Developments in Metastatic Cancer

Randall F. Holcombe, MD

Professor, Division of Hematology/Oncology

Director, Clinical Cancer Affairs,

Mount Sinai Medical Center

Deputy Director, Tisch Cancer Institute

Medical Director, Ruttenberg Treatment Center, Director, GI Medical Oncology

While progress against cancer, with an overall reduction in mortality rates, has been recently realized, advances have been small. A significant contribution to reduced cancer mortality is improved screening and discovery of disease at an early stage, which is more easily treated and cured, as well as significant advances in the neoadjuvant and adjuvant treatment of localized cancer. For patients with solid tumors, those not arising from the blood-forming tissues, the primary cause of morbidity and mortality is metastatic disease. Over the past several years, several new approaches to treatment have prolonged and improved quality of life for patients with metastases.

Treatment Options

There are about 1.6 million diagnoses of invasive cancer each year in the United States. The proportion of patients presenting with metastatic disease at diagnosis ranges from 5% to over 50%, depending on the type of cancer (Figure Below). Breast cancer is rarely metastatic initially (5%), colon cancer more frequently (15%), and lung and pancreatic cancer very commonly (>50%). Despite our best efforts, a not insignificant percentage of patients with early-stage disease eventually relapse with distant metastases. New, aggressive interventions can provide substantial benefits for these patients. Traditionally, patients with metastatic disease receive chemotherapy, with a reasonable chance of response and very small chance of remission for most solid tumors. Special approaches for patients with metastases include:

• Hepatic resections
• Thoracic resections
• Peritoneal debulking with intraperitoneal chemotherapy
• Stereotactic body radiotherapy (SBRT)
• Phase I clinical trials

Hepatic resection for metastatic colorectal cancer has been shown to significantly improve median overall survival from approximately 22 months with chemotherapy alone to up to 98 months for patients who have complete, R0 resection. Prior restrictions about the size and number of metastatic tumor have been replaced with an assessment of residual liver volume, facilitating more extensive and radical surgeries to remove all areas affected by metastatic tumor. Selective portal vein occlusion can induce left lobe hypertrophy and safely enable total right lobectomy in many patients. Resection of pulmonary metastases can often be accomplished via video-assisted thoracoscopy (VATS), reducing the morbidity of the procedure. While peritoneal debulking has been widely utilized for ovarian cancer, it has been somewhat controversial for other cancers. However, such debulking with intraperitoneal chemotherapy has been shown to prolong survival both for patients with low-grade appendiceal cancers, as well as aggressive colon adenocarcinoma. It has long been recognized that resection of brain metastases in non—small cell lung cancer patients prolonged survival, so it is not difficult to understand why selective resection of other areas of metastatic disease might have similar results.

Looking to the Future

Figure. Metastases by Disease Site

For patients who are not candidates for aggressive surgery, SBRT may be an attractive option, especially for lung metastases. This technique utilizes external-beam radiation with CT image guidance and respiratory gating to deliver a high dose of radiation in just 4 or 5 fractions. Finally, systemic options with new phase I targeted agents may be an attractive choice for patients who remain with good functional status but who have exhausted traditional chemotherapy options. Refinement of surgical and radiation oncology techniques will undoubtedly continue, expanding the options for patients with metastatic disease. Paradoxically, these aggressive approaches work best for patients in whom some element of disease control can be obtained with chemotherapy and other systemic approaches—otherwise, the disease will progress too rapidly to realize tangible benefits. New agents are being tested in early phase trials and these trials are now often specifically targeted to patients with specific diseases or even specific genetic mutations. The increasing ease of whole-exome sequencing of tumors and the incorporation of genomics platforms into cancer medicine now enables us to potentially define the specific driver mutations for an individual cancer in an individual patient. This has vast potential to define the choice of targeted agents to employ in early phase trials and to truly personalize cancer care.