this question.
`Other than for palliation, at UCLA
`our current philosophy is to perform ad-
`junctive nephrectomies in patients with
`metastatic renal cell carcinoma only in
`conjunction with immunotherapy, either
`to obtain tissue for tumor-infiltrating lym-
`
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`
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`
`Table 3
`Phase II Trials of Combination Cytokine Therapy
`for Metastatic Renal Cell Cancer
`
`Reference
`
`Mittleman et al95
`Kirchner et al98
`Atzpodien et al96
`Hirsch et al97
`Figlin et al94
`Rosenberg et al83
`Ilson et al99
`Lipton et al100
`Bergmann et al101
`Vogelzang et al102
`
`Totals
`
`Year
`
`1990
`1990
`1990
`1990
`1992
`1992
`1992
`1993
`1993
`1993
`
`Number of
`Patients
`
`Response
`(percent)
`
`18
`17
`17
`15
`52
`41
`34
`39
`30
`42
`
`22
`29
`36
`40
`25
`34
`12
`33
`30
`12
`
`305
`
`27.3
`
`phocytes (TILs) and other experimental
`protocols or to reduce tumor load in very
`large primary tumors that are either
`symptomatic or have a probability of be-
`coming symptomatic in the near future.
`Conversely, patients with small primary
`masses and/or multiple small metastatic
`lesions are first given immunotherapy.
`Those patients whose metastasis responds
`to the treatment are then subsequently
`selected for a nephrectomy.
`
`THE ROLE FOR RADIOTHERAPY
`Radiotherapy has been applied to renal
`cell carcinoma as both an adjuvant to
`surgical therapy and as a treatment for
`metastatic lesions. Palliative radiothera-
`py has been successful in treating painful
`metastasis and is a powerful tool for pain
`management. The potential role of pre-
`operative radiotherapy in delaying tu-
`
`mor recurrence and shrinking tumor size
`has already been discussed as has the
`lack of success of postoperative adjuvant
`radiotherapy.
`
`HORMONAL THERAPY AND
`CHEMOTHERAPY
`Hormonal therapy protocols were based
`on observations that progestational agents
`inhibited the growth of renal cell tu-
`mors.53 Although early reports were en-
`couraging, no studies have substantiated
`the initial results, including a study at
`UCLA in which none of 110 patients
`treated with progesterone had an objec-
`tive response.48 Other hormonal agents,
`including tamoxifen, have been equally
`ineffective.54,55
`Although cytotoxic drugs are the
`cornerstone of therapy for most solid ma-
`lignancies, the success of chemotherapy
`
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`C A C a n c e r J C l i n 1 9 9 6 ; 4 6 : 2 8 4 - 3 0 2
`
`in treating renal cell carcinoma has been
`poor.56 Vinblastine and floxuridine, the
`most common agents, have response
`rates of seven percent and 16 percent, re-
`spectively. In a review of 72 agents evalu-
`ated in phase II trials in over 3,500 pa-
`tients between 1983 and 1992, an
`objective response rate of 5.6 percent was
`noted, which was usually of very short du-
`ration. Recent studies with retinoic acid
`have demonstrated growth inhibition in
`vitro,57 and it is currently being investigat-
`ed as a potential single agent or compo-
`nent of a multiple-agent chemotherapeu-
`tic regimen.
`
`of metastatic renal cell carcinoma.61 Oth-
`er immunostimulatory cytokines have
`since been identified and purified. The
`ability to produce large quantities of
`these cytokines has resulted in their wide-
`spread use, and in a relatively short peri-
`od of time, these agents have become an
`approved treatment modality for meta-
`static disease. To date most studies inves-
`tigating the use of cytokines in the treat-
`ment of metastatic renal cell carcinoma
`have used interferon-␣ (IFN-␣), IL-2,
`combinations of these cytokines, or adop-
`tive immunotherapy with TILs or lym-
`phokine-activated killer cells (LAKs).
`
`IMMUNOTHERAPY
`Because of occasional spontaneous re-
`gression of renal cell masses, discovery of
`circulating humoral and cellular elements
`in such patients, delayed growth of
`metastatic lesions, and varying tumor
`doubling times, manipulation of the im-
`mune system has been an attractive con-
`cept for managing metastatic disease.
`
`Nonspecific Therapies
`Initial approaches to immunotherapy
`used nonspecific stimulators such as
`xenogeneic RNA-treated lymphocytes,
`bacillus Calmette-Guérin, Corynebacteri-
`um parvum, and transfer factor. Despite
`early enthusiasm, these approaches ulti-
`mately yielded no significant improve-
`ment in prognosis and are now mainly of
`historical interest with regard to treating
`renal cell carcinoma.58-60 With the advent
`of the modern era of genetic engineering
`and the mass production of molecular
`agents, new opportunities have arisen for
`immunotherapy of renal cell carcinoma.
`
`Biologic Therapy with Cytokines
`The isolation, identification, and molecu-
`lar cloning of interleukin-2 (IL-2) revolu-
`tionized the field of cancer immunothera-
`py and significantly altered the treatment
`
`Interferon
`Studies of IFN-␣ for the treatment of
`metastatic renal cell carcinoma at our and
`other institutions have documented ob-
`jective response rates of 16 to 26 percent
`lasting an average of eight to 10
`months.62-70 Improved response rates to
`30 percent and prolongations of this re-
`sponse lasting more than 27 months is
`seen in a select subset of patients.65,69
`These patients have had a prior nephrec-
`tomy, no previous chemotherapy or ra-
`diotherapy, good to excellent perfor-
`mance status, and primarily pulmonary
`metastasis, although the significance of
`this last factor has been challenged.71 Few
`complete or durable partial responses
`have been documented, and both cost
`and toxicity (e.g., fever, chills, myalgia,
`anorexia, and headache) were significant.
`Combining accessory agents with
`IFN-␣ has been investigated as a means
`of increasing responsiveness and de-
`creasing toxicity. Studies investigating
`different combinations of IFN-␣ with
`mitomycin-C and 5-fluorouracil therapy
`demonstrated a response rate of 35 per-
`cent.72 The combination of IL-2, IFN-␣,
`and 5-fluorouracil increases response
`rates to over 45 percent and is currently
`an area of intensive research.73,74 The ad-
`dition of other chemotherapeutic agents,
`such as vinblastine, doxorubicin, and
`
`Vol. 46 No. 5 September/october 1996
`
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`
`Table 4
`Phase II Trials of Combination Interleukin-2/LAK Cells
`for the Treatment of Metastatic Renal Cell Cancer
`
`Reference
`
`Parkinson et al108
`Palmer et al110
`Weiss et al91
`Foon et al111
`Thompson et al112
`Sznol et al113
`Rosenberg et al107
`Dillman et al109
`
`Totals
`
`Year
`
`1990
`1992
`1992
`1992
`1992
`1992
`1993
`1993
`
`Number of
`Patients
`
`Response
`(percent)
`
`47
`102
`94
`23
`42
`40
`72
`167
`
`587
`
`9
`18
`17
`26
`33
`20
`35
`8
`
`20.8
`
`BCNU do not appear to alter the re-
`sponse rate.75-77 While investigations into
`the use of IFN-␥ for the treatment of meta-
`static renal cell carcinoma have produced
`results similar to those for IFN-␣,78,79 stud-
`ies combining IFN-␣ and IFN-␥ to stim