Potential of Interferon-α in Solid Tumours
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The second part of this review examines the use of recombinant interferon-α (rIFNα) in the following solid tumours: superficial bladder cancer, Kaposi’s sarcoma, head and neck cancer, gastrointestinal cancers, lung cancer, mesothelioma and ovarian, breast and cervical malignancies.
In superficial bladder cancer, intravesical rIFNα has a promising role as second-line therapy in patients resistant or intolerant to intravesical bacille Calmette-Guérin (BCG). In HIV-associated Kaposi’s sarcoma, rIFNα is active as monotherapy and in combination with antiretroviral agents, especially in patients with CD4 counts >200/mm3, no prior opportunistic infections and nonvisceral disease. rIFNα has shown encouraging results when used in combination with retinoids in the chemoprevention of head and neck squamous cell cancers. It is effective in the chemoprevention of hepatocellular cancer in hepatitis C-seropositive patients. In neuroendocrine tumours, including carcinoid tumour, low-dosage (≤3MU) or intermediate-dosage (5 to 10MU) rIFNα is indicated as second-line treatment, either with octreotide or alone in patients resistant to somatostatin analogues. Intracavitary IFNα may be useful in malignant pleural effusions from mesothelioma. Similarly, intraperitoneal IFNα may have a role in the treatment of minimal residual disease in ovarian cancer. In breast cancer, the only possible role for IFNα appears to be intralesional administration for resistant disease. IFNα may have a role as a radiosensitising agent for the treatment of cervical cancer; however, this requires confirmation in randomised trials.
On the basis of current evidence, the routine use of rIFNα is not recommended in the therapy of head and neck squamous cell cancers, upper gastrointestinal tract, colorectal and lung cancers, or mesothelioma. Pegylated IFNα (peginterferon-α) is an exciting development that offers theoretical advantages of increased efficacy, reduced toxicity and improved compliance. Further data from randomised studies in solid tumours are needed where rIFNα has activity, such as neuroendocrine tumours, minimal residual disease in ovarian cancer, and cervical cancer. A better understanding of the biological mechanisms that determine response to rIFNα is needed. Studies of IFNα-stimulated gene expression, which are now feasible, should help to identify molecular predictors of response and allow us to target therapy more selectively to patients with solid tumours responsive to IFNα.
The first part of this review examined the biology of interferon-α (IFNα) and its clinical use in malignant melanoma and renal cell carcinoma. Here we survey its use in other solid tumours: superficial bladder cancer, Kaposi’s sarcoma, head and neck cancer, gastrointestinal cancers, lung cancer, mesothelioma and ovarian, breast and cervical malignancies.
1. Superficial Bladder Cancer
Superficial bladder cancers [SBCs; stages Ta or Tcis (tumours confined to the mucosa) or stage T1 (tumours invading the lamina propria)] account for about 80% of primary bladder neoplasms. They recur in more than two-thirds of patients after surgical resection only.[3, 4, 5, 6] Immunotherapy plays an important role in the management of SBCs. Intravesical bacillus Calmette-Guérin (BCG) is currently the most common form of immunotherapy used in the management of SBCs.
IFNα, in addition to its antiproliferative, antiangiogenic and immunoregulatory effects, has specific antiproliferative activity against bladder cancer cells.[8,9] Intravesical IFNα produces its immunomodulatory effect through various mechanisms, such as increased production of interferon-γ (IFNγ). Several studies have examined the ability of IFNα to eradicate residual tumours (therapeutic) and prevent tumour recurrences (prophylactic). Intravesical IFNα has been investigated both as monotherapy and in combination with BCG and other chemotherapeutic agents.
1.1 Monotherapy in the Therapeutic Setting
The clinical studies indicate that IFNα has significant activity in SBCs. Unlike BCG, the tolerability of intravesical IFNα is good. Torti and co-workers, on behalf of the Northern California Oncology Study Group, noted a response rate of 43%, with 67% of treatment-naive patients responding as opposed to a 30% response rate in patients with prior intravesical therapy. There is also the suggestion that higher doses of IFNα are needed for maximum efficacy in the therapeutic setting. Glashan, in a randomised trial evaluating two dose levels of IFNα, found that 100MU of intravesical IFNα, administered initially weekly for 3 months and then monthly for 12 months, produced a response rate of 66% (complete response 43%, partial response 23%), whereas a lower dose (10MU) produced a response rate of only 5%. Similar dose-response correlation was also noted in another randomised trial using IFNα doses of 10 and 100MU (response rates of 5 and 43%, respectively).
1.2 Monotherapy in the Prophylactic Setting
The results from nonrandomised trials prompted several randomised trials comparing IFNα monotherapy with BCG and other chemotherapeutic agents. A multicentre Italian trial randomised 287 patients to either IFNα or mitomycin following complete transurethral resection of the tumour. Overall, mitomycin was superior to IFNα except in terms of local tolerability. Other randomised trials have also confirmed the inferiority of IFNα in SBCs when compared with BCG, mitomycin or epirubicin.[18, 19, 20, 21, 22, 23, 24]
It is clear that BCG and other cytotoxic agents are superior to IFNα in the treatment of SBC. One hypothesis put forward, based on preclinical studies, to explain the smaller magnitude of the effect of IFNα, is that IFNα treatment requires frequent administration of optimal biological doses rather than the conventional maximum tolerated dose. Moreover, there is a dose-response correlation in the prophylactic setting as well, and a randomised trial has found 80MU to be significantly more effective than 40MU and slightly better than 60MU. It is unknown if the dose-response correlation could partially account for the inferior results of the IFNα prophylactic treatment in these SBC trials.
1.3 Second-Line and Combination Therapy
Even though IFNα is inferior as a first-line agent, it has the potential to be a second-line agent in patients who have had prior intravesical therapy. Torti and co-workers found that seven of 23 patients who did not respond to prior intravesical chemotherapy or immunotherapy responded to intravesical IFNα, and Glashan reported that six of nine patients responded to IFNα therapy after failure of intravesical BCG. Although BCG is clearly superior to IFNα as a first-line treatment, BCG therapy has problems with tolerability, toxicity and tumour resistance in a significant proportion of patients. IFNα, with its proven but inferior efficacy, can be added to BCG with a view to increasing the overall therapeutic ratio of intravesical treatment. The efficacy of IFNα in BCG-resistant tumours and its preclinical evidence of synergistic activity with BCG provides support for combination therapy.[11,12,28, 29, 30] The toxicity of BCG is dose-dependent, and IFNα offers an avenue to reduce the dose of BCG without compromising overall efficacy. From a practical point of view, IFNα is pharmacologically compatible with BCG and can be administered intravesically with it.
The rationale for combining IFNα with other cytotoxic agents comes from preclinical studies showing synergism between IFNα and other agents such as doxorubicin and mitomycin. Engelmann and co-workers, in a three-arm study of 67 patients, found that the combination of IFNα + mitomycin was more effective than either agent administered alone. Further confirmatory large studies are needed, since this study was small and the mean follow-up was only 6.2 months. In a trial of 85 patients comparing single-agent IFNα with IFNα + epirubicin, the recurrence rates were 24 and 16%, respectively, thus favouring the chemoimmunotherapy arm. Another recent paper also reported good response rates for the combination of IFNα and epirubicin. The group treated with IFNα combination therapy had a recurrence rate of 21%, whereas those treated by transurethral resection alone had a recurrence rate of 54%. The combination of IFNα + fluorouracil has also shown good response rates in a small study of 11 patients. The combinations of IFNα with BCG and other chemotherapy agents need to be assessed in prospective randomised trials before firm conclusions can be drawn.
In summary, IFNα has efficacy in the therapeutic setting of SBC. There are no randomised studies comparing IFNα with BCG in the therapeutic setting, but the response rates to IFNα therapy are clearly inferior to those of BCG as a first-line agent.[12,13,41] Hence, the role of IFNα as a first-line agent is limited to patients who are intolerant of BCG. In the prophylactic setting, IFNα monotherapy has been confirmed to be inferior to BCG and other cytotoxic agents in randomised studies.[18, 19, 20, 21, 22, 23, 24] The role of IFNα as a second-line agent, particularly in patients resistant to BCG, needs to be clarified by randomised studies. The role of IFNα in combination with BCG and other chemotherapy agents is an avenue for future research.
2. Kaposi’s Sarcoma
IFNα inhibits angiogenesis and downregulates various proangiogenic factors (such as VEGF, bFGF, IL-8, MMP-2, MMP-9 and PDGF) that are involved in the pathogenesis of Kaposi’s sarcoma[25,68, 69, 70, 71, 72, 73, 74]
IFNα inhibits proliferation of Kaposi’s sarcoma spindle cells by downregulating expression of the oncogene c-myc
IFNα inhibits various inflammatory cytokines involved in the pathogenesis of Kaposi’s sarcoma.
2.1 Monotherapy and Combination Therapy
One of the largest trials, which assessed the combination of IFNα + zidovudine, was the Canadian HIV Clinical Trials Network study. This randomised study looked at different dose levels of IFNα and found that the higher dose of 8MU, even though more toxic, produced a significantly higher response rate than low-dose IFNα (3MU) [31 vs 8%]. It is noteworthy that low-dose IFNα in combination with zidovudine was effective even in patients with low CD4+ count, in whom IFNα monotherapy is ineffective.[62,96] The combination of IFNα + zidovudine is complicated by dose-limiting neutropenia. Granulocyte-macrophage colony-stimulating factor (GM-CSF) can be used to circumvent this problem, without adversely affecting the antiviral properties of the combination.[94,103]
The other attempt to improve the therapeutic ratio of IFNα was to combine it with chemotherapeutic agents. Various studies using vinblastine, etoposide and other agents have so far failed to demonstrate any significant improvements in the response rates. Moreover, the toxicity due to the combination therapy was severe in many studies.[102,104,105]
Many factors are correlated with a response to IFNα therapy. There is a dose-response effect with IFNα monotherapy, but dose escalation is limited by the high toxicity rates.[89,91,92] The patients more likely to respond to IFNα treatment are those with a high CD4+ count (>150 to 200 cells/mm3), those with low-stage disease, those without B symptoms (fever, night sweats and body-weight loss), those without a history of opportunistic infections and those with undetectable endogenous IFNα.[62,90,91,93,104] In particular, patients with low CD4+ counts (<100 cells/mm3) do not seem to derive any benefit from IFNα monotherapy. With combination treatment (IFNα + antiretroviral), a high CD4+ count, absence of B symptoms and absence of opportunistic infections are again strong predictors of response to IFNα treatment.[95,96,98,101,106,107]
There is also a dose-response effect with IFNα combination therapy. Unlike IFNα monotherapy, low doses of IFNα in combination with antiretrovirals are effective even in patients with low CD4+ counts, but response rates are lower than those observed in patients with high CD4+ counts.[96,98,101,106,107]
In summary, IFNα is an effective agent in Kaposi’s sarcoma. The combination of zidovudine + IFNα seems to be more effective than IFNα monotherapy, but this comes at a price of greater toxicity. The patients benefiting most from IFNα treatment are those with high CD4+ counts (>200 cells/mm3) and no prior opportunistic infections, and those receiving antiretroviral therapy.[62,90,92,104]
3. Head and Neck Squamous Cell Cancer
Head and neck squamous cell cancers (HNSCCs) are characterised by a number of synchronous and metachronous second primary tumours of the aerodigestive tract.[108, 109, 110] Survival rates in patients with HNSCCs have not improved significantly, despite advances in detection, treatment and local control, because of the toll on survival by the second primary tumours. This has led to chemoprevention efforts with various agents such as retinoids and β-carotene. The results of many randomised trials have been mixed, and chemoprevention of second primary tumours with pharmacological agents is yet to become the standard of care.[111, 112, 113, 114, 115, 116] IFNα has been evaluated as a therapeutic and a chemopreventive agent in HNSCC.
The antitumour activity of IFNα observed in the pilot studies of HNSCC led to phase II trials.[117, 118, 119] The phase II trials of IFNα in combination with other cytotoxic agents showed response rates of 30% in patients with recurrent HNSCCs. They also suggested the feasibility of combining IFNα with cisplatin and fluorouracil, which is one of the most active chemotherapy regimens in HNSCC.[120,121] However, a phase III trial failed to show any benefit for the combination of cisplatin, fluorouracil and IFNα in the therapeutic setting. In this randomised trial, patients with recurrent and metastatic HNSCCs were randomised to receive both cisplatin and fluorouracil ± IFNα. There was no difference in response rates or overall survival (OS).
A phase II study using a novel combination of IFNα, isotretinoin (13-cis-retinoic acid) and α-tocopherol in patients with locally advanced HNSCC has recently been reported. The addition of α-tocopherol to the isotretinoin was intended to reduce toxicity and enhance effectiveness. The aim of the trial was to reduce recurrence rates as well as to prevent second primary tumours. This combination showed a 2-year OS rate of 91% [2-year disease-free survival (DFS) 84%] The toxicities of this combination regimen noted in the trial were fatigue (grade 2/3: 40%), myalgia (grade 2/3: 28%), infection (grade 4: 2%), dry skin and mucositis (grade 2/3: 40%) and hypertriglyceridaemia (grade 1/2: 30%). The results of this trial warrant evaluation in further large randomised phase III clinical trials.
Premalignant lesions of the upper aerodigestive tract carry a high risk for transformation into an invasive cancer.[125,126] Hence, chemoprevention strategies are being tried to reduce the risk of transformation. Isotretinoin and α-tocopherol are the agents that have been widely studied in this setting.[115,128] The novel strategy of combining IFNα with the retinoids has been based on preclinical studies that showed remarkable synergism between these agents in inhibition of HNSCC proliferation and angiogenesis.[129, 130, 131]
A recent chemoprevention trial of the upper aerodigestive tract used the combination of IFNα, isotretinoin and α-tocopherol. The 36 participants in this prospective trial did not have invasive cancer and had only advanced premalignant lesions of the head and neck region. The investigators observed ten pathological complete responses and seven partial responses at 6 months. The overall histological response rate and clinical response rates were 48 and 57%, respectively, at treatment completion in 12 months. When the response rates were analysed by the site of lesions, premalignant lesions of the larynx were found to have high response rates, whereas oral lesions had a low response rate (at 12 months, complete response 50 and 0%, respectively). This indicates that future trials should stratify patients according to the site of lesions. The tolerability of this combination regimen was reasonable. Only three patients dropped out of the trial because of toxicity. None of the patients experienced any grade 4 toxicity, but 13 (36%) experienced grade 3 toxicity. If these results are replicated in a large trial, this regimen of IFNα, isotretinoin and α-tocopherol could become the standard of care.
Systemic IFNα therapy has no proven role in the therapy of HNSCCs. The role of IFNα in the chemoprevention setting, in combination with the retinoids, is encouraging, but because of the small sample size of the trials its role is undefined.
4. Oesophageal Cancer
IFNα has shown no activity as a single agent, and has been used in a small number of phase II studies in combination with fluorouracil.[132,133] It has been tried unsuccessfully with high-dosage retinoids such as etretinate and isotretinoin.[135,136] It has also been combined with fluorouracil and cisplatin given pre-operatively with chemoirradiation,[137,138] as neoadjuvant therapy in locally advanced oesophageal cancer, and in the metastatic setting. These trials, however, were single-arm studies and the contribution of IFNα to the efficacy of treatment was uncertain. The above data cannot be used to draw firm conclusions, but it seems unlikely that IFNα will have a role in therapy of oesophageal cancer.
5. Gastric Cancer
Four phase I/II trials of intermediate-dosage IFNα (IDIFN) [5MU] combined with fluorouracil ± leucovorin[142, 143, 144, 145] included 121 evaluable patients and averaged a 28% response rate. One study of low-dosage IFNα (LDIFN) [3MU three times weekly] and continuous fluorouracil infusion combined with leucovorin and etoposide reported a response rate of approximately 37%, and an Italian group achieved similar results (response rate 32%) with fluorouracil, leucovorin, LDIFN and epirubicin. Despite comparable response rates, median survival was 15 months in the former study and only 8 months in the latter. The above response rates are comparable to those reported with fluorouracil-doxorubicin-methotrexate combination chemotherapy,[148, 149, 150] but inferior to the 45% response rate reported with the epirubicin-cisplatin-fluorouracil regimen.
Despite recent data confirming that IFNα inhibits the growth of gastric carcinoma cells in vitro and increases the intratumoral concentration of fluorouracil in vivo, the response rates to treatment with fluorouracil (+ leucovorin) combined with either LDIFN or IDIFN are lower than can be achieved with epirubicin-cisplatin-fluorouracil chemotherapy. There is therefore insufficient evidence to routinely use IFNα in the treatment of gastric cancer.
6. Pancreatic Cancer
IFNα has been tested in a number of phase II studies, in combination with leucovorin and fluorouracil. Unfortunately, response rates have been poor (0 to 23%). In 204 patients treated within phase II studies,[154, 155, 156, 157, 158, 159, 160] the response rate was just 10%. All of these studies used IFNα + fluorouracil ± leucovorin. Adding etoposide to the above combination did not improve the response rate, which remained low at 11%. The addition of cisplatin in another study achieved a higher response rate (38%), but at the expense of considerable toxicity. IFNα combined with isotretinoin was well tolerated but the response rate was disappointingly poor (only 5%). The lack of a survival benefit and the severity of toxicities observed in some of these studies have precluded any role for IFNα in the treatment of pancreatic adenocarcinoma.
One recent phase II study used IFNα with cisplatin + fluorouracil in the adjuvant chemo-irradiation setting after resection of pancreatic adenocarcinoma, and reported excellent OS at 2 years (84%). These data, however, are immature, and more importantly the contribution of IFNα is difficult to determine without a randomised study.
7. Hepatocellular Carcinoma
Early studies showed that IFNα alone or combined with cytotoxic agents[166, 167, 168, 169] was inactive in hepatocellular carcinoma (HCC). One phase II study of 28 patients showed that continuous fluorouracil infusion + LDIFN induced durable partial responses in nearly one-third of patients with low α-fetoprotein levels or 50% liver involvement. IFNα has also been tested with other cytokines such as tumour necrosis factor (TNF)-α and high-dosage IL-2 in this setting, but without success.[171,172] More recently, attempts with intra-arterial[173,174] or combination chemotherapy have been more fruitful in terms of response rate (26 to 47%). However, this has not translated into a survival benefit, with reported median survival times of 5 to 9 months.[173, 174, 175] The only study where IFNα alone has shown activity in HCC used high-dosage IFNα (HDIFN) [50 MU/m2 three times weekly], but despite a response rate of 31% this failed to prolong survival.
Despite these results, a randomised chemoprevention study from Japan showed that 3 to 6 months of IFNα were sufficient to achieve a nearly 10-fold reduction in the incidence of HCC in hepatitis C-positive patients. This has been confirmed in a larger study. The full potential of IFNα in HCC therefore needs further evaluation. This view is supported by a recent meta-analysis that examined the role of IFNα and other medical therapies for unresectable HCC.
The routine use of IFNα for treatment of HCC cannot be recommended in the light of available evidence to date, except for chemoprevention in hepatitis C. One study has shown that the critical factor influencing the incidence of HCC is the total dose of IFNα used (>500MU).
8. Neuroendocrine Tumours
Recombinant IFNα has been tested in phase II trials as first-or second-line therapy for neuroendocrine tumours, including carcinoid. Pooled data have reported a 42% biochemical response rate and a 70% symptomatic response rate in 111 patients with malignant carcinoid tumours. More recent data on >300 patients with neuroendocrine tumours treated with LDIFN/IDIFN have reported a biochemical response rate of 44% and a symptomatic response rate of 65%, which occurred despite tumour reductions observed in just 11% of patients. Comparable figures have been seen in other studies: biochemical and symptomatic response rates of 58 and 80%, respectively, biochemical response rate 75%, symptomatic response rate 64%, all in carcinoid tumours. IFNα may be particularly useful for midgut carcinoids, which are frequently resistant to chemotherapy, unlike foregut carcinoids.
Two phase II studies examined the role of LDIFN given with fluorouracil, and both reported very low response rates: biochemical response rate 14% in one study and objective response rate 7% in the other. These response rates are much lower than those achieved with cytotoxic agents such as fluorouracil and streptozocin combined (33%)[189,190] or with single-agent doxorubicin (23%). Moreover, the LDIFN + fluorouracil combination was associated with significant toxicity (nausea, diarrhoea, fatigue).[187,188] In a Norwegian study of 42 patients, IFNα was given after hepatic artery embolisation and improved survival in patients who continued therapy for more than 1 year compared with those who stopped at 1 year. The contribution of therapy with IFNα, however, remains uncertain.
Somatostatin analogues are usually first-line therapy in metastatic carcinoid tumours; however, for patients who fail to respond or are intolerant to these, IFNα offers an alternative. Symptomatic and biochemical response rates of about 50% and 69 to 77%, respectively, have been achieved using IFNα as second-line treatment.[193,194] In another study, disease stabilisation was seen in 13 of 14 patients for a median 12 months. The biochemical and symptomatic responses seen despite measurable tumour regression suggest that the effect of IFNα combined with octreotide is antiproliferative. This is difficult to reconcile with the interesting observation that expression of the antiapoptotic bcl-2 gene is induced in neuroendocrine gut tumours from patients treated with and responding to IFNα. One study has suggested that the kinetics of responses seen in 16 chemotherapy-naive patients with carcinoid tumours are consistent with an anti-angiogenic effect. IFNα in combination with octreotide is better tolerated than monotherapy. Treatment with HDIFN entails significant toxicity, whereas LDIFN has been shown to have equivalent efficacy, in terms of symptom control, to IDIFN; therefore, as second-line therapy we advocate LDIFN (3MU) with octreotide or LDIFN alone in patients resistant or intolerant to somatostatin analogues.
9. Colorectal Cancer
thymidine phosphorylase-independent mechanisms.
9.1 Pharmacokinetic Interaction Between Fluorouracil and Interferon-α
The early studies focused on the pharmacokinetic interactions between fluorouracil and IFNα. IFNα slows the breakdown of fluorouracil in peripheral blood mononuclear cells. Several studies have demonstrated decreased clearance and increased concentrations of fluorouracil.[211, 212, 213, 214] A smaller recent study used 19F magnetic resonance spectroscopy and demonstrated, in vivo, increases in the half-life of fluorouracil in a small number of patients treated with fluorouracil and IFNα. Conversely, two studies have shown no pharmacokinetic interaction between fluorouracil and IFNα.[215,216] Sparano and coworkers showed increased gastrointestinal toxicity when IFNα was administered with infusional fluorouracil, but without any pharmacokinetic interaction, thus supporting the existence of nonpharmacokinetic mechanisms for enhanced fluorouracil cytotoxicity. The reasons for these discrepancies are unclear. Nevertheless, the findings of Presant and colleagues are consistent with the results of earlier studies on the effect of IFNα on fluorouracil pharmacokinetics.[211, 212, 213, 214]
Subsequent clinical trials of IFNα and fluorouracil can be grouped into four categories, as discussed in the following sections.
9.2 Single-Arm Trials of Fluorouracil and Interferon-α
Nine phase II studies with 316 evaluable patients have reported response rates of 24 to 63% (mean 35%).[217, 218, 219, 220, 221, 222, 223, 224, 225] Significant grade 3/4 toxicities were observed; however, the results were promising, as the response rates were higher than with fluorouracil alone and comparable to those seen with other fluorouracil biomodulators.
9.3 Single-Arm Trials of Fluorouracil, Interferon-α and Leucovorin
Following the results of the above studies, attempts focused on improving response rates even further. Therefore, many phase II trials combined fluorouracil with IFNα and leucovorin.[226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237] The scientific basis of the double modulation of fluorouracil by IFNα and leucovorin was the enhanced cytotoxicity observed in colorectal cell lines. This, however, conflicts with the observation made 1 year earlier by Schuller and co-workers, who showed that leucovorin abrogated the pharmacokinetic interaction between fluorouracil and IFNα.
The response rates ranged from 13 to 54% and the toxicity was similar to that seen with fluorouracil modulated by either IFNα alone or leucovorin alone. Consequently, the addition of leucovorin to the fluorouracil + IFNα combination offers no extra benefit.
9.4 Randomised Trials of Fluorouracil With or Without Interferon-α
A possible explanation as to why these studies showed no survival advantage for the IFNα arm may have been the failure to administer IFNα simultaneously with the fluorouracil. Fluorouracil has a short in vivo half-life, and for effective synergy with IFNα both drugs must be present simultaneously. For example, in the Royal Marsden study, IFNα was administered 2 to 4 hours after the bolus dose of fluorouracil. In the study by Greco and colleagues, IFNα was administered before fluorouracil, i.e. as given in previous phase II studies, and in another study, although IFNα was administered before fluorouracil, specific timing was not requested. Although the differences in response rates between the fluorouracil and fluorouracil + IFNα arms in these three randomised trials were not statistically significant, there was a trend for higher response rates in two studies that administered IFNα before fluorouracil.[241,243]
9.5 Randomised Trials of Fluorouracil + Leucovorin With or Without Interferon-α
9.6 Interferon-α in Combination with Other Agents
Of three phase II studies using IFNα + IL-2,[255, 256, 257] only one showed, albeit very modest, activity in advanced colorectal cancer (response rate 14%); therefore, this combination cannot be recommended in this setting. Multimodal biochemical modulation of fluorouracil with methotrexate + leucovorin + IFNα, leucovorin + IFNα + IL-2 or IFNα combined with other cytotoxic agents such as etoposide has also proved ineffective.
A meta-analysis based on data from more than 3000 patients showed that IFNα did not enhance the efficacy of fluorouracil either alone or with leucovorin. The fluorouracil + IFNα combinations were found to be inferior to fluorouracil + leucovorin in advanced colorectal cancer. Therefore, on the basis of current data, IFNα cannot be recommended for routine use in advanced colorectal cancer. This accords with previous reviews in this field.[141,262]
10. Lung Cancer
10.1 Small-Cell Lung Cancer
IFNα has been used in small-cell lung cancer (SCLC) with induction chemotherapy and as maintenance therapy.
10.1.1 Induction Chemotherapy
Three randomised trials examined the role of IFNα as part of induction therapy. The largest study showed no survival benefit with either natural or rIFNα given with six cycles of cisplatin + etoposide. In a smaller study, the response rate for IFNα was higher and there was a tendency for longer time to progression, although this was not statistically significant. Zarogoulidis and colleagues showed no difference in response rate, although survival in the IFNα group was prolonged.
These studies were relatively small, and as the data published to date are inconclusive a large multicentre study should be conducted to evaluate IFNα given with induction therapy in SCLC. In vitro data have shown that IFNα increases the radiosensitivity of SCLC. This may be one of the reasons why the only trial that showed improved survival for IFNα given with induction chemotherapy used radiotherapy to both the primary site and brain (prophylaxis); in contrast, the two other studies[263,264] did not use radiation concomitantly with IFNα.
10.1.2 Maintenance Therapy
Results on the use of IFNα for maintenance therapy after response to chemotherapy have been mixed. The largest study of maintenance therapy in SCLC involved 237 patients who responded to induction chemotherapy and radiotherapy. This three-arm trial compared low-dosage natural IFNα with maintenance chemotherapy and with no maintenance therapy. Although there was no significant difference in median survival, there was a long-term survival benefit for limited stage disease in the IFNα arm. A more recent analysis confirmed the earlier findings, as the IFNα-treated patients were five times more likely to be alive at 5 years than were patients in the other two arms. A smaller phase III study was too small for any survival advantage to be detected.
Two other randomised studies[270,271] that used LDIFN/IDIFN maintenance therapy after initial response to chemotherapy failed to show a survival advantage, whereas a third trial reported a better 2-year survival for IFNα-treated patients. The trials by Jett and colleagues and Kelly and colleagues showed a trend for poorer median survival in the IFNα-treated groups. A randomised phase II trial showed that maintenance treatment with IFNα and isotretinoin, after dose-intensive chemotherapy, was feasible. Median survival in this arm was about 4 months longer than that in the control arm (no maintenance therapy), but the difference was not statistically significant. This combination needs testing in a large randomised study.
Overall, these studies do not support the use of rIFNα as maintenance treatment in SCLC.
10.2 Non–Small-Cell Lung Cancer
Most studies on non–small-cell lung cancer (NSCLC) have been small phase II trials of IFNα and chemotherapy in advanced disease. Cisplatin has been most commonly used, either as a single agent or with other cytotoxic agents. The response rates reported vary from 6 to 51%.[275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286] In total, well over 400 patients have been treated in phase II studies, with an average response rate of 30%. Two of these phase II studies combined IFNα with isotretinoin or tretinoin, but no benefit was seen.[278,280] The largest reported randomised trial treated 192 patients with cyclophosphamide, epirubicin and cisplatin ± IFNα, but showed a tendency for poorer survival in the IFNα arm.
Some NSCLC cell lines are resistant to IFNα alone; however, inhibition of proliferation was seen when combining IFNα with IFNγ. Although work on NSCLC cell lines has shown no synergistic interaction between IFNα and cisplatin, fluorouracil, tretinoin or isotretinoin, potentiation of cisplatin activity by rIFNα was shown against human NSCLC established as a xenograft in nude mice. IFNα combined with the angiogenesis inhibitor AGM-1470 has also inhibited primary tumour growth and growth of lung metastases in mice. Despite these encouraging preclinical data, however, the use of IFNα has not translated into a therapeutic benefit in patients.
IFNα has also been tested with IL-2 in a small phase I/II trial, but without success. A much larger phase II study where this combination was given to patients responding to chemotherapy reported an response rate of 53%.
Three studies have reported on the use of IFNα with radiotherapy. A 46% response rate has been reported by combining LDIFN/IDIFN with radiotherapy and cisplatin. Low- and intermediate-dosage natural IFNα has been combined with radiotherapy in two small studies with 60 and 23% response rates.
In summary, although the existing evidence does not support routine use of IFNα in NSCLC, its activity and toxicity in combination with radiotherapy or chemoradiotherapy should be further evaluated.
The susceptibility of mesothelial cells to immune effector cells and cytokines in vitro and in vivo led to the use of IFNα in this disease. Work using mesothelioma cell lines and murine xenograft models showed IFNα to be effective early in tumour development, and the combination of IFNα with other antiproliferative agents (e.g. β-carotene) had an additive effect. Studies showed activity of either IFNα alone[298,301] or IFNα combined with IFNγ and methotrexate in mesothelioma cell lines.
Two clinical studies tested IFNα alone,[303,304] but the response rate was low (12%). Several phase II studies in which nearly 100 patients have been treated using combinations of IFNα and cisplatin + tamoxifen or other cytotoxic agents have yielded response rates of about 20% (range 7 to 42%).[306, 307, 308, 309, 310] These results are similar to those reported in a recent review of phase II trials of chemoimmunotherapy, which included 98 patients treated at the Institute Gustave Roussy (response rate 15 to 40%). One phase II study showed that increasing the IFNα dosage enhanced toxicity but did not affect the response rate or survival.
A phase II study of LDIFN combined with mitomycin + cisplatin reported a response rate of 23%. No difference in survival was seen between the treatment group and patients treated with supportive care alone, although the median survival for responding patients was significantly longer. A more recent Italian phase II study used LDIFN combined with cisplatin + doxorubicin and reported a response rate of 29%. Toxicity was significant and median survival was approximately 9 months. Intracavitary IFNα, though inferior to IL-2, has been reported to be effective for symptomatic control of malignant pleural effusions.
The above data do not support routine clinical use of systemic IFNα in mesothelioma.
12. Ovarian Cancer
There have been no randomised trials in the last 10 years to examine the role of IFNα as systemic therapy in ovarian cancer. Most studies used intraperitoneal IFNα given alone or with other cytotoxic agents. Pharmacokinetic studies demonstrated that the intraperitoneal concentration of IFNα was much higher than the blood concentration, thus delivering more IFNα to the tumour by the former route. The same author suggested, in another study, that intraperitoneal IFNα should be given to patients with minimal residual disease (MRD) and platinum-sensitive tumours. IFNα on its own is as effective as in alternating combination with cisplatin. This is supported by another study that showed that combining intraperitoneal IFNα and intraperitoneal carboplatin resulted in more toxicity without any substantial survival benefit.
Since 1990, about 170 patients in total have been treated with intraperitoneal IFNα combined with cytotoxic drugs (cisplatin, carboplatin, cisplatin + mitoxantrone), with response rates varying from 0% to 62%. All of these studies used IFNα in the setting of MRD detected after second-look laparotomy. The presence of small-volume disease (<2cm) appeared to correlate with likelihood of response. Current evidence supports the use of intraperitoneal IFNα in ovarian cancer with MRD, i.e. after debulking surgery and cytoreductive chemotherapy. Conclusive evidence, however, requires a randomised clinical trial.
13. Breast Cancer
IFNα has antiproliferative effects on some but not all breast cancer cell lines. Natural IFNα can sensitise tamoxifen-resistant or medroxyprogesterone acetate-resistant breast cancer cells by increasing estrogen/progesterone receptor expression. Most studies examining the role of IFNα in breast cancer have been small phase II trials. These used IFNα with IL-2, TNFα or tamoxifen without success. One large randomised study of doxorubicin + cyclophosphamide ± IFNα with more than 300 patients showed that DFS was not different in the two groups.
Breast cancer was one of the first solid tumours where tumour regression was seen with natural IFNα.[328,329] It is unclear why rIFNα has not shown greater or at least equivalent activity. One possibility is that interferon species other than IFNα-2 have greater activity. Intralesional IFNα has been used with some success in treating recurrences in disseminated breast cancer resistant to radio/chemotherapy and hormones. The complete regression rate was nearly 50% in a group of 12 patients.
In summary, current evidence does not support the routine use of IFNα as systemic therapy in breast cancer. Intralesional IFNα for resistant breast cancer recurrences may have a role, although this requires further evaluation.
14. Cervical Neoplasia
14.1 Cervical Intraepithelial Neoplasia
Cervical cancer has a well characterised premalignant phase — cervical intraepithelial neoplasia (CIN). If untreated, CIN could progress to frank invasive cancer. There is considerable evidence to implicate the human papillomavirus (HPV), especially HPV 16 and HPV 18, in the pathogenesis of cervical cancer. There is also evidence to indicate that altered immunological mechanisms might be involved in the carcinogenic process.[331, 332, 333, 334] Hence, IFNα, with its antiviral and immunomodulatory properties, along with its ability to suppress HPV-encoded oncogenes, can be potentially useful in the treatment of CIN.[335,336]
Both systemic and local IFNα therapies have been explored in the treatment of CIN. IFNα local therapy was found to cause regression of CIN in many uncontrolled studies, and the response rates were found to be as high as 85%.[337, 338, 339, 340, 341, 342, 343, 344, 345, 346] However, placebo-controlled studies of local IFNα therapy have found no significant beneficial effects.[347, 348, 349] Systemic IFNα therapy was also found to cause regression of CIN in smaller studies.[350,351] Systemic IFNα therapy has not been evaluated in randomised trials and there are no ongoing phase III trials to confirm its potential. Interestingly, randomised trials of IFNα therapy for HPV genital infection found no beneficial effects.[352,353] These studies suggest that both local and systemic IFNα is unlikely to have significant benefits in treatment of CIN, which is strongly associated with HPV. Since women with CIN are healthy and have a good chance of surgical cure, IFNα therapy with its modest efficacy is unlikely to have a significant role in management of CIN.
14.2 Invasive Cervical Cancer
The antiproliferative properties of IFNα on cervical cell lines led to their evaluation in the invasive cancer setting.[335,355] Many phase II studies have evaluated the role of IFNα in invasive cervical cancer. Because of preclinical synergism, IFNα was also evaluated in combination with isotretinoin. In recurrent cervical cancer, the efficacy of IFNα is poor both as a single agent and in combination with other agents.[357, 358, 359, 360, 361, 362, 363, 364] An Eastern Cooperative Oncology Group study of 31 patients with recurrent cervical cancer found low response rates for IFNα therapy. Similarly, a recent Gynecologic Oncology Group trial and a Southwest Oncology Group trial found no evidence of benefit for the combination of IFNα + isotretinoin in recurrent cervical cancer.
In contrast, IFNα has a potential role in the first-line treatment of cervical cancer. Two phase II studies[365,366] reported response rates of about 60%. LDIFN combined with isotretinoin produced a 58% response rate in patients with locally advanced disease after a 2- to 4-month period of treatment. In another study, LDIFN was administered with radiotherapy to patients with clinical stage III/IV disease and resulted in a response rate of 64%. In a study by Stock and coworkers LDIFN was combined with weekly cisplatin chemotherapy and irradiation, and achieved excellent control of local disease (100% at 2 years). However, this was at the expense of late complications, which were most probably related to the high doses of radiation used (median 93Gy).
Recently, Ikic and colleagues, who used IFNα preoperatively for just 3 weeks in stage I/II disease, have reported better results. In a randomised phase II study they reported a statistically significant survival benefit (74 vs 47% at 20 years; p < 0.05) for patients treated with neoadjuvant human natural IFNα applied topically in the form of pessaries before surgery.
Unfortunately, these phase II studies are small and, except for one trial, all are nonrandomised. Therefore, it is difficult to evaluate the contribution of IFNα therapy to responses and survival. Prospective randomised trials are therefore urgently needed to help establish the role of IFNα in advanced cervical cancer and as adjuvant therapy after curative surgery or radical radiotherapy. In vitro studies suggest that IFNα can have a radiosensitising effect. This is significant, since radiotherapy is a curative therapeutic modality in cervical cancer. Furthermore, the combination of isotretinoin and IFNα has been found to improve cervical tumour oxygenation. Although tumour hypoxia negatively affects the efficacy of radical radiotherapy, it is not known whether this improvement in hypoxia will lead to survival benefits.
15. Future Prospects for Interferon-α in Solid Tumours
Other factors are pharmacokinetic, such as insufficient exposure of malignant cells to IFNα because of the anatomical and physiological characteristics of solid tumours (e.g. abnormal vasculature and high interstitial pressure, respectively). Also, the toxicity of high-dosage IFNα therapy may prevent delivery of sufficient quantities of IFNα locally. Locoregional administration of IFNα in some solid tumours such as ovarian and breast cancers has led to tumour regression.[330,376] Despite these obstacles, IFNα can occasionally produce some remarkable responses even in some of the most chemo- and radioresistant tumours, such as malignant melanoma and renal cell carcinoma.[378, 379, 380]
In some cancers, survival and possibly antitumour activity may be facilitated by low tumour burden. Two recently published randomised studies[381,382] have shown that in patients with renal cell carcinoma, radical nephrectomy prior to IFNα immunotherapy confers a significant survival benefit compared with IFNα alone. Although the objective response rates were not different between the two groups, the survival benefit seen is likely to be related to the reduced tumour burden, as all patients had metastatic disease. Responses can take a long time to be seen (median time in most trials being 2 to 3 months). A recent study, however, has reported delayed responses occurring at 12 to 16 months after disease stabilisation in three patients with metastatic renal cell carcinoma treated with escalating doses of IFNα.
More work is urgently needed to establish the mechanism of action of IFNα in patients who respond versus those who do not; this is the only way to fully understand the mechanism of action of this agent. Such studies may allow the development of molecular predictors of response and more selective use of IFNα. The antiangiogenic properties of IFNα are likely to be important in established solid tumours, and this might necessitate long-term treatment that should not be interrupted. Clinical trials in metastatic renal cell carcinoma have demonstrated the feasibility of long-term therapy with IDIFN.[385,386] This point must be taken into account in the design of clinical trials using IFNα to avoid premature cessation of therapy.
IFNα may need to be administered over long periods in the adjuvant setting. This hypothesis is based on data from Fidler and colleagues,[25,68] who showed that daily administration of very low doses of IFNα (5 to 10kU) had antiangiogenic effects in human bladder carcinomas implanted orthotopically in nude mice, and on the rebound in relapse rates observed in adjuvant trials of malignant melanoma (World Health Organization 16 stage III and French trial stage II patients). The above findings provide support for the ongoing European Organization for Research and Treatment of Cancer 18991 study, which compares long-term (5 years) therapy with pegylated IFNα and observation in patients with stage III malignant melanoma. Trial design is also important in testing the activity of IFNα with fluorouracil, because only administration of fluorouracil shortly after IFNα will ensure maximum potentiation of fluorouracil-mediated cytotoxicity.
Pegylated IFNα is an important development that will need thorough evaluation in malignancies where rIFNα-2 is being used either in routine clinical practice or in clinical trials. It has demonstrated comparable safety and pharmacodynamic profiles to nonpegylated IFNα. Its 40-hour half-life (compared with 4 hours for rIFNα-2b) means that once-weekly administration is sufficient. Pegylated IFNα has better bioavailability and, because of pegylation, may have reduced metabolic adverse effects; this may avoid the need for dosage reduction in patients with impaired renal function, while being more convenient for patient use. Tumour regressions in renal cell carcinoma and melanoma have been seen in phase I trials; however, whether this agent will prove more efficacious in randomised studies remains to be seen.
IFNα has not proved to be the miracle cure for cancer as might have been expected in the 1980s. In some haematological malignancies (for example chronic myeloid and hairy cell leukaemias) the response rates to IFNα are high: 70 to 80% and 80 to 90%, respectively. In contrast, in solid tumours responses to IFNα therapy are much lower (table VI), usually 15% for metastatic melanoma and renal cell carcinoma and <10% for common solid tumours such as lung, breast and colorectal cancer. IFNα is effective treatment in AIDS-related Kaposi’s sarcoma and is useful in many patients with neuroendocrine tumours, where good symptomatic control is seen in 50 to 70% of treated patients despite a low objective response rate. It also has a role as locoregional therapy in superficial bladder cancer where intravesical BCG has failed, and as intraperitoneal therapy in MRD of ovarian carcinoma. Results of phase II studies in ovarian cancer have been very encouraging, and therefore randomised studies are needed to test the hypothesis that intraperitoneal IFNα, in selected women with small-volume disease, improves OS or progression-free survival after surgery and first-line chemotherapy. If IFNα is used widely for the chemoprevention of HCC in hepatitis C– positive individuals, it should help reduce the incidence of HCC, which, worldwide, affects significant numbers of people.
Perhaps the greatest potential of IFNα lies in the adjuvant setting after tumour cytoreduction is achieved with other modalities of treatment. The identification of potential responders to IFNα therapy is an important priority. This may be achieved by studies of IFNα-stimulated gene expression. DNA micro-array technology allows us to identify IFNα-stimulated genes, which may be categorised on the basis of their function. This may enable us to understand why some patients respond to IFNα but others do not, and allow us to predict response through characteristic gene expression patterns. If IFNα is active as an adjuvant treatment, it may take considerable work to identify the correct dose, schedule and route of administration. However, it is anticipated that it will be used more effectively in patients with ‘IFNα-sensitive tumours’.
S. Santhanam and M. Decatris contributed equally to this work. No sources of funding were used to assist in the preparation of this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this manuscript.
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