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An appraisal of chemotherapy as an adjuvant to surgery for cancer
The
American VOLUME
97
Journal JUNE 1959
of Surgery NUMBER
SIX
An Appraisal of Chemotherapy As an Adjuvant to Surgery for Cancer be disseminated into the bIood stream and into the wound by operation. This may suggest that the most significant factor responsibIe for surgica1 faiIure is the high percentage of seeding of cancer ceIIs occurring during operations for malignant tumors. More discriminating evaluation, however, reveaIs that this implied causeeffect reIationship is more apparent than real. ThoughtfuI study of the avaiIabIe data reveals that in most instances these “escaping” cells are destroyed before they can become established as metastases. These studies further suggest that heavy dissemination of cancer ceIIs into the circulation must occur daily over the entire Iife span of a malignant growth. If the daily reIease of multitudes of cancer ceIIs into the blood stream were to result very frequentIy in metastases, surgica1 cure rates would be virtuaIIy zero. It foIIows therefore that the presence of cancer ceIIs in the blood stream does not necessarily, or often, imply an impending metastasis. In this regard it is pertinent to take cognizance of the Iaboratory data demonstrating that the implantation of a singIe cancer ceI1 only rarely resuIts in a tumor and that, generaIIy, a certain size inocuIum of cancer cells has been found necessary to initiate tumor growth consistently. It would appear then that the presence of seedings of cancer cells is only infrequently associated with metastases. The wide discrepancy between these facts and the relatively high incidence of surgical faiIures that are observed, argues strongIy that the major reason for surgica1 faiIure must lie in the existence of
HERE is increasing experimenta evidence that chemotherapy, emptoyed as an adjuvant to surgery for cancer, may lead to increased cure rates of neoplastic disease. The growing interest in this concept suggests that full appraisa1 may serve a useful function. The frequent lack of success attending “resection for cure” is ascribed to the continued presence of neoplastic ceIIs despite apparentIy compIete removal. These residua1 malignant ceIIs faI1 into the following categories: Category I: ceIIs already established (“rooted”) at the time of surgery. These are distant metastases, the existence of which is not initiaIIy appreciated. Category 2: ceIIs that are reIeased into the circulation and/or Iymphatics at the time of surgery. Th ese possess the potentia1 of becoming established and thereby result in metastases. Category 3: ceIIs reIeased into the operative area by direct seeding at the time of surgery. These aIso possess the potential of becoming established, and thereby result in IocaI tumor impIants. To dehne accurately the pIace of chemotherapy as an adjuvant to the surgica1 treatment of cancer, the relative importance of these three categories in producing surgica1 failure must be assessed. Although insuffrcient information is avaiIabIe at present to aIIow precise quantitation of the roIe pIayed by each of these three groups, enough data have been accumuIated to permit comparison. It has been documented by wound washings, examination of bIood and IocaI tumor recurrences at the suture line that cancer ceIIs may
T
685
American
Journal of Surgery,
Volume 97. June, rgm
Martin
established tumor ceIIs at the time of surgerythe unsuspected metastases. If the major cause for faiIure in surgery for cancer exists in the form of the missed metastasis, the greatest success in augmenting surgical cure rates by employing adjuvant chemotherapy can come only from agents capable of destroying residua1 established cancer cells. The discovery of such compounds is the major probIem in the fieId of adjuvant chemotherapy. At this time, unfortunateIy, a11 those compounds shown capabIe of producing cure of earIy tumor transplants have been found markedIy Iess effective (merely inhibitory) against the same type tumor transpIants rn a we11 estabIished phase of growth. Recent experimenta1 evidence [I] reveaIs that surgica1 excision of the buIk of such we11 estabIished tumors renders a residual smaI1 tumor mass (stiI1 estabIished) once again vuInerabIe to chemotherapeutic cure. These preliminary Iaboratory resuIts suggest that surgical removal of a11 gross cancer tissue may render smaI1 metastatic Iesions susceptibIe to appropriate chemotherapy, Thus it wouId appear that chemotherapy may serve a most useful function with surgery for cancer. On the other hand, surgeons stand to make a substantia1 contribution to cancer chemotherapy. Removing the bulk of tumor tissue may provide, at a clinical IeveI, the necessary conditions for optima1 detection of appropriate and effective agents. Thus surgeons may be in the best position to find the agents that wiI1 prove most usefu1. There is evidence to suggest that freely floating cancer ceIIs are more vulnerable to chemotherapeutic attack (category z) than estabIished ceIIs. It is well known that transpIanted tumors are more susceptibIe to chemotherapy during the first few days after transpIantation before they become estabIished. On the same basis, it may be that freely floating cancer ceIIs wiI1 be destroyed by systemic administration of onIy a smaI1 dose of a chemotherapeutic agent. There is experimenta evidence demonstrating the effectiveness of nitrogen mustard anaIogues in destroying cancer ceIIs before they become estabIished, and clinica tria1 of certain of these aIkyIating agents as adjuvant therapy to surgery for cancer is currentIy under way. To place such
studies in proper perspective, however, it is necessary to point out that agents Iimited in their carcinocida1 power to non-established cancer cells can at best eIiminate onIy an estimated small percentage of the total group of surgical failures. A very smaI1 percentage of the tota group of surgica1 faiIures wouId seem to be due to implantation of cancer ceIIs into the IocaI wound (category 3). It is within this category that adjuvant chemotherapy might be expected to be most readiIy successful. Since wounds ma3 be washed with much higher concentrations of chemotherapeutic compounds than could safely be administered systemicaIIy, it should be easier to destroy residual, freshly sown cancer cells. However, any drug utilized for this purpose must necessarily be of Iimited vaIue as an adjuvant to surgery for cancer, since apparently 0nIy a tiny percentage of surgica1 faiIure is due to Iocal tumor implants. For this reason, proper clinica evaluation of this type of drug might be best accompIished by restricting cIinica1 study to cancer types having reasonab1) high IocaI recurrence rates undoubtedly due to impIantation (e.g., anterior resections for recta1 cancer) as opposed to Iymphatic permeation. DoubtIess in the near future numerous agents wiI1 be judged potentially useful as adjuvant chemotherapy to the surgica1 treatment of cancer. Inasmuch as no correlation between Iaboratory tumors and human neopIasms has been demonstrated, clear transIation of provocative experimental resuIts into simiIarIJ successfu1 cIinica1 use is not predictable. This situation permits the possibility of inadequate evaIuation of these potential agents. Aside from erroneousIy concluding that a compound is active, there is the greater danger that negative resuIts may permit the abortive dismissal of adjuvant chemotherapy as a non-fruitful approach and lead to its abandonment. Thoughtfu1 consideration of the experimenta data associated with each candidate compound, keeping in mind the many compIexities invoIved in the study of adjuvant chemotherapy, should lead to intelligent formulation of cIinicaI studies with the attainment of meaningfu1 answers in relation to the three genera1 categories of target tumor ceIIs outIined herein, and their reIative importance.
1SHAPIRO,D. M. and FUGMANN,R. A. A role for chemotherapy as an adjunct tv surgery. Cancer Res., 17: 1098, 1957.
686
DANIEL S. ~UARTIN,
M.D.,
Department of Surgery, Jackson Memorial Hospital, hfiami, Florida
American VOLUME
97
Journal JUNE 1959
of Surgery NUMBER
SIX
An Appraisal of Chemotherapy As an Adjuvant to Surgery for Cancer be disseminated into the bIood stream and into the wound by operation. This may suggest that the most significant factor responsibIe for surgica1 faiIure is the high percentage of seeding of cancer ceIIs occurring during operations for malignant tumors. More discriminating evaluation, however, reveaIs that this implied causeeffect reIationship is more apparent than real. ThoughtfuI study of the avaiIabIe data reveals that in most instances these “escaping” cells are destroyed before they can become established as metastases. These studies further suggest that heavy dissemination of cancer ceIIs into the circulation must occur daily over the entire Iife span of a malignant growth. If the daily reIease of multitudes of cancer ceIIs into the blood stream were to result very frequentIy in metastases, surgica1 cure rates would be virtuaIIy zero. It foIIows therefore that the presence of cancer ceIIs in the blood stream does not necessarily, or often, imply an impending metastasis. In this regard it is pertinent to take cognizance of the Iaboratory data demonstrating that the implantation of a singIe cancer ceI1 only rarely resuIts in a tumor and that, generaIIy, a certain size inocuIum of cancer cells has been found necessary to initiate tumor growth consistently. It would appear then that the presence of seedings of cancer cells is only infrequently associated with metastases. The wide discrepancy between these facts and the relatively high incidence of surgical faiIures that are observed, argues strongIy that the major reason for surgica1 faiIure must lie in the existence of
HERE is increasing experimenta evidence that chemotherapy, emptoyed as an adjuvant to surgery for cancer, may lead to increased cure rates of neoplastic disease. The growing interest in this concept suggests that full appraisa1 may serve a useful function. The frequent lack of success attending “resection for cure” is ascribed to the continued presence of neoplastic ceIIs despite apparentIy compIete removal. These residua1 malignant ceIIs faI1 into the following categories: Category I: ceIIs already established (“rooted”) at the time of surgery. These are distant metastases, the existence of which is not initiaIIy appreciated. Category 2: ceIIs that are reIeased into the circulation and/or Iymphatics at the time of surgery. Th ese possess the potentia1 of becoming established and thereby result in metastases. Category 3: ceIIs reIeased into the operative area by direct seeding at the time of surgery. These aIso possess the potential of becoming established, and thereby result in IocaI tumor impIants. To dehne accurately the pIace of chemotherapy as an adjuvant to the surgica1 treatment of cancer, the relative importance of these three categories in producing surgica1 failure must be assessed. Although insuffrcient information is avaiIabIe at present to aIIow precise quantitation of the roIe pIayed by each of these three groups, enough data have been accumuIated to permit comparison. It has been documented by wound washings, examination of bIood and IocaI tumor recurrences at the suture line that cancer ceIIs may
T
685
American
Journal of Surgery,
Volume 97. June, rgm
Martin
established tumor ceIIs at the time of surgerythe unsuspected metastases. If the major cause for faiIure in surgery for cancer exists in the form of the missed metastasis, the greatest success in augmenting surgical cure rates by employing adjuvant chemotherapy can come only from agents capable of destroying residua1 established cancer cells. The discovery of such compounds is the major probIem in the fieId of adjuvant chemotherapy. At this time, unfortunateIy, a11 those compounds shown capabIe of producing cure of earIy tumor transplants have been found markedIy Iess effective (merely inhibitory) against the same type tumor transpIants rn a we11 estabIished phase of growth. Recent experimenta1 evidence [I] reveaIs that surgica1 excision of the buIk of such we11 estabIished tumors renders a residual smaI1 tumor mass (stiI1 estabIished) once again vuInerabIe to chemotherapeutic cure. These preliminary Iaboratory resuIts suggest that surgical removal of a11 gross cancer tissue may render smaI1 metastatic Iesions susceptibIe to appropriate chemotherapy, Thus it wouId appear that chemotherapy may serve a most useful function with surgery for cancer. On the other hand, surgeons stand to make a substantia1 contribution to cancer chemotherapy. Removing the bulk of tumor tissue may provide, at a clinical IeveI, the necessary conditions for optima1 detection of appropriate and effective agents. Thus surgeons may be in the best position to find the agents that wiI1 prove most usefu1. There is evidence to suggest that freely floating cancer ceIIs are more vulnerable to chemotherapeutic attack (category z) than estabIished ceIIs. It is well known that transpIanted tumors are more susceptibIe to chemotherapy during the first few days after transpIantation before they become estabIished. On the same basis, it may be that freely floating cancer ceIIs wiI1 be destroyed by systemic administration of onIy a smaI1 dose of a chemotherapeutic agent. There is experimenta evidence demonstrating the effectiveness of nitrogen mustard anaIogues in destroying cancer ceIIs before they become estabIished, and clinica tria1 of certain of these aIkyIating agents as adjuvant therapy to surgery for cancer is currentIy under way. To place such
studies in proper perspective, however, it is necessary to point out that agents Iimited in their carcinocida1 power to non-established cancer cells can at best eIiminate onIy an estimated small percentage of the total group of surgical failures. A very smaI1 percentage of the tota group of surgica1 faiIures wouId seem to be due to implantation of cancer ceIIs into the IocaI wound (category 3). It is within this category that adjuvant chemotherapy might be expected to be most readiIy successful. Since wounds ma3 be washed with much higher concentrations of chemotherapeutic compounds than could safely be administered systemicaIIy, it should be easier to destroy residual, freshly sown cancer cells. However, any drug utilized for this purpose must necessarily be of Iimited vaIue as an adjuvant to surgery for cancer, since apparently 0nIy a tiny percentage of surgica1 faiIure is due to Iocal tumor implants. For this reason, proper clinica evaluation of this type of drug might be best accompIished by restricting cIinica1 study to cancer types having reasonab1) high IocaI recurrence rates undoubtedly due to impIantation (e.g., anterior resections for recta1 cancer) as opposed to Iymphatic permeation. DoubtIess in the near future numerous agents wiI1 be judged potentially useful as adjuvant chemotherapy to the surgica1 treatment of cancer. Inasmuch as no correlation between Iaboratory tumors and human neopIasms has been demonstrated, clear transIation of provocative experimental resuIts into simiIarIJ successfu1 cIinica1 use is not predictable. This situation permits the possibility of inadequate evaIuation of these potential agents. Aside from erroneousIy concluding that a compound is active, there is the greater danger that negative resuIts may permit the abortive dismissal of adjuvant chemotherapy as a non-fruitful approach and lead to its abandonment. Thoughtfu1 consideration of the experimenta data associated with each candidate compound, keeping in mind the many compIexities invoIved in the study of adjuvant chemotherapy, should lead to intelligent formulation of cIinicaI studies with the attainment of meaningfu1 answers in relation to the three genera1 categories of target tumor ceIIs outIined herein, and their reIative importance.
1SHAPIRO,D. M. and FUGMANN,R. A. A role for chemotherapy as an adjunct tv surgery. Cancer Res., 17: 1098, 1957.
686
DANIEL S. ~UARTIN,
M.D.,
Department of Surgery, Jackson Memorial Hospital, hfiami, Florida