Importance of Local Control in an Era of Systemic Therapy

Abundant laboratory and clinical research suggests that carcinogenesis is a multi-step genetic process resulting from mutations, which produce the malignant phenotype. The capacities for unlimited proliferation either from loss of senescence or apoptotic potential, and increased angiogenesis, invasion, and distant seeding and growth, are components of tumor progression. Clinical data support the concept that many steps characteristic of malignancy occur during the clinically apparent phase of tumor development.^[1] Examples of such steps include: in situ tumors becoming invasive; the occurrence of micrometastases without angiogenesis; increases in tumor size, recurrence or progression correlated with an increase in histologic grade; increases in tumor size or progression related to increased metastatic likelihood; and mutations in the genes expressing p53,^[2] E-cadherin,^[3] nm23^[4] and loss of function of other genes associated with a poor prognosis. Clinically apparent cancer is best described as a spectrum or continuum of malignant capacities that result from tumor progression by evolutionary means.^[5,6]

Currently cancer is being diagnosed earlier, when there is relatively less malignant potential. This is exemplified by the increase in the diagnosis of in situ and early-stage cancers as a result of improved screening methods and increased public awareness. The current presentation of breast cancer in the US is unlike that seen by Halsted when he described the centrifugal orderly spread of cancer and the resultant therapeutic strategy of en bloc resection. The series described by Halsted comprised patients with locally advanced primary breast cancers, the majority of whom had clinically involved axillary lymph nodes. In contrast, currently more than half of the breast cancer cases seen in the US are either intraductal or stage I tumors. There is also a revolution in tumor imaging that has resulted in better delineation of the primary lesion and earlier detection of metastases. Improved tumor diagnosis has caused significant stage migration with more homogeneous stages and has identified metastases that were previously undetected or had a questionable diagnosis. This is an evolving process, and with PET scanning and molecular imaging just beginning to be utilized in the clinic, even earlier detection and further stage migration can be expected.

Therapy of cancer has also changed in the past 50 years. With the paradigm of metastatic proclivity, which is largely predetermined before clinical appearance, becoming the predominant model in the last quarter of the 20^th century, systemic adjuvant therapy has become a widely used and effective form of treatment for a number of different tumors. Systemic therapy for overt metastatic disease has also improved although not cured most tumors, but with a few remarkable successes such as lymphomas and testicular cancer. With these changes in tumor paradigm, diagnosis, stage at presentation and therapy, what now is the place of local treatment in a curative treatment strategy? Local control is or may be an important element of a curative treatment strategy in four instances in the evolving natural history of cancer: before tumors metastasize; when combined with adjuvant chemotherapy for the treatment of occult metastatic disease; to treat oligometastases, i.e. metastases limited in number and location;^[7] and finally to potentially eradicate residual metastatic deposits remaining after largely effective systemic treatment.

Treatment of cancers before they have metastasized is the ideal strategy. Mammography has reduced breast cancer deaths by ~30% in women 50–70 years old. The explanation for this must be that the cancers were found before metastases had disseminated and that metastases would have occurred if the primary tumors had not been detected until they were clinically evident. Screening and early diagnosis have also been effective in the improvement in survival of cervix, prostate, and possibly colon and lung cancers. There is also an interesting lesson to be learned from the trials of post-mastectomy radiation treatment in breast cancer patients receiving adjuvant systemic therapy.^[8,9] This local treatment improved survival by an absolute amount similar to that produced by the systemic treatment. These two treatments, one directed at eradicating local and regional disease and the other directed at occult metastatic deposits when administered in an initial therapeutic program, improved breast cancer survival by about 20% (10% from systemic treatment and an additional 10% from effective local therapy.)

Perhaps most exciting is the potential cure of metastases utilizing local treatment methods. While it has been well known that oligometastases can be cured in the lung and liver in 25–40% of cases, aggressive local treatment of metastasis has been considered limited to only a few tumors in somewhat rare circumstances. Soft tissue and bone sarcomas can be cured by resection of a limited number of pulmonary metastases, likewise hepatic metastases can be resected in some patients with colorectal cancer. Identification of oligometastases has improved in terms of determination of their number and extent and identification of previously undetected deposits. For example, positron emission tomography scanning has resulted in occult metastases being determined in ~20% of patients with non-small-cell lung cancer.^[10] If this and other imaging techniques can identify occult disease in seemingly early-stage patients from this and other primary sites, these lesions often may be oligometastases. Aggressive but focused local treatment of these lesions may lead to cancer cures because it will affect patients destined to fail utilizing the current therapeutic strategies. There are a number of advances in surgery and radiation therapy as well as newer modalities such as radiofrequency ablation and focused ultrasound tumor destruction. These all offer the possibility of applying minimal or non-invasive treatment directed at very small tumor deposits utilizing imaging guidance. The final group of patients that may benefit from discrete treatment of metastatic cancer are those patients who—while they may have had widespread metastases before systemic treatment—have only limited discrete foci of tumor amenable to focal ablation after such therapy. Examples are currently limited and include residual metastasis in patients with testicular cancer, Wilms' tumor, and small cell lung cancer. This concept may eventually be applied to patients with stable disease treated with new targeted therapies, such as anti-angiogenic therapy or kinase inhibitors, in addition to patients treated with conventional chemotherapy and hormonal treatment. An example might be patients with gastrointestinal stromal tumors treated with imatinib mesylate.

While this Viewpoint might seem overly optimistic, we believe it to be fair and equally likely to be too cautious. It is clear is that the presentation of cancer is quite different than that on which both the Halsted and predeterminist paradigms are based. A spectrum of disease proclivities that are the result of tumor progression, including both contiguous spread as well as early dissemination but with most tumors somewhere in between, seems to describe best the cancer seen today. With current screening and imaging methods tumors are being detected earlier in this spectrum. Hopefully, genetic or proteomic approaches may help place individual tumors within this continuum. Emerging diagnostic and molecular imaging methods as well as new and refined treatments all augur well for more opportunities for local therapies to improve tumor cure as a part of a multi-modality strategy.

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Nat Clin Pract Oncol. 2005;2(2):60-61. © 2005 Nature Publishing Group

Cite this: Importance of Local Control in an Era of Systemic Therapy - Medscape - Feb 01, 2005.