Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as 'occult cancer'. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use.

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Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression

Few diagnoses in medicine engender as much pessimism as the diagnosis of metastatic cancer of an unknown primary site. Patients with this syndrome often have widespread metastatic disease, with involvement of multiple visceral sites such as the liver, lungs, and bones, and are often debilitated at the time of diagnosis. Early reports of chemotherapy in these patients documented low rates of response and no effect on the dismal median survival of three to four months, thereby strengthening arguments for a nihilistic approach1–4. Recently, however, the treatment of some patients with cancer of an unknown primary site has improved . . .

Treatment of Patients with Cancer of an Unknown Primary Site

Background. Chemotherapy for metastatic breast cancer is palliative, and the optimal duration of therapy is unknown. We designed a trial to determine whether continuous treatment is superior to stopping treatment after a brief induction period and resuming treatment when the disease progresses. Methods. We treated 250 women with metastatic breast cancer with six courses of cyclophosphamide, doxorubicin, and fluorouracil given every three weeks. At the completion of this induction period, women whose disease either regressed or remained stable were randomly assigned to receive either continued treatment with cyclophosphamide, methotrexate, and fluorouracil (maintenance therapy) or no further treatment (observation) followed by treatment with cyclophosphamide, methotrexate, and fluorouracil when disease progression became evident (reinduction). Results. The combined rate of complete and partial response after initial therapy was 30 percent (71 of 233 patients who could be evaluated; 95 percent conf...

https://www.nejm.org/doi/pdf/10.1056/NEJM199111073251904

Interrupted versus Continuous Chemotherapy in Patients with Metastatic Breast Cancer

A systematic review of chemotherapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for the evaluation of the scientific literature are described separately (Acta Oncol 2001; 40: 155-65). This synthesis of the literature on chemotherapy for breast cancer is based on 233 randomised studies, 9 meta-analysis of randomised studies, a population-based cohort study and 18 overviews/retrospective analyses including a total of 155,243 patients. The conclusions reached can be summarised into the following points: Adjuvant treatment-- There is solid scientific support from randomised studies that adjuvant polychemotherapy at 10 years will result in an absolute mortality reduction for patients younger than 50 years by 12% for node positive (34% relative mortality reduction corresponding to an estimated median survival prolongation of several years) and 6% for node negative patients. For women aged 50 to 69 years, the corresponding figures for node positive and node negative patients are 6% and 2%, respectively (approximately 11% relative mortality reduction). Anthracycline-containing combinations result in an absolute survival benefit at five years of 3%, compared with non-anthracycline based polychemotherapy. There are indications that the taxane paclitaxel may further improve the survival compared with anthracyclines. However, the limited data preclude conclusions for the routine care. The addition of tamoxifen to chemotherapy further enhances the survival benefit for receptor positive subgroups. The roles of more dose-intensive regimens, including high-dose therapy with stem cell support, are presently studied in randomised investigations. The data presented so far are conflicting but they do not in general support high-dose therapy. Quality of life, based on analyses of randomised studies, demonstrate that adjuvant polychemotherapy has an initial detrimental effect, but long-term follow-up of treated patients demonstrates no impairment of quality of life compared with untreated patients. Polychemotherapy in standard doses should be offered to premenopausal node positive patients, and the corresponding postmenopausal group with a receptor-negative breast cancer and to node negative patients with high risk factors. Polychemotherapy should be combined with tamoxifen to all patients with receptor-positive tumours. Due to a need of more knowledge in this field, patients should be included in investigational protocols. Locally advanced breast cancer-- Based on current knowledge, treatment of patients with locally advanced breast cancer should include neoadjuvant/preoperative polychemotherapy since there is evidence from controlled studies that such therapy will statistically significantly increase the number of patients who can be offered breast-conserving surgery. Indirect comparisons also demonstrate survival improvements, but the scientific support is equivocal. Metastatic breast cancer-- The median survival for patients with metastatic disease treated with conventional chemotherapy doses and regimens is 12 to 24 months. Retrospective cohort studies indicate that the use of non-anthracycline containing chemotherapy compared with no chemotherapy might add a survival gain of six to nine months. However, this estimation is based on equivocal data. Based on overview data, polychemotherapy results in a statistically significant survival gain compared with single-agent therapy. Based on repeated randomised studies, the addition of anthracyclines increases the response rate and statistically significantly improves the survival compared with non-anthracycline containing chemotherapy, except for CMF combined with prednisone/prednisolone, which will statistically significantly improve the survival compared with some anthracycline combinations. Second line therapy using vinorelbine or docetaxel is statistically significantly better than other regimens with a time to progression and survival benefit in the order of one to three months based on few randomised studies. The role, if any, of third line therapy is yet to be demonstrated. In the metastatic setting, conventional chemotherapy improves the quality of life. In standard care, first line therapy should contain an anthracycline and second line therapy using vinorelbine or docetaxel could be offered to selected patients failing first line therapy. Based on numerous randomised studies, breast cancer demonstrates a positive dose-response relationship both in the adjuvant situation and for metastatic disease. However, in the conventional dose-range there seems to be a plateau in the dose-response curve, with no further survival gains for high

https://www.tandfonline.com/doi/pdf/10.1080/02841860120784

A systematic overview of chemotherapy effects in breast cancer.

• An isolated axillary lymph node metastasis in a woman without an obvious clinical primary site most frequently originates from the breast. Mastectomy has been the historical treatment of choice. A retrospective study of 35 patients was undertaken to evaluate the roles of modern mammography, breast preservation, and adjuvant systemic therapy in the management of these patients. Twenty-eight patients underwent a mastectomy, while 7 were managed by a combination of limited resection and/or axillary dissection and radiation therapy. Twenty-two (67%) of the 33 breast specimens contained carcinoma. Comparison of the pathologic results with the preoperative mammograms showed a specificity of 73%, while the sensitivity was only 29%. Actuarial 5-year survival after mastectomy or breast preservation was similar (77% and 65%, respectively). Patients with more than one positive lymph node benefited from adjuvant therapy. Mammography does not locate the majority of occult stage II breast cancers, and both breast preservation and adjuvant therapy may have roles in the management of these patients. ( Arch Surg . 1990;125:210-215)

Occult breast cancer presenting with axillary metastases. Updated management.

Twenty-nine cases were reviewed in which carcinoma manifested first as the enlargement of an axillary node from an occult breast carcinoma. A small hidden breast cancer was identified in 16 patients. In the remaining 13, the breast tumor was never discovered. Regardless of whether the primary tumors were discovered, the metastasis-free survival rates were comparable to those of patients with breast carcinoma with axillary nodal metastasis. The authors recommend that carcinoma found in an axillary node should be treated as a breast cancer, even in the absence of the breast tumor. Extensive investigative procedures in an attempt to uncover an extramammary primary site were largely unproductive and should either be omitted or performed selectively. Mammography, if positive or suspicious, can lead to the primary tumor in 75% of the patients, but, when negative, it does not necessarily exclude the breast as the source of the carcinoma. A carcinoma of the breast was found by pathologic examination in 44% of the patients with negative mammograms.

Axillary lymph node metastasis from an occult breast cancer

In 126 postmenopausal women with metastatic breast cancer, four chemotherapeutic combination programs were tested. Patients were stratified and randomized to one of the four programs: (1) fluorouracil, cytoxan and prednisone (CFP): (2) fluorouracil, cytoxan and Adriamycin (CAF); (3) cytoxan and Adriamycin (CA); or (4) alternating combinations of CFP-CA. Objective response rates were 17% for 18 patients on CFP, 25% for 40 patients on CAF, 42% for 41 patients on CA and 63% for 19 patients on CFP-CA. CFP-CA provided a significantly higher response rate than either CFP or CAF. The response rate of CA was intermediate. The duration of remission and survival were similar for all four groups. When progression or relapse following remission was demonstrated, patients were rerandomized to either adrenalectomy or tamoxifen. There were no responders either in the 15 patients undergoing adrenalectomy or the 11 patients receiving tamoxifen. In a crossover study, nine adrenalectomized patients received tamoxifen and four tamoxifen-treated patients underwent adrenalectomy. None responded. It appears that response rates to hormonal modalities are reduced in patients previously treated by combination chemotherapy.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/1097-0142%2819820515%2949%3A10%3C1988%3A%3AAID-CNCR2820491007%3E3.0.CO%3B2-L

Comparison of four-combination chemotherapy programs in metastatic breast cancer: comparison of multiple drug therapy with cytoxan, 5-FU and prednisone versus cytoxan and adriamycin, versus cytoxan, 5-FU and adriamycin, versus cytoxan, 5-FU and prednisone alternating with cytoxan and adriamycin.

Dutzu Rosner

Papers

Axillary lymph node metastasis from an occult breast cancer

Comparison of four-combination chemotherapy programs in metastatic breast cancer: comparison of multiple drug therapy with cytoxan, 5-FU and prednisone versus cytoxan and adriamycin, versus cytoxan, 5-FU and adriamycin, versus cytoxan, 5-FU and prednisone alternating with cytoxan and adriamycin.