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Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma
Article first published online: 18 AUG 2004
Copyright © 2004 American Cancer Society
Volume 101, Issue 7, pages 1545–1551, 1 October 2004
How to Cite
Nanus, D. M., Garino, A., Milowsky, M. I., Larkin, M. and Dutcher, J. P. (2004), Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer, 101: 1545–1551. doi: 10.1002/cncr.20541
- Issue published online: 17 SEP 2004
- Article first published online: 18 AUG 2004
- Manuscript Accepted: 23 JUN 2004
- Manuscript Revised: 17 JUN 2004
- Manuscript Received: 23 JAN 2004
- Robert H. McCooey Memorial Cancer Research Fund
- Cancer Research Foundation Kidney Cancer Research Fund
- sarcomatoid renal carcinoma;
- kidney carcinoma
Immunotherapy is generally ineffective in patients with sarcomatoid renal cell carcinoma (RCC) and in patients with rapidly progressive metastatic or locally recurrent disease, with a median time to progression of approximately 2 months and a median survival of 4–7 months. Gemcitabine-based regimens have modest antitumor activity, whereas doxorubicin is often used to treat sarcomatoid RCC. Based on the antitumor activity of doxorubicin and gemcitabine in collecting duct carcinoma of the kidney, the authors used this combination to treat selected patients with sarcomatoid or rapidly progressing RCC.
Eighteen patients (11 males and 7 females; median age, 53 years; range, 31–81 years) with RCC (56% sarcomatoid; 44% other) were treated at 2 institutions in a collaborative study that was not institutional review board reviewed. Seven patients received previous treatment with interferon or interleukin-2. Sites of metastases included the lung, soft tissue, bone, liver, and brain with 88% of patients having ≥ 3 sites of disease. Treatment consisted of doxorubicin (50 mg/m2) and gemcitabine (1500 or 2000 mg/m2) every 2–3 weeks with granulocyte–colony-stimulating factor support.
A median of 5 courses was administered (range, 2–12 cycles). Therapy was well tolerated with no Grade 4 toxicities. Two patients had a complete response, five had a partial response, three had a mixed response, and one had stable disease. The median duration of response was 5 months (range, 2–21+ months).
These data suggested that the combination of doxorubicin and gemcitabine has antitumor activity in patients with sarcomatoid RCC or with rapidly progressing RCC. A prospective investigation of this combination in RCC is warranted. Cancer 2004. © 2004 American Cancer Society.
Renal cell carcinoma (RCC) is highly resistant to chemotherapy.1 In 1993, Yagoda et al.2 analyzed 72 cytotoxic chemotherapeutic agents used singly or in a limited number of 2-drug combinations in 3502 patients, and found reports of objective responses (complete [CR] and partial remissions [PR]) in only 197 (5.6%) of these patients (95% confidence interval [CI], 4.8–6.4%). More recent studies have resulted in similarly low response proportions.3, 4 Over the last few years, clinical trials using gemcitabine-containing regimens have been more encouraging, with major responses occurring in 5–17% of patients.5 Nevertheless, results using chemotherapy in this disease have been disappointing as indicated by the low response proportions and no study showing an improvement in survival. Immunotherapy with interferon (IFN) and/or interleukin (IL)-2–based regimens remains the mainstay of treatment for patients with advanced RCC with low, but reproducible, response rates of 10–20% and a durable response rate of ≤ 5%.6
Sarcomatoid differentiation in RCC indicates an aggressive subtype of renal parenchymal tumors, and is associated with a poor prognosis.7, 8 Some investigators believe that patients with metastatic RCC with sarcomatoid differentiation will not respond to immunotherapy and should be treated with combination chemotherapy.9–11 Although doxorubicin-containing regimens are often administered, only rarely do patients experience clinical benefit.12 In a recent Phase II trial of doxorubicin in combination with ifosfamide in patients with metastatic sarcomatoid RCC, no objective responses occurred in 25 patients, and the median time to progression was only 2.2 months.13 We recently reported the use of doxorubicin and gemcitabine in a patient with collecting duct carcinoma of the kidney, a rare variant of RCC that is associated with an aggressive course and extremely poor prognosis.14 The regimen consisted of doxorubicin (50 mg/m2) and gemcitabine (2000 mg/m2) every 2 weeks with growth factor support and was modeled after a highly effective and well tolerated regimen used to treat patients with advanced bladder carcinoma.15 Based on this experience, we elected to use this regimen to treat patients with sarcomatoid RCC, and well as patients with rapidly progressive RCC of other histologies who may have progressed after immunotherapy
MATERIALS AND METHODS
All patients treated had histologic confirmation of RCC, and unresectable metastatic RCC that was bidimensionally measurable. Patients had sarcomatoid RCC, or RCC with rapid clinical progression with objective clinical progression as determined on imaging and physical examination over 1 month, and/or had objectively progressed after receiving immunotherapy with either IL-2 or IFN-based regimens. Patients with brain metastases who had received radiotherapy were eligible for therapy provided there was evidence of progression of systemic disease. Normal cardiac function, as judged by chest radiography, an electrocardiography (ECG), and nuclear medicine gated cardiac scan or echocardiagram, was required. Patients who had evidence of New York Heart Association functional Class III or IV heart disease or severe arrhythmias, including first, second, or third-degree heart block, were not considered for treatment. The current study was not a formalized clinical trial (i.e., institutional review board approval and signed consent forms were not obtained) and was performed collaboratively across two institutions. Risks and benefits of chemotherapy were discussed in detail with each patient before initiation of treatment.
Treatment Plan and Toxicity Evaluation
Pretreatment evaluation included a complete medical history with Eastern Cooperative Oncology Group (ECOG) performance status and physical examination. Indicator lesions were measured either during a physical examination or by the appropriate radiographic study. Baseline studies included complete blood count with differential, serum chemistries including measurement of creatinine levels, liver function tests (including measurement of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase, bilirubin levels), chest radiograph, ECG, radionuclide left ventriculogram or echocardiogram with ejection fraction, and computerized tomography (CT) scans of metastatic disease. Bone scans were performed if there was clinical evidence of bone metastases or an elevated alkaline phosphatase concentration. Patients received doxorubicin by intravenous (i.v.) bolus infusion plus gemcitabine by i.v. infusion over 1 hour. The starting dose of doxorubicin was 50 mg/m2. The initial dose of gemcitabine was administered at either 1500 mg/m2 (Our Lady of Mercy Cancer Center [OLM]) or 2000 mg/m2 (New York Presbyterian Hospital [NYPH]). Patients were instructed in the administration of recombinant human granulocte–colony-stimulating factor and self-administered 5 μg/kg per day by subcutaneous injection on Days 3–11 of each cycle, or until the total leukocyte was > 10,000. Dose attenuations were at the discretion of the investigators, but generally included a 20–25% reduction in the dosage of gemcitabine and/or an increase in the treatment interval from every 2 weeks to every 3 weeks. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria, Version 2.0.
Tumor response evaluations were performed by physical examination, chest X-ray, and/or CT scans every 3 cycles (6–9 weeks). A CR was defined as the disappearance of all clinical evidence of tumor by physical examination, radiographic studies, or both for a minimum of 4 weeks. A PR was defined as a 50% decrease in the summed products of the perpendicular diameters of all measurable lesions for ≥ 4 weeks, without the simultaneous increase in the size of any lesion or the appearance of any new lesion. Progression was defined as a > 25% increase in tumor size or the appearance of any new lesion.
Eighteen patients were treated. Table 1 indicates the characteristics of the patients and tumor histology. The median age of the patients was 53 years (range, 31–81 years). Of the 18 patients, 7 were female and 11 were male. Also, 14 patients had undergone nephrectomy and 4 patients who presented with a renal mass and rapidly progressive metastatic disease had a needle biopsy that was compatible with RCC. Ten of 18 (56%) had sarcomatoid differentiation. The percent of sarcomatoid tumors within each specimen was not measured. Two patients each had clear cell carcinoma (classical RCC) and papillary histology. Eleven patients were treatment naive, and seven patients had been treated previously with IFN or IL-2. All patients had metastatic disease at the time of enrollment, and 16 of 18 (88%) had ≥ 3 sites of metastases. Lung metastases were present in 78% of the patients whereas 33% had bone metastases. Other sites of metastases are listed in Table 1.
|Characteristic||No. of patients (%)|
|Median age (range) in yrs||53 (31–81)|
|ECOG performance status|
|No. of disease sites|
|≥ 3||16 (88)|
|Lymph nodes||11 (61)|
|Local disease recurrence||5 (28)|
|Clear cell carcinoma||2 (11)|
|Renal cell carcinomaa||4 (22)|
In the current study, 96 chemotherapy treatments were available for evaluation of toxicity (Table 2). A median of 5 courses per patient (range, 2–12 courses) was administered. Therapy was generally well tolerated with no Grade 4 toxicities. Fatigue, nausea, and mucositis were the most common side effects. One patient who received steroids for brain metastases developed Pneumocystis carinii pneumonia requiring hospitalization. The patient was treated with trimethoprim/sulfamethoxazole and recovered from the infection. Two patients required dose attenuation, 1 for Grade 3 mucositis and 1 for Grade 3 fatigue. Both Grade 3 toxicities resolved after the patients received the lower dose of chemotherapy.
|Toxicity||CTC (Version 2.0) grade|
Response information is summarized in Table 3. Two patients experienced a CR, both with sarcomatoid histology. One patient had rapidly recurrent disease in retroperitoneal lymph nodes and the second patient had local disease recurrence in the renal bed involving the omentum as well as lung metastases. This latter patient underwent surgery after receipt of eight treatments (Fig. 1) and was rendered free of disease (surgical CR). He received 4 more treatments postoperatively with infusional doxorubicin and was without evidence of disease 1 year postsurgery (Fig. 1D). Six months later, he developed an enlarging 1-cm lung metastasis that was removed surgically. The histology of the lung metastasis was clear cell carcinoma and he remains disease free. Five additional patients experienced a PR lasting a median of 4 months, including 1 patient who had liver metastases (Fig. 2). Among the seven patients who experienced a major response, there were three with sarcomatoid differentiation, three with rapidly progressive RCC for whom the diagnosis of RCC was made after needle biopsy (and for whom it therefore is unknown whether sarcomatoid differentiation was present), and one with clear cell carcinoma.
|Chemotherapy regimena||No. of doses||Response||Histology||Time to progression (mos)|
|A 50/G 1.5||5||None||Sarcomatoid||2|
|A 50/G 1.5||6||Partial||Clear cell||4|
|A 50/G 1.5||12||Complete||Sarcomatoid||21+|
|A 50/G 1.5||3||None||Sarcomatoid||1.5|
|A 50/G 1.5||2||None||Sarcomatoid||1|
|A 50/G 1.5||5||Mixed||Papillary||3|
|A 50/G 1.5||5||Mixed||Sarcomatoid||3|
|A 50/G 1.5||2||None||Papillary||1|
|A 50/G 1.5||12||Stable||Sarcomatoid||11|
|A 50/G 1.5||9||None||Clear cell||5|
|A 50/G 1.5||6||Complete||Sarcomatoid||4+|
|A 50/G 2.0||4||Partial||Sarcomatoid||4|
|A 50/G 2.0||6||Stable||Sarcomatoid||4|
|A 50/G 2.0||4||Mixed||Carcinomab||2|
|A 50/G 2+|
|A 30/G 1.0||2||Partial||Carcinomab||2+c|
|A 50/G 2||3||None||Sarcomatoid||2|
|A 50/G 2+|
|A 37.5/G 1.5||4||Partiald||Carcinomab||5|
|A 50/G 2.0||6||Partiald||Carcinomab||4|
Chemotherapy has been considered to be ineffective in the treatment of advanced clear cell carcinoma. Recently, investigators at the University of Chicago explored the combination of weekly gemcitabine and continuous infusion 5-fluorouracil.5 The dose of gemcitabine was 600 mg/m2, which was administered on Days 1, 8, and 15 of a 28-day cycle. The authors reported PRs (objective response rate, 17%; 95% CI = 8–34%) in 39 evaluable patients, in addition to 5 minor responses (25–50% decreased tumor size). A number of gemcitabine-containing regimens have subsequently been explored in patients with RCC with similar response rates (Table 4). Of note, the highest response proportion was reported in a study that administered 1000 mg/m2 in contrast to the dose of 600 mg/m2 in the other studies.16 We used a higher dose of gemcitabine in the current study originally designed as a dose-dense schema, and treated patients with poor prognosis RCC with either sarcomatoid differentiation or rapidly progressive disease that would be unlikely to respond to biologic therapy.
|Regimen||Dose||Responses (% of all patients)||Reference|
|Gemcitabine||800–1250 mg/m2 on Days 1, 8, and 15 of 28||1 PR (6)||Mertens et al., 199327|
|Gemcitabine||800 mg/m2 on Days 1, 8, and 15 of 28||1 CR, 2 PRs (8.1)||de Mulder et al., 199628|
|Gemcitabine + CIV 5-FU||Gemcitabine: 600 mg/m2 on Days 1, 8, and 15 of 28; 5-FU: 150 mg/m2 per day on Days 1–21||0 CRs, 7 PRs (17)||Rini et al., 20005|
|Gemcitabine + cisplatin + CIV 5-FU||Gemcitabine: 600 mg/m2 on Days 1, 8, and 15 of 28; cisplatin: 20 mg/m2 on Days 1, 8, and 15; 5-FU: 150 mg/m2 per day on Days 1–21||0 CRs, 1 PR (5)||George et al., 200229|
|Gemcitabine + CIV 5-FU + thalidomide||Gemcitabine: 600 mg/m2 on Days 1, 8, and 15 of 28; 5-FU: 150 mg/m2 per day on Days 1–21; thalidomide: administered on Days 1–28||0 CRs, 2 PRs (10)||Desai et al., 200230|
|Gemcitabine + IFN + IL-2||Gemcitabine: 1000 mg/m2 on Days 1, 8, and 15 of 28; IFN: 3 IU administered IM 3 times weekly; IL-2: 4.6 × 10−6 MU administered SQ 5 days per week||1 CR, 3 PRs (28)||Neri et al., 200216|
|Gemcitabine + 5-FU + IL-2||Gemcitabine: 600 mg/m2 on Days 1, 8, and 15 of 28; 5-FU: 150 mg/m2 per day on Days 1–21; IL-2: 11 × 10−6 IU administered SQ 4 days per week||1 CR, 5 PRs (14.6)||Ryan et al., 200231|
Sarcomatoid differentiation of RCC occurs in all histologic subtypes of RCC, with the incidence ranging from 1.2% to 23.6% of RCCs.9 It is uniformly associated with a poor prognosis, with a median survival ranging from 2 to 9 months.7–9, 13 Surgery alone is often inadequate to cure patients, although there is no proven role for adjuvant therapy. Cangiano et al.17 reported that patients with sarcomatoid differentiation who received high-dose IL-2 had an improved survival. however, this may represent patient selection. Although some reviews suggest that the presence of > 50% of sarcomatoid features in the primary tumor portends a worse prognosis,7 other studies do not support this premise.17 Recent analysis of prognostic factors for survival in patients continues to show that sarcomatoid differentiation is associated with an inferior prognosis.18–20
Systemic therapy for patients with metastatic sarcomatoid RCC has routinely been ineffective. Sella et al.21 reviewed the M. D. Anderson Cancer Center experience and found that patients who received a doxorubicin-based regimen were the only long-term survivors. Responses have also been reported using the MAID regimen (sodium mercaptoethanesulfonate, doxorubicin, ifosfamide, and dacarbazine),22 and recently using gemcitabine, docetaxel, and carboplatin.23 In contrast, no responses were observed in patients receiving doxorubicin and ifosfamide. In the current study, we also elected to use chemotherapy to treat patients without a histologic diagnosis of sarcomatoid RCC but with rapidly progressive clinical disease. In our experience, many of these patients are young, with either locally advanced or metastatic disease at the time of initial presentation. Immunotherapy regimens are ineffective and patients typically die within a few months of diagnosis. As reported in the current study, chemotherapy with doxorubicin and gemcitabine can reverse clinical deterioration in some patients, and cause stabilization or regression of metastases. It is unclear why the combination of gemcitabine and doxorubicin appeared to be more effective in our study than that observed in previous regimens with either drug alone. This may result from the high dose of gemcitabine in the current regimen compared with that used in the Phase II single-agent studies for patients with RCC, or that the combination of an anthracylcine and gemcitabine results in improved efficacy, as has been suggested by other clinical trials in a variety of malignancies using this combination.15, 24–26
In summary, RCC is correctly considered a chemotherapy-resistant tumor with most patients with clear cell carcinoma resistant to cytotoxic agents. However, we suggest that in certain instances, such as patients with sarcomatoid RCC or patients with rapidly progressing tumors (i.e., 25–50% objective progression over 1–2 months), combination chemotherapy should be considered for therapy. A proposed clinical ECOG trial will formally study this regimen in patients with RCC with sarcomatoid differentiation using a dose of 1500 mg/m2 of gemcitabine and 50 mg/m2 of doxorubicin every 2 weeks with growth factor support. Clearly, molecular studies are needed to more accurately characterize RCCs to identify which patients will specifically benefit from this approach, as well as which patients will benefit from immunotherapy or other newer therapies.
The authors thank Alyssa Rosmarrin and Jodi Kaplan for providing nursing assistance and Ms. Heather Orkin for providing secretarial support.
- 12Therapy for patients with uncommon histologic varieties of renal cell carcinoma. In: BukowskiRM, NovickAC, editors. Renal cell carcinoma: molecular biology, immunology, and clinical management. Totowa, NJ: Humana Press, 2000: 397–405..
- 30A high rate of venous thromboembolism in a multi-institutional phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma. Cancer. 2002; 95: 1629–1636., , , , , .