Ongoing trials in patients with head and neck cancer

Clinical trials

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47. Benner SE, Pajak TF, Lippman SM, et al. Prevention of second primary tumors with isotretinoin in patients with squamous cell carcinoma of the head and neck: Long-term follow-up. J Nail Cancer hast 1994; 86: 140-1. 48. Bolla M, Lefur R, Ton Van J, et al. Prevention of second primary tumours with etretinate in squamous cell carcinoma of the oral cavity and oropharynx. Results of a multicentric double-blind randomized study. Eur J Cancer 1994;30: 767-72. 49. BlotWJ, Li JY, Taylor PR, et al. Nutrition intervention trials in Linxian, China supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specificmortality in the general population. J Natl Cancer hast 1993;85: 1483-92. 50, The Alpha-.toeopherol,Beta Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the

incidence of lung cancer and other cancers in male smokers. N l~ngl J Med 1994; 330: 1029-35. 51. Albanes D, Olli PH, Taylor PR, et al. Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene Cancer Prevention Study: effects of base-linecharacteristics and study compliance. J Natl Cancer hlst 1996; 88: 1560-70. 52. Hennekens CH, Buring JE, Manson JE, et al. Lack of effect of long term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med 1996; 334: 1145-9. 53. Omenn GS, Goodman GE, Thorquist MD, et al. Effects of a combination of beta-carotene and vitamin A on lung cancer and cardiovascular diseases. N Engl J Med 1996; 334: 1150-5.

Ongoing trials in patients with head and neck cancer Dirk Schrijvers*, Jean Louis Lefebvrel" and Jan B. Vermorken* *Department o f Medical Oncology, Universi O, o f Antwerp, Wih'ijkstraat 10, B-2650 Edegem, Belgiwn; ~fDepartement d'O.R.L, et de Carcinologie Cervico-Faciale, Centre Oscar Lambret, B P 307, F-59020 Lille ( Cedex), France

Treatment of squamous cell carcinoma of the head and neck has recently undergone several important changes. New approaches to treating these tumours are now being evaluated. An overview of the surgical, radiotherapeutic and chemotherapeutic therapies or multimodality approaches currently under study are described. In addition, the design of ongoing chemoprevention trials is reported.

Key words: head and neck cancer; surgery; radiotherapy; chemotherapy; chemoprevention.

Introduction Head and neck cancer (HNC) represents about 5% of the total cancer cases and approximately 40,000 new cases in the United States (USA) are diagnosed each year. Worldwide more than 500,000 new cases are expected annually. One third of these patients will present with early stage disease, two thirds will have loco-regional advanced disease. In less than 20% of patients with HNC, distant metastases are found at initial diagnosis. ~ Risk factors for HNC are well known. It is associated with cigarette and alcohol abuse, particularly when their use is combined.2 This abuse may also lead to co-morbidity at the time of diagnosis, including cardiovascular, pulmonary and hepatic disease as well as malnutrition. The majority of HNC in the western world is of squamous cell origin and only a minority is of a different cell type

Correspondence to: Jan B. Vermorken, MD, PhD, Dept Medical Ontology, Universityof Antwerp, Wilrijkstraat 10, B-2650Edegem, Belgium (E-mail: [email protected]).

(adenocarcinoma, undifferentiated naso-pharyngeal carcinoma, sarcoma and lymphoma). HNC may occur at various sites with differing prognoses, outcomes and clinical implications, since vital functions such as nutrition, respiration and speech may be more or less affected, t The treatment of HNC is influenced by the histological subtype, localization and stage. Primary treatment modalities for localized and Ioco-regional disease are surgery and/or radiotherapy. Early stage disease is treated with curative intent using single modality strategies (surgery or radiotherapy). With this approach 60% to 90% of patients will be free of disease after 2 years. ~ Locally advanced resectable disease may be treated with surgery followed by radiotherapy, However, this combination treatment will only cure a minority of patients and less than 30% of these patients will be alive at 5 years. Recurrence of Ioco-regional disease is the most common cause of death while some patients develop distant metastases in the liver, lungs and skeleton. In patients with advanced resectable disease,

Clinical trials chemotherapy in combination with radiotherapy can induce the same survival rate as surgery and radiotherapy, with the advantage of avoiding radical surgery) In patients with distant metastases, chemotherapy may be used in a palliative setting to alleviate symptoms. Chemotherapy also has a role in patients with recurrent disease with a response rate of 30-45% and response durations of 3 to 6 months. 4's'6 A variety of chemotherapeutic agents have shown activity in HNC. Response rates of 20% or more have been reported for single agent methotrexate, cisplatin (CDDP), 5fluorouracil (5-FU), bleomycin, anthracyclines, docetaxel and paclitaxel, topotecan, ifosfamide, vinorelbine and gemcitabine. 7 The combination of cisplatin with 5-FU can induce response rates of 80% in first line treatment and 45% in recurrent disease.~ However, there is little effect on survival when chemotherapy is used in advanced or metastatic disease: " This paper will give an overview of the ongoing randomized trials of different treatment modalities for squamous cell carcinoma of the head and neck (SCCHN).

Surgery Clinical research in head and neck surgery is difficult to accomplish. Major technical advances have been made over the past 15 years (laser surgery, functional surgery, reliable flaps such as pectoralis major myocutaneous flaps or reliable free transfers such as antebrachial or fibula free flaps). There is no indication that a completely new surgical technique is likely to modify surgical practice in this disease in the near future unlike the advances that laparoscopic (or endoscopic) surgery made for other primary sites. Actually, clinical research, as far as HNC is concerned, is mainly orientated towards avoiding surgery. There are two major issues: (I) how to avoid unnecessary surgery; and (2) how to avoid radical surgery? A classical example of the first-issue is the unresolved problem of elective neck dissection for early oral squamous cell carcinoma. It is generally accepted that TI-T2,N0,M0 lesions as judged by palpation of the neck are, actually, accompanied by positive (metastatic) lymph nodes in 30% or fewer cases. This means that elective neck dissection is not justified in over 70% of cases. It would be a logical step to carry out a randomized trial comparing elective neck dissection with a wait-and-see policy in such patients and in fact this is being carried out by a Canadian study group (NCIC-Clinical Trial Group). That group has initiated a randomized trial for stage 1, II (TI-2, NO, M0) squamous cell carcinoma of the oral cavity comparing elective neck dissection with observation following surgery of the primary, site. Patients with tumours of the hard palate, the retromolar trigone, the lips, the buccal mucosa, the upper and lower alveolar ridges are excluded. The largest tumour diameter should be >1 cm but not >4cm, and patients should be suitable for transoral resection. Prior irradiation to local sites or regional lymph nodes or prior neck dissection are not allowed. Study endpoints are disease-free and overall survival. The surgical morbidity and Ioco-regional recurrence rate with these two

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approaches will be compared and the health-related quality of life of these patients will be evaluated. The number of patients needed is 500. At present, there are more sophisticated and more reliable tools (ultrasound, CT scan, Magnetic Resonance Imaging (MRI), fine needle aspiration biopsies guided by imaging) to diagnose a 'negative neck' with more certainty. As a result, the risk of false-negative examination of the neck is decreasing. The second issue, i.e. avoiding radical surgery, has been explored extensively in particular in the field of larynx preservation. For a long time, either surgery or irradiation, according to institutional protocols, were considered to be the standard treatment of advanced larynx and hypopharynx cancer. A randomized trial comparing both treatment modalities proved to be impossible due to lack of a consensus between1 ENT surgeons and radiation oncologists. The availability of platinum-based chemotherapy regimens which showed a high immediate response rate, reopened the discussion. The frequently observed correlation between chemo- and radiosensitivity led many teams to explore the possibility of selecting patients for either surgery or irradiation depending on the response to induction chemotherapy. One randomized trial in patients with laryngeal cancer was carried out in the USA under the auspices of the Veteran Affairs (Larynx Study Group)) A second study was conducted in patients with hypopharynx cancer by the European Organisation of Research and Treatment of Cancer (EORTC) Head and Neck Cancer Cooperative Group ( H N C C G ) : The design of both trials was quite similar: in the standard therapy arm, patients underwent radical surgery with post-operative irradiation; in the experimental arm, they received induction chemotherapy followed by irradiation in complete responders or by the standard treatment in incomplete responders. Preliminary results of the EORTC trial (EORTC-24891) were published in 1996. One hundred and ninety-four patients were evaluable (100 in the chemotherapy arm and 94 in the immediate surgery arm). As of December 1994 (18 months after the last randomization), there was no difference in survival between both arms but the medial duration of longterm survival was much longer in the chemotherapy arm. The explanation for this apparent contradiction was the delay in appearance of distant metastases in the chemotherapy arm. This delay gave an early advantage in survival, which disappeared after 5 years. As far as larynx preservation was concerned, the 3- and 5-year estimations of retaining a functional larynx (that is to say without tracheotomy, feeding tube or local progression) in patients treated in the chemotherapy arm were 42% and 35%, respectively. The updated analysis in June 1996 (3 years after the last randomization) showed that exactly half of the survivors in the chemotherapy arm at 3 and 5 years had retained a functional larynx while data on survival and median duration of survival were comparable to the previous analysis. These promising data confirmed the results of the American Larynx preservation trial) In that study, twothirds of the survivors had retained their larynx at 4 years. Several non-randomized mono-institutional series further confirmed that the induction chemotherapy approach for

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larynx preservation did not jeopardize the chances for cure and survival. The question was raised whether induction chemotherapy was really needed. Modification of radiotherapy (fractionation) or concurrent use of chemotherapy and radiation were able to give an improved local control also. For this reason a large survey was done throughout Europe to investigate the feasibility of a 3-arm trial, i.e. induction chemotherapy followed by radiotherapy vs radiotherapy alone vs concurrent chemoradiation. Unfortunately, there was not enough support for such a study. Therefore, it was decided to carry out two parallel randomized trials: one comparing induction chemotherapy with alternating chemotherapy and irradiation (EORTC24954), and the other comparing irradiation alone with concurrent chemoradiation (EORTC-22954). Both trials (with the excep/:ion of the inclusion of unilateral N3 in protocol EORTC-22954) have the same entry criteria (only resectable ~arynx or hypopharynx cancers amenable to total laryngectomy). Each participating institution has to decide beforehand which type of patients they will enter in each of these trials. In addition, an evaluation of quality of life during and after treatment, an evaluation of the quality of the preserved function and, finally, an evaluation of cost/ effectiveness ratio will be added to the classical assessments (survival, disease free survival, larynx preservation rates).

Radiotherapy Tun~our cell proliferation may be influenced by different radiotherapeutic options. The impact of the fraction of dose and the number of fractions per day on the damage of normal tissue has been studied intensively, resulting in different fractionation schedules. Some of these fractionation schedules result in an increase in total dose or dose intensity, with higher antitumour activity and less late damage to the normal tissues. Acutely responding tumour cells in HNC have a higher a/13 ratio than normal tissues. Hence, since most tumours have a less curved cell survival slope than late responding normal tissues, an increase in total dose will result in an increased tumour cell kill.9 The increase in dose or dose intensity of radiotherapy can be obtained in different ways: by acceleration or by hyperfractionation. In accelerated fractionation the overall time of treatment is reduced; the total dose and the dose per fraction are either unchanged or somewhat reduced, depending on the extent of overall time reduction. In hyperfractionated radiotherapy, the total dose is increased; the dose per fraction is reduced and the fraction number is increased; the overall time is relatively unchanged. In randomized trials it has been shown that hyperfractionation and accelerated radiotherapy are superior to conventional radiotherapy in terms of local control) ° To confirm these results, the National Cancer Institute (NCI) co-operative programme in the USA has initiated a randomized prospective trial in laryngeal cancer. The main objective of this .trial is to compare the local response rate to hyperfractionated vs conventionally fractionated radiotherapy in patients with T2NOM0 squamous cell carcinoma of the vocal cord. The acute and

late toxic effects associated with each fractionation schedule will-be assessed, and the overall and disease-free survival patterns associated with each fractionation schedule will be studied. A total of 240 patients is needed for this study. A multicentre Australian trial (TROG) randomizes patients with stage Ill/IV 1-1NC to conventional vs accelerated radiotherapy. The objectives of that trial are to study the impact of the two forms of radiotherapy on locoregional control rate, overall survival rate and side-effects. Moreover, the study will evaluate possible differences in these results according to disease site and stage. In addition, patient tumours will be evaluated according to various biological characteristics by using flow cytometry (DNA ploidy) and monoclonal antibodies (proliferation antigens). In total, 342 patients (171 per arm) are planned to be accrued. Eligible patients will have histologically proven, invasive stage Ill/IV squamous cell carcinoma of the oral cavity, the oropharynx, the hypopharynx or the larynx, without distant metastases. Synchronous primaries of the above sites are allowed if at least one site is stage Ill/IV disease. No prior therapy is allowed. In both arms of the study, patients are irradiated to the primary tumour and draining lymph nodes. The NC1 in the USA is also sponsoring a randomized study of post-operative accelerated fractionation radiotherapy vs conventional radiotherapy in patients with stage Ill/IV SCCHN. In these patients, the calculated risk of recurrence following surgery and conventional postoperative radiotherapy must be greater than 10% based on extracapsular nodal disease or presence of at least two of the following factors: oral cavity as primary site, microscopically positive mucosal margins, nerve invasion, two or more positive neck nodes; more than one involved nodal group, any node >3cm in diameter or delay in the start of radiotherapy for more than 6 weeks. The objectives are: (1) to determine prospectively the efficacy of post-operative accelerated fractionation using a concomitant boost technique vs conventional fractionation in maintaining local tumour control; (2) to determine whether the potential doubling time of tumour cells measured prior to surgery predicts which patient will benefit from accelerated post-operative radiotherapy, and (3) to evaluate the influence of intrinsic radiosensitivity of tumour cells from the operative specimen on the predictive value of potential doubling time measurements. For this purpose 132 patients per treatment arm are needed. In France, an Institute Gustave Roussy study called RAN F compares a twice daily regimen of 2 Gy per fraction up to 60Gy in 3 weeks vs a conventional once-a-day regimen of 70 Gy in 35 fractions in 7 weeks. A Danish trial (DAHANCA) will be activated comparing definite radiotherapy with 6 weekly sessions vs a treatment of a concomitant boost radiotherapy delivering two sessions per day during the last third of the treatment. Radiotherapy can induce important acute and chronic side-effects. The next two trials focus on methods to reduce these effects. In order to study the influence of growth factors on acute toxicity during radiotherapy, the NCI in the USA is sponsoring a phase III double-blind randomized trial on the effect of granulocyte colony stimulating factor (G-CSF)

Clinical trials during post-operative radiotherapy in patients with locally advanced HNC, i.e. with stage 11, 111 or IV disease and/or histological confirmation of cervical lymph node metastases with gross resection and negative surgical margins. The treatment protocol should start within 8 weeks of surgery. The trial evaluates whether G-CSF will reduce the need for tube feeding during radiotherapy. Other objectives are: ( I ) to study whether G-CSF reduces the severity of the radiationinduced mucositis; (2) whether it decreases the level of interventions required for mucositis; and (3) whether it reduces the number of interruptions of radiotherapy for radiation-induced mucositis. The initial accrual will be 33 patients per arm. If there is a significant difference in the number of patients requiring tube feedings in the two arms, the trial will stop; otherwise an additional 33 patients will be accrued to each arm for a total of 132 patients. A pharmaceutical sponsored (US Bioscience) trial in the USA evaluates the influence of amifostine (Ethyol ®) on the acute and chronic toxicities of radiotherapy in HNC patients. Patients for this trial will have histologically confirmed squamous cell carcinoma of the nasopharynx, the oral cavity or the oropharynx. They are scheduled to receive definitive or adjuvant radiotherapy without hyperfractionation or acceleration within 12 weeks after surgery with curative intent. In the experimental arm, patients receive amifostine intravenously 15-30min prior to each radiotherapy session, 5 days per week for 6-7 weeks. The trial compares: (1) the incidence, duration, and severity of oral radiation toxicity (including acute mucositis and acute or late xerostomia) as measured by the Radiation Therapy Oncology Group Acute and Late Radiation Morbidity Scoring Criteria; (2) the I-year Ioco-regional control rate; and (3) the toxic effects associated with both treatment arms. For these comparisons, a total of 300 patients will be randomized. The ability of amifostine to reduce the severity of xerostomia will be assessed by measuring whole saliva production and parotid saliva production; the ability of amifostine to reduce the global effects of oral discomfort and dryness will be assessed by using a patient questionnaire.

Chemotherapy Induction therapy Induction chemotherapy prior to the definitive treatment by surgery or radiotherapy has theoretical advantages. According to the Goldie and Coldman model of spontaneous mutations, the fraction of drug-resistant cells increases with increasing tumour size. Early treatment by chemotherapy may minimize the risk that the tumour will develop drug resistance. Other potential ad~vantages of induction chemotherapy are the reduction in size of the primary tumour and regionally nodal disease, thereby enhancing the local control by subsequent surgery or radiotherapy and facilitating surgical resection; the identification of patients with responding lesions, who can effectively be managed by single modality surgery or radiotherapy; the identification of patients who may benefit

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from additional therapy after Ioco-regional treatment; arrd the treatment of occult metastatic disease. Potential disadvantages are the delay in loco-regional treatment, which could be associated with the regrowth arid dissemination of the tumour; the selection of drug- and radio-resistant tumour cells; and the increase of local toxicity of subsequent surgery or radiotherapy. Several phase III trials have studied the effect of induction therapy." ~8Although many of these studies had important flaws in their design, some important conclusions can be made. Induction chemotherapy does not compromise the delivery of radiotherapy or surgery and thus would be unlikely to lead to a worse prognosis due to postponing definitive treatment. These studies also showed that the response to chemotherapy depends on the stage of disease. A few trials showed significant reduction in metastatic rate, s's'L''~s however, induction chemotherapy did not have any positive influence on survival. Even though induction chemotherapy may not improve cure rates, its ability to achieve high response rates serves another purpose, that of organ preservation. As mentioned earlier, the Veterans Administration Cooperative Study Project (VACSP) 3 and the EORTCHNCCG study, s'~9 both showed that larynx preservation was possible by induction therapy without a negative impact on disease-free or overall survival. The question remains whether induction chemotherapy followed by radiotherapy is any better than radiotherapy alone to preserve the larynx in patients with resectable disease. This question is addressed by the NCI in the USA. In a high priority clinical trial, 546 patients with resectable stage I l l - I V squamous cell cancer of the glottic and supraglottic region will be treated according to three treatment arms. Patients are randomized to receive radiotherapy alone vs induction chemotherapy with cisplatin/5-FU followed by radiotherapy vs concomitant radiotherapy and cisplatin. This study will compare the overall and disease-free survival while preserving the laryngeal function as well as the tumour response after chemotherapy, radiotherapy or the combined approach. Other objectives are the reduction of the Ioco-regional recurrence rate, metastatic rate. the incidence of acute and late toxicities and the assessment of quality of life of these patients. Other treatment regimens with the newer drugs, including biological response modifiers, may improve the complete response rate and their impact on survival should be studied in randomized trials. However, these new drugs, whether given alone or in combination, may be more toxic and may induce more haematological or non-haematological toxicities. New methods to abrogate these toxicities, such as the use of haematopoietic growth factors or the use of cytoprotective agents may increase the therapeutic index for chemotherapy and limit normal tissue toxicity. A randomized phase II1 trial, initiated by the Italian Consiglio Nazionale Ricerche, investigates the influence of peri-lymphatic interleukin-2 (1L-2) for squamous cell carcinoma of the oral cavity or oropharynx in 260 patients. Eligible patients are those with operable stage T2-4, N0-3 and M0 unilateral disease. In both arms of the study, radiotherapy is waived for N0-2 patients when they are NO

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or have no capsular rupture during surgery. The other patients do receive radiotherapy after surgery. The trial compares the disease-free and overall survival with or without the use of 1L-2, determines the response rates to Ioco-regional IL-2 induction therapy, and evaluates local and systemic effects of Ioco-regional 1L-2 on host-tumour interaction and immune properties. Another phase III randomized study by the same group evaluates the value of neoadjuvant chemotherapy (CDDP/ 5-FU) in patients treated with surgery with and without radiotherapy for stage Ill//l/IV squamous cell carcinoma of the oral cavity (T2>3 cm, T3, T4, N0-3, M0). Endpoints of the study are the short- and long-term local control rates, disease-free survival and overall survival. Furthermore, the study tries to assess the prognostic significance of clinical and pathological responses obtained by neoadjuvant chemotherapy and to compare the short- and long-term toxic effects of these two regimens. Two hundred and forty patients ,~ill be needed for this study.

Adjuvant chemotherapy Adjuvant chemotherapy is given after definitive local treatment in order to treat micrometastases. Theoretical advantages of adjuvant chemotherapy include the immediate start of effective treatment such as radiotherapy and surgery, the absence of pre-operative decrease of the general and nutritional status due to upfront chemotherapy, the absence of intercurrent haematological and immunological suppression clue to upfront chemotherapy, and the absence of possible interference with dose and delivery of radiotherapy due to chemotherapyinduced toxicity. Theoretical disadvantages include impaired chemotherapy delivery after surgery and/or radiotherapy by alteration of the blood flow, the lack of acceptance or tolerance of the patients to any systematic treatment due to functional and cosmetic deformities after Ioco-regional treatment, the absence of immediate gratification for either patient or physician with poor patient compliance as a result, the overtreatment of patients who do not benefit from a toxic treatment, because of chemoresistant cell lines. The val~ae of adjuvant chemotherapy has been studied in several randomized trials. 2°-24 The data from these randomized trials do not support routine adjuvant chemotherapy in patients with HNC after Ioco-regional treatment, since survival is not improved. Nevertheless, the occurrence of distant metastases is diminished in some of these trials, suggesting a positive impact of chemotherapy. Adjuvant treatment may thus play a role in survival when Ioco-regional treatment may decrease local recurrence. However, many of these trials had problems in administering the prescribed dose of chemotherapy. Bettertolerated chemotherapeutic regimes have to be developed to make adjuvant chemotherapy possible for most HNC patients. There are no ongoing randomized trials examining the role of adjuvant chemotherapy'after curative local treatment with surgery and/or radiotherapy, although a study of chemoradiation after surgery compared with radiotherapy

alone is being performed by the EORTC-HNCCG (EORTC229.31; see concomitant chemo- and radiotherapy).

Alternathlg chemotherapy and radiotherapy Rapidly alternating chemotherapy with radiotherapy may have theoretical advantages. According to the Goldie and Coldman model of spontaneous mutations, the fraction of drug-resistant cells increases with increasing tumour size. Rapid sequencing of different non-cross-resistant treatment modalities may minimize the risk that the tumour will become resistant. Moreover, by alternating these treatments, the full therapeutic dose of chemotherapy and radiotherapy could possibly be given with limited side-effects. However, potential disadvantages have also been mentioned such as: (I) prolongation of the loco-regional treatment, associated with interval regrowth; (2) increased toxicity leading to delay of treatment or decreased dose intensity; (3) early dissemination of disease; and (4) increase of local toxicity of subsequent surgery. Merlano et al. reported several randomized studies utilizing this approach -'s--'7and showed a benefit in complete response rate, progression-free survival and overall survival. The Italian 'Consiglio Nazionale Ricerche' randomizes patients with a previously untreated and non-resectable HNC to receive either accelerated radiotherapy or alternating radiotherapy and chemotherapy with cisplatin/ 5-FU. In this multicentre phase Ill study, 240 patients will be entered to compare the response rate and overall survival and to correlate tumour cell kinetics with clinical outcome by evaluating in vivo bromouridine uptake and DNA flow cytometry. In order to be included in this trial, patients need to have histologically confirmed inoperable stage/I/l/I/IV SCCHN. Stage II tumours (T2,N0) can be included only when localized at the base of the tongue, the lateral and posterior oropharynx and the hypopharynx; stage III/1V tumours (T3-4 NO, T I - 4 NI-3, MC) of the hypopharynx, larynx, nasopharynx, oral cavity and oropharynx are all included. The EORTC also examines this approach in a larynx preservation trial in patients with resectable hypopharynx and larynx cancer (EORTC-24954).

Concurret~ chemo- and radiotherapy The rationale for concurrent use of chemotherapy and radiotherapy is that if they are independently active against cancer cells, they may enhance each other's activity in combination. They may also overcome resistant cell clones by differences in resistance patterns. Resistance to chemotherapy may be due to decreased activation or increased metabolization of cytotoxic drugs, decreased uptake or increased efflux, and changed target enzymes or enzymatic activity. The activity of radiotherapy is independent of these mechanisms and .~hows cytotoxicity in cells resistant on the basis of these changes. Another advantage of the concomitant use of both treatment modalities is that it shortens the overall treatment duration. Moreover, it may have an effect on micrometastases and may improve Ioco-regional control.

Clinical trials

A potential disadvantage is the increased local toxicity of the treatment resulting in a decrease in dose of either chemotherapy or radiotherapy. 28 Chemoradiation was compared with radiotherapy alone in several phase III studies. In the first studies reported, the chemotherapy was used as a radiosensitizer in suboptimal doses. A survival benefit was seen in a study of 600 patients when radiotherapy given in a dose of 60 Gy was compared with the same dose of radiotherapy in combination with bolus injections of 5-FU. -'9 Similar results were seen by Browman et al. ~° when conventional radiotherapy was compared to radiotherapy and two concurrent 72-h 5-FU infusions. Other single agents in combination with radiotherapy have shown a survival benefit in some studies, but not in others. A randomized trial of cisplatin 20 mg/m2/week given in combination with concurrent radiotherapy in 319 patients with non-resectable disease, showed no survival benefit over radiotherapy alone. However, the total dose of cisplatin was only 140 mg/m2? ~ To explore the influence of a higher total dose ofcisplatin, several studies have been initiated. A phase Iii randomized s t u d y , o f hyperfractionated radiotherapy with or without two courses of simultaneous cisplatin for patients with locally moderately advanced and advanced HNC has been initiated by the Swiss Institute for Applied Cancer Research (SWS-SAKK-10/94, EU-94039). For the hyperfractionated external-beam irradiation (twicea-day fractionation up to 66Gy) use is made of photon energies of 4-6 MV or electrons of 6-12 MV (interstitial brachytherapy boost to lesions of the oral cavity is allowed) and this is followed in both arms of the study, if indicated, by surgery with resection of the primary tumour or involved nodes. At least 400 patients will need to be accrued and an interim analyses will be performed to allow early stopping after entry of 50 and 100 patients. The objectives of this trial are to assess the time to treatment failure (local and regional) in patients with moderately advanced and advanced SCCHN (no distant metastases) when treated with hyperfractionated radiotherapy with or without two courses of simultaneously administered cisplatin (20 mg/m2/day the first and the fifth week of radiation); to assess the time to distant metastatic relapse, overall survival, and toxicity; and to evaluate whether the potential tumourdoubling time is an indicator for risk of treatment failure. Several studies have been initiated within the EORTC Radiotherapy group and the EORTC-HNCCG. The first is a randomized phase III study of post-operative radiotherapy with or without cisplatin for patients with locally advanced HNC (EORTC-22931). This is a study of the Radiotherapy group, jointly with the EORTC-H N CCG. Patients are randomized after surgery to post-operative radiotherapy only (66 Gy/33 fractions/6.5 weeks) or postoperative radiotherapy (same fractions, same dose) plus cisplatin 100 mg/m 2 for three courses. , The main endpoint of the study is disease-free survival. Patients eligible for this study are those with histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or the larynx, with the following stages: T3-4, any N, M0 (except T3N0 of the larynx with sufficient safety margins) or any T, N2-3, M0 disease resected with curative intent. In case of T<3 and N<2 at

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least one of the following conditions need to be present: histopathologically positive surgical margins, peri-neural involvement, extranodal spread, oral cavity or oropharyngeal tumours with metastatic nodes at level four or five, or vascular embolism in the neck. The total number of patients required for the study is 338. The second EORTC trial on concomitan,t radiotherapy and chemotherapy is one of the larynx preservation trials (EORTC-22954), again a joint venture of the Radiotherapy group and the EORTC-HNCCG. The two treatment arms consist of radiotherapy alone or concomitant chemo- and radiotherapy. Within both treatment arms, patients may receive either conventional radiotherapy in single daily fractions, 5 days per week for 7 weeks, or hyperfractionated radiotherapy in two daily fractions, 5 days per week for 7 weeks, according to institutional policy. Use is being made of two options with respect to the time of evaluation, i.e. either after 50 Gy or after completion of radiotherapy (70 Gy). Patients assigned to the chemoradiation arm will receive three doses of cisplatin 100mg/m 2 once every 3 weeks, beginning on day I of radiotherapy. A total of 428 events will be required to detect an increase of 10% (that is from 35% with radiotherapy alone to 45% with the combined approach) with a two-sided type I error of 0.05 and a power of 80%. For such a trial 282 patients need to be randomized per treatment arm. Endpoints of the trial are, apart from laryngeal preservation, disease-free survival, quality of life and determination of the cost-benefit ratio. Major eligibility criteria are: (I) resectable T3 and T4 larynx and T2, T3 and T4 hypopharynx carcinomas, with N0-2 or unilateral N3; (2) WHO performance status 0, 1 and 2; and (3) no prior therapy. A third phase Ili trial investigates and compares conventional vs hyperfractionated radiotherapy in SCCHN with or without concomitant chemotherapy (EORTC22962). The chemotherapy in this trial is the same as in the previously discussed trials, i.e. cisplatin 100mg/m 2 on day 1, day 22 and day 43. The objectives of this trial are two-fold, i.e. (I) to assess whether there is an improved progression-free survival with hyperfractionated radiotherapy; and (2) whether the concomitant use of cisplatin with any of the two forms of radiotherapy (hyperfractionated or conventionally fractionated) leads to an improvement of progression-free survival. Eligible patients should have histologically confirmed squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx. The following stages of disease are permitted: stage II, III or IV (T2-4, any N, M0) for tumours in the oral cavity and oropharynx; stage II, III or IV of the larynx and hypopharynx (T2, any N, M0; T3-4, any N, M0) excluded from EORTC trials 22954 and 24954; or stage II, 11I or IV (T2--4, any N, M0) for centres not participating in EORTC trials 22954 and 24954. The NCI of the USA is sponsoring a phase 1II trial of post-operative radiotherapy with or without cisplatin for resectable high-risk SCCHN. Included in this trial are patients with a squamous cell carcinoma of the hypopharynx, the larynx, the oral cavity and the oropharynx. They should haveat least one of the following high-risk factors: histological extracapsular nodal extension, histological involvement of two or more regional lymph

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CIh+ical trials

nodes and/or microscopically positive mucosal margins. Complete resection of all visible and palpable disease is necessary and post-operative treatment should start within 8 weeks. Patients are randomized to involved-field irradiation using Co60, I-6 MV photons, or electrons and radiotherapy plus cisplatin. A total of 438 patients will be entered to evaluate loco-regional control rates, patterns of first failure, and overall and disease-free survival. The Radiotherapy Oncological group (RTOG) is performing a randomized phase Ill trial to study postoperative radiotherapy with or without concomitant cisplatin in patients with untreated resectable high-risk HNC. Patients should have biopsy-proven squamous cell carcinoma of the hypopharynx, larynx, oral cavity and oropharynx with at least one of the following high-risk factors: histological extracapsular nodal extension, histological involvement of two or more regional lymph nodes and microscopically positive mucosal margins. Complete resection of all visible and palpable disease is necessary. Neck dissection is not required for T4,N0 and truly midline supraglottic tumours. Exclusion criteria are tumours of the lip, nasopharynx, sinuses, synchronous or concurrent head and neck turnouts or evidence of distant metastasis. Therapy should start within 8 weeks of surgery. Patients are randomized to involved-field irradiation using Co60, I-6 MV photons, or electrons or irradiation and cisplatin. The objectives of this study are to evaluate locoregional control rates, patterns of first failure, and overall and disease-free survival in patients with advanced SCCHN at ,high risk of Ioco-regional recurrence who are treated post-operatively with concurrent cisplatin and radiotherapy, and to compare the toxicity of concurrent chemoradiotherapy vs radiotherapy alone in the postoperative setting. Four hundred and thirty-eight patients will be entered. The Yale Comprehensive Cancer Center is organizing a randomized study of mitomycin C vs porfiromycin as an adjunct to radiotherapy for SCCHN. Eligible patients are those with epidermoid carcinoma of the naso-, oro- and hypopharynx, larynx, oral cavity and those with epidermoid carcinomas of unknown primary origin and positive neck nodes. All patients must have stage 1-IV or recurrent disease, but no distant metastases. Patients with a carcinoma of the true vocal cord or other condition with greater than 90% probability of cure are excluded. Prior therapy is allowed, but with some restrictions, i.e. the interval since last chemotherapy should be at least 3 years and no prior radiotherapy is allowed to areas of current disease. Patients will receive irradiation to the involved neck sites by external-beam radiotherapy alone, brachytherapy alone (using permanent or removable radiation sources), or both plus mitomycin or porfiromycin. In order to compare the efficacy of both treatments, 200 patients will be entered in this study. Chemoradiation with the use of combination chemotherapy has been studied also with variable outcome in the past? 2"33An American NCI-sponsored phase lit trial examines standard radiotherapy vs standard radiotherapy plus cisplatin or split-course radiotherapy plus cisplatin/5FU in patients with non-resectable stage III/IV SCCHN. Patients should have biopsy-proven measurable or evaluable

squamous cell carcinoma or undifl'erentiated carcinoma of the oral cavity, base of tongue, tonsil area, larynx or hypopharynx and deemed non-resectable according to strictly specified criteria. Patients whose disease becomes potentially curatively resectable will undergo surgery. The surgical procedure is total resection of residual tumour with, if indicated, neck dissection. Patients in arm I are treated with standard irradiation of the primary tumour and neck using Co60 equipment or linear accelerators with energies no greater than 6 MeV and (if indicated) electron boosts. In arm II they receive standard irradiation as in arm I plus cisplatin. In arm I11 the treatment is a split-course radiotherapy of the primary tumour and neck using equipment as in arm I plus cisplatin and 5-FU. The objectives of this trial are: (I) to compare the efficacy of the three arms in terms of complete response rate, time to treatment failure, and overall survival; and (2) to compare the relative toxic effects of these three treatment arms. In addition, a comparison will be made with respect to the pattern of relapse or treatment failure among these regions, and an assessment of the role, timing and success of surgical resection will be made in patients achieving a response to non-operative therapy. A total of 420 eligible patients will be entered. The Institute Gustave Roussy has initiated several trials with accelerated radiotherapy in the past (see above). The same accelerated radiotherapy programme is also compared to accelerated radiotherapy combined with concomitant high dose cisplatin/5-FU in patients with advanced SCCHN, with a high risk of distant metastases (inoperable N2-3). Two trials are studying the concomitant use ofcarboplatin/ 5-FU and radiotherapy vs radiotherapy alone; one in France with conventional radiotherapy and one in Italy using hyperfractionated radiotherapy. Trials addressing the timh+g o f chemotherapy The optimal integration of the different treatment modalities in the primary therapy of HNC patients is still unclear, in particular with respect to the optimal timing of chemotherapy. Therefore, comparative trials evaluating different chemotherapy-containing strategies are of interest. A randomized comparison of neoadjuvant cisplatin and 5FU infusion followed by radiotherapy vs concurrent chemoand radiotherapy in advanced HNC was reported by Taylor et al. ~ TlTree cycles of combination chemotherapy (CDDP 100mg/m-' on day I and 5-FU 1.0g/m" on days 1-5, q3 weeks x 3) were given before definite radiotherapy to 107 patients with non-resectable HNC and compared with 107 patients treated with seven cycles of biweekly cisplatin (60mg/m 2 day I) and 5-FU (800rag/m-' days I-5) concomitant with the radiotherapy. The survival duration was similar in both groups, although more patients died of cancer in the segmental treatment arm. The Cancer Research Campaign Clinical Trials Centre of the. University of London randomizes patients with advanced HNC to (I) radiotherapy alone vs (II) radiotherapy and concurrent chemotherapy vs (II1) radiotherapy plus subsequent chemotherapy vs (IV) radiotherapy plus concurrent and subsequent chemotherapy. The chemotherapy in this trial consists of

Clhffcal trials single agent methotrexate with leucovorin rescue or combination chemotherapy with vincristine, bleomycin, methotrexate and 5-FU (VBMF) with leucovorin rescue. The radiotherapy in this trial will be given according to one of two regimens (Manchester 3-week schedule or SECOG 6-week schedule) using megavoltage equipment. All patients included in this trial will have histologically confirmed SCCHN suitable for treatment with radiotherapy and defined as T2, T3 or T4 primary lesions, any N and no distant metastasis. Patients without prior surgery are randomized 1:2 to arms I:II-IV, while those with prior surgery are randomized I:1 between arms I and I1 only. The trial will determine whether the addition of single agent methotrexate or VBMF to radiotherapy for advanced SCCHN (with or without primary surgery) influences Iocoregional control and prolongs survival; whether an effect on Ioco-regional control or survival is apparent when chemotherapy is given during or following radiotherapy and whether it is increased when chemotherapy is given at both times. In a separate randomization of patients with cancer of the oral cavity or oropharynx, the influence of neck irradiation on the improvement of Ioco-regional control and survival will be studied. It is anticipated that a total of 1000 patients will be entered in this trial. The EORTC has initiated a phase III randomized study of sequential vs alternating cisplatin/5-FU and radiotherapy for larynx preservation in resectable cancers of the hypopharyx and the larynx (EORTC-24954). Included in this trial are patients with stage l/l/IV (T3-4, N0-N2b, M0) cancr of the glottic or supraglottic larynx and stage II/III/IV (T2-4, N0-N2b, M0) cancer of the pyriform sinus or of the hypopharyngeal aspect of the aryepiglottic fold (with or without extension to the postcricoid area). Massive destruction of the thyroid cartilage or continuity between the primary tumour and a lymph node are exclusion criteria. They are randomly assigned to sequential chemotherapy and radiotherapy or to alternating chemotherapy and radiotherapy. Patients in the sequential arm ( =control arm) receive two to four cycles ofcisplatin and infusional 5-FU as described earlier by the same group 8 followed by radiotherapy (70 Gy/35 fractions/ 7 weeks). Patients with stable or progressive disease on day 42 proceed immediately to surgery with or without postoperative radiotherapy. Patients with a complete or partial response on day 42 receive two additional courses of chemotherapy, followed by 7 weeks of radiotherapy beginning on day 80. Following radiotherapy, patients with a complete remission enter follow-up; those with a partial remission proceed to surgery. Patients in the experimental arm (alternating chemoradiotherapy) also receive cisplatin and 5-FU but according to the Merlano approach. -'7 However, there are two options: the first option is a full 10-week programme wi~h response evaluation 2 months later; the second option has an inbetween evaluation on day 42. Patients with progressive or stable disease at that time undergo surgery, those with a complete or partial response proceed with the full programme and are treated according to treatment option I. Endpoints of the study are disease-free survival, laryngeal preservation, quality of life and cost-benefit ratio. For these

483

objectives 564 patients are required (282 by treatment arm'), which, it is hoped, will be accomplished in the following years.

Recurrent, locally advanced and metastatic disease Sixty per cent of patients with HNC will relapse after primary treatment. Distant metastases develop in 5-25% of patients and second primary tumours will develop in 20-40% of them. The optimal treatment of patients with local recurrence or metastatic disease is not known. Local recurrence may be salvaged by surgery. In addition, a recent phase I1 study reported long-term survival in some patients retreated with irradiation in combination with chemotherapy. 3s The impact of chemotherapy in patients with recurrent or metastatic disease has not been evaluated vs best supportive care. Therefore, the EORTC-HNCC has tried to set up such a trial whereby best supportive care with or without weekly methotrexate was studied in these patients (EORTC24941). T h e endpoints of this trial were quality of life and survival. Major eligibility criteria were histologically/ cytologically proven SCCHN (naso-, oro-, hypop.harynx, larynx, oral cavity and maxillary sinus) either progressing after primary therapy and no longer suitable for local therapy or with distant metastases, WHO performance status 0, 1 or 2, no prior chemotherapy, no prior radiotherapy within 4 weeks before entry, no CNS metastases and no third space fluids. Unfortunately, this study had to be stopped early because of insufficient accrual. The study proved to be not feasible. A pharmaceutical-sponsored (Matrix Pharmaceutical) phase III study examines, in a double-blind design, the effect of intratumoral cisplatin/epinephrine injectable gel (CDDP-e TI) vs placebo for recurrent or refractory SCCHN. Patients for this trial should have histologically confirmed SCCHN that is recurrent or refractory following at least one course of therapy. Primary or metastatic tumours involving skin, nodes (palpable and biopsy-proven), subcutaneous tissue or muscle are all allowed. No involvement of a major artery or any visceral organ is permitted and the measurable lesions should be accessible for direct intratumoral injection with no immediate risk of haemorrhage or embolization. No fibrotic lesions (e.g. previously irradiated lesion with no subsequent disease progression) will be included. An interval of more than 28 days since any antineoplastic therapy or therapy with investigational agents and full recovery from side-effects of prior treatment are additional inclusion criteria. Treatments in both arms are given intratumorally every week for 6 weeks. Endpoints are effect on total local tumour volume, time to response and time to progression for the most 'troublesome' tumour lesions. In addition, the improvement in or stabilization of quality of life in these patients as measured by the FACT-H&N questionnaire is evaluated. Up to 120 patients will be studied to provide 80 evaluable patients on the experimental arm and 40 evaluable patients on the control arm (2:1 randomization). Another randomized study sponsored by the NCI in the USA compares the efficacy and toxicity of 3-h paclitaxel plus cisplatin vs 96-h 5-FU plus cisplatin in patients with

484

Clinical trials

advanced HNC. The entry is limited to patients with histologically confirmed SCCHN considered incurable by surgery or radiotherapy, newly diagnosed extensive Iocoregional disease or distant metastases, Ioco-regionally recurrent or persistent disease, or distant metastases occurring after initial surgery or radiotherapy. Patients should have measurable or evaluable disease and documentation of progressive disease or biopsy-proven residual carcinoma is required if the sole measurable lesion is in a previously irradiated site. No prior chemotherapy for recurrent disease is allowed and a period of at least 12 months since induction or neoadjuvant chemotherapy with paclitaxel or 5-FU (6 months since cisplatin) is necessary. They should have recovered from major surgery. The chemotherapy regimens in both arms are given every 3 weeks until disease progression or unacceptable toxicity, whichever comes first. However, when complete response is reached~t least two more courses will be given (a minimum of six courses). Patients with stable disease may continue treatment after six courses. Endpoints of the study are overall survival at 1 year, response rate, toxicity, and quality-of-life. A total of 212 patients will be accrued. An important study of the EORTC-HNCCG (EORTC 24922) compares two administration schedules of singleagent paclitaxel (3-h and 24-h infusion given at 175 mg/m-" every 3 weeks) with weekly methotrexate (40-60 mg/m~). This is done in a randomized phase 11 setting in patients with advanced or recurrent HNC in order to select the most feasible direct phase 111 comparison. In the phase II1 setting antitumour activity and the toxicity of both agents will be compared.

Chemoprevention Chemoprevention studies determine the influence of interventions on the reversal of pre-cancerous lesions, the reduction of secondary cancers in patients successfully treated for HNC and prevention of developing a primary tumour in high-risk populations. To determine the role of different d r u g s on the development of secondary cancers, several phase II1 studies are under way. An NCI cooperative group programme (USA) studies in a double-blind randomized design the influence of low-dose isotretinoin (13-Cis-Retinoid Acid (13-CRA)) daily for 3 years on the prevention of second primaries in 1080 patients with totally resected stage I/I1 SCCHN. Between 75 and 200 patients are entered annually to determine the efficacy of 13-CRA in preventing dysplastic changes and second malignancies in this patient group. The study compares the time to diagnosis of a second primary and survival between patients treated with 13-CRA vs placebo and determines the cost-benefit ratio for 13-CRA by assessing the toxic effects experienced in patients treated with 13-CRA vs those treated with placebo. Patients have histologically confirmed SCCHN (oral cavity, oropharynx, and larynx, T1-2,N0,M0 and hypopharynx, TINOM0) rendered disease-free following

primary surgery and/or radiotherapy. Patients must have no prior biological, endocrine or chemotherapy and surgical resection, or radiotherapy must have been completed within 2 years prior to randomization. The EORTC has completed a phase Ill randomized comparison of the influence of chemoprevention with vitamin A and/or N-acetylcysteine or no treatment on the development and detection of second primary cancers in patients curatively treated for oral, laryngeal and lung cancer (EUROSCAN). This study started in 1988, accrual ended in 1994 and intervention ended in August 1996. Two thousand, five hundred and ninety-two patients were entered (1566 treated for HNC, 1026 for lung cancer) to compare the frequency and time to occurrence of second primary tumours after random assignment to treatment with vitamin A (retinol palmitate) or N-acetylcysteine, both drugs or no drugs. HNC patients included had curatively treated tumours of the upper aerodigestive tract defined as carcinoma in situ of the larynx, invasive squamous cell carcinoma of the larynx stage (TI-3, N0-1, M0) or invasive squamous cell carcinoma of the oral cavity (T1-2, N0-1, M0). No results have been reported as yet.

Conclusions The ongoing trials will give answers to important questions of the three modalities involved in the treatment of patients with HNC. The place of lymph node dissection of the neck in patients with oral cancer will be determined. The importance of fractionated or accelerated radiotherapy compared with conventional radiotherapy will be further determined and the value of different biological markers to differentiate patients who will benefit from a more intensive radiotherapy will become clear. Also the role of different supportive treatments to reduce or overcome side-effects due to radiotherapy will be determined. Different chemotherapeutic approaches combined with radiotherapy in operable or locally advanced inoperable disease are being investigated and will perhaps define which combined approach is the optimal one for different patient categories. Finally, the results of chemotherapy in recurrent and metastatic disease is still extremely disappointing. Weekly methotrexate remains the drug of choice against which n~wer drugs should be compared. The role of chemoprevention is still under investigation, and final answers are awaited.

Acknowledgement The authors would like to thank E. Feigal and J. Bernier for their contribution.

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