Chemotherapy and Radiotherapy

Radiotherapy

Chemotherapy

Preoperative and postoperative radiation therapy

Preoperative chemotherapy

Chemotherapy and Radiation (Chemoradiotherapy)

Radiation Therapy

External Beam Radiation

External beam radiation therapy may be used alone in the treatment of oesophageal carcinoma but is not considered curative. For curative attempts, chemotherapy and/or surgery generally accompanies this technique. Used alone, there is a 5-10% 5 year survival. The rate may be low because of patient selection, many of these patients being unworthy of resection. The treatments have a low mortality and relieves oesophageal obstruction in most patients in 4-7 days. However, this relief of dysphagia is short lived and reoccurrence occurs in more than half of the cases within 6 months. Radiation therapy is contraindicated in the presence of a fistula or likely fistula formation. Radiation shrinks the tumour and often leads to fistula formation when the tumour has spread to the trachea or bronchus. 

The goal of radiation therapy is to bombard the cancerous tumour and its microscopic extensions and other local sites of metastases with radiation in an effort to destroy the cancer cells while not crossing the radiation threshold of normal adjacent cells. To make certain that local invasion has been adequately treated, the target includes a 5 cm margin on either side of the tumour. In addition to irradiating the tumour, lymph node stations are irradiated as well to treat possible metastatic disease. The supraclavicular and celiac lymph nodes are targets if the tumour is in either the upper or lower oesophagus respectively.

Normal structures are avoided if possible or care taken to not exceed the radiation limits of these structures. In the chest, the critical structures to avoid as much as possible are the lung, heart, spinal cord and bone marrow. Standard dosages have been calculated for each of these critical structures. A safe dose is the level where there is a 5% chance of developing a complication in 5 years. Limits of the entire lung are 1750 cGy or 4500 cGy for one third of the lung. The heart's tolerance is 4000 cGy and 6000 cGy for the entire and one third of the heart, respectively. The spinal cord is probably the most critical structure to avoid when developing a radiation plan for the oesophagus. Because the spinal cord lies just posterior to the oesophagus, the prone position is the position of choice in order to take advantage of gravity to maximize the distance between the spinal cord and the oesophagus. Radiation exposure to the spinal cord should rarely exceed 4000-4500 cGy. The bone marrow radiation threshold should not exceed 3000-4000. 

Therefore, because of the need to avoid specific sensitive structures in the chest, specific oblique fields must be used when administering the radiation. It is necessary then to be able to easily reproduce the set up during each treatment day. Typically, custom-molded casts or cradles are used to achieve immobilization and reproducibility. CT scans are used as a basis to set up the radiation field. The patient's planned radiation fields are determined and simulated films of the treatment parts are taken with barium contrast. CT scans are then taken of the oesophageal area while the patient is fixed in the pre-made immobilization device. Target volumes of each CT scan slide are determined and these scan slices are superimposed onto the simulator films. This allows calculation of the target volumes.

The dosage of radiation used depends upon several factors. One is the choice of treatment. Treatment can be given in a hyperfractionation (small fractions 2-3 times a day), accelerated fractionation (normal-sized fractions given more than once a day), or conventionally (normal-sized fractions (180-250 rads) once a day). The range is between 5000 cGy in 20 treatments over 4 weeks to 6600 cGy in 33 treatments over 7 weeks. Definitive radiotherapy such as this commonly results in a median survival of less than 12 months and 5 year survival of less than 20%.¹³³ Chemotherapy is often used one to two weeks after treatment is initiated. This is when there is a loss of the epithelial layer of the oesophagus. The tumour begins to be affected two to three weeks into the treatment.

As mentioned before, radiation without the addition of surgery or chemotherapy is not typically implemented because of the attempt to achieve better results. A 1980 review article summarizing the results of 8500 cases of radiation alone placed the 5 year survival rate at 5%. However, regardless of treatment, long-term survival is dependent upon stage. Five year survival of patients with early disease treated with radiation alone can reach 14%.

Radiation carries with it little long term complications and a very low death rate due to complications of the treatment. Some of the complications seen are pneumonitis, pericarditis, myocarditis, stricture (40%), fistula formation, or spinal cord damage.

Intracavitary Radiation (Intraluminal Brachytherapy)

Intracavitary radiation is a technique that involves implanting a radiation source in or around the tumour. The radioactive source then delivers about 1000 cGy doses approximately 1-1.5 cm in diameter in or around the tumour. The tumour must therefore be quite small in order for this technique to work. It is used most often as a boost before or after external beam radiation therapy. Once external beam radiation therapy has shrunk the tumour to a desirable mass for intracavitary radiation, it is useful because it can deliver a cancercidal dose to cancerous cells without further radiating the spinal cord or lungs. Contraindications include stenosis, fistula, or deep ulceration. 

In one study, high dose radiation boost therapy (HDRBT) of 12 Gy in 2 fractions for one week was implemented one week after the completion of 6 weeks of 60 Gy in 30 fractions over 6 weeks. Complications included ulceration (28%), stricture (10%) and fistula (4%). Fistulas proved to be fatal complications. The overall 5 year survival rates of stage I and II cancers was 18%; there were no survivors of stage III and IV.

Chemotherapy

As a single modality, chemotherapeutic agents have a clinical response rate, or percentage of patients with a >50% reduction in the size of tumour, of 6-42% depending on the drug used and is not effective for combating local-regional disease. It is used more commonly in conjunction with radiation and/or surgery. Chemotherapy is used preoperatively alone or combined with radiation to treat micrometastases and to reduce the size of the tumour in order to improve resectability rates. Also, if surgery is not an option, it is used with radiation to palliate and possibly improve survival.

Chemotherapy is typically given in a combination of two or more chemotherapy drugs. The most prescribed drug is cisplatin. It has been most commonly combined with 5-fluorouracil (5-FU), vindesine, or bleomycin. Cisplatin and 5-FU is the most commonly prescribed combination in clinical trials. Cisplatin was used regularly in combination with bleomycin in the past, however, because of the pulmonary toxicity caused by bleomycin, trials have been discontinued. Paclitaxel, which is beginning to be tested with cisplatin and cisplatin based compounds, and vinorelbine are the newest chemotherapuetic drugs.

Chemotheraputic agents fall into five descriptive categories based on activities, source, and resultant toxicities:

1) Antibiotics include bleomycin, mitomycin, idarubicin and amonafide, deoxorubicin (Adriamycin) and methotrexate. The antibiotics' side effects include pulmonary toxicity such as fibrosis and decreased carbon monoxide diffusing capacity.

2) Antimetabolites include 5-fluorouracil, methotrexate, dichloromethotrexate, aminothidiazole, and trimetrexate. Toxicity to the gastrointestinal mucosa and bone marrow increases with the dosage.

3) Cisplatin and carboplatin are heavy metals whose dosage related and potentially reversible side effects include nephrotoxicity, ototoxicity, and peripheral neuropathy.

4) Plant alkaloids are vindesine, etoposide, taxol, and navelbine. They may cause myelosuppression, hypersensitivity reactions, cardiac arrhythmias.

5) Ifosphamide is in the alkylating agent group. Other general side effects of chemotherapy agents include nausea, vomiting, alopecia (loss of hair), stomatitis and diarrhea.

Combined modalities 

Preoperative and postoperative radiation therapy

The goal of preoperative radiation therapy is to reduce the tumour size, control the amount of local spread of the tumour before surgery, and reduce the risk tumour spread at the time of surgical manipulation. Despite 60-70% response rates, preoperative radiotherapy alone does not significantly improve the 5 year survival. Dosage has ranged from 3300-6000 cGy and 5 year survival has ranged between 10-25%. Although the results of these randomised trials suggest that radiation before surgery offers little benefit, many physicians are convinced of its advantages and further investigation is necessary.

The goal of postoperative radiation therapy is to destroy residual malignant cells after surgical resection. Surgical handling of the tumour and adjacent tissues will cause a seeding of the tumour. Postoperative radiation may control this unwanted occurrence. The most used situation of this type of therapy is if positive tumour margins are discovered after resection. These margins can be labelled with clips at the time of surgery and radiotherapy can be directed precisely at this location. There is no proof of the benefits of postoperative radiotherapy.

Table 1 Preoperative Radiotherapy

*: total number of patients in both groups
**: () indicate number of patients resected

med: median
preop: preoperative;
postop: postoperative

Table 2 Postoperative Radiotherapy

*: total number of patients in both groups

med: median
preop: preoperative;
postop: postoperative

Preoperative chemotherapy

The goals of preoperative chemotherapy are the same as those for preoperative radiation therapy; to reduce the size of the tumour, to improve resectability, and to decrease surgical seeding. Patients appear to respond very well to chemotherapy. The partial or complete response rate is high. Between 40-60% show a partial or complete response. After resection, between 50-80% of the tumour show negative margins. Furthermore, studies show that preoperative chemotherapy does not seem to increase surgical morbidity. However, less than 5% of patients have a histologic complete response (no viable tumour in the resected oesophagus). Despite the positive effects of treatment before surgery, median survival is only about 10 months, ranging from 8-23 months.

Treatment regimens typically include the use of more than one drug. Cisplatin based therapy is used in most trials. The most widely used therapy regimen is cisplatin given on day one and infusional 5- fluorouracil administered for 4-5 days. In addition, vindesine, bleomycin, mitoguazone, etoposide, or deoxorubicin are also used with cisplatin in varying combinations. The dosage of cisplatin in combination with other drugs is about 3 mg/kg or 100 mg/m2 on one day of the week. 5-FU is usually given in dosages of 900-1000 mg/m2 via continuous intravenous infusion (C.I.V.I.) on days 1-4 or 1-5. Vindesine is typically given in the same dosage as cisplatin. Bleomycin is administered at 10 mg/m2 on day 3 and 10 mg/m2 C.I.V.I. on days 3-6. In most studies 1-2 cycles of chemotherapy are given preoperatively.

Unfortunately, there is no significant increase in the survival of patients undergoing preoperative chemotherapy compared with surgery alone. Although patients that respond to chemotherapy have better survival, only 45-64% show response, and very few patients experience a complete histologic response. As is the case with preoperative radiation, there have been few large randomised trials evaluating the technique of preoperative chemotherapy. The utility, dosages and duration of the protocol is still considered to be in the investigative stages.

Table 3 Preoperative Chemotherapy

(): # of patients underwent surgery
±: randomized phase III trial
**: () indicate the number of patients resected

preop: preoperative;
rad: radiation;
med: median;
mo: months;
CP: cisplatin;
VD: vindesine;
BM: bleomycin;
5-FU: 5-fluorouracil;
EP: etoposide;
DR: doxorubicin;
MC: mitomycin C;
VB: vinblastine

Chemotherapy and Radiation (Chemoradiotherapy)

Chemotherapy with and without surgery is still under investigation. Results of this regimen have had higher success rates than either preoperative chemotherapy, preoperative radiation, or surgery alone.

Chemoradiotherapy uses three approaches to fight oesophageal cancer. Typically the cancer begins in the oesophagus as a tumour and spreads to the regional structures and lymph nodes. If the disease is advanced, distant metastasis has occurred. The rationale of a trimodality treatment is logical. Radiation and surgical resection aim at destroying the cancer at the local-regional level. Systemic treatment, like chemotherapy, fights the malignancy on a local-regional and systemic level.

The three most common chemotheraputic drugs used with radiation are 5-fluorouracil (5-FU), cisplatin, and mitomycin. These drugs have also been found to enhance the body's sensitivity to radiation. More than one combination is used in this approach. Chemotherapy has included the use of fluorouracil in weeks 1 and 6 (900-1000 mg per square meter of body weight daily, for five days) and cisplatin (75 mg per square meter of body-surface area on day 7). Fluorouracil has also been used in combination with mitomycin C or with mitomycin C, methotrexate, and cisplatin. The radiotherapy portion of the preoperative treatment includes a dose of about 50-60 Gy if no surgery is to follow or 25-45 if an eosphagectomy is to be performed. These doses are typically administered in 15 fractions over 3 weeks.

Chemoradiotherapy can be given preoperatively or can be administered to patients who are not surgical candidates. Without surgery, the median survival time for chemoradiotherapy is between 9-25 months. All studies have indicated this therapeutic approach has a higher percentage of complete response than radiotherapy alone. Figures of a complete response (reduction in >50% of the tumor) from chemoradiotherapy range from 58-86%. The survival of those patients who had a complete response has been significantly higher than those patients that did not achieve a complete response. Nevertheless, the results have shown a significant advantage to the chemotherapy and radiation approach over radiation alone. Partial or complete response rates hover around 75% with the combined approach compared to 15% with radiation alone. Median survival is also slightly higher (14.1-14.8 compared to 9.1 months

If surgery is implemented after chemoradiotherapy, results appear to be slightly better than with radiation alone or chemoradiotherapy alone; average median survival is 16.4 months. This appears to offer the greatest potential for a cure of any curative approach. It implements the systemic control of chemotherapy and the local-regional control method of radiation. If surgery is used in conjunction, it is a further technique used to rid the local and regional areas of residual malignancies. When this course of action is taken, histologic complete response rates are consistently between 25-30% (compared with <5% with preoperative radiation or chemotherapy). As is seen with any other trial involving radiation and chemotherapy, survival rates are dramatically increased when no residual cancer is found in the tumor specimen. Five year survival rates approach 60% when this occurs and 35% when only residual malignancy is discovered using preoperative chemoradiotherapy. When preoperative chemoradiotherapy is compared to surgery without preoperative treatment, a majority of the studies indicate that preoperative treatment is superior.

From evidence of trials undergone thus far implementing the multimodality approach of chemotherapy, radiation, and surgery, Ajani believes we have reached a plateau. More phase III controlled randomised studies are needed with the addition of new therapeutic drugs and schemas. Nevertheless, it seems that this approach will be the method of the future for patients who can tolerate aggressive treatment when attempting to combat this illusive and deadly cancer.

Table 4 Chemoradiotherapy Without Surgery

±: study terminated because of excessive toxicity
*: number of patients in entire trial
°: Not all trials taken into account because of lack of median survival time.
CR: complete response (> 50% reduction of tumor size) measured diagnostically.
NR: not reported
for other abbreviations, see table 1.

Table 5 Chemoradiotherapy With Surgery

(): # of patients resected
±: randomized trial
**: () indicate number of patients resected
*: Number of patients in entire trial
°: Not all trials taken into account because of lack of median survival data.
CR: pathological complete response (no tumor at resection)
NR: not reported
RT/rad: radiation therapy
chemo: chemotherapy