to-good prognostic features, clear cell his- CASE STUDY · · 2008-10-14to-good prognostic...
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Which of the following do you recom- mend: cytoreductive nephrectomy (CN), high-dose interleukin-2 (IL-2), sunitinib, sorafenib, temsirolimus, bevacizumab ± interferon α (IFNα), gemcitabine + capecitabine, or investigational therapy? Dr Jonasch: Because this patient appears to have most of the disease in his primary tumor, with a relatively small amount of systemic disease and a resectable renal mass, CN followed by cytokine (immunotherapy) therapy would be a reasonable choice. It is not clear whether CN would provide any addition- al benefit if this patient was treated with targeted therapy. Dr Pili: At my facility, our general approach is laparoscopic CN to shorten recovery and to reduce length to initiation of systemic therapy. Tumor burden, espe- cially with implicated symptoms and absence of extensive systemic disease, guide the decision to perform CN. Dr Hutson: When choosing to per- form CN, the patient must be surgically fit, and the tumor must be surgically oper- able, with some consideration given to tumor volume. Dr Jonasch: Performance status of the patient should be considered, but is not always significantly improved post-CN. CN before cytokine therapy seems to show benefit regardless of performance status, site of metastases, and the presence of measurable disease (Southwest Oncology Group 8949 and European Organization for Research and Treatment of Cancer 30947 clinical trials), 1,2 although this benefit is of significantly greater magnitude in patients with good performance status and lung-only disease. We generally will not perform up-front resection of patients with poor perfor- mance status or extensive metastatic dis- ease. It is not clear if this applies to targeted therapies. Dr Hutson: Although data do seem to support CN for RCC, does the presence or absence of CN dictate your choice of systemic therapy? Dr Pili: Although it is patient specific, high-dose IL-2 seems to show more bene- fit than IFNα. Dr Hutson: In my view, high-dose IL- 2 is a good option for selected patients (including this particular case) in whom studies have demonstrated a complete response. Predictors of favorable response to IL-2 include prior CN, intermediate- to-good prognostic features, clear cell his- tology, and high carbonic anhydrase IX expression (commercially unavailable test for this case). 3 Metastasis to a single organ, typically the lung, tends to be a predictor of response to cytokine therapy. 4 However, targeted agents may be a more suitable option if the goal of therapy is to shrink the tumor. Dr Jonasch: High-dose IL-2 is most beneficial in patients who have the highest probability of response and who have had a major debulking of their disease. Dr Hutson: Would histology influ- ence one’s selection? Dr Pili: The best data for response to immunotherapy are in patients with clear cell histology. It is unclear if immunother- apy will benefit mixed histology types of RCC. Tyrosine kinase inhibitors (TKI) and mammalian target of rapamycin (mTOR) inhibitors seem to show activity in clear cell and other types of RCC. Dr Jonasch: I agree that the patient will probably not respond to immunotherapy unless clear cell features predominate. There are emerging data suggesting that targeted therapies are the agents of choice for non-clear cell histolo- gies, particularly temsirolimus for papil- lary RCC. 5 Dr Hutson: In summary, CN is not appropriate for all patients and should be based on physician experience and on a case-by-case basis. With the newer target- ed agents, CN does not appear to be nec- essary to enhance response to therapy. The role of high-dose IL-2 remains to be debated and may be appropriate in select- ed patients. Dr Pili: Can you comment about your facility’s criteria for total versus partial nephrectomy? Dr Hutson: It is based on the urolo- gist’s surgical skill, which is probably the same criterion used in many other facilities. Dr Jonasch: It is a fairly complex algo- rithm that takes into consideration other criteria, such as central tumor, multifocal- ity, and surgical history. We also have to determine how much of the renal parenchyma is safe and reasonable to remove. 8 Vol. 8, No. 1 ■ February 2008 RENAL CELL CARCINOMA 65-YEAR-OLD MALE WITH RENAL CELL CARCINOMA AND LUNG METASTASES Thomas E. Hutson, DO, PharmD BACKGROUND A 65-year-old male with superior physiologic appearance presented to his family physician for routine checkup. His medical history, social history, and family history were all unremarkable, and he had no significant complaints. Baseline laboratory data were within normal limits. However, his physician noted a left upper quadrant mass. Upon further studies, abdominal computed tomography (CT) scan discovered a 10-cm right renal mass. CT scan of the chest demonstrated enlargement of the mediastinal and hilar lymph nodes, as well as scattered pulmonary nodules, the largest approaching 2 cm. Bone scan results were negative. Bronchoscopy and transbronchial needle biopsy identified lung malignancy, and CT-guided biopsy of the renal mass revealed histolog- ic findings compatible with clear cell renal cell carcinoma (RCC). (Continued below) CASE STUDY
Transcript of to-good prognostic features, clear cell his- CASE STUDY · · 2008-10-14to-good prognostic...
Which of the following do you recom-mend: cytoreductive nephrectomy (CN),high-dose interleukin-2 (IL-2), sunitinib,sorafenib, temsirolimus, bevacizumab ±interferon α (IFNα), gemcitabine +capecitabine, or investigational therapy?
Dr Jonasch: Because this patientappears to have most of the disease in hisprimary tumor, with a relatively smallamount of systemic disease and aresectable renal mass, CN followed bycytokine (immunotherapy) therapy wouldbe a reasonable choice. It is not clearwhether CN would provide any addition-al benefit if this patient was treated withtargeted therapy.
Dr Pili: At my facility, our generalapproach is laparoscopic CN to shortenrecovery and to reduce length to initiationof systemic therapy. Tumor burden, espe-cially with implicated symptoms andabsence of extensive systemic disease,guide the decision to perform CN.
Dr Hutson: When choosing to per-form CN, the patient must be surgicallyfit, and the tumor must be surgically oper-able, with some consideration given totumor volume.
Dr Jonasch: Performance status of the
patient should be considered, but is notalways significantly improved post-CN.CN before cytokine therapy seems toshow benefit regardless of performancestatus, site of metastases, and the presenceof measurable disease (SouthwestOncology Group 8949 and EuropeanOrganization for Research and Treatmentof Cancer 30947 clinical trials),1,2
although this benefit is of significantlygreater magnitude in patients with goodperformance status and lung-only disease.We generally will not perform up-frontresection of patients with poor perfor-mance status or extensive metastatic dis-ease. It is not clear if this applies totargeted therapies.
Dr Hutson: Although data do seem tosupport CN for RCC, does the presenceor absence of CN dictate your choice ofsystemic therapy?
Dr Pili: Although it is patient specific,high-dose IL-2 seems to show more bene-fit than IFNα.
Dr Hutson: In my view, high-dose IL-2 is a good option for selected patients(including this particular case) in whomstudies have demonstrated a completeresponse. Predictors of favorable responseto IL-2 include prior CN, intermediate-
to-good prognostic features, clear cell his-tology, and high carbonic anhydrase IXexpression (commercially unavailable testfor this case).3 Metastasis to a single organ,typically the lung, tends to be a predictorof response to cytokine therapy.4 However,targeted agents may be a more suitableoption if the goal of therapy is to shrinkthe tumor.
Dr Jonasch: High-dose IL-2 is mostbeneficial in patients who have the highestprobability of response and who have hada major debulking of their disease.
Dr Hutson: Would histology influ-ence one’s selection?
Dr Pili: The best data for response toimmunotherapy are in patients with clearcell histology. It is unclear if immunother-apy will benefit mixed histology types ofRCC. Tyrosine kinase inhibitors (TKI)and mammalian target of rapamycin(mTOR) inhibitors seem to show activityin clear cell and other types of RCC.
Dr Jonasch: I agree that the patientwill probably not respond toimmunotherapy unless clear cell featurespredominate. There are emerging datasuggesting that targeted therapies are theagents of choice for non-clear cell histolo-gies, particularly temsirolimus for papil-lary RCC.5
Dr Hutson: In summary, CN is notappropriate for all patients and should bebased on physician experience and on acase-by-case basis. With the newer target-ed agents, CN does not appear to be nec-essary to enhance response to therapy. Therole of high-dose IL-2 remains to bedebated and may be appropriate in select-ed patients.
Dr Pili: Can you comment about your facility’s criteria for total versus partial nephrectomy?
Dr Hutson: It is based on the urolo-gist’s surgical skill, which is probably the same criterion used in many otherfacilities.
Dr Jonasch: It is a fairly complex algo-rithm that takes into consideration othercriteria, such as central tumor, multifocal-ity, and surgical history. We also have todetermine how much of the renalparenchyma is safe and reasonable toremove.
8 Vol. 8, No. 1 n February 2008
RENAL CELL CARCINOMA
65-YEAR-OLD MALE WITH RENAL CELL CARCINOMA AND LUNG METASTASES
Thomas E. Hutson, DO, PharmD
BACKGROUND
A 65-year-old male with superior physiologic appearance presented to his familyphysician for routine checkup. His medical history, social history, and family historywere all unremarkable, and he had no significant complaints. Baseline laboratory datawere within normal limits. However, his physician noted a left upper quadrant mass.Upon further studies, abdominal computed tomography (CT) scan discovered a 10-cmright renal mass. CT scan of the chest demonstrated enlargement of the mediastinal andhilar lymph nodes, as well as scattered pulmonary nodules, the largest approaching 2cm. Bone scan results were negative. Bronchoscopy and transbronchial needle biopsyidentified lung malignancy, and CT-guided biopsy of the renal mass revealed histolog-ic findings compatible with clear cell renal cell carcinoma (RCC).
(Continued below)
CASE STUDY
Johns Hopkins Advanced Studies in Medicine n 9
Dr Pili: I agree, and tumor location isalso important. The criterion for totalnephrectomy is usually a tumor size of 4to 7 cm or greater. However, partialnephrectomy is preferred over totalnephrectomy to avoid future renal insuffi-ciency and dialysis requirements.
The patient was referred for opennephrectomy, in which a 10.5-cm tumorwas removed (class T4: invasion intoregional lymph nodes and the surround-ing kidney envelope called the Gerota’sfascia). Pathology reported FuhrmanNuclear Grade III cancer cells with focalareas of sarcomatoid differentiation andconfirmed the RCC type as conventional(or clear cell). The patient was referred toan academic oncology clinic for systemictreatment of metastatic RCC. At the timeof clinic presentation, he was asympto-matic with good performance status(Eastern Cooperative Oncology Groupperformance status = 0 and Karnofsky’sindex of performance status = 90). ChestCT scan confirmed an increase in lymphnode enlargement. Abdominal CT scanrevealed a 3-cm left retroperitoneal (RP) lymph node, an indication ofregional metastasis. Brain magnetic reso-nance image and bone scan showed noevidence of metastasis, which remainedconsistent throughout the course of thisdiscussion. Serum creatinine was slightlyelevated (as expected postnephrectomy),whereas remaining laboratory values were within acceptable limits. CN was performed. What would be the nexttherapeutic option?
Dr Jonasch: This patient has goodperformance status and does not appear tomeet the criteria for poor risk as definedby the temsirolimus study. (Common riskfactors associated with shorter survivalinclude metastasis within 1 year of diag-nosis, metastases in multiple organs, poorperformance status, anemia, and elevatedserum lactate dehydrogenase [LDH] andcalcium.6) However, the presence of sarco-matoid cells and high-grade cell histologyis associated with poorer prognosis.7 Thesefeatures and the presence of intra-abdom-inal adenopathy, which is unconfirmed in
this patient, is associated with failure tohigh-dose IL-2.8 Temsirolimus would notbe my first choice either, because patientswith clear cell histology seem to derive lessbenefit from this agent.6 Bevacizumab ±IFNα is not approved by the US Foodand Drug Administration for this indica-tion to date but could be a promisingoption. Sorafenib as compared to otheragents does not appear to demonstrate asmuch benefit in the front-line setting. Mychoice for systemic therapy would be suni-tinib or investigational therapy.
Dr Pili: Because sarcomatoid featuresare a morphological classification subjectto limitations, it is unclear if its presence isan indicator of poor response to high-doseIL-2. Observation is a reasonable decisionfor some small, slow-growing renal mass-es, even if high-grade tumors exist.However, this choice is typically reservedfor elderly patients, particularly with sig-nificant comorbidities, or if metastasis isabsent or at low risk. It should be notedthat a delay in systemic therapy for larger,aggressive tumors should be avoided,because tumor burden seems to affecttherapy response.
Dr Hutson: Because of the variablenatural history of RCC in individuals, itis not uncommon for patients to be inthe observation mode, especially forsmall-volume disease. Based on treat-ment algorithms and published phase IIItrials, an option for first-line therapycould be sunitinib for patients withgood-to-intermediate risk factors, whichwould be my choice for this patient.9
Bevacizumab ± IFNα would be an attrac-tive alternate. High-dose IL-2 would bean option for a select group of patients;however, results of a pivotal clinical trialare still pending.
The patient was enrolled in the treat-ment arm of a randomized phase II clini-cal trial of sorafenib 400 mg twice dailyversus IFNα. After 12 months of therapy,he remained minimally symptomaticwith no change in his performance status.However, chest CT scan showed progres-sive disease. Abdominal CT scan foundno liver lesions, but the left RP lymphnode had increased to 5.7 cm. Despite
disease progression, a favorable centralnecrosis was noted in the RP lymph nodesoft tissue mass, an effect seen withantiangiogenic therapy. Moderate-to-severe adverse effects were reported, butthey were acceptable to the patient.Although laboratory values remainedwithin acceptable limits, serum calcium(11 mg/dL) and LDH (190 U/L) werenow elevated from baseline. The patientdesires additional therapy.
Dr Pili: Investigational therapy orchanging to an anti-vascular endothelialgrowth factor therapy (bevacizumab ±IFNα) to combat induced resistance wouldbe reasonable options. Sorafenib dose esca-lation would also be reasonable, because arecent phase II trial showed that sorafenibdose escalations up to 1600 mg per dayproduced antitumor activity in tolerantpatients with metastatic RCC.10 However,refractory disease may not respond to doseescalation, thus I would be more apt tochange to sunitinib based on recentAmerican Society of Clinical Oncologydata that suggested lack of cross resistancebetween sorafenib and sunitinib.11
Dr Hutson: Dr Jonasch, could youcomment further on the definition of dis-ease progression and dose escalation versuschanging to agents with alternate mecha-nisms of action (mTOR inhibitors)?
Dr Jonasch: It is not clear if disease pro-gression differs between patients onimmunotherapy versus targeted therapy.However, if a patient is tolerating a drugwith limited, nonthreatening pulmonarynodules without new organ involvement,continuing therapy or dose escalation couldbe reasonable options. Switching to IL-2after sorafenib therapy may not be appro-priate because of potential additive car-diotoxicity associated with these agentsindividually.12,13 Gemcitabine pluscapecitabine has demonstrated an objectiveresponse in studies.14 However, toxicitiesassociated with this combination requirevigilant patient selection and dosage adjust-ments. My choice for this patient would beinvestigational therapy or sunitinib.
As per trial protocol, dose escalationto sorafenib 600 mg twice daily was per-
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mitted. Nine months after dose escalation,CT scans discovered new lesions in thechest and abdomen, as well as an increasein the size of the pulmonary and mediasti-nal lymph nodes. No new sites of diseasemetastasis were found, and serum calciumand LDH remained elevated. Because heremained asymptomatic with good perfor-mance status, the patient elected to receivefurther therapy.
In order for dose escala-tion to be permitted, it appears that thetoxicities improved in this patient, anoccurrence that has been observed inpatients receiving TKIs.
With continual dosing,tolerance to the side effects of targetedagents can develop, particularly withsorafenib because it does not require atreatment break.
Systemic therapy was changed to axi-tinib 5 mg twice daily, an experimentalagent. He experienced low-grade, manage-able toxicities (diarrhea and hyperten-sion). Because CT scans demonstrated anunconfirmed partial response, he is cur-rently continuing on axitinib therapy.
Axitinib is a multitarget-ed TKI with a profile similar to that ofthe TKIs sunitinib and pazopanib. Thisapproach is similar to what we have dis-
cussed as second-line therapy options forpatients who have received sorafenib.15
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