Combining Radiation and Chemotherapy May Improve Outcomes

Like many people with cancer, Gordon Cole underwent a variety of treatments. After receiving a diagnosis of stage 4 rectal cancer in August 2003, the 63-year-old commercial real estate appraiser in Greensboro, N.C., endured multiple surgeries, several rounds of different chemotherapy agents and targeted therapies, and radiation.

As part of his treatment regimen, Cole also received chemoradiotherapy (CRT)—chemotherapy and radiation given concurrently (at the same time)—on two occasions. The first time was just after his diagnosis, with an oxaliplatin-based regimen, Cole says, while the second time was more recent, sandwiched between two three-month segments of standard chemotherapy.

“Side effects weren’t too bad,” he says, “just fatigue toward the last quarter of radiation, and of course, the usual sensitivity to cold from the oxaliplatin.” Radiation therapy and chemotherapy—established treatments for an array of cancer types—were traditionally given at separate intervals. But CRT is rapidly becoming the regimen of choice in a growing number of cases.

Chemoradiation is now the standard of care for several types of solid tumors that are intermediate stage,” says Everett E. Vokes, chairman of the department of medicine at the University of Chicago. For example, it is widely used for treating lung, esophageal, and head and neck cancers, he adds.

During the past two decades, combining chemotherapy and radiation has changed the face of treatment. Certain chemotherapy agents help sensitize radiation so that it works better, and provide a systemic effect in addition to the local effect of the radiation, potentially preventing or delaying metastasis. If high doses of either modality are needed, it is sometimes possible to use a smaller dose of each to accomplish the same results, but with lower toxicity or the need for less (or no) surgery.

In many cases, the addition of chemotherapy to radiation actually leads to improvements in overall survival versus just using radiation alone.

The idea of combining drugs with radiation is not entirely new. Researchers first experimented with the combined modalities more than 50 years ago, and an early trial conducted at the Mayo Clinic in Rochester, Minn., showed that administering chemotherapy and radiation simultaneously improved the effectiveness of radiation and might, in some instances, be curative for patients with pancreatic, colorectal and stomach cancer. In 1979, researchers in England took this idea further and developed a theory about the interaction of radiation therapy and chemotherapy. Called “spatial cooperation,” the theory proposed that the action of radiation and chemotherapeutic drugs is directed toward different target sites in the body and work independently of each other. Radiation tends to target localized tumors, while chemotherapy drugs are likely to be more effective in eliminating micrometastases.

“In many cases, the addition of chemotherapy to radiation actually leads to improvements in overall survival versus just using radiation alone,” says Mitchell Kamrava, a radiation oncologist with the University of California, Los Angeles Health System. “We have seen this in many tumors, from the brain down to the pelvis.”

In addition to using CRT to treat cancers in the chest and in the head and neck, it is also used as a definitive, or sole, treatment for bladder and advanced cervical cancers, as mainstay or curative treatment in anal cancer and, to varying degrees, in gastric and pancreatic cancer, glioblastoma and sarcomas.

Head and neck cancer has been one of the “stars” of CRT , in that its use has significantly increased the cure rate of the disease. In treating locally advanced tumors, CRT has improved survival compared with radiation therapy alone.

Another benefit of CRT is that it can sometimes replace the need for surgery, or at least delay it. In advanced laryngeal cancer, for example, one of the traditional treatments has been to perform a complete laryngectomy, which involves removing the larynx and forming a permanent opening into the trachea that can alter speech and the ability to breathe through the nose and mouth. CRT, on the other hand, can provide effective and safe treatment while preserving the larynx. Studies have shown that outcomes are similar for patients who undergo surgery and those who have CRT, thus making it possible for many individuals to avoid surgery and its side effects.

The same holds true for bladder cancer. CRT is not only more effective than radiation alone, but may also be an alternative to surgery for some patients, according to a 2012 study published in The New England Journal of Medicine. “Chemoradiation is definitely a treatment option for muscle-invasive bladder cancer,” says Nicholas James, a professor of clinical oncology at the University of Birmingham in England and lead author of the study. “In the [United Kingdom], probably more patients—especially older ones—undergo radiation therapy than surgery.

“There’s no evidence that surgery is any better at preventing metastatic failure than radiation therapy, if you look at large surgical series or cancer registry data,” he says. “If bladder recurrence occurs after radiation therapy, it is surgically salvageable in many if not most cases. Fewer than 10 percent of our chemoradiation patients end up with a later cystectomy, though.”

CRT allows organ preservation in other cancers as well, including cervical, anal and esophageal. And, compared with radiation alone, CRT has been shown to improve survival in cervical and esophageal cancers.

Patients with non-small cell lung cancer have also benefited from this approach. For patients with stage 3 disease, CRT can be used as a curative approach and has boosted survival. A recent study also found that CRT is a better choice than sequential chemotherapy and radiation treatment in terms of long-term survival.

Still, as with nearly all cancer therapies, CRT is not without side effects. In fact, because of the intensity of the regimen, some effects can be more pronounced than if the chemotherapy and radiation were delivered at separate intervals.

Ronald Huang, who received a diagnosis of non-small cell lung cancer last year, experienced a variety of side effects from his treatment with CRT. The 31-year-old Seattle resident dealt with fatigue, nausea, heartburn and constipation.

“There’s the fatigue from the chemo first and then the real fatigue from the chemo and the radiation,” Huang says. “My white blood cell count also took a hit.”

But perhaps the worst side effect was a bout of radiation-induced esophagitis, an inflammation of the esophagus, which is fairly common in individuals who receive radiation therapy to the chest area. While he found eating and swallowing to be painful, Huang felt fortunate that he did not need to have artificial nutrition. Sometimes it is necessary to have a percutaneous endoscopic gastrostomy (PEG) tube inserted, which is a feeding tube that is surgically placed into the abdomen, in order to ensure adequate nutrition.

“There are a lot of ways to manage the symptoms, though,” Huang says, “and it is important to communicate your symptoms to your provider.”

Medications can help, such as mouthwashes that contain the antihistamine diphenhydramine hydrochloride and viscous lidocaine, along with pain medications that can be changed into liquid formulations and acid reducers, Huang says. He also found that dietary changes helped, such as eating soft, moist foods at room temperature and drinking an adequate amount of fluids.

In Cole’s case, radiation therapy caused some bowel issues, primarily a “lack of feeling below the waist and more urges,” he says. “The urges and other bowel issues have improved significantly since finishing chemotherapy, although apparent nerve damage remains.”

Bowel obstructions are late-term complications of CRT that can occur in patients with rectal cancer, leading to symptoms that include vomiting and abdominal pain and swelling. Some patients may develop a gastrointestinal fistula, an abnormal opening within the bowel that allows the bowel contents to leak. Both complications are uncommon, but require immediate medical attention, and, occasionally, surgery.

Radiation therapy can also lead to acute conditions such as enteritis, an inflammation of the small intestine, and proctitis (an inflammation of the lining of the rectum). These uncommon complications can occur in patients who undergo radiation for colorectal, urologic and gynecologic cancers, and treatment will vary depending on the severity of symptoms. Sometimes all that is needed is basic bowel care, which includes drinking enough fluids, or taking medications to combat diarrhea or bleeding. Surgery may be necessary for more severe symptoms.

Patients being treated for head and neck cancers are among the “hardest hit by side effects,” Kamrava says. Because of radiation and chemotherapy-related treatment changes to the oropharynx and esophagus, such as mouth sores (mucositis), they can have trouble swallowing, resulting in malnutrition and weight loss. Skin redness and blistering (dermatitis) can also be more pronounced.

Some patients may have a PEG tube placed prophylactically in anticipation of complications. However, the need for a PEG tube will vary among patients and the clinical scenario, and the data is still unclear. While several clinical trials have found that it can help ameliorate weight loss, other data show that prophylactic placement may be unwarranted in some patients.

Treating bladder and other pelvic tumors can also cause radiation cystitis in a small percentage of patients. Complications can vary from mild irritation to blood in the urine, incontinence, strictures or fistula. As with other types of complications, management largely depends on symptom severity, ranging from no treatment to surgery.

Preventing complications of CRT is more challenging than managing them, Kamrava says. “In most cases, there is not much we can do to prevent side effects from occurring, so we look more towards effectively managing them.”

Intensity-modulated radiation therapy (IMRT), an advanced mode of high-precision radiation therapy, is able to deliver radiation in a way that spares more normal tissues, lowering the risk of long-term toxicity. “That is one possibility,” Kamrava says. “We’ve seen with prostate cancer that it lowers the incidence of rectal bleeding.”

Drugs called “chemoprotectants” can lower CRT side effects but need further study to ensure effectiveness and that they are not also jeopardizing cancer treatment.

Utilizing drugs that are less toxic, and limiting the treatment volume with more advanced radiation technology, known as image guided radiation therapy (IGRT), could also reduce adverse effects. “But that needs to be studied, because we don’t want to make the treatment less effective,” says Hak Choy, chairman of the therapeutic oncology research department at University of Texas Southwestern Medical Center in Dallas. “There is a lot of work to be done with that, but with newer and advanced technology, we can define the target better.”

Advances in radiation technology have helped limit “collateral damage,” and have been a major improvement, Choy says.

Cole, however, who has been undergoing treatment for eight years, has a simpler solution: “The best treatment for side effects, as I see it, is still exercise, regardless of what the effects are,” he says. “There doesn’t seem to be anything else that improves your mood, feelings and outlook—assuming, of course, that you’re physically able to do it.”

Targeted therapies are at the leading edge in cancer care and are significantly changing the way treatment is delivered, but whether they have a place in CRT remains to be seen.

“Because current treatments are curative, the integration of targeted drugs is more difficult,” Vokes says. “You can’t easily give up on something that is already working.”

He points to a study in head and neck cancer that found adding Erbitux (cetuximab) to CRT showed no advantage, but another trial showed radiation with Erbitux was better than radiation alone, indicating a need for more research.

“In chest tumors, there is a study pending that is looking at chemoradiation with or without [Erbitux]—we don’t know the results yet, but the accrual is completed,” he says. “That is an important study.”

The best treatment for side effects, as I see it, is still exercise, regardless of what the effects are. There doesn’t seem to be anything else that improves your mood, feelings and outlook.

Looking at the current situation, Vokes says, “Studies need to be done very carefully because the treatment we have now can actually cure the disease. Simply adding these drugs have not shown a benefit in head and neck cancer, and we don’t have an answer yet for lung cancer.”

Choy agrees. “While the data is encouraging, it is yet premature to say which targeted agents should be used.” Many groups are currently working on ways to incorporate targeted agents with more standard CRT. For example, a study in breast cancer is evaluating the use of Herceptin (trastuzumab) concurrently with radiation and radiation alone for women with HER2-positive ductal carcinoma in situ, while another is looking at giving Tykerb (lapatinib) concurrently with radiation therapy to patients with breast cancer that has metastasized to the brain.

In head and neck cancer, ongoing trials are evaluating adding Erbitux to radiation therapy compared with other modalities, while a phase 3 trial is examining the use of both Tarceva (erlotinib) and CRT as adjuvant treatments in pancreatic cancer.

View Illustration: A Double WhammyView Chart: Cancers Treated with Combined Modality Therapy