Investigators at the Royal Marsden Hospital and University College in London have studied thalidomide (Thalomid) as both low-dose (100 mg orally, every night) and high-dose (600 mg, given as 300 mg twice per day)
ABSTRACT: Investigators at the Royal Marsden Hospital and UniversityCollege in London have studied thalidomide (Thalomid) as both low-dose (100 mgorally, every night) and high-dose (600 mg, given as 300 mg twice per day)therapy for patients with a variety of solid tumors. In the phase II low-dosestudy, responses were disappointing in patients with melanoma, ovarian cancer,and breast cancer. Results for patients with renal-cell carcinoma were moreencouraging. A case study of a patient with metastatic renal-cell carcinoma inthe lung and lymph nodes in the low-dose thalidomide study illustrates that (1)responses may be very slow; (2) the palliative response is separate from theoverall response, occurs much earlier, and is not consistent with anantiangiogenic action; and (3) peripheral neuropathy is a manageable sideeffect. Besides peripheral neuropathy, patients can experience severeconstipation (even on low doses) as well as headache, edema, and skin rash forwhich treatment recommendations can be made. Anecdotal benefits of thalidomideinclude enhanced or maintained appetite, improved sleeping, and reducedsweating. The high-dose study has been submitted for publication. [ONCOLOGY14(Suppl 13):17-20, 2000]
Tumors secrete growth factors that help them to grow andmetastasize. Some of these factors are angiogenic, some immunomodulatory, andseveral fall into both categories. Angiogenesis is an important new targetfor anticancer drugs. As shown in Figure 1,thalidomide (Thalomid) may interfere with the expression or release of severalangiogenic factors,[3-6] including tumor necrosis factor-alpha (TNF-alpha) andinterleukin-6 (IL-6), from renal carcinoma cells, and may interfere indirectlywith vascular endothelial growth factor (VEGF) and basic fibroblast growthfactor (bFGF).[7,8]
These factors may stimulate cell growth in a paracrine orautocrine manner. For example, the combined activity of TNF-alpha and IL-6 isquite potent as an autocrine and paracrine growth factor, at least in vitro. Anumber of patients with renal cell carcinoma appear to have metastatic bonedisease and little or no disease in other soft tissue. It is interesting tospeculate that IL-6 may be an important factor in this pattern of disease, sinceit is often expressed at high levels in bone.
Data are also accumulating for thalidomide’s effects on growthfactor suppression and immunomodulation.
Earlier this year, we published data in the British Journal ofCancer, reporting on work done primarily at the Royal Marsden Hospital. Thestudy investigated the use of low-dose thalidomide (100 mg orally, every night)in patients with a variety of advanced malignancies, including melanoma,renal-cell carcinoma, ovarian, and breast cancers. The aims of the study were toassess the toxicity and gain an early indication of the efficacy of continuouslow-dose thalidomide. We also attempted to assess biological responses by serialmeasurements of TNF-alpha, VEGF, and bFGF concentrations in stored serumsamples.
Thalidomide was administered on a continuous schedule ratherthan a shorter, higher-dose regimen because data suggest that an antiangiogenicagent may have optimum effect if given over a long period. Using thalidomideover a long period, however, increases the risk of peripheral neuropathy. Wetherefore started our study at an extremely cautious dose of 100 mg every night.
Patients and Methods
All patients in the study had histologically confirmed,measurable, progressive disease. None of them had had any anticancer therapy,including surgery, in the previous 4 weeks because of our concern that patientsreceiving thalidomide might have some interference with their ability to healafter surgery. Using our standard criterion, women of childbearing age agreed touse adequate contraception for the duration of the study and for 6 monthsafterwards. Patients showing any signs of peripheral neuropathy were excluded toavoid exacerbation.
Patients were assessed initially and at 1 month, then at 3, 6,9, and 12 months, until they showed evidence of disease progression or theyexperienced unacceptable toxicity. Assessments included full blood count, serumbiochemistry, and the sensory nerve action potential (SNAP) test for peripheralneuropathy. We also froze serum and urine for later enzyme-linked immunosorbentassay (ELISA) of biomarkers (bFGF, VEGF, and TNF-alpha). We also asked patientsto complete symptom distress scales (Hospital Anxiety and Depression [HAD] andRotterdam scores).
A total of 66 patients (37 women and 29 men; median age: 48years, range: 33-62 years) with advanced measurable cancer (19 ovarian, 18renal, 17 melanoma, 12 breast cancer) were enrolled in the study (Table1). Several patients had poor performance status and most had receivedcancer treatment prior to enrollment.
Complete response was defined as the disappearance of all knowndisease determined by two observations not less than 4 weeks apart. Partialresponse was defined as a decrease by at least 50% of the sum of the products ofthe largest perpendicular diameters of all measurable lesions as determined bytwo observations not less than 4 weeks apart.
Progressive disease was defined as a more than 25% increase inthe size of the lesion or the appearance of a new lesion. Stable disease wasdefined as where there had been a less than 50% decrease and a less than 25%increase in the sum of products of the largest perpendicular diameters of allmeasurable lesions for two observations not less than 4 weeks apart.
Three partial responses were seen in the 18 patients withrenal-cell carcinoma. Two of these patients had had extensive pretreatment. Oneresponse lasted 5 months, and the other two partial responses continued after 5and 11 months of follow-up. Thirteen patients with renal-cell carcinomaexperienced stabilization of their previously progressive disease. Three hadstable disease for 3 months or longer; 10 had stable disease for only 1 to 3months.
Objective results (partial response or stable disease) in theremaining 48 patients were disappointing. However, three patients had adifferential response; one patient with rapidly progressive skin deposits ofmelanoma on his leg experienced symptomatic improvement and was able to walkmore than 100 yards, having been previously confined to a chair. Thalidomide maybe of more interest as part of a multiple modality regimen in melanoma.
Of 15 patients who completed serial HAD and Rotterdam scores, 11experienced improvements in sleeping and 14 experienced a maintained or enhancedappetite. Both findings were statistically significant (P < .05), althoughbased on a small number of patients.
One patient’s case serves to illustrate the results of ourlow-dose study. This man had progressed on treatment for renal-cell carcinoma,with deteriorating performance status 2 months after receiving a combination ofinterleukin-2 (IL-2), interferon alfa, and fluorouracil. He had several largepulmonary and lymph node mestastases and had developed increasingly severe nightsweats and weight loss.
The patient was started on 100 mg of thalidomide at night. Athis first assessment at 1 month, he denied feeling any different. However, hiswife said that he was, in fact, a changed man. The patient’s appetite hadreturned, his sweats had stopped, and he was more active. Over the next 4 monthsof treatment with thalidomide he had a gradual disease response, which resolvedto a single residual lung mass in the right lung showing only necrotic tissue onbronchoscopy.
It is well recognized that rarely, spontaneous or late responsesto immunotherapy may be seen in patients with renal-cell carcinoma. This isunlikely to be the explanation for this man’s response for two reasons: first,the patient had rapidly progressive disease following biochemotherapy, andsecond, he obtained significant palliative benefit within a short time ofstarting thalidomide.
After 9 months in the study, a SNAP test detected peripheralneuropathy and the thalidomide was stopped, according to the study protocol. Thepatient did not want to stop treatment then because he was feeling much betterand had not noticed the peripheral neuropathy. After 1 month withoutthalidomide, his SNAP improved and he was restarted at a lower dose (50 mg). Hedeveloped peripheral neuropathy again after a month, at which time treatment wasstopped. Eleven months later progressive disease was noted in the right lung.Restaging showed no evidence of relapsed disease at other sites and apneumonectomy was performed. The patient remains well now, 3 years afterstarting thalidomide.
This case illustrates several points. First, responses tothalidomide may be slow. Second, the palliative response is separate from theobjective tumor response, and is much faster and not consistent with anantiangiogenic action. Third, although peripheral neuropathy is a problem, itcan be managed safely by appropriate dose reduction and where necessary,cessation of treatment. Fourth, responses and palliative benefit may be obtainedin patients with metastatic renal-cell carcinoma who have progressed onimmunotherapy.
We were disappointed that we had used serum instead of plasmafor measuring growth factors as treatment biomarkers. VEGF, in particular, isstored in platelets. Thus, estimation of VEGF levels in frozen serum is unlikelyto be reliable. Although we had a wide range of findings, particularly withVEGF, none were statistically significant.
We found no clear relationship between the absolute level ofVEGF and tumor response, nor were there any clear differences between differenttumor types. However, a rising VEGF level was associated with progressivedisease in 6 of 11 patients who had serial measurements. We detected bFGF onlyin the serum of 12 patients with early progressive disease. We detected no bFGFor free TNF-alpha in the urine of any patient. Free TNF-alpha was detected inthe serum of one patient with melanoma, one patient with breast cancer, and onepatient with ovarian cancer.
Thalidomide (100 mg, every night) was generally well tolerated,with no World Health Organization (WHO) grade 3 or 4 toxicities. The maintoxicity was lethargy (38 patients were grade 1; 8 patients were grade 2). For acontinuing maintenance treatment, this is far more significant than it would befor short-term administration. Grade 2 peripheral neuropathy was detectedclinically in two patients who had been on treatment for 11 months. Oninterrupting thalidomide, the neuropathy resolved and treatment restarted at 50mg. One patient developed headache and one developed peripheral edema. Both sideeffects resolved after stopping thalidomide. Ten patients developed WHO grade 1constipation and two developed an itchy grade 1 skin rash. These side effectsresponded to standard treatment measures.
We concluded from our low-dose study that patients withrenal-cell carcinoma responded to thalidomide treatment and received mildpalliative benefits from its use. There was also an indication from the low-dosestudy that patients with metastatic melanoma may benefit from thalidomide. Oneobvious question is whether we might have seen better results if we had used ahigher dose of thalidomide. To answer this question we therefore performedhigher-dose phase II studies in previously treated patients with progressivemetastatic renal-cell carcinoma and malignant melanoma.
With a starting dose of 100 mg twice a day for 1 week, patientswere treated with escalating doses of thalidomide over 6 weeks to a targetmaintenance dose of 600 mg/d. As in our low-dose study, we assessed patientsinitially and at 1, 3, 6, 9, and 12 months, with the same tests, except that wecollected plasma samples for measuring a different panel of biomarkers. Thiswork has been submitted for publication.
Managing Side Effects
Thalidomide side effects and how they are managed appear in Table2. To help prevent lethargy, gradual dose escalation is essential, andpatients are asked to take their thalidomide at least 2 hours following food.Good fluid intake and an aggressive laxative policy alleviate constipation.Nonsedating antihistamines appear to be adequate therapy in most patients withskin rashes. Stevens-Johnson syndrome has been reported in rare patients takingthalidomide who require more active management with high-dose steroids.
Management of peripheral neuropathy is changing at ourinstitution. Because the baseline and subsequent SNAP tests do not appear to begood predictors, we are now depending more on clinical findings. A baseline SNAPtest is performed to exclude patients who have subclinical neuropathy, and otherpatients are watched carefully for clinical signs. If there is clinicalsuspicion of neuropathy, a repeat SNAP test is performed to determine whether ornot patients require a dose modification.
If the SNAP result has deteriorated by 40%, the thalidomide doseis reduced by 200 mg and the SNAP test is repeated 4 weeks later. If it isworse, treatment is stopped; otherwise, treatment is continued. Patients whostop treatment may occasionally restart at a lower dose when their SNAP test hasreturned to baseline. In one patient, we observed continuing deterioration inperipheral neuropathy despite stopping thalidomide. In other cases, the aboveprotocol has been sufficient to manage the peripheral neuropathy observed in ourpatients.
Anecdotal benefits of thalidomide have included enhanced ormaintained appetite and improved sleeping, consistent with findings from otherstudies. Reduced sweating is notable, as well as improved diabetic control.Patients receiving diabetic treatment often have marked improvements in theirglucose tolerance. Diabetic patients must be monitored closely because it isoften necessary to reduce diabetic medication. This is true for both insulin-and non-insulin-dependent diabetics. Patients receiving interferon havecomplained of anorexia and other side effects and, for some of these patients,adding thalidomide reduced those effects.
The results of the low-dose (100 mg) phase II study indicatesthat thalidomide has activity in patients with metastatic renal-cell carcinoma.A study at higher dose has been completed and submitted for publication. Datafrom several investigators suggest that most patients tolerate a 400-mg dose ofthalidomide; we have adopted this in our currently accruing studies. We havestarted two new studies. One is a phase II study of interferon (9 million IUthree times per week) plus thalidomide at 400 mg/d. If results appear promising,we intend to extend this to a phase III study comparing interferon with orwithout thalidomide.
For patients who are not fit enough to receive interferon or whohave progressed on biotherapy, we have started a phase II/III study, comparingmedroxyprogesterone acetate (Provera)(300 mg/d) to thalidomide (400 mg/d) as single agents.
We are also developing a study investigating the addition ofthalidomide to combination biotherapy with low-dose IL-2, low-dose interferon,and granulocyte-macrophage colony-stimulating factor 9. This regimen wasdeveloped by Gijsbert de Gast, md, in the division of medical oncology at theNetherlands Cancer Institute, with whom we collaborate. We plan to add threelevels of thalidomide to this regimen to see if we can attenuate the TNF-alpha-driventoxicity (particularly for the regimen containing IL-2) as well as improve theefficacy of the regimen.
Question: Your experience has been consistent with otherinstitutions (eg, M. D. Anderson or Sloan-Kettering Cancer Centers) in that someresponders had very poor prognoses before they went on the drug. Would youplease comment?
Timothy Eisen, MD, PhD: The palliative benefits ofthalidomide are not limited to the good-prognosis patients. We have seenimpressive palliative benefits in a wide range of patients, but we have seenbetter responses with skin, lymph node, and lung disease than we have with liverand bone disease.
Question: Do you think that giving thalidomide twice aday for your higher-dose patients might be contributing to their lethargy?
Dr. Eisen: We think it may actually help their lethargy.Before we started this study, we tried increasing the once-daily dose and veryfew patients could actually tolerate it. Giving a twice-daily (afternoon andevening) dose, therefore, seems to be beneficial.
Question: How did you define and grade lethargy?
Dr. Eisen: We asked patients about their activities ofdaily living and what they could do for themselves. We use a scale at theMarsden Hospital, based on the Common Toxicity Criteria fatigue grading, thathas helped us to grade lethargy.
Question: How do you measure SNAP?
Dr. Eisen: The sensory nerve action potential (SNAP) testis similar to an electromyelogram. You attach one electrode peripherally on thearm and one proximally to it. You then pass a current through the electrodes,while measuring the amplitude, waveform, and time taken.
1. Folkman J: Tumor angiogenesis: Therapeutic implications. NEngl J Med 285:1182-1186, 1971.
2. Folkman J: Clinical applications of research on angiogenesis.N Engl J Med 333:1757-1763, 1995.
3. Ching LM, Xu ZF, Gummer BH, et al: Effect of thalidomide ontumor necrosis factor production and anti-tumour activity induced by5,6-dimethylxantheone-4-acetic acid. Br J Cancer 72:339-343, 1995.
4. Konig B, Steinbach F, Janocha B, et al: The differentialexpression of proinflammatory cytokines IL-6, IL-8 and TNF-alpha in renal cellcarcinoma. Anticancer Res 19:1519-1524, 1999.
5. Koo AS, Armstrong C, Bochner B, et al: Interleukin-6 andrenal cell cancer: Production, regulation and growth effects. Cancer ImmunolImmunother 35:97-105, 1992.
6. Weidmann E, Bergmann L, Stock J, et al: Rapid cytokinerelease in cancer patients treated with interleukin-2. J Immunother 12:123-131,1992.
7. D’Amato RJ, Loughnan MS, Flynn E, et al: Thalidomide is aninhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082-4085, 1994.
8. Fine HA, Figg WD, Jaeckle K, et al: Phase II trial of theantiangiogenic agent thalidomide in patients with recurrent high-grade gliomas.J Clin Oncol 18:708-715, 2000.
9. Rak J, Filmus J, Kerbel RS: Reciprocal paracrine interactionsbetween tumour cells and endothelial cells: The ‘angiogenic progression’hypothesis. Eur J Cancer 32A:2438-2450, 1996.
10. Haslett PA: Anticytokine approaches to the treatment ofanorexia and cachexia. Semin Oncol 25:53-57, 1998.
11. Eisen T, Boshoff C, Mak I, et al: Continuous low dosethalidomide: A phase II study in advanced melanoma, renal cell, ovarian andbreast cancer. Br J Cancer 82:812-817, 2000.
12. Fullerton PM, Kremer M: Neuropathy after intake ofthalidomide (Distaval). Br Med J 2:853-858, 1961.