Chemoradiotherapy

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The use of primary chemotherapy with radiation therapy in the treatment of selected head and neck cancers is an exciting and rapidly evolving area of oncologic research with substantial information available from preliminary clinical results. The goals of combining these two treatment modalities are: (1) increase locoregional control (chemotherapy acts as a radiosensitizer and has direct cytotoxic effects on the tumor in addition to the effect of the radiation),

(2) decreases distant metastasis (chemotherapeutic eradication of systemic microscopic disease), and

(3) improves survival (increased locoregional control and decreased metastases).

There are 4 categories of sequencing chemotherapy and radiation therapy: (1) induction (neoadju-vant) chemotherapy, (2) concurrent chemotherapy and radiation therapy, (3) alternating chemotherapy and radiation therapy, and (4) adjuvant chemotherapy.

In induction (neoadjuvant) chemotherapy, several cycles of drugs are given prior to initiation of radiation therapy. The chemotherapy frequently results in high response rates. However, there is no significant improvement in survival or in locore-gional control.133 It has been suggested that induction chemotherapy may cause a tumor to initially regress but also may result in the surviving tumor clonogens undergoing accelerated growth just as the radiation phase begins. This would result in a much more difficult group of tumor cells with which the radiation therapy must deal.

An important area of research in this category with significant clinical impact is the use of chemotherapy with radiation for organ preservation. The Department of Veterans Affairs Laryngeal Cancer Study Group72 data and the EORTC54 study of locally-advanced hypopharyngeal cancer are two major controlled, randomized studies supporting the use of neoadjuvant chemotherapy and radiation therapy as primary treatment for larynx preservation with total laryngectomy reserved for salvage.

Patients who have a complete response to induction chemotherapy have a better prognosis than those who have no response.134 Those who responded well to chemotherapy also tended to respond to radiation therapy. While severe and sometimes fatal toxicities occurred with chemotherapy, the morbidity of subsequent radiotherapy was not increased.135

Concurrent chemotherapy and radiation therapy requires that the drugs be given on days 1 and 22 with the radiation therapy. This approach has resulted in increased locoregional control, relapse-free survival and overall survival rates. There is a significantly increased acute radiation reaction, however. When more than one chemotherapeutic agent is used, the acute side effects are even worse. It is theorized that cells which have acquired resistance to radiation may be sensitive to it in the presence of chemotherapeutic drugs.136

Forastiere and colleagues61® reported on Inter-group Trial R91-11—a randomized study that evalu ated larynx preservation in the treatment of 510 patients with stage III and IV squamous cell carcinoma of the larynx. The 3 arms in this study included sequential cisplatin + 5FU and radiation therapy (control arm), concomitant cisplatin chemotherapy administered on day 1, 22, and 43 with radiation therapy, and radiation therapy alone to a dosage of 7000cGy (200cGy/fraction). 12% of patients in the concomitant arm versus 26% of patients in the sequential chemotherapy-radiation arm (control) and 31% of patients in the radiation treatment alone arm required a laryngectomy at 2 years. The time to laryngectomy was significantly improved with concomitant chemotherapy-radiation therapy. It was concluded that the standard for laynx preservation should be concomitant cisplatin chemotherapy and radiation therapy.

Alternating chemotherapy and radiotherapy sequences the drugs during the break in a split-course radiation therapy schedule. The data suggests that prolongation of the radiation therapy duration to twice the normal time of conventional fractionation does not adversely affect local control rates when aggressive cell cycle-specific drugs are given during the break intervals. Results show an improved complete response and median overall survival comparable to radiation therapy alone.136

Adjuvant chemotherapy regimens schedule the initiation of drugs after completion of the radiation therapy phase. This has shown no improvement in survival but there has been a decreased incidence in distant metastasis.

Overall, various studies suggest that the concomitant chemo-radiotherapy approach very well may result in superior locoregional control rates compared with the other sequencing schemes.61a Preliminary data also suggests that it may convey a survival advantage. However, the final answer is still forthcoming. The use of altered rather than conventional fractionation schemes in conjunction with chemotherapy also may enhance results and this approach is currently under active investigation. At this time, our practice at Memorial Sloan-Kettering Cancer Center is to use chemotherapy for larynx preservation in advanced T3 and T4 head and neck cancers where surgery would require a total laryn-gectomy. For patients with advanced nasopharyn-

geal carcinoma, cisplatin (administered on days 1 and 22) concurrent with accelerated fractionation with a concomitant boost to 7,000 cGy using intensity-modulated radiation therapy, and subsequent adjuvant cisplatin + 5-FU for 3 cycles is our standard approach. Patients with unresectable paranasal sinus tumors also are treated similarly. Active clinical investigation continues with the use of concurrent chemotherapy and radiation therapy for advanced unresectable lesions or in cases where the massive lesion may be technically resectable but associated with major functional sequelae.

TREATMENT PLANNING Simulation

The first step in setting-up the radiation fields involves simulation. This can be accomplished using either a fluoroscopically (two-dimensional treatment planning) or a CT (three-dimensional treatment planning) assisted approach. The tumor site, lymph nodes and adjacent tissues at risk are determined by the radiation oncologist at consultation.

The patient will initially have any visible, palpable and technically reachable lesion in the oral cavity or oropharynx marked by the implantation of gold seeds at strategic points along its perimeter for later radiographic visualization on the simulation films. Topical anesthetic is sprayed over the tumor region and a seed injector is employed to interstitially implant one or several gold seeds to an approximate depth of 1 cm. Direct pressure using sponges is applied to any areas of bleeding until controlled.

The patient is then placed in a supine position on the simulation table and properly adjusted using an appropriate head holder to position the head at the desired angle. A shoulder pull board is used to maximally bring the shoulders into a caudad position with the patient gripping straps that wrap around the soles of the feet. All incisional scars, strategic anatomic locations and masses are marked or outlined with appropriate material for later radiographic visualization.

A bite-block made of thermoplastic material with a lead wire placed in the longitudinal direction for later radiographic visualization is designed for those patients in whom it is desired to separate the hard palate region from the mandible to spare it from radiation. If dental guards are necessary, they should be placed into position. A thermoplastic face mask is then fabricated to firmly hold the head in proper position (Figure 21-14A).

If the patient will require conventional simulation with two-dimensional treatment planning (Figure 21-14B), then the process can begin using fluo-roscopy to determine the portal margins under the direction of the radiation oncologist. Simulation films are special radiographs with cross-hair wires marking the isocenter, delineator wires at the perimeter noting the portal margins, and graticule marks 2 cm apart creating a grid of dots approximately 3 mm in diameter which serve as reference markers. The films are evaluated and any changes are then made and repeat simulation films obtained until the setup has been approved by the radiation oncologist. Block positions are drawn on the films with a wax pencil and they will subsequently be fabricated into cer-robend blocks which will be mounted on the treatment unit head during therapy. Every effort is made to avoid irradiation of the larynx for oral cavity and oropharyngeal cancers by placing the inferior margin of the lateral portals above the thyroid notch. Therefore the larynx will be placed in the treatment vol ume of the adjacent low anterior neck portal and is completely blocked. This will also serve a dual role as a spinal cord junction block. However, if the larynx is in the treatment volume as is the case for lesions in the hypopharynx or larynx, a larynx compensator is created to make the dose more homogenous at that level, resulting in a decrease in the excessive dose to the true vocal cords. At the completion of the conventional simulation, Polaroid pictures are taken to show the patient setup. Tattoos are then strategically and discretely placed on the patient to delineate the setup reference points. The patient will then be scheduled to undergo beam films and initiation of treatment in the near future.

Patients with lesions in the nasopharynx, paranasal sinus, parotid gland and thyroid gland will require CT simulation in preparation for either three-dimensional conformal treatment planning or intensity-modulated radiation therapy treatment planning (Figure 21-15). After the initial preparation has been performed as previously presented, the patient will be moved to the CT simulation suite and repositioned. If IV contrast is required, then this will be administered using an apparatus that delivers the contrast slowly and continuously. CT cuts of 3 mm are obtained of the head and neck regions. Upon completion of the procedure, the radiation oncolo

Figure 21-14. A, Patient undergoing a fluoroscopically-assisted simulation with a customized face mask and bite block in place. B, Fluoro-scopically-assisted simulator which is used in conventional two-dimensional treatment planning techniques.
Figure 21-15. Computed tomography simulator which is used in 3DCRT and IMRT treatment planning.

gist determines the superior and inferior margins of the field on the CT images, which allows for the determination of the isocenter which is transferred to the patient by the use of tattoos for future setup reference points. The computerized data is then transferred to a treatment planning computer in the Division of Radiation Oncology Physics where contours of vital organs (eg, spinal cord, brain stem, optic nerves, optic chiasm, orbits) and the tumor region are digitized on the CT slices. At this time, the complex process of three-dimensional computerized treatment planning will begin.

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