Chemotherapy has often been combined with radiotherapy and/or surgery in the treatment of patients with advanced head and neck cancer in an attempt to improve locoregional control, decrease distant metastasis, and increase survival. Recently, induction chemotherapy has been used in the selection of patients with advanced resectable carcinoma of the larynx and hypopharynx for organ preservation.[1,2] Patients who achieve complete or partial responses to chemotherapy are candidates for organ preservation with subsequent radiotherapy.
The rationale for combining chemotherapy and radiotherapy has been reviewed previously. Chemotherapy may sterilize micrometastases outside of the radiation field, sensitize tumor cells to radiation, inhibit repair of sublethal and potentially lethal radiation damage, and decrease tumor mass, thus increasing tumor reoxygenation and radiosensitivity. Chemotherapy may also perturb cell kinetics, increasing the proportion of cells in the sensitive cell-cycle phase and proliferative state. Some drugs, such as mitomycin (Mutamycin), may preferentially kill hypoxic cells, which are more resistant to radiotherapy. Chemotherapy may also inhibit tumor repopulation during fractionated radiotherapy.
On the other hand, radiotherapy may decrease tumor mass, leading to improved blood supply and improved drug delivery and uptake. Decreased tumor mass may also lead to increased tumor proliferation and chemosensitivity. In addition, radiotherapy may inhibit the repair of drug damage.
Finally, both chemotherapy and radiotherapy can induce apoptosis. It is possible that chemotherapy may enhance radiation-induced apoptosis and that radiation may enhance chemotherapy-induced apoptosis.
When chemotherapy is combined with radiotherapy and/or surgery, it has been given as: (1) induction or neoadjuvant chemotherapy before surgery and/or radiotherapy, (2) a radiation enhancer concurrent with or alternating with radiotherapy, or (3) adjuvant therapy following primary surgery and/or radiotherapy. This paper presents an overview of the results of randomized trials of combined-modality therapy for advanced head and neck cancer.
Induction chemotherapy has been used prior to locoregional treatment for both operable and inoperable head and neck cancer. At least 10 randomized trials of induction chemotherapy for advanced operable head and neck cancer have been conducted (Table 1). [1,2,6-14] In most of these trials, the chemotherapeutic regimen consisted of a combination of drugs, such as cis-platin (Platinol), fluorouracil (5-FU), bleomycin (Blenoxane), methotrexate, and vincristine. The combination of infusional 5-FU and cisplatin or carboplatin (Paraplatin) has been the most common regimen used in recent trials.
Response rates to induction chemotherapy ranged from 37% to 98%, and complete response rates varied from 5% to 54%, depending on the drug regimen and the number of cycles of drugs administered. Despite high response rates to induction chemotherapy, no significant improvements in locoregional control or survival were observed.
There have been at least 14 randomized trials in which induction chemotherapy was used in patients with operable and/or inoperable head and neck cancer, including nasopharyngeal carcinoma.[15-28] Response rates to induction chemotherapy varied from 21% to 91%, with complete response rates ranging from 0% to 46%. Although response to induction chemotherapy appeared to predict the efficacy of subsequent radiotherapy, there was no demonstrable benefit in locoregional control or survival with induction chemotherapy.
None of the trials showed a significant difference in survival between the standard-treatment and induction-chemotherapy groups. Although one trial showed an improved 5-year survival in patients who received intra-arterial methotrexate prior to radiotherapy compared to radiotherapy alone, subset analysis showed that the difference was statistically significant only for those with stage II oral cavity tumors.
Another trial by Paccagnella et al included patients with operable or inoperable disease. Although there were fewer distant metastases in the induction-chemotherapy group than in the control group, who received surgery and/or radiotherapy, there was no difference in locoregional failure, disease-free survival, or overall survival. Subset analysis showed that induction chemotherapy improved local control and overall survival in patients with inoperable disease but not those with operable disease. However, the overall 2-year survival rate was poor in both treatment arms for patients with inoperable disease (10% in the control arm and 24% in the induction-chemotherapy arm).
The results of the combined-treatment arm in this trial are no better than those with radiotherapy alone reported in the literature. Thus, based on this trial, one cannot conclude that induction chemotherapy improves the survival of patients with inoperable head and neck cancer.
Some of the induction chemotherapy trials have been criticized on a number of grounds. These include: (1) small number of patients, (2) patient and tumor heterogeneity, (3) use of ineffective drugs and drug combinations, (4) suboptimal drug dose and/or schedule, (5) variable standard treatment in the control arm, (6) delay of standard treatment in nonresponders, and (7) poor patient compliance. Also, the high incidence of intercurrent deaths and second cancers in this patient population makes it difficult to demonstrate a survival benefit, if any exists.
Selection of Patients for Organ Preservation
Although induction chemotherapy does not improve survival, it may be useful in the selection of patients who can undergo organ preservation with subsequent radiotherapy.[1,2,11] This treatment strategy was studied in a trial conducted by the Veterans Affairs Laryngeal Cancer Study Group (VALCS), which included patients with operable stage III or IV laryngeal cancer,[1,11] and a European Organization for Research and Treatment of Cancer (EORTC) trial, which included patients with operable stage T2-4, N0-2b squamous cell carcinoma of the pyriform sinus and aryepiglottic fold.
The study design of the two trials was similar: Eligible patients were randomized to receive either surgery followed by postoperative radiotherapy or induction chemotherapy with cisplatin and 5-FU infusion. In the VALCS trial, after two cycles of induction chemotherapy, the partial or complete responders received an additional cycle of chemotherapy followed by definitive radiotherapy. Those with residual or recurrent disease after completion of radiotherapy underwent surgery for salvage. Patients who showed no response or whose disease progressed after two cycles of induction chemotherapy were treated with salvage surgery and postoperative radiotherapy. The EORTC trial differed from the VALCS trial in that only patients who had a complete response in the primary tumor after three cycles of induction chemotherapy were treated with radiotherapy; the remaining patients underwent surgery.
Neither trial showed a significant difference in overall survival between the induction-chemotherapy and standard-treatment arms. Disease-free survival was lower in the induction-chemotherapy arm in the VALCS trial but not in the EORTC trial. Distant metastasis was significantly reduced in the induction-chemotherapy group in the EORTC trial. In the VALCS trial, although distant metastasis as a first site of relapse was reduced in the induction-chemotherapy arm, the overall incidence of distant metastasis was similar in both arms.
The percentages of patients in the induction-chemotherapy arm who underwent laryngectomy because of lack of response or for salvage after radiotherapy were 38% at 4 years in the VALCS trial and 43% in the EORTC trial. In the VALCS trial, 31% of the 166 patients in the induction-chemotherapy arm were alive with a functioning larynx at 4 years. In the EORTC trial, for the 100 patients randomized to the induction-chemotherapy arm, estimated rates of survival with a functioning larynx were 28% at 3 years and 17% at 5 years. No increase in morbidity or complications of surgery or radiotherapy was observed following induction chemotherapy in either trial.
The results of these two trials suggest that induction chemotherapy followed by definitive radiotherapy in chemotherapy responders is an alternative treatment option for patients with locally advanced, resectable squamous cell carcinoma of the larynx or hypopharynx who desire organ function preservation.
Ongoing Intergroup Phase III Trial of Larynx Preservation
However, induction chemotherapy can be toxic and costly, and it is not known whether similar or better results can be achieved with concurrent chemotherapy and radiotherapy or radiotherapy alone. To address this issue, the Head and Neck Intergroup is conducting a phase III trial in which patients with operable T2, T3, or early T4 squamous cell carcinoma of the glottis or supraglottic larynx are randomized to receive: (1) induction chemotherapy followed by radiotherapy in the responders or salvage surgery and radiotherapy in the nonresponders, (2) radiotherapy and concurrent cisplatin chemotherapy, or (3) radiotherapy alone. The induction chemotherapy regimen is the same as that used in the VALCS trial. In the concurrent radiotherapy and chemotherapy arm, cisplatin is given at a dose of 100 mg/m2 every 3 weeks during radiotherapy. The radiotherapy regimen is the same in all three arms: 70 Gy in 35 fractions over 7 weeks.
This ongoing trial is targeted to accrue 546 patients. In addition to survival with preservation of the larynx, quality of life will also be prospectively assessed as a treatment end point. Results of this trial should determine the relative efficacy of induction vs concurrent chemotherapy and radiotherapy vs radiotherapy alone for larynx preservation in patients with advanced, operable carcinoma of the larynx.
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